On 2016 Oct 25, FREDERICK DOMANN commented:

U87MG cells are not what they used to be !!

The U87MG cells used in this study were obtained from ATCC. A recent (2016) DNA sequencing study by Bengt Westermark revealed that these cells were likely contaminated at some point as their genetic signature did not match the parental tumor of their origin. Below are links to the story and an interview with Dr. Westermark.

http://www.igp.uu.se/research/neuro-oncology/bengt-westermark/

http://www.the-scientist.com/?articles.view/articleNo/46929/title/Popular-Tumor-Cell-Line-Contaminated/

http://stm.sciencemag.org/content/8/354/354re3

On 2016 Aug 21, Morten Oksvold commented:

Please note that this article represents one of eleven publications which were found to contain false data, after an investigation led by ORI in 2015:

https://ori.hhs.gov/content/case-summary-dasmahapatra-girija

This article should therefor not be cited.

On 2016 Sep 24, Morten Oksvold commented:

There is a response to this reply by Kaufmann T et al., which is well worth to read. This response was published in the same number of Cell, but unfortunately hidden as a "linked article" and not searchable in PubMed.

Title of the response: "Does Bid Play a Role in the DNA Damage Response?".

Link: http://www.cell.com/cell/fulltext/S0092-8674(07)00842-2

On 2015 Dec 18, Ahmed Adeel commented:

The figures given for PCR-corrected treatment failure with AS/SP do not seem to be consistent in the Abstract and in the Results sections. This needs to be clarified.

ABSTRACT:"However, when PCR-corrected, 6.5% (5/77) of patients treated with AS/SP maintained parasites from their primary infection."

RESULTS: "In the AS/SP group, five patients (41.7 %) showed different allelic forms and were classified as reinfection, while seven (58.3) retained the same allelic pattern and were classified as recrudescence of parasites."

On 2015 Jul 18, Jan Tunér commented:

A problem with most studies trying to treat tinnitus with laser light is the lack of proper diagnosis of the patients. Quite a few of these have a somatosensory background (the problem is basicly muscluar). Irradiation into the ear will then have no effect.

References: Bjorne A, Agerberg G. Reduction in sick leave and costs to society of patients with Ménière´s disease after treatment of temporomandibular and cervical spine disorders: A controlled 6-year cost-benefit study. Cranio. 2003; 21 (2): 136-143. Bernhardt O, Gesch D, Schwahn C, Bitter K et al. Signs of temporomandibular disorders in tinnitus patients and in a population-based group of volunteers: results of the Study of Health in Pomerania. J Oral Rehabil. 2004; 31 (4): 311-319. Levine RA, Abel M, Cheng H. CNS somatosensory-auditory interactions elicit or modulate tinnitus. Exp Brain Res. 2003; 153 (4): 643-648. Tullberg M, Ernberg M. Long-term effect on tinnitus by treatment of temporomandibular disorders: a two-year follow-up by questionnaire. Acta Odontol Scand. 2006; 64 (2): 89- 96.

On 2015 Aug 02, Jorge H Ramírez commented:

Any reason not to retract this publication?

http://chaoticpharmacology.com/?s=quetiapine

On 2015 Aug 02, Jorge H Ramírez commented:

Any reason not to retract this publication?

http://chaoticpharmacology.com/?s=quetiapine

On 2013 Oct 27, Tom Kindlon commented:

"Recovery" (from fatigue) does not necessarily mean recovery from CFS (in terms, for example, of activity levels)

In this paper, some variant of the word "recovered" is used 12 times, generally to describe some of the Chronic Fatigue Syndrome (CFS) patients who had taken part in a cognitive behaviour therapy (CBT) trial for CFS[1].

Actometer data from this study has subsequently been released[2]. This paper reported that CBT did not cause an increase in physical activity at the end of treatment. Before CBT, the patients did a mean 67.4 units of activity (standard deviation(SD): 21.8); following CBT, patients did 68.8 units of activity (SD: 25.2). The authors report that a previous study [3] found healthy controls had a mean Actometer score of 91 (S.D.=25). There was also no increase in activity levels in two other CBT trials examined[4,5].

The authors[2] also found that in the three CBT studies, changes in physical activity were not related to changes in fatigue. So "recovery from fatigue" does not necessarily mean recovery from CFS in terms of achieving normal activity levels.

In another Dutch CBT study[6], 37% of patients were said to be recovered from fatigue, where recovery was defined as no longer scoring on any of the 3 negative factors of the Fatigue Quality List (FQL). However when low scores on other questionnaires were also required to fulfil "full recovery", only 23% of the sample were said to be in "full recovery". Note that only subjective measures were used in that definition of full recovery - a return to a normal level of activity, as measured by an actometer, was not required.

Incidentally, a paper was subsequently published which also examined language used to describe fatigue by CFS patients and healthy controls[7]. It is slightly different as phrases rather than adjectives were used to describe the fatigue e.g. "Mentally tired after the slightest effort", "Lack the energy to talk to anyone", etc. Factor analyses revealed a five-factor structure for participants with ME/CFS but only a one-factor solution for the control group. The five factors for fatigue in ME/CFS participants were described as: "Post-Exertional", "Wired", "Brain-Fog", "Energy" and "Flu-Like".

References:

[1] Prins JB, Bleijenberg G, Bazelmans E, Elving L, de Boo Th, Severens JL, van der Wilt GJ, Spinhoven Ph, van der Meer JWM: Cognitive behaviour therapy for chronic fatigue syndrome: A multicentre randomised controlled trial. Lancet 2001, 357:841-847.

[2] Wiborg JF, Knoop H, Stulemeijer M, Prins JB, Bleijenberg G. How does cognitive behaviour therapy reduce fatigue in patients with chronic fatigue syndrome? The role of physical activity. Psychol Med. 2010 Jan 5:1 -7. [Epub ahead of print]

[3] van der Werf SP, Prins JB, Vercoulen JH, van der Meer JW, Bleijenberg G (2000). Identifying physical activity patterns in chronic fatigue syndrome using actigraphic assessment. Journal of Psychosomatic Research 49, 373–379.

[4] Knoop H, van der Meer JW, Bleijenberg G (2008). Guided self-instructions for people with chronic fatigue syndrome: randomised controlled trial. British Journal of Psychiatry 193, 340-341.

[5] Stulemeijer M, de Jong LW, Fiselier TJ, Hoogveld SW, Bleijenberg G (2005). Cognitive behaviour therapy for adolescents with chronic fatigue syndrome: randomised controlled trial. British Medical Journal 330. Published online : 7 December 2004. doi :10.1136/bmj.38301.587106.63.

[6] Knoop H, Bleijenberg G, Gielissen MFM, Van der Meer JWM, White PD: Is a full recovery possible after cognitive behavioural therapy for chronic fatigue syndrome? Psychother Psychosom 2007, 76:171-176.

[7] Jason, L.A., Jessen, T., Porter, N., Boulton, A., Njoku, M.G., & Friedberg, F. Examining types of fatigue among individuals with ME/CFS. Disability Studies Quarterly, 2009, 29, 3. Full text at: http://www.dsq-sds.org/article/view/938/1113

On 2014 Dec 10, Kath Wright commented:

Other search filters are available from the InterTASC Information Specialists' Sub-Group Search Filter Resource at https://sites.google.com/a/york.ac.uk/issg-search-filters-resource/home

On 2016 May 26, Jeff Kiefer commented:

It looks like DAVID has been updated May 2016 https://david-d.ncifcrf.gov/content.jsp?file=release.html.

On 2015 May 07, Jeff Kiefer commented:

DAVID is continuously being used as evidenced by its numerous citations in current biomedical literature http://bit.ly/1FS1JgT. However, the data resources used by DAVID appear to not have been updated since 2009 http://david.abcc.ncifcrf.gov/helps/update.html. The fact that DAVID has not been updated going on 5 years calls into question the current utility of using this tool.

On 2014 Jan 06, Tom Kindlon commented:

Caution required when making numerical comparisons between Wessely (1997) and the current study

In his editorial[1], Prof. White says: "Comorbid psychiatric conditions may have inflated the prevalence. A previous study found an equally high point prevalence of CFS (2.6%), by surveying United Kingdom primary care patients [10]. However, when those patients who also had a comorbid psychiatric disorder were excluded, the prevalence fell to 0.5%."

Reference to this paper[2] is also made in the editorial's concluding paragraph and in the accompanying Reeves paper[3].

A close inspection of table 2 of the referenced paper[2] reveals some strange figures (with regard to the estimates for the CDC '94 criteria mentioned above): (i) The Oxford criteria for CFS were found to have a lower prevalence, of 2.2%. Given that the CDC 94 criteria would be seen as more restrictive than the Oxford criteria (e.g. requiring symptoms as well as fatigue lasting six months), this suggests an error with one or both of the figures? (ii) the mean and 95% confidence intervals given for the prevalence rates without co-morbid psychological disorders for CFS (CDC 94) are given as 0.5 (0.1, 0.3) which makes no sense (the confidence intervals should be above and below the mean).

So these two observations mean that I'm not sure how much faith should be placed with some of the figures given in that study.

The methodology of the Wessely study was also different, using attendance at primary care physicians to screen for patients, which could lead to skewed data. The random number methodology in the Reeves study seems stronger.

It should also be remembered that the authors of the Reeves study[3] did exclude many patients with psychological disorders before giving the diagnosis of CFS. So even if one accepts the curious data presented in Table 2 in Wessely et al[2], it seems unlikely we can extrapolate from the drop in the figures found the Wessely study to produce a similar drop in figures found in the current study[3].

References:

[1] How common is chronic fatigue syndrome; how long is a piece of string? Peter D White Population Health Metrics 2007, 5:6 doi:10.1186/1478-7954-5-6

[2] Wessely S, Chalder T, Hirsch S, Wallace P, Wright D. The prevalence and morbidity of chronic fatigue and chronic fatigue syndrome: a prospective primary care study. Am J Pub Health 1997, 87:1449-1455.Available online at:http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1380968

[3] Prevalence of chronic fatigue syndrome in metropolitan, urban, and rural Georgia. William C Reeves, James F Jones, Elizabeth Maloney, Christine Heim, David C Hoaglin, Roumiana S Boneva , Marjorie Morrissey and Rebecca Devlin. Population Health Metrics 2007, 5:5 doi:10.1186/1478-7954-5-5

On 2014 Jan 06, Tom Kindlon commented:

Obesity and arbitrary criteria

Firstly, I thought I would clarify that I did not make my point about obesity rates based simply on the one study, the Wichita study[1]: the Chicago Study[2] found a prevalence of 0.422% using the same (or very similar) methodology and method of operationalizing the criteria as the Wichita study, producing a much higher score than the 0.235% score found in the Wichita study.

However this correspondence has caused to me to reflect on the issue: I still remain to be convinced that because the residents of Wichita were more obese than the general population, the prevalence figure for CFS (as defined then) of 0.235% was artificially increased; however perhaps if the new broadened criteria lack sensitivity and specificity, the figures in the latest studies could be artificially inflated because of a higher background obesity rate?

I think there is an important issue of a lack of sensitivity and specificity with the new method of operationalizing the criteria. As Peter White says, the current criteria are "arbitrary". Whether they are being used by a "jobbing physician", an epidemiologist or a researcher, one of the aims of criteria should be that they have good sensitivity and specificity rates. Perhaps a direction for discourse and research in the future should be trying to arrive at CFS criteria that reach that aim?

If necessary, having different criteria for different circumstances: for example, have one set of criteria when looking for expensive biological work but perhaps less stringent criteria for use in some clinical settings?

References:

[1] Prevalence and Incidence of Chronic Fatigue Syndrome in Wichita, Kansas Michele Reyes, PhD; Rosane Nisenbaum, PhD; David C. Hoaglin, PhD; Elizabeth R. Unger, PhD, MD; Carol Emmons, PhD; Bonnie Randall, MCP; John A. Stewart, MD; Susan Abbey, MD; James F. Jones, MD; Nelson Gantz, MD; Sarah Minden, MD; William C. Reeves, MD, MSPH Arch Intern Med. 2003;163:1530-1536.

[2]. Jason LA, Richman JA, Rademaker AW, Jordan KM, Plioplys AV, Taylor RR, McCready W, Huang CF, Plioplys S: A community-based study of chronic fatigue syndrome. Arch Int Med 1999, 159:2129-2137.

On 2014 Jan 06, Tom Kindlon commented:

Reference to obesity a red herring?

In his editorial, Prof White says: "Georgia may not be representative of the USA as a whole. For instance, we do not know the body mass index (BMI) of the Georgian sample. The Wichita sample of CFS cases contained 43% of subjects with a BMI of 30 or over, representing significant obesity [9]. This compares with 20% in the USA as a whole [13]. Since obesity is associated with fatigue [14], a similar proportion in Georgia might inflate the prevalence of CFS."

Firstly, just because obesity can cause fatigue is quite a different from obesity causing the syndrome CFS. Using this logic, perhaps we should be saying that prevalence studies on any condition which can involve disabling fatigue (for example multiple sclerosis) may be questionable if there is a higher rate of obesity within the sample population. It is important to consider cause and effect i.e. just because people with a condition may be more obese when they are sampled years after having the illness is not the same as saying they were more obese before getting the illness and this caused them to develop the condition.

Also the Wichita study[1], to which Prof. White refers, found a relatively low prevalence rate, of 0.235%, for CFS compared to other random-number studies including the one under review. So it seems curious to refer to this study to try to justify a hypothesis that the obesity rate in the Georgia study artificially increased the prevalence rate.

References:

[1] Prevalence and Incidence of Chronic Fatigue Syndrome in Wichita, Kansas Michele Reyes, PhD; Rosane Nisenbaum, PhD; David C. Hoaglin, PhD; Elizabeth R. Unger, PhD, MD; Carol Emmons, PhD; Bonnie Randall, MCP; John A. Stewart, MD; Susan Abbey, MD; James F. Jones, MD; Nelson Gantz, MD; Sarah Minden, MD; William C. Reeves, MD, MSPH Arch Intern Med. 2003;163:1530-1536.

On 2014 Jan 06, Tom Kindlon commented:

Caution required when extrapolating prevalence rates to the full population

This editorial [1] says, with regard to the CDC study[2]: "The CDC has now repeated and extended the Wichita study in Georgia, and found a prevalence of between six and ten times greater, with 2.5% of the population suffering from CFS. If this prevalence was both accurate and representative of the USA as a whole, this would suggest that some 7.5 million Americans were sufferers, compared to the previous estimates of 0.7 to 1.2 million."

Before the 7.5 million figure is quoted, it might be useful to point out that the figure makes a number of assumptions, including that the prevalence rate for those under 18 and over 60 would be similar. However previous studies have suggested this is unlikely to be the case, with prevalence rates for young children in particular being much lower.

The round figure of 7.5 million would be equivalent to a population of 295,275,591. Using this data the population estimate for 2005 was 296,410,404 (i.e. a similar figure). Using the same data: The population under 18 years was 73,469,580, the population over 60 was 49,791,976 and population aged 18-60 was 173,148,444.

For a population of those aged over 18 and under 60 of this size, a back of the envelope calculation for CFS prevalence using the prevalence rate of 2.64%[2] would give: (173,148,444*0.0264)= 4,397,971.

References:

[1] How common is chronic fatigue syndrome; how long is a piece of string? Peter D White Population Health Metrics 2007, 5:6 doi:10.1186/1478-7954-5-6

[2] Prevalence of chronic fatigue syndrome in metropolitan, urban, and rural GeorgiaWilliam C Reeves , James F Jones , Elizabeth Maloney , Christine Heim , David C Hoaglin , Roumiana S Boneva , Marjorie Morrissey and Rebecca Devlin. Population Health Metrics 2007, 5:5 doi:10.1186/1478-7954-5-5

On 2014 Jan 08, Tom Kindlon commented:

Questioning the use of the Role Emotional (RE) subscale of the SF-36 questionnaire in the diagnosis of CFS

As background to my previous comment, I thought I'd point out that if people would like to see what makes up the Role Emotional (RE) subscale of the SF-36, a copy of a sample SF-36 questionnaire can be seen at: https://clinicalresearch.ccf.org/fsgs/docs/WEBdocs/Form36.pdf .It is question 14 i.e. 3 questions with only yes or no as possible answers.

The cut off point used in the current study is less than or equal to a score of 66 [1], so two "yes" answers (out of the three questions) is the cut off point for functional impairment.

References:

[1] Chronic Fatigue Syndrome – A clinically empirical approach to its definition and study. William C Reeves, Dieter Wagner, Rosane Nisenbaum, James F Jones, Brian Gurbaxani, Laura Solomon, Dimitris A Papanicolaou, Elizabeth R Unger, Suzanne D Vernon and Christine Heim BMC Medicine 2005, 3:19 doi:10.1186/1741-7015-3-19 http://www.biomedcentral.com/1741-7015/3/19

On 2014 Jan 08, Tom Kindlon commented:

Does the use of the "Role emotional" subscale of the SF-36 help with sensitivity and specificity rates? Can we find out the prevalence rate if this subscale hadn't been used?

It is to be welcomed that attempts are being made to operationalize the CDC (94) CFS criteria [1], enabling easier comparisons between studies and making it easier for researchers to try to replicate findings. So, for example, having some sort of numerical value on a symptom so that one can say whether a symptom is present or not in a patient seems to be a good idea.

However, if one is aiming to do this, it would seem preferable to choose methods that have good sensitivity and specificity rates for the condition in question. And it's questionnable whether the methods used in this study have good sensitivity and specificity.

The authors claim that they "used stringent (i.e., <= 25th percentile population norms on any of the 4 SF-36 scales) to define severe functional impairment". One of the SF-36 subscales in question is the "role emotional" subscale. This involves questions such as: "During the past 4 weeks, have you accomplished less than you would like as a result of any emotional problems?" Does this really capture whether there has been a "substantial reduction in previous levels of .. personal activities"? [Full quote from paper[1]: 1) clinically evaluated, unexplained, persistent or relapsing chronic fatigue that is of new or definite onset [has not been lifelong]; is not the result of ongoing exertion; is not substantially alleviated by rest; and results in substantial reduction in previous levels of occupational, educational, social, or personal activities] Perhaps the other three sub-scales cover this? For example, a better measure of whether the condition is having an effect on somebody's "personal activities" might be got from using the physical functioning subscales which asks about ability to walk distances, bath or dress oneself, etc. If this score is low, it's likely one's ability to do "personal activities" has been impaired.

Baraniuk[2] used the CDC '94 not operationalized in the same way as this study and found that CFS patients scores did have lower scores on some of the SF-36 subscales - but role emotional was one of the ones that weren't different (the others that weren't different were mental health and general health change). Would it be possible for the authors to calculate the all important overall prevalence rate if those people who only satisfied this part of the "functional impairment" criteria are excluded? This data would be be useful not just in the US but around the world - countries around the world have been depending on the US to undertake such large scale (and expensive) studies on CFS.

Even before the recent broadening of the criteria, it had been felt by some that the CDC '94 criteria lacked specificity. For example, Kennedy[3] investigated "patients with self-reported symptoms which developed sporadically (sCFS, n=48); after Gulf War service (GW, n=24); and following exposure to organophosphate insecticides (OP, n=25)" all of whom fulfilled the CDC '94 criteria[1]. Based on their findings, they concluded that "differences in simple, easily performed clinical outcome measurements can be observed between groups of patients, all of whom fulfill the CDC-1994 criteria for CFS. It is likely that their response to treatment may also vary. The specificity of the CFS case definition should be improved to define more homogeneous groups of patients for the purposes of treatment and research."

Perhaps what is required is a totally new set of criteria?

References:

[1] Fukuda, K., Straus, S.E., Hickie, I., Sharpe, M.C., Dobbins, J.G., & Komaroff, A. (1994). The chronic fatigue syndrome: A comprehensive approach to its definition and study. Annals of Internal Medicine, 121 (12):953-959. http://www.annals.org/cgi/content/full/121/12/953

[2] James N Baraniuk, Begona Casado, Hilda Maibach, Daniel J Clauw, Lewis K Pannell and Sonja Hess S. A chronic fatigue syndrome - related proteome in human cerebrospinal fluid. BMC Neurology 2005, 5:22 doi:10.1186/1471-2377-5-22http://www.biomedcentral.com/1471-2377/5/22

[3] Kennedy G, Abbot NC, Spence V.A, Underwood C, Belch JJF. The specificity of the CDC-1994 criteria for chronic fatigue syndrome: comparison of health status in three groups of patients who fulfil the criteria. Ann Epidemiol 2004; 14: 95–100.

On 2014 Jan 11, Brett Snodgrass commented:

Dear Authors,

Thank you for the excellent article. Please provide your kind attention to the distinction between the Thebesian veins and the vessels of Wearn.

1. http://bit.ly/JTWearn

2. http://bit.ly/vasaThebesii

3. http://bit.ly/ThebesianByPratt

4. http://www.ncbi.nlm.nih.gov/pubmed/22704295

The vessels described are probably better described as vessels of Wearn as they are (1) not Thebesian veins*, (2) not studied by Thebesius, and (3) they were described by Wearn et al.

Given that there was the prior intervention of stent placement, it may be possible that these connections are "true fistula" in that they are not normally present. Perhaps angiogenesis formed the fine connections identified by injection of contrast material into the left coronary artery.

Another hypothesis is that the procedure caused tissue injury which resulted in vasodilation and increased prominence of the normally present vessels of Wearn.

My opinion is that accurate anatomic terminology is a basic principle underlying good medical science, and I ask others to consider whether the aforementioned definitions are appropriate. If this comment is not helpful, please let me know how it might be improved.

Comments and suggestions are welcome.

Thank you very much.

On 2014 Nov 23, Harri Hemila commented:

A comment is available at: http://hdl.handle.net/10250/8280

On 2016 May 24, Daniel Schwartz commented:

Calculate the Alvarado score online or using a mobile app http://qxmd.com/calculate/calculator_269/alvarado-score-for-acute-appendicitis

Conflict of interest: Medical Director, QxMD

On 2014 Jun 25, Chandra Boosani commented:

Many articles from this journal are not found on their website including this one.

On 2014 Apr 01, Christopher Southan commented:

This is Open Access with full text in the Transactions link. Note also the approaches outlined were used in a 2013 paper on the evolutionary history of BACE1 and BACE2 and their substrates http://www.ncbi.nlm.nih.gov/pubmed/24381583

On 2015 Jun 23, Prof.Dr.Jogenananda Pramanik commented:

Delayed diagnosis of MDR-TB and TB with co-infection of HIV – A major concern!

Tuberculosis (TB) is emerging as an dreaded communicable disease in Malaysia, with the death rate even higher than that of dengue (Ministry of Health, Malay Mail, 2014). Besides being a deadly disease, TB is also an expensive disease which is adding additional economic burden to the health system of the country. Delayed diagnosis of tuberculosis (TB) may lead to an increased period of infectivity in the community, a delay in treatment and a severe form of the disease like MDR-TB and TB with HIV co-infection.(1-7) We appreciate the insightful attempts of Chang CT1, Esterman A.(1) in analyzing the delay in diagnosis of tuberculosis in two perspectives: (A) period between the onset of TB symptoms to any first medical consultation (patients' delay); and (B) period between the first medical consultation to the diagnosis of TB (diagnosis delay). Moreover, we would like to emphasize that there is a need to reduce the time lag between the first inoculations of patient’s sample in solid or liquid culture media till appearance of macroscopically detectable AFB colonies. One of the priorities in the control of tuberculosis is to cure patients with the disease, given that the most effective way to prevent transmission and avoid the appearance of drug-resistant strains is to detect cases of tuberculosis early and treat them appropriately. As a routine practice, all patients suspected of having PTB should submit at least two sputum specimens for microscopic examination in a quality-assured laboratory. These techniques while remaining an important baseline modality of investigations currently, they lack the desired sensitivity or are time consuming. Hence, Nucleic Acid Amplification Tests for the detection of Mycobacterium tuberculosis are useful tools for rapid diagnosis of TB, both pulmonary and extra-pulmonary. These tests are also useful for the rapid screening of patients suspected of MDR-TB. Nucleic Acid Amplification Tests (NAAT) provide rapid results within 24 - 48 hours and has greater PPV (>95%) with AFB smear positive specimens. They have the ability to confirm rapidly the presence of Mycobacterium in 50 - 80% AFB smear negative, culture positive specimens. However, Molecular assays may supplement but cannot replace conventional methods for culture and sensitivity. Moreover their high cost and requirement for sophisticated laboratory infrastructure limit their use in routine diagnosis. Laboratories with advanced infrastructure are limited in most of the peripheral diagnostic laboratories in Malaysia(6-7).

To balance the lack of sophisticated laboratory infrastructure for performing TB identification and drug sensitivity tests to exclude MDR-TB cases with speed and accuracy, there is an urgent need of inexpensive, non-invasive, robust diagnostic and culture sensitivity test. To achieve this goal an attempt was made to incorporate thyroxine hormone in solid and liquid media for culture of AFB in vitro (8-12) Presently, we planned to evaluate the effectiveness of this thyroxine supplemented culture media for culture of AFB from clinical samples in vitro and also to standardize use of this method in comparison to routine AFB culture procedure. This study may prove to be a useful technique for rapid culture isolation of AFB in vitro.

References:

1.Chang CT1, Esterman A.Diagnostic delay among pulmonary tuberculosis patients in Sarawak, Malaysia: a cross-sectional study. Rural Remote Health. 2007 Apr-Jun;7(2):667. Epub 2007 May 11. 2. Alison Rodger, Shabbar Jaffar, Stuar Paynter et al., Delay in the diagnosis of pulmonary tuberculosis, London, 1998-2000: analysis of surveillance data: BMJ 2003; 326 doi: http://dx.doi.org/10.1136/bmj.326.7395.909 (Published 26 April 2003)<br> 3. Zahar JR, Azoulay E, Klement E et al., Delayed treatment contributes to mortality in ICU patients with severe active pulmonary tuberculosis and acute respiratory failure. Intensive Care Med 2001; 27: 513–520 4. Wares D.. Delay in diagnosis of tuberculosis: of remaining concern in England and Wales. J Public Health Med 1999; 21: 355–356 5. Aldhubhani AH1, lzham MI, Pazilah I, Anaam MS (2013)Effect of delay in diagnosis on the rate of tuberculosis among close contacts of tuberculosis patients. East Mediterr Health J. 2013 Oct;19(10):837-42. 6. Ying Li1†, John Ehiri2†, Shenglan Tang et al., 3(2013)Research article Factors associated with patient, and diagnostic delays in Chinese TB patients: a systematic review and meta-analysis:BMC Medicine 2013, 11:156 doi:10.1186/1741-7015-11-156 7. Timothy William123, Uma Parameswaran12, Wai Khew Lee4 et al., Pulmonary tuberculosis in outpatients in Sabah, Malaysia: advanced disease but low incidence of HIV co-infection: BMC Infectious Diseases 2015, 15:32 doi:10.1186/s12879-015-0758-6 8. Pramanik J, Lodam AN, Reddy MVR, Narang P and Harinath BC. Increased yield of excretory-secretory antigen with thyroxine supplementation in in vitro culture of tubercle bacilli. Ind. J. tub. 1997; 44: 185-190. 9. Pramanik J, Lodam AN, Badole CM, Reddy MVR, Patond KR and Harinath BC. Detection of tubercular antibody and antigen in sera of bone and joint tuberculosis. Ind. J. Clin. Biochem. 2000; 15 (1): 22–28. 10. Lodam AN, Pramanik J, Reddy MVR and Harinath BC. Diagnostic potential of fractionated Mycobacterium tuberculosis H37Ra excretory-secretory (EST-DE1) antigen in pulmonary tuberculosis. Ind. J. Clin. Biochem. 1997; 12 (1): 71-77. 11. Pramanik.J. BMJ.2003.http://www.bmj.com/rapid-response/2011/10/30/delays-diagnosis-tuberculosislet-us-use-thyroxine-supplemented-culture-med: Delays in diagnosis of tuberculosis? Let us use thyroxin supplemented culture medium for early lab-diagnosis. 12. Pramanik.J. BMJ: 2004.http://www.bmj.com/rapid-response/2011/10/30/early-diagnosis-tuberculosis-reported-third-world-country Early diagnosis of tuberculosis-reported from third world country:A research letter from India.

On 2014 Aug 31, Ivan Oransky commented:

This paper has been retracted: http://retractionwatch.com/2014/08/28/cancer-researcher-has-correction-upgraded-to-retraction/ It's the second retraction for the last author: http://retractionwatch.com/2014/08/28/cancer-researcher-has-correction-upgraded-to-retraction/

On 2014 Jan 08, Tom Kindlon commented:

Numerous exercise abnormalities been found in Chronic Fatigue Syndrome (CFS)

One curious omission from this interesting review[1] is Chronic Fatigue Syndrome (CFS), which is also sometimes known as Myalgic Encephalomyelitis (ME). An abnormal response to physical activity is an essential part of widely used ME/CFS clinical criteria for adults[2] and children[3]. The most frequently used research criteria for CFS [4] require that patients, along with suffering from chronic debilitating fatigue lasting at least 6 months, have at least 4 out of a list of 8 symptoms, one of which is “postexertional malaise lasting more than 24 hours.”

There is a growing body of research on abnormal responses to exercise in CFS. A recent review[5] covers the issue in a fairly comprehensive manner - here's a summary: “Exertion induces post-exertional malaise with a decreased physical performance/aerobic capacity, increased muscoskeletal pain, neurocognitive impairment, "fatigue", and weakness, and a long lasting "recovery" time. This can be explained by findings that exertion may amplify pre-existing pathophysiological abnormalities underpinning ME/CFS, such as inflammation, immune dysfunction, oxidative and nitrosative stress, channelopathy, defective stress response mechanisms and a hypoactive hypothalamic-pituitary-adrenal axis.”

High rates of adverse reactions to graded exercise programs have been reported in patients with CFS – sometimes 50% or greater[6].

CFS remains a fairly poorly understood condition. There is increasing evidence that CFS is heterogeneous and this heterogeneity could be of relevance to therapeutic programs involving exercise [7,8]. Those interested in researching abnormal responses to physical activity, including dysregulated inflammatory responses, could find much of interest if they chose to study CFS.

References:

1) Cooper DM, Radom-Aizik S, Schwindt C, Zaldivar F Jr. Dangerous exercise: lessons learned from dysregulated inflammatory responses to physical activity. J Appl Physiol. 2007 Aug;103(2):700-9. Epub 2007 May 10.

2) Carruthers BM, Jain AK, De Meirleir KL, Petersn DL, Klimas MD, Lerner AM, Bested AC, Flor-Henry P, Joshi P, Powles ACP, Sherkey JA, van de Sande MI (2003). "Myalgic encephalomyelitis.chronic fatigue syndrome: Clinical working definition, diagnostic and treatment protocols". Journal of Chronic Fatigue Syndrome 11 (1): 7-36.

3) Jason LA, Porter N, Shelleby E, Bell DS, Lapp CW, Rowe K, & De Meirleir K. (2008). A case definition for children with Myalgic Encephalomyelitis/ chronic fatigue syndrome. Clinical Medicine: Pediatrics, 1, 53-57.

4) Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A. The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med. 1994 Dec 15;121(12):953-9.

5) Twisk FN, Maes M. A review on cognitive behavorial therapy (CBT) and graded exercise therapy (GET) in myalgic encephalomyelitis (ME) / chronic fatigue syndrome (CFS): CBT/GET is not only ineffective and not evidence-based, but also potentially harmful for many patients with ME/CFS. Neuro Endocrinol Lett. 2009;30(3):284-99.

6) Kindlon T, Goudsmit EM. Graded exercise for chronic fatigue syndrome: too soon to dismiss reports of adverse reactions. J Rehabil Med. 2010 Feb;42(2):184; author reply 184-6.

7) Jason LA, Corradi K, Torres-Harding S, Taylor RR, & King C. Chronic fatigue syndrome: The need for subtypes. Neuropsychology Review 2005, 15, 29-58.

8) Kindlon T. Stratification using biological factors should be performed in more CFS studies. Psychol Med. 2010 Feb;40(2):352. Epub 2009 Oct 12.

On 2016 Apr 30, Ivan Oransky commented:

Ben Ashby, who reviewed a later paper by Hanna Kokko, one of the authors, in which she corrected an error in this paper, says it should not have been retracted: http://retractionwatch.com/2016/04/29/why-that-evolution-paper-should-never-have-been-retracted-a-reviewer-speaks-out/

On 2013 Dec 28, Tsuyoshi Miyakawa commented:

We failed to replicate most of the behavioral phenotype reported here in these mutant mice. The possible reasons for this discrepancy are discussed in our paper(Shoji H, 2012).

On 2014 Dec 10, Kath Wright commented:

Other search filters are available from the InterTASC Information Specialists' Sub-Group Search Filter Resource at https://sites.google.com/a/york.ac.uk/issg-search-filters-resource/home

On 2013 Nov 24, John Sotos commented:

The history and physical examination of the patient with ischemic cardiomyopathy that was presented in the May 2 Clinical Crossroads column (*) fell short of JAMA’s standards.

First, reporting patterns of “chest pain” in a patient with ischemic heart disease invites errors in history taking because ischemic chest discomfort is often not painful, but “squeezing,” “heavy,” etc.

Second, reporting jugular venous pressure on the basis of venous distention is crude and, unless the patient’s posture is provided, useless.

Third, reporting that a patient’s “pulses were intact,” leaving the arteries anonymous and the pulse-amplitude unspecified, communicates little.

Finally, a typographical error describing the patient’s “normal S1 and S1″ [sic] reinforces the inattention given to the case description.

All professions have their slang and verbal short-cuts, but these temptations to substitute reflex for reflection should be resisted.

(*) Zimetbaum PJ. A 59-year-old man considering implantation of a cardiac defibrillator. JAMA. 2007; 297: 1909-1916.

On 2017 Dec 08, Jesper M Kivelä commented:

Vivarelli and colleagues stated that late hepatic artery thrombosis (HAT) was diagnosed 0.4% (1/236) of patients with antiplatelet prophylaxis (AP) and 2.2% (13/592) of patients without AP. P-value for comparison between these groups was 0.049. The authors used Fisher’s exact test with SPSS version 10, and significance threshold for P-value was 0.05.

Based on my calculations, 2-tailed P-value is 0.130 (1-tailed 0.059) with Fisher’s exact test. I used three different statistical software (i.e. SPSS 22, Stata 12.1 and R 3.1.1).

Research colleague of mine tried to independently replicate (SPSS 22) the aforementioned result presented by Vivarelli and colleagues but without success. Our results, however, were identical.

Naturally, the proportion of late HAT cases is lower in patients with AP (0.4%) compared to patients without AP (2.2%) no matter what the P-value but the results should align with the methods used.

Of course, our calculations can also be wrong. However, we hope that Vivarelli and colleagues could re-examine their calculations.

On 2014 Jun 23, A Rus Hoelzel commented:

This is an odd comment, in that we have had no contact from Genbank, only PubMed about the existence of a comment, and only just today. Also there are only two haplotypes from the archaeological samples not 5 (see Table 2), and both match 100% to Tursiops sequences from various sources found on Genbank using BLAST. However, the two haplotypes mentioned do match mostly Delphinus, but also retrieve Stenella and Tursiops sequences. They are up to 3 bp different from Delphinus, and 2 bp different from Tursiops and Stenella haplotypes. The delphinid radiation is shallow based on mtDNA control region data and polytomous even for multi-locus trees for these three genera. This sequence is only 171 bp long, and generates only a complete polytomy in phylogenetic reconstructions. These two haplotypes that match Delphinus for this short sequence could conceivably represent misidentified samples (from modern stranded animals on the UK coast), but I wouldn’t have much confidence in using 171bp of control region as a barcode to identify species from this group of genera even from a phylogeny, and BLAST is really a very imperfect tool for this. Note that from this same study samples with these two haplotypes assigned with other UK Tursiops samples based on microsatellite DNA genotypes.

On 2014 Jun 17, Andrew Foote commented:

Caution: Two out of the five mtDNA haplotypes generated from the archeological samples (GenBank accession nos: EF540867 and EF540868) are a 100% match for common dolphin (Delphinus delphis) and only a 98% match for any other bottlenose dolphin (Tursiops truncatus) sequences when using the BLAST search implemented in GenBank. The NCBI have been made aware of this taxonomic misidentification and have contacted the sequence submitter (Dr A. Rus Hoelzel), but at present any change requires permission from the sequence submitter. Unfortunately in this case the data submitter does not appear willing to correct the taxonomic classification.

On 2014 Sep 29, Ivan Oransky commented:

This paper has been retracted, one of three studies by the late first author to have been retracted: http://retractionwatch.com/2014/09/26/deceased-researcher-has-two-more-papers-retracted/

On 2015 May 13, Hilda Bastian commented:

This review contributed analysis that has been critical to the debate about editorial peer review. However, the date of the last search for studies was in June 2004. As the eligible literature was sparse, even a few good studies shifts the picture on some questions.

It seems to me likely that the number of relevant studies published in the last decade is now substantive. I include below studies that would be relevant to an update, particularly on the question of blinding/masking of authors' and/or peer reviewers' identities and affiliations, and open publication of peer review reports. A recent systematic on training is also relevant (Galipeau J, 2015).

There are some issues that I believe would be helpful for a new/updated review on editorial peer review to address:

(1) The scope of this review does not include potential sources of editorial/reviewer bias, in particular that related to racial background, gender, country of residence, and institutional prestige. The objective of the review is "to estimate the effect of processes in editorial peer review" and its key focus is the quality of published articles. However, the degree to which these types of biases are minimized in the scientific editorial process has important bearing on the fairness of the processes, as well as the overall quality of literature that may get the most attention in a field.

"Soundness of ethics" is one of the outcome measures of concern, including the avoidance of harm to research subjects. I believe avoidance of harm to authors, who are in a subordinate power relationship in the editorial process, is also a matter of ethics. Publishing mediocre papers from some groups preferentially over higher quality submissions from others, would patently undermine both the fairness and the value of the peer review process at a journal. That may have the power to influence career progress.

Systematic reviews should also point to key areas for further research. The lack of studies into methods to reduce editors’ biases is an important gap to point out, as so much of the literature is concerned primarily with peer reviewers’ bias.

(2) This review did not report on the methods used a priori to systematically assess the risk of bias of included studies, a critical omission in reporting the results of a systematic review (see Oxman AD, 1991, Moher D, 1999, and Liberati A, 2009). A wide variety of study types are eligible for inclusion, raising particular issues specific to them. And studies in this field have a range of specific potential biases. It would be helpful if the experience gained in this review led to an explicit set of criteria for assessing the risk of bias of included studies.

(3) Given the similarities in editorial processes and challenges across scientific disciplines, I believe a systematic review without this restriction would be more valuable, even if the search strategy may have more limitations.

Jefferson T, 2007 included studies with designs that were experimental and other comparative studies that included an attempt to control for confounding. I identified the following additional studies of blinding authors/peer reviewers or publishing peer review reports, that I think need to be considered by reviewers on these questions:

Biomedical science

• Laband DN, 1994
• Nylenna M, 1994 (English abstract, Swedish article Karlsson Y, 1995 - excluded by Jefferson et al)
• Isenberg SJ, 2009
• van Rooyen S, 2010
• Alam M, 2011
• Vinther S, 2012
• Kowalczuk, 2013 (Abstract only)

In addition, Hopewell S, 2014, while addressing another objective in relation to the impact of peer review, was conducted on published pre-publication peer reviews and subsequent manuscript versions.

Non-biomedical sciences

• Ferber MA, 1980
• Blank RM, 1991
• Lloyd ME, 1990
• Laband DN, 1994
• Budden AE, 2008
• Borsuk RM, 2009

I have written more about the evidence base on anonymity and openness in peer review in this blog post.

Finally, a trial of blinding critical appraisers of clinical trials in the context of systematic reviewing was included in this systematic review (Jadad AR, 1996). That is not the context of peer reviewing for publication of those trials. (As it only involves 7 reviewers, including it or not has little effect on overall conclusions on this body of evidence.)

(Disclosure: Part of my job includes working on PubMed Commons, which does not allow anonymous commenting.)

On 2013 Nov 04, Steven Salzberg commented:

This is the first in a series of reports, all coming from the same lab, claiming to have found extant protein sequences in 68-million-year-old fossils. The technical comments published subsequently in Science, and comments published elsewhere, showed convincingly that these results were likely due to contamination or simply misinterpretation. Buckley et al (http://www.ncbi.nlm.nih.gov/pubmed/18174420) show that the amino acids in the mass spec data appear to be modern. Pevzner et al. (http://www.ncbi.nlm.nih.gov/pubmed/18719266) explain that they may represent statistical artifacts. Others have also published results showing that the "soft tissue" reported by Schweitzer and colleagues here and elsewhere is consistent with a bacterial biofilm.

These results have never been replicated by anyone other than the original authors. The prior likelihood of extant proteins or soft tissue in T. rex fossils is near zero, and the evidence supplied here is consistent with several other, far more likely interpretations. Nonetheless, these authors (but no others) have continued to publish papers asserting that they've found dinosaur peptides.

On 2014 Nov 23, Harri Hemila commented:

A manuscript version is available at handle

On 2016 Sep 29, Alem Matthees commented:

This study did not have a control group, therefore reliable conclusions cannot be drawn about whether CBT helped CFS patients to recover from their illness. The recovery rates in the PACE trial, based on the published trial protocol, were not significantly higher in the CBT or GET groups when compared with specialist medical care alone.

Matthees A, Kindlon T, Maryhew C, Stark P, Levin B. A preliminary analysis of ‘recovery’ from chronic fatigue syndrome in the PACE trial using individual participant data. Virology Blog. 21 September 2016. http://www.virology.ws/wp-content/uploads/2016/09/preliminary-analysis.pdf

On 2014 Nov 23, Harri Hemila commented:

This letter was commented on Marmor M, 2008 and a reply to the comment is available at at DOI

On 2014 Feb 05, Michael Kraus commented:

We read this paper in the journal club I sponsor at the University of Illinois (each week we read an interesting social psychology article!). In general I find this topic to be fascinating--that one's mindset could change physiology and behavior in ways that lead to real gains in health is pretty neat!

I do have a question about the mean differences observed in the analysis: The groups have a standard deviation in weight that is about 22lbs (both at time 1 and time 2), and yet the standard error of the means used for the analysis is less than 1 lb. The repeated measures analysis must have accounted for a sizable portion of variability in weight, but I'm estimating, given how standard errors are calculated, that it wouldn't reduce the standard errors this drastically. My question: were there any data transformations or statistical techniques used to analyze the data that are not currently reported in the paper?

On 2016 Nov 18, Morten Oksvold commented:

An investigation committee at Wayne State University (WSU) recommends that 42 articles from Fazlul Sarkar to be retracted (report finished August 31, 2015). This article represents one of them.

This information was published by Retraction Watch (November 17, 2016) and you can find a link to the full report here:

http://retractionwatch.com/2016/11/17/details-of-investigative-report-into-sarkar-released-by-aclu/

This articles should therefore no longer be cited.

On 2018 Feb 01, Misha Koksharov commented:

Use of metallochromic dyes and potentiometric pH-meter titration to detect binding of divalent cations to “Good’s” buffers: 4-morpholinepropanesulfonic acid (Mops) does not bind Mg2+

This is a very useful report and an educative methodological note. I also use MOPS buffer with Mg²⁺ in my work and I was a bit concerned if MOPS could affect the amount of free Mg²⁺ given some uncertainty in the literature.

In a recent review Ferreira et al (RSC Adv., 2015) also summarize that "there is no evidence of complex formation for MES, MOPSO and MOPS with the main metals present in environmental and biological studies. [...] Despite these reports of complexation, most of the authors agree that there is no evidence of significant bonding to metals and several studies specifically chose MES or MOPSO due to their inability to interfere with the most important metals in biological and environmental applications." Though, unfortunately they have missed the current paper.

On 2014 Feb 20, Tom Kindlon commented:

References:

[1] White PD, Sharpe MC, Chalder T, DeCesare JC, Walwyn R; PACE trial group. Protocol for the PACE trial: a randomised controlled trial of adaptive pacing, cognitive behaviour therapy, and graded exercise, as supplements to standardised specialist medical care versus standardised specialist medical care alone for patients with the chronic fatigue syndrome/myalgic encephalomyelitis or encephalopathy. BMC Neurol. 2007 Mar 8;7:6.

[2] Schulz KF, Altman DG, Moher D; CONSORT Group. CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials. BMC Med. 2010 Mar 24;8:18. http://www.biomedcentral.com/1741-7015/8/18/

[3] Moher D, Hopewell S, Schulz KF, Montori V, Gøtzsche PC, Devereaux PJ, Elbourne D, Egger M, Altman DG. CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. BMJ. 2010 Mar 23;340:c869. doi: 10.1136/bmj.c869 http://www.bmj.com/cgi/content/full/340/mar23_1/c869

[4] Boutron I, Moher D, Altman DG, Schulz K, Ravaud P, for the CONSORT group. Methods and Processes of the CONSORT Group: Example of an Extension for Trials Assessing Nonpharmacologic Treatments. Ann Intern Med. 2008:W60-W67. http://www.consort-statement.org/index.aspx?o=1416

[5] Boutron I, Moher D, Altman DG, Schulz K, Ravaud P, for the CONSORT group. Extending the CONSORT Statement to randomized trials of nonpharmacologic treatment: explanation and elaboration. Ann Intern Med. 2008:295-309. http://www.consort-statement.org/index.aspx?o=1415

[6] Psychiatry, Neuroscience and Clinical Psychology University of Edinburgh submission. http://www.rae.ac.uk/submissions/ra5a.aspx?id=176&type=hei&subid=3181

On 2014 Feb 20, Tom Kindlon commented:

CONSORT statement recommends sufficient details to allow replication (for nonpharmacologic treatments, the publishing of manuals is recommended)

(This was originally posted as an e-letter here in 2010: http://www.biomedcentral.com/1471-2377/7/6/comments#415670. However, many people will not read the paper on PubMed Central and so not see it there)

The publishing of this trial protocol [1] is to be welcomed – it is something that the CONSORT statement on Randomized Control Trials (RCTs) recommends[2].

Item 5 of the checklist in the CONSORT guidelines [2] states the following information should be given: "The interventions for each group with sufficient details to allow replication, including how and when they were actually administered."

The explanation for this is given as [3]: "Explanation—Authors should describe each intervention thoroughly, including control interventions. The description should allow a clinician wanting to use the intervention to know exactly how to administer the intervention that was evaluated in the trial.102 For a drug intervention, information would include the drug name, dose, method of administration (such as oral, intravenous), timing and duration of administration, conditions under which interventions are withheld, and titration regimen if applicable. If the control group is to receive “usual care” it is important to describe thoroughly what that constitutes. If the control group or intervention group is to receive a combination of interventions the authors should provide a thorough description of each intervention, an explanation of the order in which the combination of interventions are introduced or withdrawn, and the triggers for their introduction if applicable.

"Specific extensions of the CONSORT statement address the reporting of non-pharmacologic and herbal interventions and their particular reporting requirements (such as expertise, details of how the interventions were standardised).43 44 We recommend readers consult the statements for non-pharma-cologic and herbal interventions as appropriate."

The equivalent item in the Extension for Trials Assessing Nonpharmacologic Treatments is:

"Precise details of both the experimental treatment and comparator

4A Description of the different components of the interventions and, when applicable, descriptions of the procedure for tailoring the interventions to individual participants

4B Details of how the interventions were standardized

4C Details of how adherence of care providers with the protocol was assessed or enhanced"

Here is an extract from the explanation for part a[5]: “It is important to provide a detailed description of nonpharmacologic treatments, which are usually complex interventions involving several components (75), each of which may influence the estimated treatment effect (27–32).”

[..]

“The description of any standardization methods is essential to allow adequate replication of the nonpharmacologic treatment. We recommend that authors allow interested readers to access the materials they used to standardize the interventions, either by including a Web appendix with their article or a link to a stable Web site. Such materials include written manuals, specific guidelines, and materials used to train care providers to uniformly deliver the intervention.”

[..]

“In a review of behavioral medicine interventions, insufficient intervention detail was a barrier to assessment of evidence and development of guidelines (80–82).”

[..]

“For rehabilitation, behavioral treatment, education, and psychotherapy, authors should report qualitative and quantitative data. Qualitative data describe the content of each session, how it is delivered (individual or group), whether the treatment is supervised, the content of the information exchanged with participants, and the instruments used to give information. Quantitative data describe the number of sessions, timing of each session, duration of each session, duration of each main component of each session, and overall duration of the intervention. It is also essential to report how the intervention was tailored to patients’ comorbid conditions, tolerance, and clinical course.”

Here is an extract from the explanation for part b which seems particularly relevant as treatment manuals are referred to in the protocol (but they have not been published):

“The description of any standardization methods is essential to allow adequate replication of the nonpharmacologic treatment. We recommend that authors allow interested readers to access the materials they used to standardize the interventions, either by including a Web appendix with their article or a link to a stable Web site. Such materials include written manuals, specific guidelines, and materials used to train care providers to uniformly deliver the intervention.”

The descriptions of Cognitive Behaviour Therapy (CBT) and Graded Exercise Therapy (GET) are 73 and 68 words respectively. These are not sufficient for replication. For example, what is the advice a therapist should give if a patient experiences an exacerbation of symptoms, which is common with this condition e.g. should they maintain their level of activity or exercise or reduce? And if they maintain their level of activity, how long should this continue for? Also what constitutes treatment adherence? In a previous comment, I pointed out a patient who is counting minutes spent doing housework as minutes for her exercise program.

This estimated cost for this trial is now 5m UK pounds of taxpayers' money[6]. It is important that it is reported as well as possible.

On 2014 Feb 20, Tom Kindlon commented:

New paper lists 3 CFS studies where there was no improvement in the actometer readings but an improvement was reported in subjective outcome measures

(This was originally posted as an e-letter here in 2010: http://www.biomedcentral.com/1471-2377/7/6/comments#387679. However, many people will not read the paper on PubMed Central and so not see it there)

I know it might perhaps have seemed to some who have read these posts that I might be concerned about something that was not important (when I was calling for actometers to be used if possible for at least some of the patients at the end of the trial). So I feel "vindicated" in a way by a review[1] that has just been published. It found that in the three Dutch CFS trials looked at, studies which all found improvements in fatigue[2-4], there was no statistically significant increase in physical activity levels as measured by actometers.

The review also found that "changes in physical activity were not related to changes in fatigue."

The authors of the review (who include people who were involved in all the studies) say that, in the three studies, "treatment was based on the manual of CBT for CFS described in detail by Bleijenberg et al. (2003)" [5]. This form of CBT is comparable to the form of CBT being assessed in the PACE Trial [6].

It is useful to point out that fatigue wasn't the only subjective outcome measure that was said to have improved (in these trials where there was no increase in physical activity).

In all of the three studies [2-4], improvements were reported in functional impairment (as measured by questionnaires). In two of the studies [2,3], improvements in physical functioning as measured by the SF-36 physical functioning subscale were reported (this questionnaire does was not used in the third study[4]). So the patients reported improvements in "physical functioning" (as measured by the SF-36 physical functioning subscale) but there was no improvement in physical activity as measured by the actometers. The SF-36 physical functioning subscale is one of the primary outcome measures in the PACE Trial[6].

This discrepancy between objective measures of activity and questionnaire is similar to data I have previously drawn attention to[7] in a study by Friedberg and Sohl[8].

References:

[1] Wiborg JF, Knoop H, Stulemeijer M, Prins JB, Bleijenberg G. How does cognitive behaviour therapy reduce fatigue in patients with chronic fatigue syndrome? The role of physical activity. Psychol Med. 2010 Jan 5:1 -7. [Epub ahead of print]

[2] Stulemeijer M, de Jong LW, Fiselier TJ, Hoogveld SW, Bleijenberg G (2005). Cognitive behaviour therapy for adolescents with chronic fatigue syndrome: randomised controlled trial. British Medical Journal 330. Published online : 7 December 2004. doi:10.1136/bmj.38301.587106.63.

[3] Knoop H, van der Meer JW, Bleijenberg G (2008). Guided self-instructions for people with chronic fatigue syndrome: randomised controlled trial. British Journal of Psychiatry 193, 340–341.

[4] Prins JB, Bleijenberg G, Bazelmans E, Elving LD, de Boo TM, Severens JL, van der Wilt GJ, Spinhoven P, van der Meer JW (2001). Cognitive behaviour therapy for chronic fatigue syndrome: a multicentre randomised controlled trial. Lancet 357, 841–847.

[5] Bleijenberg G, Prins JB, Bazelmans E (2003). Cognitive-behavioral therapies. In Handbook of Chronic Fatigue Syndrome (ed. L. A. Jason, P. A. Fennell and R. R. Taylor), pp. 493–526. Wiley: New York.

[6] White PD, Sharpe MC,Chalder T, DeCesare JC and Walwyn R for the PACE trial group. Protocol for the PACE trial: A randomised controlled trial of adaptive pacing, cognitive behaviour therapy, and graded exercise as supplements to standardised specialist medical care versus standardised specialist medical care alone for patients with the chronic fatigue syndrome/myalgic encephalomyelitis or encephalopathy. BMC Neurology 2007, 7:6

[7] Kindlon T. Further evidence showing why objective measures are preferable in CFS trials particularly where cognitions could be changed following the intervention http://www.biomedcentral.com/1471-2377/7/6/comments#333618

[8] Friedberg F, Sohl S. Cognitive-behavior therapy in chronic fatigue syndrome: is improvement related to increased physical activity? J Clin Psychol. 2009 Feb 11.

On 2014 Feb 20, Tom Kindlon commented:

Discrepancies between momentary fatigue and recalled fatigue can exist

(This was originally posted as an e-letter here in 2009: http://www.biomedcentral.com/1471-2377/7/6/comments#338630. However, many people will not read the paper on PubMed Central and so not see it there)

One of the primary outcome measures in this study is the bimodal Chalder Fatigue Scale [1] (possible individual scores 0 and 1, total scores can range from 0-11). One of the secondary outcome measures is the Chalder Fatigue Scale[1] using a different method of scoring (possible individual scores: 0-3, total scores can range from 0-33). This asks questions about the last month: "For the next few questions, we would like to know whether or not you have had any problems with feeling tired, weak, or lacking in energy in the last month".

But is it recalled fatigue, or the memory for fatigue, exactly equal to the fatigue people actually felt during a period?

Friedberg and Sohl have investigated this using electronic diaries[2]. Here is a description of what was involved: "In order to obtain a representative diurnal sample of symptoms without undue subject burden (Stone & Shiffman, 2002), the palm pilots prompted subjects for 21 days, 6 times a day, every 2 hr plus or minus a randomly programmed 1-20 min interval (Stone & Shiffman, 1994). The first daily prompt occurred within 1 hr of the subject's wakening and the last daily prompt approximately 12 hr later. No prompt signals occurred during the subject's reported sleep time. After each prompt, a screen was displayed with a numerical rating scale (0-10) that was labeled "Fatigue Now." The end point anchors on the numerical scales were None (0) and Highest (10). Subjects were instructed to record intensity ratings on the numerical scale for their current levels of fatigue."

What they found was "average weekly recall of fatigue intensity was significantly higher than average momentary ratings" (8.5% higher on average). If one used a scale like the Chalder Fatigue Scale[1] which asked for a period of over the preceding month, one could speculate that the discrepancy would be even higher.

This suggests that self-report fatigue questionnaires may not be ideal for intervention studies particularly in expensive trials like this one where one might be willing to pay a bit extra for greater accuracy; just as it has been shown that self-report questionnaires may not correlate strongly with more objective measures of activity (such as actometers)[3,4] (of course, in this study, the reason actometers are not being used does not seem to be due to the cost of obtaining them or the need to train participants to use them, as baseline measurements from actometers are being used).

References:

[1] Chalder T, Berelowitz G, Hirsch S, Pawlikowska T, Wallace P, Wessely S, Wright D: Development of a fatigue scale. J Psychosom Res 1993, 37:147-153.

[2] Friedberg F, Sohl SJ. Memory for fatigue in chronic fatigue syndrome: the relation between weekly recall and momentary ratings. Int J Behav Med. 2008 Jan-Mar;15(1):29-33.

[3] Friedberg F, Sohl S. Cognitive-behavior therapy in chronic fatigue syndrome: is improvement related to increased physical activity? J Clin Psychol. 2009 Feb 11.

[4] Vercoulen JH, Bazelmans E, Swanink CM, Fennis JF, Galama JM, Jongen PJ, Hommes O, Van der Meer JW, Bleijenberg G. Physical activity in chronic fatigue syndrome: assessment and its role in fatigue. J Psychiatr Res. 1997 Nov-Dec;31(6):661-73.

On 2014 Feb 20, Tom Kindlon commented:

Further evidence showing why objective measures are preferable in CFS trials particularly where cognitions could be changed following the intervention

(This was originally posted as an e-letter here in 2009: http://www.biomedcentral.com/1471-2377/7/6/comments#333618. However, many people will not read the paper on PubMed Central and so not see it there)

Since writing my previous posts, further data on the subject has come to my attention.

Friedberg and Sohl [1] have just published the results of a study on an intervention involving Cognitive Behavior Therapy (CBT) which included encouraging patients for going for longer walks. It found that on the SF-36 Physical Functioning (PF) scale, patients improved from a pre-treatment mean (SD) of 49.44 (25.19) to 58.18 (26.48) post-treatment, equivalent to a Cohen's d value of 0.35. On the Fatigue Severity Scale (FSS), the improvement as measured by the cohen's d value was even great (0.78) from an initial pre-treatment mean (SD) of 5.93 (0.93) to a 5.20 (0.95) post-treatment.

However on actigraphy there was actually a numerical decrease from a pre-treatment mean (SD) of 224696.90 (158389.64) to 203916.67 (122585.92) post-treatment (cohen's d: -0.13). So just because patients report lower fatigue and better scores on the SF-36 PF scale, doesn't mean they're doing more, which is what GET and CBT based on GET claim to bring about. These results seem particularly pertinent for this study given the primary outcome measures are the SF-36 PF scale and a fatigue scale.

Further reading show that another study[2], published over a decade ago, showed the problem of using self-report data in CFS patients. The authors' rationale for the study was: "It is not clear whether subjective accounts of physical activity level adequately reflect the actual level of physical activity. Therefore the primary aims of the present study were to assess actual activity level in patients with CFS to validate claims of lower levels of physical activity and to validate the reported relationship between fatigue and activity level that was found on self-report questionnaires. In addition, we evaluated whether physical activity level adequately can be assessed by self-report measures. An Accelerometer was used as a reference for actual level of physical activity.". The authors reported on the correlations on 7 outcome measures in relation to the actometer readings: "none of the self-report questionnaires had strong correlations with the Actometer. Thus, self-report questionnaires are no perfect parallel tests for the Actometer."

Prof. White seems to be aware of the findings of this study as he has been co-authored at least two papers [3,4] which quoted the findings. One of the times this paper was referenced even shows the problem I'm highlighting e.g. "support for this explanation comes from investigations that have described discrepancies between subjectively reported impairments and objective measures of activity" [4].

The authors of the 1997 study[2] pointed out that "The subjective instruments do not measure actual behaviour. Responses on these instruments appear to be an expression of the patients' views about activity and may be biased by cognitions concerning illness and disability." This was re-iterated in another paper[5]: "In earlier studies of our research group, actual motor activity has been recorded with an ankle-worn motion-sensing device (actometer) in conjunction with self-report measures of physical activity. The data of these studies suggest that self-report measures of activity reflect the patients' view about their physical activity and may have been biased by cognitions concerning illness and disability."

A corollary of the last statement is that reports of improvement in self-report measures in interventions which change "cognitions concerning illness and disability" may not be reliable. "Improvements" in self-report measures may simply show that patients have changed their cognitions with regard to how they view their illness, disability, symptoms, etc rather than actually representing improvements in activity levels and functional capacity.

Thus, I would suggest that actometers should be used whenever possible in CFS trials where one is investigating whether an intervention has brought about increased activity.

It is also interesting to note that in the large Van der Werf (2000) study[5], which involved 277 CFS patients (and 47 healthy controls), the authors divided the patients up "pervasively passive" (representing 24% of the patients), "moderately active" and "pervasively active". They found that "levels of daily experienced fatigue and psychological distress were equal for the three types of activity patterns". So one can't necessarily tell how active a patient is from the fatigue levels they report.

Incidentally they also "there were no significant group, gender or interaction effects for the number of absolute large or relatively large day-to-day fluctuations (Table 2 and Table 3)." "The day-to-day fluctuation measures were based on somewhat arbitrary criteria (1 S.D. and 33% activity change). However, when we post hoc tested alternative criteria (50% or 66% activity change), again no significant group differences between controls and CFS patients emerged." Part of the rationale of many behavioural interventions in CFS patients is said to be to reduce "boom and bust" (sample reference,[6]). However, it may be the case that the frequency of this activity pattern in CFS has been exaggerated.

References:

[1] Friedberg F, Sohl S. Cognitive-behavior therapy in chronic fatigue syndrome: is improvement related to increased physical activity? J Clin Psychol. 2009 Feb 11.

[2] Vercoulen JH, Bazelmans E, Swanink CM, Fennis JF, Galama JM, Jongen PJ, Hommes O, Van der Meer JW, Bleijenberg G. Physical activity in chronic fatigue syndrome: assessment and its role in fatigue. J Psychiatr Res. 1997 Nov-Dec;31(6):661-73.

[3] Fulcher KY, White PD. Strength and physiological response to exercise in patients with chronic fatigue syndrome. J Neurol Neurosurg Psychiatry. 2000 September; 69(3): 302–307.

[4] Smith WR, White PD, Buchwald D. A case control study of premorbid and currently reported physical activity levels in chronic fatigue syndrome. BMC Psychiatry. 2006 Nov 13;6:53.

[5] van der Werf SP, Prins JB, Vercoulen JH, van der Meer JW, Bleijenberg G. Identifying physical activity patterns in chronic fatigue syndrome using actigraphic assessment. J Psychosom Res. 2000 Nov;49(5):373-9.

[6] Deary V, Chalder T: Chapter 11, "Conceptualisation in Chronic Fatigue Syndrome" in Formulation and Treatment in Clinical Health Psychology Edited by Ana V. Nikcevic, Andrzej R. Kuczmierczyk, Michael Bruch Competing interests

On 2014 Jan 04, Tom Kindlon commented:

Does housework count as exercise for somebody in the GET leg of the trial?

I wonder could the authors answer a question which is relevant to the real world application of Graded Exercise Therapy (GET). I have heard a participant in the Graded Exercise Therapy (GET) leg of the trial say that they are counting 10 minutes housework in lieu of a 10-minute walk. I think it would be very useful for the authors to clarify whether they think x minutes housework can be used in lieu of x minutes of walking or whether this is not in compliance with the protocol? I think attention to detail in this matter is very important if one is to apply the findings in the real world. With a drug it is easy to check whether the dosage is the same as published trials. With Graded Exercise Therapy (GET), we need clarification from the authors about what is meant by exercise, so that the protocol can be applied as in the trial, so that people either don't get too low a "dose" or too high a "dose" at the wrong stage.

On 2014 Jan 04, Tom Kindlon commented:

References:

[1] PD White, MC Sharpe, T Chalder, JC DeCesare, R Walwyn, for the PACE trial management group: Response to comments on "Protocol for the PACE trial" http://www.biomedcentral.com/1471-2377/7/6/comments#306608

[2] Goudsmit EM, Stouten B, Howes S: Fatigue in Myalgic Encephalomyelitis. Bulletin of the IACFS/ME - Volume 16, Issue 3. http://tinyurl.com/3zcgw8 i.e. http://www.iacfsme.org/BULLETINFALL2008/Fall08GoudsmitFatigueinMyalgicEnceph/tabid/292/Default.aspx

[3] Bazelmans E, Bleijenberg G, van der Meer JWM, Folgering H. Is physical deconditioning a perpetuating factor in chronic fatigue syndrome? A controlled study on maximal exercise performance and relations with fatigue, impairment and physical activity. Psychol Med 2001; 31: 107–14.

[4] Black CD, O’Connor PJ, McCully KK. Increased daily physical activity and fatigue symptoms in chronic fatigue syndrome. Dyn Med 2005; 4: 3.

[5] Sisto SA, Tapp WN, LaManca JJ et al. Physical activity before and after exercise in women with chronic fatigue syndrome. Q J Med 1998; 91:465–73.

[6] Vercoulen JHMM, Bazelmans E, Swanink CMA et al. Physical activity in chronic fatigue syndrome assessment and its role in fatigue. J Psych Res 1997; 31: 661–73.

[7] Van der Werf SP, Prins JB, Vercoulen JHM, van der Meer JWM, Bleijenberg G. Identifying physical activity patterns in chronic fatigue syndrome using actigraphic assessment. J Psychosom Res 2000; 49: 373–79.

[8] Nijs J, Almond F, De Becker P, Truijen S, Paul L. Can exercise limits prevent post-exertional malaise in chronic fatigue syndrome? An uncontrolled clinical trial. Clin Rehabil. 2008 May;22(5):426-35.

[9] Clapp LL, Richardson MT, Smith JF, Wang M, Clapp AJ, Pieroni RE. Acute effects of thirty minutes of light-intensity, intermittent exercise on patients with chronic fatigue syndrome. Phys Ther 1999; 79: 749-56.

[10] Lapp, C (1997). Exercise limits in chronic fatigue syndrome. Am J Med, 103: 83-84.

[11] DL Arnold et al. Excessive intracellular acidosis of skeletal muscles on exercise in the post viral exhaustion / fatigue syndrome: a 31P-NMR Study. Proceedings of third Annual Meeting of the Society for Magnetic Resonance in Medicine, New York, 1984, 12-13.

[12] Jammes Y, Steinberg JG, Mambrini O, Bregeon F, Delliaux S: Chronic fatigue syndrome: assessment of increased oxidative stress and altered muscle excitability in response to incremental exercise. Journal: J Intern Med., 2005 Mar;257(3):299-310.

[13] Black CD, McCully KK: Time course of exercise induced alterations in daily activity in chronic fatigue syndrome. Dyn Med. 2005 Oct 28;4:10.

On 2014 Jan 04, Tom Kindlon commented:

The dropping of actometers as an outcome measure and other points relating to the outcome measures being used

(I'm posting this e-letter/comment from 2008 here for the same reason as the first e-letter below)

In their reply to my comments, Peter White and colleagues say they are using [i]"several objective outcome measures"[/i] [1]. If they think these tests are useful as objective outcome measures, why is at least one of them not being used as a primary outcome measure rather than the current situation where there are only two subjective outcome measures being used.

I have already made some points on the outcome measures but another one is that the bimodal Chalder Fatigue Scale hardly seems a very good outcome measure for a "CFS/ME" trial where there is likely going to be so many maximum or near maximum scoring initially[2]

Also, there are so many (14) secondary outcome measures in this study, along with so many (18) predictor variables, that it seems unlikely all the different methods of looking at the secondary outcome measures can be explored in the final published paper, given authors are encouraged not to make papers too long (especially journals that have paper editions). The protocol itself is 20 pages long when all the different aspects of it are listed! At least some of the information will need to be re-iterated in the final paper.

It is of course important to take the burden on participants into account when deciding what outcome measures to use. However I find the following point very strange: "Although we originally planned to use actigraphy as an outcome measure, as well as a baseline measure, we decided that a test that required participants to wear an actometer around their ankle for a week was too great a burden at the end of the trial." Firstly they clearly don't find it that great a burden that they drop it altogether as it is being used on patients before the start. If they feel it was that big of a burden, it should probably have been dropped altogether.

Of course, other studies in the area have used measuring over a similar or longer period. For example, Bazelmans [3] used an actometer over 14 days, Black [4] used actigraphy over 14 days, Sisto[5] used actigraphy over 7 days, Vercoulen[6] used an actometer over 12 days and Van der Werf [7] used an actometer for 12 days.

Also if one wants to reduce the burden on patients, why not take out one or both of the exercise tests instead. As the clinicians in the study would know, post-exertional symptoms are part of the condition.

For example, Nijs[8] performed a gentle walking exercise on patients where they walked on average 558m(+/-340) (range: 120-1620) at a speed of 0.9m/s (+/-0.2) (range: 0.6-1.1). This resulted in a statistically significant (p<0.05) worsening of scores in the following areas when comparing pre-exercise, post-exercise and 24 hour post-exercise scores using ANOVA: VAS fatigue, VAS musculoskeletal pain, VAS sore throat, SF-36 bodily pain and SF-36 general health percention. 14 out of 24 subjects experienced a clinically meaningful change (worsening) in bodily pain (i.e. a minimum change of the SF-36 bodily pain subscale score of at least 10).

Those results are similar to another study[9] which involved the acute effects of 10 discontinuous 3-minute exercise bouts on a treadmill in 10 CFS patients. In between exercise bouts, there was a 3-minute recovery period between exercise bouts. The participants walked at a comfortable walking pace self-selected by the subjects. On average, the subjects walked at a speed of 0.71+/-0.20 m/s. Some patients reported experiencing headaches, leg pain, fatigue or sore throats.

In another study, Lapp [10] (not to be confused with Clapp[9]) reported on the effects of 31 patients to his practice who were asked to monitor their symptoms three weeks before to 12 days after a maximal exercise test. 74% of the patients experienced worsening fatigue and 26% stayed the same. None improved. The average relapse lasted 8.82 days although 22% were still in relapse when the study ended at 12 days. There were similar changes with exercise in lymph pain, depression, abdominal pain, sleep quality, joint and muscle pain and sore throat.

These are just a small selection of the studies which show patients experience an exacerbation of their symptoms following exercise testing. So these are the sorts of symptoms the patients may expect following the exercise. This reminds me that there seems to be a lot of concentration on measuring fatigue in this study - there are many other symptoms that are part of "CFS/ME".If they had used actometers instead of, say, doing one of the exercise tests, the response to the exercise could have been followed to see how long and how severe an effect the exercise had on the patient. Or they could have dropped both the exercise tests altogether.

As well as "subjective" findings following exercise testing, there have also been objective findings. Arnold et al[11] found excessive intracellular acidoss of skeletal muscles with exercise. Jammes[12] found an increase of damaging oxidative stress following exercise testing. So patients could not just endure temporary sysptom but possibly also longer-term harm from exercise testing. There are numerous other exercise abnormalities.As the clinicians involved in the study probably hear from patients, one of the frustrating things about ME or CFS is that people don't realise the payback that they can have from doing things. This would have been an opportunity to investigate this as part of the study. But now the effort patients will put in and the payback they will feel in some ways is being wasted as the effects won't be measured.

Anyway, to repeat again, given the authors familiarity with the literature, I find it strange that they would decide using an actometer would be worse than putting patients through two exercise tests.

I also find it surprising that in a study part-funded by the Department of Work and Pensions (DWP) that the objective outcome measures (not involving questionnaires) are all once-off exercise tests. It has been established that patients need to be able to do things on several days during a week before they can be passed fit for work. I have mentioned using actometers following exercise tests after an exercise test above; of course, actometers wouldn't have to be used at that time but also during a "normal week".

Proponents of pacing methods including APT would say that there is a "ceiling of activity" that patients can't go above without experiencing a worsening of symptoms. Black[13] has found evidence of this. Proponents of CBT or GET for "CFS/ME" would suggest that patients can gradually just increase how much activity they can do. Actometers would also have tested the hypothesis. As it stands, the study will not give us information on this as just because patients answer questionnaires saying they're improved (which could simply be because they think they're better) or improve their exercise results (which might simply be because they're willing to push themselves more) doesn't prove that they don't have an activity ceiling above which they experience disabling symptoms (esp. when, as in this study, there is no follow-up period following the exercise testing). This is the real "heart" of the issue but given the current design, the question won't be answered.

On 2014 Jan 03, Tom Kindlon commented:

Further information on existing data on management strategies for CFS

(I'm posting this e-letter/comment from 2008 here for the same reason as the first e-letter below)

As well as giving the protocol for the PACE Trial, this paper also gives information and data from some previous studies in the area.

Depending on which pieces of data are presented for any treatment in medicine, a treatment can often look more or less useful or effective. Readers of this paper may be interested to know about a recent meta-analysis of the efficacy of CBT for CFS[1]. The studies involved a total of 1371 patients. This involved calculating the size of an effect measure, the Cohen's d value.They calculated d using the following method: "Separate mean effect sizes were calculated for each category of outcome variable (e.g., fatigue self- rating) and for each type of outcome variable (mental, physical, and mixed mental and physical). Studies generally included multiple outcome measures. For all analyses except those that compared different categories or types of outcome variables, we used the mean effect size of all the relevant outcome variables of the study."d was calculated to be 0.48.

For anyone unfamiliar with Cohen's d values, they are not bounded by 1; also, the higher the score, the bigger the "effect size" i.e. the more "effective" a treatment was found to be. Cohen's d values are considered to be a small effect size at 0.2, a moderate effect size at 0.5, and a large effect size at 0.8[2]. CBT had a more general definition in this paper and included some papers on GET. For example, the current paper gives some information on a study by Fulcher and White[3]. Malouff et al[1] calculated the d value for this study as 0.46 (95% CI: 0.03-0.95).

References:

[1] Malouff, J. M., et al., Efficacy of cognitive behavioral therapy for chronic fatigue syndrome: A meta-analysis. Clinical Psychology Review (2007), doi:10.1016/j.cpr.2007.10.004

[2] Cohen J: Statistical power analysis for the behavioural sciences. Edited by: 2. New Jersey: Lawrence Erlbaum; 1988.

[3] Fulcher KY, White PD: Randomised controlled trial of graded exercise in patients with the chronic fatigue syndrome. BMJ 1997, 314:1647-1652.

On 2014 Jan 03, Tom Kindlon commented:

If CBT for CFS is "to help patients improve activity levels and quality of life", would not actometers be useful for measuring outcomes?

(I'm posting this e-letter/comment from 2007 here for the same reason as the first e-letter below)

Just following up on a previous point: I have just read an oft-quoted paper on CBT for CFS[1], which was co-written by one of the co-authors and principal investigators in the current study, Prof Chalder. [CBT was provided, to the best of my knowledge, in one of the places where CBT will be offered in the PACE Trial].

The current paper says "Two independent systematic reviews have found that rehabilitative cognitive behaviour therapy (CBT) and GET were the most promising treatments for CFS/ME in secondary care". The two reviews reference this paper[1]. The paper[1] states that "cognitive behavior therapy was to help patients improve activity levels and quality of life". Unfortunately there is no mention of pedometers or actometers being used. So it seems disappointing that, according to the design presented, the researchers in the current trial (which many are hoping might be the definitive paper on the subject) will use actometers before the patients start the intervention but will not assess whether the treatment improves activity levels using the sort of measurements actometers can provide.

References:

[1] Deale A, Husain K, Chalder T, Wessely S. Long term outcome of cognitive behavior therapy versus relaxation therapy for chronic fatigue syndrome: a 5-year follow-up study. Am J Psychiatry 2001;158: 2038-42.

On 2014 Jan 03, Tom Kindlon commented:

CFS intervention studies - lessons can be learned from a previous review

(I'm posting this e-letter/comment from 2007 here for the same reason as the first e-letter below)

I have just been reminded that many of the points I have been made, such as suggesting the use of the actometer as an outcome measure, were covered in the Whiting et al review (2001) [1].

The review recommended the use of more objective outcome measures e.g. "Outcomes such as "improvement," in which participants were asked to rate themselves as better or worse than they were before the intervention began, were frequently reported. However, the person may feel better able to cope with daily activities because they have reduced their expectations of what they should achieve, rather than because they have made any recovery as a result of the intervention. A more objective measure of the effect of any intervention would be whether participants have increased their working hours, returned to work or school, or increased their physical activities."

This review also recommended long-term follow-up: "The relapsing nature of CFS suggests that follow-up should continue for at least an additional 6 to 12 months after the intervention period has ended, to confirm that any improvement observed was due to the intervention itself and not just to a naturally occurring fluctuation in the course of the illness."

It is slightly disappointing that the follow-up period in this study is scheduled at 52 weeks, only 16 weeks after the session at 36 weeks.

It is particularly disappointing that this current trial didn't learn from the Whiting et al review [1] as both White and Sharpe have shown awareness of the review, having made reference to it in articles [2-5].

Perhaps it is not too late to collect data from even some subjects, using the actometers?

References:

[1] Penny Whiting, Anne-Marie Bagnall, Amanda J. Sowden, John E. Cornell, Cynthia D. Mulrow, Gilbert Ramírez: Interventions for the Treatment and Management of Chronic Fatigue Syndrome - A Systematic Review JAMA. 2001;286:1360-1368 http://jama.ama-assn.org/cgi/content/full/286/11/1360

[2] Peter White: Commentary. Adv. Psychiatr. Treat. 2002;8:363-365. (September 2002)http://apt.rcpsych.org/cgi/content/full/8/5/363

[3] Peter White: Chronic unexplained fatigue.Postgrad. Med. J. 2002;78:445-446. (August 2002) http://pmj.bmj.com/cgi/content/full/78/922/445

[4] Peter White: What causes chronic fatigue syndrome?BMJ 2004;329:928-929.http://www.bmj.com/cgi/content/full/329/7472/928

[5] Michael Sharpe: The symptom of generalised fatigue.PN 2006;6:72-77.http://pn.bmj.com/cgi/content/full/6/2/72

On 2014 Jan 03, Tom Kindlon commented:

Another example as to why objective measures would be useful

(I'm posting this e-letter/comment from 2007 here for the same reason as the first e-letter below)

Another example of why objective measurements are important in studies involving CBT was shown in a recently published study by Knoop et al [1]. Their results state that "the level of self-reported cognitive impairment decreased significantly more after CBT than in the control conditions. Neuropsychological test performance did not improve."

References:

[1] Knoop H, Prins JB, Stulemeijer M, van der Meer JW, Bleijenberg G:The effect of cognitive behaviour therapy for chronic fatigue syndrome on self-reported cognitive impairments and neuropsychological test performance. Journal of Neurology and Neurosurgery Psychiatry. 2007 Apr;78(4):434-6.

On 2014 Jan 03, Tom Kindlon commented:

Would it not be preferable if objective outcome measures were used?

This was originally posted at: http://www.biomedcentral.com/1471-2377/7/6/comments but the line gaps have been removed so don't think many will fancy reading it there (also may click on the PubMed Central link for the paper and not see it).

I find it strange that, particularly in such a costly trial (over UK£3m* [2013: final estimate is around UK£5m]), only subjective outcome measures are being used.

The participants are assessed using actigraphy watches at the baseline assessment stage. Why are not these being used either during and particularly at the end of the trial? This is important given previous studies in the area.

One study (on a single patient)[1] found "using a 26-session graded activity intervention involved gradual increases in physical activity" that "from baseline to treatment termination, the patient’s self-reported increase in walk time from 0 to 155 min a week contrasted with a surprising 10.6% decrease in mean weekly step counts."

Another study [2], investigating CBT this time, found that (of 278 eligible) "241 patients had complete data (83 CBT, 80 support groups, 78 natural course) at 8 months. At 14 months CBT was significantly more effective than both control conditions for fatigue severity (CBT vs support groups 5.8 [2.2-9.4]; CBT vs natural course 5.6 [2.1-9.0]) and for functional impairment (CBT vs support groups 263 [38-488]; CBT vs natural course 222 [3-441]). Support groups were not more effective for CFS patients than the natural course. Among the CBT group, clinically significant improvement was seen in fatigue severity for 20 of 58 (35%), in Karnofsky performance status for 28 of 57 (49%), and self-rated improvement for 29 of 58 (50%)." Yet if one examines the actometer data from this study from the group given CBT, the increases in activity were minimal[3]. For instance, the baseline average was 67.9, which increased to 68.8 after treatment and to 72.2 at follow-up. About 4 points. Not unlike the medical care controls, who went from 64.9 to 68.7 in the same period. [3]

One of the aims of CBT (for CFS) has been said to be "increased confidence in exercise and physical activity"[4]

Thus it may be the case that when asked questions about one's ability to do things, such as in the physical functioning subscale of SF-36 (one of the two primary outcome measures), the patients might say that they are "Limited A Little" or "Not Limited At All" but may be just as limited as patients in other arms of study who say "limited a lot".

Ideally more than one more objective measure would be used. White himself has found immunological changes after both exercise and activity in Chronic Fatigue Syndrome [5]. It would have been interesting to see whether any of these treatments had an effect on such cytokines.

References:

[1]. Friedberg, F. Does graded activity increase activity? A case study of chronic fatigue syndrome. Journal of Behavior Therapy and Experimental Psychiatry, 2002, 33, 3-4, 203-215

[2]. Prins JB, Bleijenberg G, Bazelmans E, et al. Cognitive behaviour therapy for chronic fatigue syndrome: a multicentre randomised controlled trial. Lancet 2001; 357: 841-47.

[3]. Van Essen, M and de Winter, LJM. Cognitieve gedragstherapie by het vermoeidheidssyndroom (cognitive behaviour therapy for chronic fatigue syndrome). Report from the College voor Zorgverzekeringen. Amstelveen: Holland. June 27th, 2002. Bijlage B. Table 2.

[4]. O'Dowd, H., Gladwell, P., Rogers, CA., Hollinghurst, S and Gregory, A. Cognitive behavioural therapy in chronic fatigue syndrome: a randomised controlled trial of an outpatient group programme. Health Technology Assessment, 2006, 10, 37, 1-140.

[5]. White, PD., Nye, KE., Pinching, AJ., Yap, TM., Power, N., Vleck, V., Bentley, DJ., Thomas, JM., Buckland, M and Parkin, JM. Immunological changes after both exercise and activity in chronic fatigue syndrome: a pilot study. Journal of Chronic Fatigue Syndrome, 2004, 12, 2, 51-66.

On 2016 May 25, Margaret Sampson commented:

For an update, please see: Page MJ, Shamseer L, Altman DG, Tetzlaff J, Sampson M, Tricco AC, Catalá-López F, Li L, Reid EK, Sarkis-Onofre R, Moher D. Epidemiology and Reporting Characteristics of Systematic Reviews of Biomedical Research: A Cross-Sectional Study. PLoS Med. 2016 May 24;13(5):e1002028. doi: 10.1371/journal.pmed.1002028. eCollection 2016 May. PubMed PMID: 27218655.

On 2014 Dec 05, Alberto Halabe Bucay commented:

My work about treatment of cancer with citric acid (citrate) based on my hypothesis about biological competition between the cell and the mitochondria.

On 2014 Mar 27, Eduardo Fox commented:

The present paper was retracted as of August 2011. Details on detected issues and retraction notice can be found online.

On 2015 Jul 06, Bill Cayley commented:

A good example of when "Less" is actually "More": https://lessismoreebm.wordpress.com/2015/07/06/comparing-hospice-and-nonhospice-patient-survival-among-patients-who-die-within-a-three-year-window/

On 2016 Nov 20, Morten Oksvold commented:

An investigation committee at Wayne State University (WSU) recommends that 42 articles from Fazlul Sarkar to be retracted (report finished August 31, 2015). This article represents one of them.

This information was published by Retraction Watch (November 17, 2016) and you can find a link to the full report here:

http://retractionwatch.com/2016/11/17/details-of-investigative-report-into-sarkar-released-by-aclu/

This article should therefore no longer be cited.

On 2015 Jul 30, Keith Bradnam commented:

As of 2015, development of CEGMA v2 has ceased completely and we can no longer respond to support requests. While the latest version still runs, it should be pointed out that the underlying set of orthologs that CEGMA uses is based on the KOGs database that was published back in 2003.

We would advise potential users of CEGMA to consider newer tools like BUSCO which perform a similar role, are easier to install, take less time to run, and which are based on more modern sets of orthologous genes.

We don't rule out making a completely new version of CEGMA some day, but for now we consider CEGMA v2 an end-of-life product.

On 2014 Aug 18, Paul Brookes commented:

I did not discover the following; these comments were sent to me by an anonymous correspondent, and I agree with their assessment of the data, so am posting here using my own name even though this is not a paper I have either read, or am familiar with the field of...

In Figure 2C, the anti-Flag blot (bottom panel) contains several bands which bear a striking resemblance (more than would be expected by pure coincidence) to bands in the anti-Myc blot of Figure 2B (middle panel). In fact, it's almost as if the latter is a longer exposure of the former.

Also in Figure 2C, the central panel (anti-GST blot), the bands in the top left appear strikingly similar to bands in the anti-tubulin blot (lower panel) in Figure 5A, with 180 degree rotation.

FYI, another paper from the same group Schwamborn JC, 2007 has also been flagged by the same person, and I have/will left a comment there too. I am reliably informed that the DFG (German equivalent of the NIH) is aware of these data problems, as are the journals involved. However more than 6 months has now passed with no actions taken.

On 2017 Sep 25, Peter Gøtzsche commented:

The primary outcome in the trial called TORCH (“Towards a Revolution in COPD Health”) was total mortality. GlaxoSmithKline randomised 6184 patients to four groups: placebo; salmeterol; fluticasone; and both drugs together. This factorial design is powerful, as it allows the investigators to study three research questions with a sample size that would usually only allow one question to be answered. Such a trial can tell us whether the two drugs are effective, and whether the combination is better than any of its components.

However, nowhere in the 15-page trial report is the factorial analysis to be found, and the abstract gives the readers the impression that the combination was better than any of its components. The analysis in the TORCH trial included only half of the patients, thereby spoiling the advantage of the factorial design, although the published trial protocol stated that a factorial analysis was to be performed (1).

The authors of a letter to the editor used a factorial analysis and showed that the effect of the combination was entirely due to salmeterol (2); the hazard ratio for fluticasone was 1.00 (0.87 to 1.15), p = 0.99. In other similar trials, both GlaxoSmithKline and AstraZeneca did not perform a factorial analysis (3).

1 Gøtzsche PC. Questionable research and marketing of a combination drug for smoker’s lungs. J R Soc Med 2014;107:256-7.

2 La Vecchia C and Fabbri LM. Prevention of death in COPD. N Engl J Med 2007;356:2211–2.

3 Suissa S, Ernst P, Vandemheen KL, et al. Methodological issues in therapeutic trials of COPD. Eur Respir J 2008;31:927–33.

On 2017 Sep 07, Peter Gøtzsche commented:

The primary outcome in the trial called TORCH (“Towards a Revolution in COPD Health”) was total mortality, which was not analysed correctly. GlaxoSmithKline randomised 6184 patients to four groups: placebo; salmeterol; fluticasone; and both drugs together. This factorial design is powerful, as it allows the investigators to study three research questions with a sample size that would usually only allow one question to be answered. Such a trial can tell us whether the two drugs are effective, and whether the combination is better than any of its components.

However, in violation with the published trial protocol (1), nowhere in the 15-page trial report is the correct factorial analysis to be found, and the abstract gives the readers the clear impression that the combination was better than any of its components. The misleading analysis in the TORCH trial included only half of the patients, thereby spoiling the advantage of the factorial design.

The authors of a letter to the editor showed the correct factorial analysis. The effect of the combination was entirely due to salmeterol (2). In contrast, the hazard ratio for fluticasone was 1.00 (0.87 to 1.15), p = 0.99. There was no good reason why a factorial analysis was not done and published (1). Both GlaxoSmithKline and AstraZeneca have not performed the appropriate analysis in other similar trials as well (3).

1 Gøtzsche PC. Questionable research and marketing of a combination drug for smoker’s lungs. J R Soc Med 2014;107:256-7.

2 La Vecchia C and Fabbri LM. Prevention of death in COPD. N Engl J Med 2007;356:2211–2.

3 Suissa S, Ernst P, Vandemheen KL, et al. Methodological issues in therapeutic trials of COPD. Eur Respir J 2008;31:927–33.

On 2017 Aug 28, Peter Gøtzsche commented:

None

On 2014 Dec 10, David Keller commented:

This study was funded by the manufacturer of MiraLax brand polyethylene glycol laxative

Braintree Laboratories, the manufacturer of MiraLax, funded this year-long open-label study of the safety of their product. However, given the large number of consumers who ingest polyethylene glycol 3350 on a chronic basis, often for many years, it would be helpful to obtain longer-term follow-up of the participants in this study. In addition, a larger and longer-term study, not manufacturer-funded, is warranted, given the unrestricted over-the-counter sale and unmonitored use of PEG-3350 by consumers.

Ethylene glycol is known to be a toxic substance, as are its short multimers, di-ethylene glycol and tri-ethylene glycol. Even if polymerization of 54 ethylene glycol monomers, to an average molecular weight of 3350, renders the resulting long-chain polymers harmless, can we rely on this polymerization to hold up under all circumstances? Human digestion is largely the process of depolymerization of polysaccharides and polypeptides. To what extent does PEG-3350 de-polymerize to ethylene glycol or its toxic short multimers, during digestion or during preparation of the laxative? Are trace amounts of toxic monomers or short multimers produced under any circumstances - including mixture with various beverages and at various temperatures which consumers might use?

Even in the absence of de-polymerization, how much PEG-3350 is found in the serum and urine of humans during chronic daily use? What subtle long-term effects might be caused by the presence of trace amounts of these chemicals in the diets of diverse humans, for years on end? Only a larger, longer-term, independently-funded study can answer these questions.

On 2014 Dec 10, Kath Wright commented:

Other search filters are available from the InterTASC Information Specialists' Sub-Group Search Filter Resource at https://sites.google.com/a/york.ac.uk/issg-search-filters-resource/home

On 2015 Jul 28, Christina Niederstadt commented:

The authors of this article are not very accurate regarding their citation of the available literature and their summaries of cited papers. E.g. the following paragraph: "Another controversial approach has involved the immunization of RCC patients with hybrids of DC fused to autologous RCC tumour cells. Early phase I trial results, reported by Kugler et al. [29], described tumour regressions in seven of 17 RCC patients using allogenic monocyte-derived mature DC fused in an electric field to autologous tumour cells. However, a follow-up phase II study failed to confirm these promising early results [30]."

Reference [29]: Kugler A, Stulher G, Walden P, et al. Regression of human metastatic renal cell carcinoma after vaccination with tumor cell-dendritic cell hybrids. Nat Med. 2000;6:332–6. [PMID: 10700237] Reference [30]: Kugler A, Stuhler G, Walden P, et al. Retraction: regression of human metastatic renal cell carcinoma after vaccination with tumor cell-dendritic cell hybrids. Nat Med. 2003;9:1221. [PMID: 12949529]

The denotation "a follow-up phase II study" seems to be a rather inappropriate description of a retraction notice!

On 2016 Jun 19, Jacob H. Hanna commented:

We noted that Dr. Hendrich states : "Furthermore, we previously showed that Mbd3 null ES cells generated by genetic manipulation in vitro are viable. ".

I find using the above-mentioned result as a predictor and indication that it must be possible to derive Mbd3 null ESCs from ICMs, as wrong and misleading. We all know that in the case of Nanog, it can be deleted in previously established ESCs, however it cannot be derived from Nanog null ICMs since pluripotency is not formed in the absence of Nanog in vivo. This is not the case for Mbd3. In my opinion, you should retract this paper that purports Mbd3 as an essential factor for eastblishing pluripotency and ES cells.

On 2016 Jan 26, K Kaji commented:

Hi Jacob, FYI, our conclusion in this paper is that Mbd3 is required for development of pluripotent cells in peri-implantation embryos, from ICM in blastocyst to post-implantation epiblast.

On 2016 Jan 25, Jacob H. Hanna commented:

Thank you for the response. As a scientist I have been trying to understand the biology of Mbd3/NuRD in pluripotency during early mouse development in vivo and in vitro, and it is not about whether a certain sentence is actually explicitly stated or not (this is typically the job of patent lawyers:) ). We have absolute confidence in the data presented in this paper, however we believe that the interpretation is misleading and wrong.

There are two aspects of pluripotency formation that are being addressed:

1) In vivo formation of pluripotency at E3.5: your paper concludes that Mbd3 is required for formation of pluripotent cells in vivo. However, by viewing immunostaining for Oct4/Nanog in E3.5 epiblasts, the formation of pluripotent cells is not compromised at all based on the data presented in Figure 2B from Kaji et al. Development 2007. We have highlighted this in the following summary slide ( http://imgur.com/lsM6kbV ), and contrasted this with data on Nanog null ICMs, where pluripotent cell stability is compromised in vivo (and subsequently Nanog knockout ESCs could not be derived from Nanog null embryos). You recent gene-expression data on Chd4 null ICMs further validates the emergence of the pluripotent epiblast at E3.5-E4.5 O'Shaughnessy-Kirwan A, 2015. Therefore in our opinion, the adequate conclusion based on your data is that pluripotency formation is not compromised in vivo by ablation of Mbd3/Chd4/NuRD complex.

2) In vitro formation and derivation of ESCs: There have been many instances in science where new technologies emerge and allow us to revisit old findings (e.g. new microscopy, new growth conditions etc.) and prove that old conclusions were in fact erroneous due to the inability of the tools available at that time to conduct the best experiment. As we are interested only in unraveling the true biology (which is timeless), the fact that Oct4+/Nanog+ cells emerge in vivo in Mbd3 and Chd4 null embryos (see comment 1 above - http://imgur.com/lsM6kbV ), and that ESCs can accordingly be derived under optimized conditions (Rais et al. Nature 2013), in our opinion this indicates that Mbd3/NuRD is not required for in vitro derivation of pluripotent ESCs and does not even compromise this process.

Jacob (Yaqub) Hanna M.D. Ph.D.

Department of Molecular Genetics

Weizmann Institute of Science | 234 Herzl St, Rehovot 7610001, Israel

Email: jacob.hanna@weizmann.ac.il

Lab website: http://hannalabweb.weizmann.ac.il/

Twitter: @Jacob_Hanna

On 2016 Jan 25, Brian Hendrich commented:

Our paper describes the function of Mbd3/NuRD in pluripotent cells in the early mouse embryo. Whether one can derive ES cells from Mbd3 null blastocysts is not relevant to the message of this paper.

Figure 4 shows that Mbd3-/- ICMs taken from C57Bl/6 mouse embryos did not proliferate when cultured in Serum/LIF conditions. This paper predates the advent of 2i culture media, reported by Ying et al. 2008, and therefore the possibility that Mbd3-/- ES cells can be derived in 2i/LIF conditions is not inconsistent with what is reported in our paper. Furthermore, we previously showed that null ES cells generated by genetic manipulation in vitro are viable. Nowhere in this paper do we state “it is absolutely impossible to derive Mbd3-/- ESCs from Mbd3 null E3.5 embryos”.

On 2016 Jan 23, Jacob H. Hanna commented:

After posting our comment and critiques below (http://1.usa.gov/1HeRjpX), we have noted a similar doubt was raised by Dr. Silva and Sr. Smith in 2007 in their Essay titled: "Capturing Pluripotency" Cell 2007 - http://www.sciencedirect.com/science/article/pii/S0092867408002079 Silva J, 2008

"A critical test is whether repair of a gene defect is sufficient to restore differentiation capability. For example, ES cells in which the NuRD repressor complex is inactivated by deletion of the Mbd3 subunit are compromised in prosecuting differentiation, but this defect is eliminated upon re-expression of Mbd3, meaning that the pluripotent state has been preserved throughout ( Kaji et al., 2006). A specific requirement in maintaining the pluripotent state should only be claimed when a change in developmental potential is irreversible, as for example when Oct4 or Sox2 is deleted (Niwa, 2007). Interestingly, Mbd3 appears necessary for derivation of ES cells, but this is because in its absence the epiblast does not form properly (Kaji et al., 2007) and not because Mbd3 is required by ES cells."

Regarding the last sentence, we now know that Mbd3 is NOT necessary for deriving mouse Mbd3 null ESCs from KO mouse ICMs that retain Nanog and Oct4 expression in vivo (Rais et al. Nature 2013).

Jacob (Yaqub) Hanna M.D. Ph.D.

Department of Molecular Genetics

Weizmann Institute of Science | 234 Herzl St, Rehovot 7610001, Israel

Email: jacob.hanna@weizmann.ac.il

Lab website: http://hannalabweb.weizmann.ac.il/

Twitter: @Jacob_Hanna

On 2015 Mar 08, Jacob H. Hanna commented:

This Kaji et al. 2007 paper claims that it is absolutely impossible to derive Mbd3-/- ESCs from Mbd3 null E3.5 embryos. This result is surprising considering that the authors show in the same paper presence of Oct4+/Nanog+ cells in Mbd3-/- ICMs. Further, Mbd3-/- ESCs are "hyper-naive" and resist differentiation even in the absence of LIF (Kaji et al. Nature Cell Biology 2006, Reynolds et al. Cell Stem Cell 2012). Our group has revisited this result in Rais et al. Nature 2013, and was able to efficiently derive Mbd3-/- ESCs in serum free enriched 2i/LIF conditions. This suggests that the main conclusion of Kaji et al. 2007 Development paper titled "Mbd3 is required for development of pluripotent cells", is invalid and constitutes an artifact likely due to using a low quality fetal bovine serum (FBS) batch.

Jacob (Yaqub) Hanna M.D. Ph.D.

Department of Molecular Genetics

Weizmann Institute of Science | 234 Herzl St, Rehovot 7610001, Israel

Email: jacob.hanna@weizmann.ac.il

Lab website: http://hannalabweb.weizmann.ac.il/

Twitter: @Jacob_Hanna

On 2016 Sep 07, Nalini M Rajamannan commented:

Thank you to open trials.net, we are grateful for your stringent checking of clinical trials.gov registration number. You are correct the exact registration number is NCT0014491.

The number 1 in the middle of the registration was missing in the final publication,

The typo was brought to our attention, and we did request for the final number 1 to be added to the publication, but the time to correct the typo was not possible due to the date of the original publication in 2007, according to the editorial office.

We agree that the discovery of the published NCT number: "The ID given is NCT0014491. We believe the correct ID, which we have found in the text in an embedded link, is NCT00114491."

On behalf of the RAAVE investigators, we are grateful for your diligent work and the correction of our registration in Clinicaltrials.gov as listed in PubMed Commons.

Sincerely

Nalini M. Rajamannan, MD

On 2016 Aug 30, Ben Goldacre commented:

This trial has the wrong trial registry ID associated with it on PubMed: both in the XML on PubMed, and in the originating journal article. The ID given is NCT0014491. We believe the correct ID, which we have found in the text in an embedded link, is NCT00114491.

This comment is being posted as part of the OpenTrials.net project^[1] , an open database threading together all publicly accessible documents and data on each trial, globally. In the course of creating the database, and matching documents and data sources about trials from different locations, we have identified various anomalies in datasets such as PubMed, and in published papers. Alongside documenting the prevalence of problems, we are also attempting to correct these errors and anomalies wherever possible, by feeding back to the originators. We have corrected this data in the OpenTrials.net database; we hope that this trial’s text and metadata can also be corrected at source, in PubMed and in the accompanying paper.

Many thanks,

Jessica Fleminger, Ben Goldacre*

[1] Goldacre, B., Gray, J., 2016. OpenTrials: towards a collaborative open database of all available information on all clinical trials. Trials 17. doi:10.1186/s13063-016-1290-8 PMID: 27056367

* Dr Ben Goldacre BA MA MSc MBBS MRCPsych<br> Senior Clinical Research Fellow<br> ben.goldacre@phc.ox.ac.uk<br> www.ebmDataLab.net<br> Centre for Evidence Based Medicine<br> Department of Primary Care Health Sciences<br> University of Oxford<br> Radcliffe Observatory Quarter<br> Woodstock Road<br> Oxford OX2 6GG

On 2014 Nov 23, Harri Hemila commented:

A manuscript version is available at handle

On 2016 Mar 29, Jonathan Wren commented:

URL relocated to: http://bioinf.gen.tcd.ie/casbah/

On 2014 Feb 23, Farrel Buchinsky commented:

An interesting prospective cohort. Would like to find studies where there is randomization and a control group.

Looks as if my answer is in Guilleminault C, 2008

On 2015 May 02, Martine Crasnier-Mednansky commented:

The role of cAMP in the glucose-acetate diauxie was not taken into account by the authors however if it is taken into account, interesting possibilities arise.

Acetate utilization by the fast-switchers is suppressed during growth on glucose as shown by a biphasic growth curve indicating preferential use of glucose over acetate (Figure 1A, blue circles), and a nearly constant concentration of acetate in the medium to the switch point (Figure 1C, blue circles). In contrast, an extended diauxic lag is observed with the slow-switchers (Figure 1A, red circles). Both switchers however show identical growth rate during the first growth phase (red and blue circles in Figure 1A), same switching point in time, and same glucose use (red and blue circles in Figure 1B).

A diauxic lag disappearance and biphasic growth are typically associated with addition of cAMP to the growth medium (Ullmann A, 1968). It was established that, during a downshift from glucose to acetate, the CRP-cAMP complex peaked during the first hour of transition, which correlated with an increase in cAMP (Kao KC, 2004). Therefore addition of cAMP to a typical glucose-acetate diauxie most likely will affect the diauxic lag. Moreover, a cAMP-dependent regulation of the aceBAK operon was previously inferred by the presence of CRP-binding sites within the operon and a strong glucose repression, as indicated by transcriptome data (Table 1 in Zhang Z, 2005).

So, what if the fast-switchers are no longer 'dependent' on the cAMP signal upon entry in the second phase of growth on acetate (in other words there is no need for CRP-cAMP in the absence of IclR for the transcription of the aceBAK operon). It is then expected that the fast-switchers with an 'ancestral' iclR will exhibit a typical diauxic growth, which is what is observed (Figure 4A).

As regards the slow-switchers, their growth pattern does not significantly vary from the growth pattern of the ancestor. They both resume growth on acetate after an extended lag, but very poorly as compared to the fast-switchers. It is therefore not surprising that introduction of the iclR^IS1 in the ancestor bares no consequences on the growth pattern.

A final note; micromolar concentrations of glucose were used for growth in the presence of both glucose and acetate (as indicated in M&M under Growth curve assay). The increased concentration of acetate in the medium from the slow-switchers (Figure 1C, red circles) should not occur at glucose concentrations used in Figure 1A as dissimilation of acetate occurs under aerobiosis in excess glucose.

On 2014 Nov 17, Raphael Levy commented:

There is a detailed discussion of this paper at PubPeer, including the publication of technical comment that was considered, but not published by Science.

More broadly, the evidence behind the structure and special properties of “striped” nanoparticles has been challenged by Cesbron Y, 2012. The publication in 2012 of Cesbron Y, 2012 took three years and has been followed by post-publication peer review of the various existing and new stripy articles on my blog, PubPeer, etc.

A detailed analysis of this body of work is published today in PloS One by Stirling et al; from the abstract: “through a combination of an exhaustive re-analysis of the original data with new experimental measurements of a simple control sample comprising entirely unfunctionalised particles, we conclusively show that all of the STM evidence for striped nanoparticles published to date can instead be explained by a combination of well-known instrumental artefacts, strong observer bias, and/or improper data acquisition/analysis protocols.”

On 2017 Jan 01, Donald Forsdyke commented:

PURINE LOADING AS A THERMAL ADAPTATION (This comment was original posted as a reader response to the original PLOS CompBiol article 20 Feb 2008.)

This paper draws conclusions tending to oppose those of myself and coworkers (cited). A "key question" is held to be: "Which factor - amino acid or nucleotide composition - is primary in thermal adaptation and which is derivative?" Previous evidence is considered "anecdotal." Now there is evidence for "an exact and conclusive" relationship, based on an "exhaustive study" that provides a "complete picture." A set of amino acids - IVYWREL - correlates well with growth temperature. It is noted:

"Signatures of thermal adaptation in protein sequences can be due to the specific biases in nucleotide sequences and vice versa. ... One has to explore whether a specific composition of nucleotide (amino acid) sequences shapes the content of amino acid (nucleotide) ones, or thermal adaptation of proteins and DNA (at the level of sequence compositions) are independent processes."

In other words, are primary adaptations at the nucleic acid level driving changes at the protein level, or vice- versa? To what extent are the two processes independent? Their conclusion:

"Resolving the old-standing controversy, we determined that the variation in nucleotide composition (increase of purine-load, or A + G content with temperature) is largely a consequence of thermal adaptation of proteins."

Thus, the superficial reader of the paper, while noting the purine-richness of some of the codons corresponding to the IVYWREL amino acids, will conclude that the "independent processes" alternative has been excluded. Reading the paper (e.g. Figure 7) one can question the validity of this conclusion. Many of the IVYWREL amino acids have purine-poor alternative codons (especially IYLV, which at best can only change one purine unit in their codons). One of the IVYWREL amino acids has relatively purine-rich alternative codons (R, which at best can change two purine units). Two (EW) are always purine-rich, and there are no alternatives.

Displaying more EW's as the temperature got hotter would satisfy a need both for more purines and for more tryptophan and glutamate, so here there is no discrimination as to whether one "shapes" the organism’s content of the other. Displaying more IYLVs gives only minimal flexibility in accommodating a purine-need. Most flexibility is provided by R codons.

The authors do not give statistics for the differences between the slopes of Figs. 7a (unshuffled codons) and 7b (shuffled codons), but they appear real, presumably reflecting the choice biologically of purine-rich codons, a choice the organisms might not have to make if there were no independent purine-loading pressure. Thus, the authors note, but only in parenthesis, that the slopes "are somewhat different suggesting that codon bias may be partly responsible for the overall purine composition of DNA."

An analogy may help. Passing from winter to summer, you change your outdoor attire. Many people (Imelda Marcos excepted) have a wider range of shirts and sweaters than of footwear. There may be items which provide more reliable indices of outside temperature than others. For example, the weight of your shirt + sweater might more finely correlate with temperature than the weight of your shoes. If you wanted to predict outside temperature from attire, you would choose shirt-sweater weights, rather than shoe weights. But if your clothes (shirt + sweater) weigh more, you might need sturdier shoes to cope with the extra weight. Thus, shoe-weight would depend on clothes-weight. The latter would be primary and the former would be secondary ("derivative"). But showing a better correlation with temperature in the case of shirt + sweater, does not establish a dependence of shoe-weight on shirt-sweater weight. More likely, you wear lighter shoes in warm weather because they keep your feet cooler! Both depend on temperature. It just so happens that the correlation with temperature is coarser and not so finely tuned for shoe weight, as for shirt-sweater weight.

On 2017 Nov 10, Anne Niknejad commented:

GenBank reference (fig.1) for Bacillus subtilis YcsK (LipC) should be BSU04110, not BSU041110

On 2014 Nov 23, Harri Hemila commented:

A manuscript version is available at handle

On 2014 Jan 08, Brett Snodgrass commented:

Dear Author,

Thank you for the excellent article. Naming this is the "modified Nail Psoriasis Severity Index" when there was already a published "modified Nail Psoriasis Severity Index," may cause some confusion.

The modified NAPSI was published in 2005. http://www.ncbi.nlm.nih.gov/pubmed/16198816/

In contrast to your scale, the "2005, mNAPSI" was not validated.

Perhaps referring to your article as the "2007, mNAPSI" may reduce some confusion...

Comments and suggestions are welcome.

Thank you kindly.

On 2014 Dec 10, Kath Wright commented:

Other search filters are available from the InterTASC Information Specialists' Sub-Group Search Filter Resource at https://sites.google.com/a/york.ac.uk/issg-search-filters-resource/home

On 2016 Mar 28, Michelle Kraft commented:

https://orcid.org/0000-0001-8821-4828 Other medical library articles by this author

On 2016 Mar 16, Levi Waldron commented:

This study is now literally a textbook example of confounding between batches and the primary observational unit: http://genomicsclass.github.io/book/pages/confounding.html

On 2016 Aug 23, Ben Goldacre commented:

This trial has the wrong trial registry ID associated with it on PubMed: both in the XML on PubMed, and in the originating journal article. The ID given is NCT002770192. We believe the correct ID, which we have found by hand searching, is NCT00270192.

This comment is being posted as part of the OpenTrials.net project^[1] , an open database threading together all publicly accessible documents and data on each trial, globally. In the course of creating the database, and matching documents and data sources about trials from different locations, we have identified various anomalies in datasets such as PubMed, and in published papers. Alongside documenting the prevalence of problems, we are also attempting to correct these errors and anomalies wherever possible, by feeding back to the originators. We have corrected this data in the OpenTrials.net database; we hope that this trial’s text and metadata can also be corrected at source, in PubMed and in the accompanying paper.

Many thanks,

Jessica Fleminger, Ben Goldacre*

[1] Goldacre, B., Gray, J., 2016. OpenTrials: towards a collaborative open database of all available information on all clinical trials. Trials 17. doi:10.1186/s13063-016-1290-8 PMID: 27056367

* Dr Ben Goldacre BA MA MSc MBBS MRCPsych<br> Senior Clinical Research Fellow<br> ben.goldacre@phc.ox.ac.uk<br> www.ebmDataLab.net<br> Centre for Evidence Based Medicine<br> Department of Primary Care Health Sciences<br> University of Oxford<br> Radcliffe Observatory Quarter<br> Woodstock Road<br> Oxford OX2 6GG

On 2014 Dec 10, Kath Wright commented:

Other search filters are available from the InterTASC Information Specialists' Sub-Group Search Filter Resource at https://sites.google.com/a/york.ac.uk/issg-search-filters-resource/home

On 2014 Dec 10, Kath Wright commented:

Other search filters are available from the InterTASC Information Specialists' Sub-Group Search Filter Resource at https://sites.google.com/a/york.ac.uk/issg-search-filters-resource/home

On 2014 Mar 26, Tom Kindlon commented:

I posted some comments on, and extracts from, this paper here: http://forums.phoenixrising.me/index.php?threads/managing-chronic-fatigue-syndrome-in-u-k-primary-care-challenges-and-opportunities-wearden-06.29212/#post-445534

On 2015 Jul 16, Md. Shahidul Islam commented:

An important issue is whether TRPV1(+) pancreatic sensory neurons are present in the human islets. Immunohistochemistry of human islets and human insulinomas does not show presence of any TRPV1 positive cells in these tissues.

Islets. 2012 Jan-Feb;4(1):56-63. doi: 10.4161/isl.18915. Epub 2012 Jan 1. Insulin-secreting INS-1E cells express functional TRPV1 channels. Fågelskiöld AJ, Kannisto K, Boström A, Hadrovic B, Farre C, Eweida M, Wester K, Islam MS.

On 2014 Dec 10, Kath Wright commented:

Other search filters are available from the InterTASC Information Specialists' Sub-Group Search Filter Resource at https://sites.google.com/a/york.ac.uk/issg-search-filters-resource/home

On 2018 Jan 31, Denise N Slenter commented:

The pathway outlined in Figure 2, is available as free machine readable data in WP4210 in WikiPathways: https://www.wikipathways.org/index.php/Pathway:WP4210 . This pathway can be used for data analysis with e.g. Pathvisio and Cytoscape!

On 2014 Feb 04, Martine Crasnier-Mednansky commented:

Comment concerning the AUTHOR’S CORRECTION:

In 1942, Jacques Monod indeed reported that associating any compound A (Glucose, Mannose, Fructose, Mannitol) with any compound B (the 'less preferred' carbon source) invariably resulted in diauxic growth with Bacillus subtilis. With Escherichia coli, he reported a diauxic growth with Glucose or Mannitol in combination with the 'less preferred' carbon source, but not with Fructose or Mannose. Therefore, Monod labeled Fructose and Mannose as 'indifférents' sugars for E. coli.

However, in his 1947 publication entitled 'The phenomenon of enzymatic adaptation' Monod emphasized what was true for B. subtilis was "equally true with many Escherichia coli strains, although with others, Fructose and Mannose are often found not to produce diauxic growth in any combination."

Researchers should therefore be aware that with E. coli production of diauxie is most likely strain-dependent when Fructose or Mannose is used in combination with a 'less preferred carbon source'. The strains used by the present reviewer did not produced diauxie with Fructose and a 'less preferred carbon source' (in agreement with Monod 1942 publication) but diauxie was observed with fruR strains (lacking the fructose repressor) in the presence of Fructose and a 'less preferred carbon source'. Therefore the widely used E. coli strain MC4100 which has been reported to be disrupted for fruR Ferenci T, 2009 should exhibit diauxie with Fructose and any compound B.

On 2017 Mar 23, Daniel Haft commented:

Note that this paper is about YdgR. Several mentions of YgdR (a lipoprotein, not a transporter) appear to represent typographical errors.

On 2017 Jun 28, Daniel Corcos commented:

The discrepancy may be related to the fact that women in the screened arm who have dropped out the screening are not willing to report their cancer because they think they have broken the trial.

On 2017 Aug 17, Randy Blakely commented:

For those citing this paper, please note that the name of Susan L Andersen was misspelled. Please change this in your citation managers

On 2013 Nov 07, Pierre Lindenbaum commented:

!DEPRECATED http://research.imb.uq.edu.au/rnadb/ "In June 2012, the RNAdb 2.0 database was officially retired"

On 2014 Nov 23, Harri Hemila commented:

A comment on the paper is available at: http://hdl.handle.net/10250/135144

On 2017 Jun 15, Ahmet Erdemir commented:

Data on elastomeric foams investigated as part of this study are now available at https://simtk.org/projects/elastomericfoam

On 2016 Aug 19, Morten Oksvold commented:

Please note that this article has been retracted and should therefore not be cited in the future.

http://onlinelibrary.wiley.com/doi/10.1002/ijc.30269/full

On 2014 Jan 10, Helmi BEN SAAD commented:

The second author name is "BEN SAAD H" not "BENSAAD H"

On 2014 Jan 10, Helmi BEN SAAD commented:

None

On 2016 Nov 20, Morten Oksvold commented:

An investigation committee at Wayne State University (WSU) recommends that 42 articles from Fazlul Sarkar to be retracted (report finished August 31, 2015). This article represents one of them.

This information was published by Retraction Watch (November 17, 2016) and you can find a link to the full report here:

http://retractionwatch.com/2016/11/17/details-of-investigative-report-into-sarkar-released-by-aclu/

This article should therefore no longer be cited.

On 2014 Sep 10, Gerard Ridgway commented:

This is one of two papers that independently introduced the concept of voxel-specific design matrices to neuroimaging for the purpose of multi-modal analysis. The other is Casanova R, 2007.

On 2014 Jan 25, Dylmitr Rittoo commented:

Potentially interesting study. Need to know exactly which type of cardiac Troponin was compared with CK-MB.

On 2014 Jan 08, Tom Kindlon commented:

New or "Unusual" definition for CFS used in this study

(This was originally posted on the journal's website here: http://www.biomedcentral.com/1471-2377/6/41/comments. However, the formatting has been removed meaning few may read it there)

People reading this study need to be aware that it uses a new or "unusual" definition of Chronic Fatigue Syndrome (CFS)[1] so the results may not apply to CFS cohorts as usually defined[2].This definition selects a group covering 2.54% of the adult population[3]. This is much higher than previous estimates of the prevalence of CFS. For example, members of the team in this study have previously estimated the prevalence as 0.235%[4] i.e. the prevalence rate using this definition is 10.8 times the rate found using the more usual CFS definition[2].

There has been some criticism of this new definition[5]. Unlike previous times when the CDC produced definitions for CFS[2,6], the definition used in this study is generally only being used by the CDC-funded CFS research team.

References:

[1] Reeves WC, Wagner D, Nisenbaum R, Jones JF, Gurbaxani B, Solomon L, Papanicolaou DA, Unger ER, Vernon SD, Heim C: Chronic Fatigue Syndrome – A clinically empirical approach to its definition and study. BMC Medicine 2005, 3:19 (15 December 2005)

[2] Fukuda, K., Straus, S.E., Hickie, I., Sharpe, M.C., Dobbins, J.G., & Komaroff, A. (1994). The chronic fatigue syndrome: A comprehensive approach to its definition and study. Annals of Internal Medicine, 121 (12):953-959. http://www.annals.org/cgi/content/full/121/12/953

[3] Reeves WC, Jones JF, Maloney E, Heim C, Hoaglin DC, Boneva RS, Morrissey M, Devlin RPrevalence of chronic fatigue syndrome in metropolitan, urban, and rural Georgia. Population Health Metrics 2007, 5:5 (8 June 2007)

[4] Reyes M, Nisenbaum R, Hoaglin DC, Unger ER, Emmons C, Randall B, Stewart JA, Abbey S, Jones JF, Gantz N, Minden S, Reeves WC: Prevalence and incidence of chronic fatigue syndrome in Wichita, Kansas. Arch Int Med 2003, 163:1530-1536.

[5] Jason Leonard: Issues with CDC Empirical Case Definition and Prevalence of CFS. IACFS website http://tinyurl.com/2qdgu4 i.e. http://www.iacfsme.org/IssueswithCDCEmpiricalCaseDefinitionandPrev/tabid/105/Default.aspx

[6] Holmes GP, Kaplan JE, Gantz NM, Komaroff AL, Schonberger LB, Straus SE, et al. Chronic fatigue syndrome: a working case definition. Ann Intern Med. 1988; 108:387-9.

On 2016 Mar 29, Jonathan Wren commented:

Appears to be relocated: http://carolina.imis.athena-innovation.gr/index.php?r=mirgenv3

On 2014 Dec 10, Kath Wright commented:

Other search filters are available from the InterTASC Information Specialists' Sub-Group Search Filter Resource at https://sites.google.com/a/york.ac.uk/issg-search-filters-resource/home

On 2016 Jul 08, Daniel Haft commented:

The novel macrolide 2'-phosphotransferase introduced in this paper, CAJ98570.1, called mph(E) here, has been renamed mph(F). The name mph(E) has been assigned to ABI20451.1 (see PMID:17261525). The revised nomenclature for macrolide phosphotransferases can be found in table 4 of PMID:23162539, by Roberts, et al.

On 2014 Jan 09, Tom Kindlon commented:

Accumulating evidence that CFS patients were actually more active on average than controls before becoming ill

(This is a comment originally posted in 2008. However, the change meaning it's not formatted on the site http://www.biomedcentral.com/1471-244X/6/53/comments means few will read it there. Also, many may not see it there)

The main finding in this study is that "patients with chronic, unexplained fatigue rated themselves as more active before their illness (p < 0.001)" and that "these differences remained significant for the subset of patients who met strict criteria for chronic fatigue syndrome or fibromyalgia"[1]. The authors then spend a lot of time speculating about whether this could have been an "overestimation of previous activity" and giving the "altered perception" hypothesis.

Given that they only had self-report data to go on, it is interesting to read a recent prospective population study on the illness[2]. It followed 4779 people from birth for the first 53 years of their lives. At age 53, 34 reported a diagnosis of CFS. Amongst other things, it found that "increased levels of exercise throughout childhood and early adult life and a lower body mass index were associated with an increased risk of later CFS." As it was a prospective study, there was no issue of recall bias. It also wasn't simply self-rated, as it also involved reporting by a teacher at age 13. Also they used the subject's BMI index - patients who went on to have CFS at age 53 had a (statisically significant) lower BMI than those who did not go on to develop CFS at ages 36 and 43 (before they had CFS). The authors say this "this may provide some indirect but objective evidence of increased levels of activity at these ages, especially as this difference had resolved by the age of 53 years" (when the people with CFS were no longer more active).

In the current study[1], the authors say "the only prospective cohort study of risk factors for CFS found that sedentary behavior at 10 years of age doubled the risk of self-reported CFS in adulthood"[3]. I thought I would give more information on that finding as it only related to a small percentage of the "CFS/ME" patients and doesn't show that on average patients were more inactive: in response to the question, about the amount of sport played in spare time at 10 years, 16% of the people who ever had CFS/ME by age 30 were in the "never or hardly ever" category compared to 8% in the people who didn't go on to have CFS/ME (so 8% more than expected - but it still meant that 84% in the "sometimes" and "often" categories). However the authors of the study[3] didn't combine this data in some way with a question on sports played within school: for the category "Played >2 hours/week of sport at school at 10 years", 52% of those who ever had CFS/ME by age 30 were in this category compared to 44% of those who never had CFS/ME by age 30. The unadjusted OR for this at 1.4 nearly reached statistically significance (95% confidence intervals: 0.9 to 2.2). Some sort of combination of the two pieces of data would have been preferable - a person's body doesn't distinguish between activity done within schools hours and in their spare time.

In the current study[1], the authors point out that their "findings are congruent with those of 3 retrospective studies reporting that CFS patients perceived themselves as more active before their illness began than healthy controls"[4-6]. They also said that "the high levels of physical activity reported by patients have been corroborated by their spouses, partners, or parents."[7]

With all this evidence from various sources about pre-morbid levels, researchers perhaps need to start showing more evidence before they will convince many of us of any speculative theories about CFS patients misperceiving how much activity and exercise they used to do.

References:

[1] Smith WR, White PD, Buchwald D: A case control study of premorbid andcurrently reported physical activity levels in chronic fatigue syndrome. BMCPsychiatry 2006, 6:53. http://www.biomedcentral.com/1471-244X/6/53

[2] Harvey SB, Wadsworth M, Wessely S, Hotopf M: Etiology of Chronic FatigueSyndrome: Testing Popular HypothesesUsing a National Birth Cohort Study. Psychosom Med. 2008 Mar 31

[3] Viner R, Hotopf M: Childhood predictors of self reported chronic fatiguesyndrome/myalgic encephalomyelitis in adults: national birth cohort study.BMJ 2004, 329:941. http://www.biomedcentral.com/pubmed/15469945

[4] Riley MS, O'Brien CJ, McCluskey DR, Bell NP, Nicholls DP: Aerobic workcapacity in patients with chronic fatigue syndrome. BMJ 1990, 301:953-6.

[5] Van Houdenhove B, Onghena P, Neerinckx E, Hellin J: Does high"action-proneness" make people more vulnerable to chronic fatigue syndrome?A controlled psychometric study. J Psychosom Res 1995, 39:633-40.

[6] MacDonald KL, Osterholm MT, LeDell KH, White KE, Schenck CH, Chao CC,Persing DH, Johnson RC, Barker JM, Peterson PK: A case-control study toassess possible triggers and cofactors in chronic fatigue syndrome. Am J Med1996, 100:548-54.

[7] Van Houdenhove B, Neerinckx E, Onghena P, Lysens R, Vertommnen H:Premorbid "overactive" lifestyle in chronic fatigue syndrome andfibromyalgia: an etiological relationship or proof of good citizenship? JPsychosom Res 2001, 51:571-6.

On 2014 Dec 10, Kath Wright commented:

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