On 2013 Oct 23, Rae Thomas commented:

We recently presented this paper at our Journal Club to discuss “How could meta-analyses convey meaningful results regarding effective interventions in child mental health to clinicians?”

There seems a lack of evidence-based treatments provided to children within child mental health settings •Hoagwood & Olin, 2002 reported 90% of publicly funded child mental health services didn’t use EBTs •Allen, Gharagozloo, & Johnson, 2012 reported clinicians could identify less than 2/5 expert nominated EBTs from a list of 15 •Thomas, Zimmer-Gembeck, & Chaffin, 2013 reported 58% of clinicians could defined an EBT using broad criteria and indicated use but 24% identified broad frameworks and of those 58% of actual EBTs in use, 88% of clinicians said they modified the EBTs

Previous meta-analyses considered intervention effectiveness using other variables •Individual interventions (Geeraert et al., 2004) •Settings (e.g., clinic vs home; Selph et al., 2013) •Components of interventions (Kaminski et al., 2008) •Components and Implementation of interventions (Durlak et al., 2011)

Our Group Discussion •Because of intervention heterogeneity, often meta-analyses in these formats provide little information for clinicians about what intervention is most effective for which population, even so, cost to implement an intervention may be prohibitive for some organisations. In this paper, effects of social and emotional learning programs were moderated by how the program was implemented. •A meta-regression of studies to consider the unique contributors to effective interventions may provide more useful information to clinicians (i.e., quality of studies, components of effective interventions). However, if possible, clinicians should be given both options (i.e., an effective intervention and components of effective interventions).

On 2016 Mar 18, ZHONGMING ZHAO commented:

My lab recently moved to the University of Texas Health Science Center at Houston. The source code is now available at https://www.uth.edu/bioinfo/software.htm.

On 2014 Feb 27, FREDERICK DOMANN commented:

For a recent review on PHD3 see http://www.dovepress.com/getfile.php?fileID=17843

On 2016 Sep 06, Hilda Bastian commented:

The conclusions of this review are not supported by the findings of the studies included in it, and much of the evidence cited contradicts the authors’ conclusions. The review suffers from extensive methodological weaknesses, particularly study selection bias and selective reporting. Out of hundreds of studies that were likely to be eligible in the 3 main areas they address (Dehdarirad, 2015), they include only 35. It is not a review of 20 years of data: it is a review based on selected data from the last 20 years. The basis for that selection is not reported.

Their description of the results of these studies includes, in my opinion, severe levels of 2 key types of review spin (Yavchitz A, 2016): misleading reporting and misleading interpretation. The review contains numerous errors in key issues such as reporting numbers and the methodology of studies. Conclusions about the quality of some evidence are drawn by the authors, but the basis for these judgments is unclear and no methodical process for assessing quality is reported or evident.

The 3 main areas covered by the review – journal publications, grant applications, and hiring – are also at high risk of publication bias, which is not addressed by the review. Discrimination against women is the subject of legislation in most, if not all, the countries in which these studies were done. Journals, funding agencies, and academic institutions may not be enthusiastic about broadcasting evidence of gender bias.

For example, of the many thousands of science journals published in 2011, only 6 studies are cited, conducted in 8 to 13 journals in 2 areas of science. In one of those, the author approached 24 journals: only 5 agreed to participate (Tregenza, 2002).

Ceci and Williams conclude that only 4 of the 35 unique studies they cited suggest the possibility of some gender bias. However, in my opinion an additional 7 studies clearly concluded gender bias remained a problem needing consideration, and others found signs suggesting bias may have been present. Altogether, in 19 studies (54%), there is either selective reporting and descriptions that spin study results in the direction of this review’s conclusions, or inaccurate reporting that could affect the weight placed on the evidence by a knowledgeable reader.

I identified no instance of spin that did not favor the authors’ conclusions. Some of the studies referenced did not address the questions for which they were cited. Several are short reports in letters, 1 relies on a press release, and another is a news report of a talk.

Variations in disciplines are not adequately addressed. The authors concentrate on time periods as critical, but the evidence shows that not all disciplines have reached the same level of development in relation to gender participation. Issues related to international differences, and different experiences for groups of women who may experience additional discrimination are not addressed. Although the conclusions are universally framed, they do not address women in science outside academia.

The authors address only 3 possible explanations for women’s underrepresentation in science: discrimination, women’s choices and preferences (especially relating to motherhood), and gender differences in mathematics ability. They argue that only women’s choices, particularly in relation to family, are a big enough factor to explain women’s underrepresentation. What is arguably the dominant hypothesis in the field is not addressed: that men are overrepresented in science because of cumulative advantage. Advantages do not have to be large individually, to contribute to the end result of underrepresentation in elite institutions and positions. (I have also commented on another paper in which they advance their hypothesis about motherhood and women scientists (Williams WM, 2012) - link to comment.)

In addition, they do not address the full range of issues within the 3 areas they consider. For example, in grants and hiring, they do not address analyses of potential bias in letters of recommendation (e.g. Van Den Brink, 2006, Schmader T, 2007).

In my opinion, this review is irredeemably flawed and should be retracted.

My methodological critique and individual notes on studies are included at my blog.

Disclosures: I work at the National Institutes of Health (NIH), but not in the granting or women in science policy spheres. The views I express are personal, and do not necessarily reflect those of the NIH. I am an academic editor at PLOS Medicine and on the human ethics advisory group for PLOS One. I am undertaking research in various aspects of publication ethics.

On 2016 Oct 12, Stephen Ceci commented:

Below Hilda Bastian criticizes our 2011 article in the Proceedings of the National Academy of Sciences. The criticisms reflect a simplistic rendering of the rich data landscape on women in academic science. Our conclusion was valid in 2011 and since then new scholarship has continued to support it. Below is an abbreviated response to Bastian’s claims, but a somewhat longer account can be found at: http://www.human.cornell.edu/hd/ciws/publications.cfm Claim 1: Our work failed to represent all research on the topic. This criticism does not take into account the quality of the research and the need to use judgment on study inclusion. Rather than calculate mean effect sizes based on all published studies, it is important to down-weight ones that have been refuted or supplanted. We did this in our narrative review in 2011. Nothing we wrote has changed and the intervening research has reinforced our conclusion of gender-neutrality in journal reviews, grant reviews, and tenure-track hiring. For example, Marcia McNutt, editor of Science, wrote "there was some good news from a panel representing major journals…such as the American Chemical Society (ACS) and the American Geophysical Union (AGU)…female authors are published either at a rate proportional to that at which they submit to those journals, or at proportionally higher rates, as compared with their male colleagues." McNutt, 2016, p. 1035) This may surprise those who read claims that women were selected as reviewers less often than their fraction of the submission pool, but it is true: women’s acceptance rates were, if anything, in excess of men’s. This is not cherry-picking, nor can it be erased by aberrations. These are large-scale analyses of acceptance rates of major journals, and it shows the landscape is either gender-fair or women actually have an advantage—in contrast to what Dr. Bastian alleges. The same is true of funding. To illustrate why it is important to move beyond factoring all the studies into a mean effect size, we offer three examples at http://www.human.cornell.edu/hd/ciws/publications.cfm For example Bornmann et al.’s finding of gender bias in funding using a large sample of grant applications. However, Marsh et al. reanalyzed these findings using a multilevel measurement model and arrived at a different conclusion. Bornmann himself was a coauthor on the Marsh et al. publication and agreed that the new finding of gender-neutrality supplanted his earlier one of gender bias. Marsh et al. found that the mean of the weighted effect sizes based on the 353,725 applicants was actually +.02--in favor of women! (see p. 1301): "The most important result of our study is that for grant applications that include disciplines across the higher education community, there is no evidence for any gender effects in favor of men, and even some evidence in favor of women…This lack of gender difference for grant proposals is very robust, as indicated by the lack of study-to-study variation in the results (nonsignificant tests of heterogeneity) and the lack of interaction effects. This non effect of gender generalized across discipline, the different countries (and funding agencies) considered here, and the publication year.” (p. 1311) Marsh, Bornmann, et al. (2009) (DOI: 10.3102/0034654309334143)

The rest of our paper concerned hiring and journal publishing. We stand by our conclusion in these two domains as well, as the scientific literature since then has supported us. We do not have time or space here to describe in detail the evidence for this assertion, but the interested reader can find much of it in our over 200 analyses (http://psi.sagepub.com/content/15/3/75.abstract?patientinform-links=yes&legid=sppsi;15/3/75 DOI:10.1177/1529100614541236)Unsurprisingly, the PNAS reviewers were knowledgeable about these domains and agreed with our conclusion. It is incumbent on anyone arguing otherwise to subject their evidence to peer review and show how it overturns our conclusion. Does our claim that gender bias in hiring and publishing lacks support mean there are no gender barriers? Of course not; we have written frequently about them: we have discussed an article that Bastian appears to believe we are unaware of—showing differences in letters of recommendation written for women and men. And we have written about other barriers facing women scientists, such as their teaching ratings downgraded and their lower tenure rates in biology and psychology. However, we stand by our claim that the domains of hiring, funding, and publications are largely gender-neutral. Unless peer reviewers who are experts in this area agree there is compelling counter-evidence, we believe our conclusion reflects the best scientific evidence. Claim 2: We failed to specify what we meant by “women”. Bastian points out differences between women of color, class, etc. We agree these are potentially important moderating factors and we applaud researchers who report their data broken down this way. But the literature on peer review, funding, and hiring rarely reports differences by ethnicity, class, or sexual orientation. Most of the few studies to do so emerged after our study was published. Claim 3: Bastian criticized us for not taking into consideration the size and trajectory of fields, suggesting those with large numbers of scholars may overwhelm smaller ones, or the temporal trajectory of some fields is ahead of others. Field-specific gender differences are a valid consideration but in funding they have been small or non-existent according to several large-scale analyses. Jayasinghe et al.’s (2004) comprehensive analysis of gender effects in reviews of grant proposals (10,023 reviews by 6,233 external assessors of 2,331 proposals from 9 different disciplines), found no gender unfairness in any discipline nor any disciplinary x gender. If anyone has compelling evidence of disciplinary bias against women authors and PIs, they should submit it and allow the peer review process judge how compelling it is. As far as differences among fields in their trajectories, we have done extensive analyses on this, which can be found at the same site above. In these analyses we examined temporal changes in 8 disciplines in salary, tenure, promotion, satisfaction, productivity, impact, etc. With some exceptions we alluded to above, the picture was mainly gender-fair. Finally, Bastian raises analytic issues. We agree these are central. This is why we minimized small-scale, poorly-analyzed reports. We gave more attention to large journals and grant agencies that allowed multilevel models, instead of or in addition to Fixed and Random effects analyses that sometimes violated fundamental statistical assumptions. Both Fixed effect and Random-effects models have limitations. (The latter assumes features of the studies themselves contribute to variability in effect sizes independent of random sampling error, whereas multilevel models permit multiple outcomes included without violating statistical assumptions such as the independence of effect sizes from the same study due to using the same funding agency or multiple disciplines within the same funding agency.) Mean effect sizes are not the analytic endpoint when there is systematic variation among studies beyond that accounted for by sampling variability, which is omnipresent in these studies; it is important to determine which study characteristics account for study-to-study variation. In the past, some have cherry-pick aberrations to support claims of bias, and our 2011 report went beyond doing this to situate claims amidst large-scale, well-analyzed studies, minimizing problematic studies. Although women scientists continue to face challenges that we have written about elsewhere, these challenges are not in the three domains of tenure-track hiring, funding, and publishing.

Steve Ceci and Wendy M. Williams

On 2014 Aug 11, Tom Kindlon commented:

Estimate for prevalence of CFS in the population may be an underestimate:

Many people affected by chronic fatigue syndrome (CFS) are unable to work [1-3]. This suggests to me that the sample was not ideal to estimate the prevalence of CFS, and presumably a more representative sample would find a higher prevalence.

Extract:

Design and setting:

We designed a cross-sectional study to assess the characteristics of Japanese with CFS in participants in a medical health checkup program at Murakami Memorial Hospital, Gifu, Japan. We randomly invited 3000 participants to enroll in the study, who received the health checkup programs between September 2006 and August 2007. The study was approved by the ethics committee of Murakami Memorial Hospital.

The purpose of medical health checkup programs are to promote public health through early detection of chronic diseases and their risk factors. Medical service of this kind, known as“a human dock,”is very popular in Japan [37]. The health checkup center at Murakami Memorial Hospital was founded in 1994 and is currently performing health checkups in more than 8000 examinees annually. Most of the participants were employees of private companies and local governmental organizations in Gifu, Japan, and their spouses. These companies and organizations recruit employees each year according to requires recruits to be checked in Murakami Memorial Hospital. The cost of the medical examination was largely paid for by the employers. Fewer than 10% of the participants individually registered in this program and paid checkup-costs by themselves, and they were all citizens of local communities.

Also

“All the CFS participants, who answered short sleep duration, unrefreshing sleep, disturbance of sleep, and/or insufficient sleep, stated that their sleep duration was inadequate because of social factors, mainly job-related ones.” – 13 of 14 CFS patients had sleep problems suggesting many/most of those with CFS in the sample were working.

References:

1. Comiskey C, Larkan F. A national cross-sectional survey of diagnosed sufferers of myalgic encephalomyelitis/chronic fatigue syndrome: pathways to diagnosis, changes in quality of life and service priorities. Ir J Med Sci. 2010 Dec;179(4):501-5.

2. Collin SM1, Crawley E, May MT, Sterne JA, Hollingworth W; UK CFS/ME National Outcomes Database. The impact of CFS/ME on employment and productivity in the UK: a cross-sectional study based on the CFS/ME national outcomes database. BMC Health Serv Res. 2011 Sep 15;11:217.

3. Reynolds KJ, Vernon SD, Bouchery E, Reeves WC. The economic impact of chronic fatigue syndrome. Cost Eff Resour Alloc. 2004 Jun 21;2(1):4.

On 2014 Mar 09, Gyanshankar Mishra commented:

We did further studies on complete pulmonary function profile in Diabetics with COPD or Asthma. available online at http://www.applied-cardiopulmonary-pathophysiology.com/05_mishra.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 NCT003311032. We believe the correct ID, which we have found by hand searching, is NCT00331032.

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 21, Gerhard Nebe-von-Caron commented:

This work is unfortunatelly missing appropriate revision. There is no evidence that the authors observed single bacteria due to the fact that no pictures of scatter versus nucleic acid fluorescence are shown. It would be recommended that the authors submit the raw data listmode files to http://flowrepository.org/ for validation. The fact that the picture in their 2010 poster "Flow cytometry as a means of observing the effects of ultrasound on bacteria" shows scatter data and antibody fluorescence of white blood cells instead of bacteria and regions of interest that indicate a lack understanding of the data analysis made me search for a follow up paper from the authors and my suspicion was confirmed in this paper. For example there is no distinction made between bacteria and noise signals. Figure 5 and 7 show the settings of quadrants cutting across clusters which is scientifically incorrect, and some of the clusters are in part likely to be caused by trigger artefacts. Figure 5e include permeabilised cells and DNA negative events in the lower left quadrant which could be pumping cells, cell debris as well as bubbles and micelles, distinguishable by appropriate data analysis.

The conclusion "Although flow cytometry data were comparable to viable plate count techniques, the percentage of live cells appeared higher. This observation is considered to be almost certainly because of the ability of flow cytometry to identify and count bacteria as single cells, whereas viable plate counts only enumerate colony forming units (CFUs) which can be either single bacterial cells or agglomerates of cells" indicates a lack of understanding of the measurement principles. Apart from the problems of colony formation, discussed in several of my publications, when measuring bacteria, cell aggregation can only be detected if genome equivalents are measures or one realises that double positive cells in case of energy transfer staining combinations represent two cells with one red and permeabilised and another green and intact, either coincident or still attached to each other. Most instruments unless aligned and maintained to the standards required for microbial analysis will not detect bacteria adequately when triggering on forward scatter. Thus the separation of bacteria from instrument noise needs to be demonstrated and a comprison of the data should be based on absolute counts. Also the use of aggregated bacteria would have been preferential to compare the effect of disaggregation compared to cellular injury as an indicator for the delivered energy on the membrane.

On 2015 Apr 22, Bernard J Crespi commented:

With regard to interpretation of the results of this article, do note that of the four schizophrenia patients described here with maternal duplications, one had a duplication that spanned BP1-BP3, two showed duplications of BP2-BP3, and one had a duplication from BP1 to a region between BP4 and BP5. By contrast, of the comparison subjects with maternal duplications, two had BP1-BP3 duplications and one had a duplication of BP2-BP3. These duplications are thus rather heterogeneous, which complicates inferences regarding causation.

Restricting the analysis to the BP2-BP3 region (and noting also that BP1-BP2 region deletions have been associated statistically with schizophrenia in previous work), yields two patients and one control with the maternal duplication (Fisher’s exact test, p = 0.061). If the BP2-BP3 duplication is considered regardless of parental origin, then two patients and two controls show the duplications (Fisher's exact test, P = 0.10). It would thus be useful if, at some point, further analysis could be done with larger samples of individuals with relevant duplications.

With regard to the causal genes, a newly-published study (Noor et al. 2015) shows that duplications encompassing just the maternally-expressed, imprinted gene UBE3A, which is in the BP2-BP3 region, segregate with psychiatric diagnoses including schizophrenia, anxiety and depression, in an extended pedigree.

Reference

Noor A, Dupuis L, Mittal K, Lionel AC, Marshall CR, Scherer SW, Stockley T, Vincent JB, Mendoza-Londono R, Stavropoulos DJ. 15q11.2 Duplication Encompassing only the UBE3A Gene is Associated with Developmental Delay and Neuropsychiatric Phenotypes. Hum Mutat. 2015 Apr 17. doi: 10.1002/humu.22800.

On 2015 Nov 25, Uday Yanamandra commented:

The second author name Uday Y should read as Yanamandra U.

On 2014 Dec 06, Harri Hemila commented:

Errors in the Cochrane review (2011) on zinc for the common cold

The Cochrane review (2011) on zinc for the common cold by Singh M, 2011; DOI; had a number of problems, which were commented on in detail in a separate document. Here the problems in the Cochrane review (2011) are listed and briefly described:

1) Search of the studies was not thorough. Singh M, 2011 did not include Eby GA, 2006 although that study was listed in Pubmed with keywords zinc and the common cold.

2) There were errors in the extraction of data. In Fig. 3 (p.15) Singh M, 2011 claimed that in the Petrus 1998 study (http://dx.doi.org/10.1016/S0011-393X(98)85058-3), the duration of colds in the zinc group was 4.4 days, whereas Petrus reported 3.8 days for the zinc group, see the link.

3) The characteristics of included studies table had errors and was not consistent in describing the included trials.

4) The characteristics of excluded studies table had errors. For example, Singh M, 2011 (p.39) claimed that the study by Turner RB, 2000 was “Not a randomised trial” though the study report clearly describes that the trial was randomised, see pp.1202-3 in DOI.

5) Different methods of administering zinc should be analyzed separately, whereas Singh M, 2011 pooled all together. Some studies administered zinc as syrup or tablets, some as lozenges. It is probable that the benefit of zinc in syrup and tablet trials is caused by biological mechanisms that are different from the mechanisms of the zinc lozenges, which are intended to be dissolved slowly in the mouth, see eg Hemilä H, 2011 and Eby GA, 2004. Combining different methods of zinc administration is the classical apples and oranges problem of meta-analysis.

6) The duration of the common cold should not be arbitrarily dichotomized as was done in Analyses 2.1 to 2.3 (pp.43-5) by Singh M, 2011. Duration is a continuous variable and should be analyzed as a continuous variable. The results of the zinc lozenge studies can be and should be analyzed using cold duration as a continuous variable, see Hemilä H, 2011.

7) Duration of the common cold should have been normalized so that placebo groups have length 100%. There is substantial variation in the duration of colds in the placebo groups of the zinc lozenge trials, from 5.1 days to 9.0 days and 10.8 days, see Hemilä H, 2011. For example, if a 5-day cold is shortened by 4 days, it is not equivalent to a 11-day cold being shortened by 4 days although both differences are equal in absolute units. The former is an 80% decrease in duration, whereas the latter is only a 36% decrease. Although part of the placebo group variation is caused by random variation, it is also caused by differences in viruses and in the severity of disease in different patient groups, and in differences in outcome definitions. Therefore, the relative effect of zinc on the common cold duration should be calculated in percentages, because the relative effect partly adjusts for the variations between patient groups and outcome definitions. In another study, the results of the zinc lozenge studies were analyzed as percentage effects, see Hemilä H, 2011.

8) Subgroup analysis should have been carried out. In the Background section (p.6), Singh M, 2011 wrote that a “significant correlation between total daily dosages of positively charged zinc species and a reduction in the mean duration of common colds” has been reported, however, they did not analyze that question. In the zinc lozenge studies, there is a 6-fold variation in the total zinc dose from 30 to 207 mg per day, see Hemilä H, 2011. Dose-response relation is a basic concept in pharmacology and thus the relation between dose and the effect of zinc lozenges should have been analyzed in the Cochrane review (2011). Hemilä H, 2011 found that none of the low zinc dose studies found effects of zinc lozenges, whereas high zinc dose studies found very strong evidence that colds were shortened by zinc. Such findings are consistent with the dose-response concept.

9) Pooling the adverse effects of all zinc trials is unsound, yet Singh M, 2011 did so in Fig. 6 (p.18). Eby GA, 2004 pointed out that the adverse effects of zinc lozenges, such as bad taste, can be explained largely by the differences in the composition of the lozenges. Furthermore, it is obvious that dissolving a zinc lozenge slowly in the mouth causes different adverse effects compared with ingesting a zinc syrup or tablet straight to the stomach. There is no justification to pool adverse effects of all zinc trials together, ignoring the considerable variations in the zinc products. As to the zinc lozenges, Eby GA, 2004 commented that “although pure zinc gluconate is bland and chalky in taste, it reacts with dextrose and related carbohydrates (excluding fructose) upon aging of lozenge compositions to produce noisome bitterness... On the other hand, zinc acetate allows the production of pleasant tasting, flavor stable lozenges”. In the most recent zinc acetate lozenge trial, Prasad AS, 2008 found no significant differences between the zinc and placebo groups in the occurrence of adverse effects although the daily dose of zinc was 92 mg.

10) Credit should be given to earlier work on the same topic. In the Introduction, Singh M, 2011 (p.7) wrote “The last review of all available RCTs of zinc for the common cold was published in 1999”, which is false. Reviews on zinc and the common cold by Jackson JL, 2000 and Caruso TJ, 2007 were published after 1999 and should have been mentioned as previous reviews on the same topic.

There is much evidence to indicate that high doses of zinc as zinc lozenges have effects on the duration of colds, see Hemilä H, 2011 and Eby GA, 2004. Therefore the topic of Singh M, 2011 is important; however, there were numerous methodological problems which limited the relevance of the conclusions.

Singh M, 2011 concluded that “In view of this and the differences in study populations, dosages, formulations and duration of treatment, it is difficult to make firm recommendations about the dose, formulation and duration that should be used.”

Had Singh M, 2011 separately analyzed the syrup and tablet studies and the lozenge studies, and had they analyzed the relation between the dose and effect, they could have reached much more clear conclusions.

Hemilä H, 2011 limited analysis to the zinc lozenge studies and found that five trials that used the lowest doses of zinc uniformly found no effect. Three trials used zinc acetate in daily doses of over 75 mg, and the pooled result indicated a 42% reduction in the duration of colds (95% CI: 35% to 48%). Five trials used zinc salts other than acetate in daily doses of over 75 mg, the pooled result indicating a 20% reduction in the duration of colds (95% CI: 12% to 28%). Thus, clear conclusions for patients and for further research could have been drawn from the studies that were available to Singh M, 2011.

On 2014 Nov 24, Tom Kindlon commented:

Letter published criticising threshold for normal functioning used in PACE Trial:

Bleijenberg and Knoop claimed a strict criterion for recovery was used in the PACE Trial. A letter has been published challenging this: it quotes some population data to show how ridiculous a threshold of 60+ on the SF-36 physical functioning is to define "normal functioning" and recovery (particularly in the PACE Trial given its own entry criteria).

Kindlon T, Baldwin A. Response to: reports of recovery in chronic fatigue syndrome may present less than meets the eye. Evid Based Mental Health doi:10.1136/eb-2014-101961 http://ebmh.bmj.com/content/early/2014/09/19/eb-2014-101961.extract

On 2016 Sep 27, Alem Matthees commented:

The 'normal range' was not a strict criterion for recovery nor was it based on healthy scores

The editorial by Bleijenberg & Knoop (2011) contains a misleading statement: “PACE used a strict criterion for recovery: a score on both fatigue and physical function within the range of the mean plus (or minus) one standard deviation of a healthy person’s score. In accordance with this criterion, the recovery rate of cognitive behavioural and graded exercise therapy was about 30%—although not very high, the rate is significantly higher than that with both other interventions.” [1]

However, the PACE publication did not report on "recovery" [2] and the PACE authors issued a statement to that effect [3] despite previously approving the editorial before it was published [4,5]. The normal range overlapped with trial eligibility criteria for severe disabling fatigue [2]. The largest overlap was with SF-36 physical function, where 13% of participants simultaneously met the normal range on this measure and the entry criteria for "significant disability" [6]. The individual participant data recently released from the PACE trial reveals that 45% (60/134) of those within the normal range at 52-week follow-up still met Oxford CFS criteria [7].

It is disappointing that the Lancet and Bleijenberg & Knoop stand by the comment on recovery despite being alerted of the problems [5]. The Press Complaints Commission ruled that the editorial was misleading [4,5]. Oddly enough, both Bleijenberg & Knoop have previously co-authored papers where a score of 60 (the threshold for normal physical function) was regarded as severe impairment [8-11].

The normal range was not based on healthy people of working age only. For example, the normal range for physical function was based on a general population that included the elderly and chronically disabled [3]. If the normal range was based on a healthy population as asserted, the threshold for normal physical function would be 85 points or more, not 60 or more [6]. A preliminary re-analysis of recovery in the PACE trial, based on the protocol-specified recovery criteria, shows that the recovery rates in the CBT and GET groups were 6.8% and 4.4% respectively, and not significantly higher than with specialist medical care alone [7].

References

1) Bleijenberg G, Knoop H. Chronic fatigue syndrome: where to PACE from here? Lancet. 2011 Mar 5;377(9768):786-8. doi: 10.1016/S0140-6736(11)60172-4. Epub 2011 Feb 18. PMID: 21334060. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60172-4/fulltext

2) White PD, Goldsmith KA, Johnson AL, Potts L, Walwyn R, DeCesare JC, Baber HL, Burgess M, Clark LV, Cox DL, Bavinton J, Angus BJ, Murphy G, Murphy M, O'Dowd H, Wilks D, McCrone P, Chalder T, Sharpe M; PACE trial management group. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet. 2011 Mar 5;377(9768):823-36. doi: 10.1016/S0140-6736(11)60096-2. Epub 2011 Feb 18. PMID: 21334061. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3065633/

3) White PD, Goldsmith KA, Johnson AL, Walwyn R, Baber HL, Chalder T, Sharpe M, [on behalf of the coauthors]. The PACE trial in chronic fatigue syndrome — Authors' reply. The Lancet, Volume 377, Issue 9780, Pages 1834 - 1835, 28 May 2011 (Published Online: 17 May 2011). doi:10.1016/S0140-6736(11)60651-X http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60651-X/fulltext

4) http://www.pcc.org.uk/cases/adjudicated.html?article=ODQwOQ

5) Continuing Correspondence Between Countess of Mar and Professor Peter White and Professor Sir Simon Wessely. 26 January 2013. http://forums.phoenixrising.me/index.php?threads/continuing-correspondence-countess-of-mar-and-prof-white-and-prof-sir-s-wessely.21545/

6) Matthees A. Re: Tackling fears about exercise is important for ME treatment, analysis indicates. BMJ Rapid Response. 21 January 2015. http://www.bmj.com/content/350/bmj.h227/rr-16

7) 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

8) van't Leven M, Zielhuis GA, van der Meer JW, Verbeek AL, Bleijenberg G. Fatigue and chronic fatigue syndrome-like complaints in the general population. Eur J Public Health. 2010 Jun;20(3):251-7. Epub 2009 Aug 18. PMID: 19689970. http://eurpub.oxfordjournals.org/content/20/3/251.long

9) Tummers M, Knoop H, van Dam A, Bleijenberg G. Implementing a minimal intervention for chronic fatigue syndrome in a mental health centre: a randomized controlled trial. Psychol Med. 2012 Oct;42(10):2205-15. doi: 10.1017/S0033291712000232. Epub 2012 Feb 21. PMID: 22354999. http://www.ncbi.nlm.nih.gov/pubmed/22354999

10) Stulemeijer M, de Jong LW, Fiselier TJ, Hoogveld SW, Bleijenberg G. Cognitive behaviour therapy for adolescents with chronic fatigue syndrome: randomised controlled trial. BMJ. 2005 Jan 1;330(7481):14. Epub 2004 Dec 7. doi: 10.1136/bmj.38301.587106.63. PMID: 15585538. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC539840

11) Heins M, Knoop H, Nijs J, Feskens R, Meeus M, Moorkens G, Bleijenberg G. Influence of symptom expectancies on stair-climbing performance in chronic fatigue syndrome: effect of study context. Int J Behav Med. 2013 Jun;20(2):213-8. doi: 10.1007/s12529-012-9253-2. PMID: 22865100. http://www.ncbi.nlm.nih.gov/pubmed/22865100

On 2013 Nov 15, Ellen M Goudsmit commented:

As a co-author of the London criteria for myalgic encephalomyelitis, I wish it to be known that this stdy did not use the criteria and that their citation refers to an incomplete and flawed version written by someone without permission from the original authors. It is therefore unclear if there were any patients with ME who participated in this trial.

Dr E Goudsmit PhD FBPsS

On 2014 Sep 28, Tom Kindlon commented:

Letter published criticising the threshold for normal functioning and recovery in the PACE Trial:

Quotes some population data to show how ridiculous a threshold of 60+ on the SF-36 physical functioning is to define "normal functioning" and recovery.

Kindlon T, Baldwin A. Response to: reports of recovery in chronic fatigue syndrome may present less than meets the eye. Evid Based Mental Health doi:10.1136/eb-2014-101961 http://ebmh.bmj.com/content/early/2014/09/19/eb-2014-101961.extract

On 2015 Oct 23, Lily Chu commented:

No study is perfect but this trial suffered from some major flaws. These are covered by Dr. David Tuller in the following link:

http://www.virology.ws/2015/10/21/trial-by-error-i/

On 2016 Jan 08, Tom Kindlon commented:

"Trial By Error, Continued: Did the PACE Trial Really Prove that Graded Exercise Is Safe?"

By two journalists: Julie Rehmeyer is a journalist and Ted Scripps Environmental Journalism Fellow at the University of Colorado, Boulder, who has written extensively about ME/CFS.

David Tuller DrPH is academic coordinator of the concurrent masters degree program in public health and journalism at the University of California, Berkeley.

I am quoted in it.

http://www.virology.ws/2016/01/07/trial-by-error-continued-did-the-pace-trial-really-prove-that-graded-exercise-is-safe/

On 2016 Aug 29, VINCENT RACANIELLO commented:

Below is the text of a letter sent to The Lancet earlier this year, asking for an independent review of the PACE trial. The Lancet invited us to submit this letter, then rejected it for no reason. To keep the text within the limits of PubMedCommons, only the first six names of those who signed the letter are shown.

Sir: The PACE trial reported that exercise and psychotherapy were effective treatments for chronic fatigue syndrome. Yet PACE was an unblinded study with subjective primary outcomes—a design already vulnerable to bias. As patients have long noted, PACE also suffered from additional methodological lapses likely to produce unreliable results. A recent investigation by David Tuller of the University of California, Berkeley, heightened public awareness of PACE’s flaws and sparked an open letter from us to The Lancet requesting an independent review.

Among PACE’s serious missteps:

*In a paradox, participants could—before treatment—already qualify as improved or “within the normal range” for fatigue and physical function, the primary outcomes. How? Because PACE’s “normal range” outcome scores actually allowed for worse health status than the eligibility scores required at entry to demonstrate serious disability. At entry, 13 percent of participants scored “within normal range” on one or both measures—details unreported in the paper. One PACE investigator described participants meeting these lax “normal ranges” as “back to normal”—a misleading statement highlighted in news coverage. An accompanying commentary, reviewed pre-publication by the PACE investigators, called this “a strict criterion for recovery.”

*PACE claimed success based solely on subjective outcomes. Participants in one arm improved slightly on a walking test but remained severely disabled. The investigators subsequently dismissed this test and other objective measures--which all failed to demonstrate success--as irrelevant or non-objective. They describe their findings as robust, but unblinded trials with subjective endpoints, even without PACE’s many other problems, can only yield low-quality evidence.

*PACE used one symptom to identify participants—six months of disabling, unexplained fatigue. A 2015 National Institutes of Health report recommended abandoning this broad definition because it generates heterogeneous samples that could “impair progress and cause harm.” PACE’s sub-group analyses of two alternate criteria are also difficult to interpret—an unknown number of patients might have met these criteria but been excluded by the initial definition and thus unobserved.

*PACE significantly revised its protocol strategy for assessing primary measures and “recovery” criteria but did not include sensitivity analyses, the accepted method of evaluating the impact and dispelling concerns about bias. Whether or not investigators made revisions before reviewing outcome data is irrelevant: Outcome trends in unblinded trials are often apparent to trial leadership early on, even if assessors do not know treatment assignment. The investigators have declined to provide the protocol results and rebuffed data requests as “vexatious.”

*A newsletter for participants--published while a third were still undergoing assessment-- included glowing testimonials from earlier participants about excellent outcomes but none reporting poor outcomes, potentially biasing subjective ratings toward the positive. The same newsletter reported that new U.K. treatment guidelines, “based on the best available evidence,” recommended the two PACE interventions favored by the investigators. Adaptive Pacing Therapy, an untested intervention developed specifically for PACE, was not mentioned.

*Despite investigators’ explicit protocol promise to inform participants of “any possible conflicts of interest,” consent forms did not mention their ME/CFS-related work for disability insurers. It is irrelevant that they disclosed these conflicts in The Lancet and that insurers played no role in PACE. Given the omission, the signed consents are of questionable legitimacy.

The investigators’ previous responses to such concerns have been unsatisfactory. We firmly believe the trial data should undergo a fully independent review.

Vincent R. Racaniello, PhD Professor of Microbiology and Immunology Columbia University

Ronald W. Davis, PhD Professor of Biochemistry and Genetics Stanford University

Jonathan C.W. Edwards, MD Emeritus Professor of Medicine University College London

Leonard A. Jason, PhD Professor of Psychology DePaul University

Bruce Levin, PhD Professor of Biostatistics Columbia University

Arthur L. Reingold, MD Professor of Epidemiology University of California, Berkeley

On 2016 Sep 27, Alem Matthees commented:

Post-hoc outcome switching inflated clinical response rates by several times

The primary outcomes as pre-specified in the published PACE trial protocol [1] were abandoned after the trial was over but before the unmasking of data [2] (although the trial was already open-label). While the new primary outcomes are useful, they were group-level and therefore not a direct replacement of the original primary outcomes, which were individual-level i.e. the proportion of participants meeting thresholds for fatigue and physical function.

The thresholds for individual-level improvement on the measures of fatigue and physical function were eventually replaced with post-hoc analyses after the unmasking of data [3], and it is unclear whether these changes were independently approved. The new thresholds have been criticised for being too lax, much less stringent than the pre-specified version, poorly calculated, and a possible example of "outcome reporting bias" [4,5].

On 8 September 2016, Queen Mary University of London (QMUL) released the PACE trial primary outcome results as defined in the published trial protocol [6]. This happened one day before the deadline to appeal the Information Tribunal’s ruling that QMUL must disclose a selection of de-identified participant-level data under the Freedom of Information Act (see EA/2015/0269).

Here is a comparison of the different rates: the clinically useful difference in both fatigue and physical function (Lancet 2011) [3] was 45% for SMC, 59% for CBT, and 61% for GET; the overall improvers or positive outcomes for both fatigue and physical function (QMUL 2016) [6] were 10% for SMC, 20% for CBT, and 21% for GET.

Without going into the issues with the nature and generalisability of the reported benefits, these new results provide a more realistic estimation of the clinical response rates of CBT and GET. However it also indicates that post-hoc outcome switching had inflated the estimated response rates in the PACE trial by several times. This exaggeration allowed proponents of CBT and GET to claim that 60% improved after these therapies (often without mentioning the SMC control rate of 45%). Outcome switching is recognised as a major problem in the research community [7].

There is also evidence that the PACE trial investigators changed the primary outcome measures in the trial registration entry (ISRCTN54285094 [8]). Using web.archive.org shows that an earlier version dated May 2005 [9] describes the primary outcomes with details about the pre-specified thresholds for improvement, but the current version only describes the primary hypotheses being tested or general objectives, without those additional details, allowing the investigators to change their primary outcomes without appearing to be deviating from the trial registration details.

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. PMID: 17397525. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2147058/

2) Walwyn R, Potts L, McCrone P, Johnson AL, DeCesare JC, Baber H, Goldsmith K, Sharpe M, Chalder T, White PD. A randomised trial of adaptive pacing therapy, cognitive behaviour therapy, graded exercise, and specialist medical care for chronic fatigue syndrome (PACE): statistical analysis plan. Trials. 2013 Nov 13;14:386. doi: 10.1186/1745-6215-14-386. PMID: 24225069. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4226009/

3) White PD, Goldsmith KA, Johnson AL, Potts L, Walwyn R, DeCesare JC, Baber HL, Burgess M, Clark LV, Cox DL, Bavinton J, Angus BJ, Murphy G, Murphy M, O'Dowd H, Wilks D, McCrone P, Chalder T, Sharpe M; PACE trial management group. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet. 2011 Mar 5;377(9768):823-36. doi: 10.1016/S0140-6736(11)60096-2. Epub 2011 Feb 18. PMID: 21334061. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3065633/

4) Giakoumakis J. The PACE trial in chronic fatigue syndrome. Lancet. 2011 May 28;377(9780):1831; author reply 1834-5. doi: 10.1016/S0140-6736(11)60689-2. Epub 2011 May 16. PMID: 21592554. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60689-2/fulltext

5) Stouten B, Goudsmit EM, Riley N. The PACE trial in chronic fatigue syndrome. Lancet. 2011 May 28;377(9780):1832-3; author reply 1834-5. doi: 10.1016/S0140-6736(11)60685-5. Epub 2011 May 16. PMID: 21592558. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60685-5/fulltext

6) Goldsmith KA, White PD, Chalder T, Johnson AL, Sharpe M. The PACE trial: analysis of primary outcomes using composite measures of improvement. 8 September 2016. http://www.wolfson.qmul.ac.uk/images/pdfs/pace/PACE_published_protocol_based_analysis_final_8th_Sept_2016.pdf

7) http://compare-trials.org/

8) http://www.controlled-trials.com/ISRCTN54285094

9) <http://web.archive.org/web/20050524130106/http://www.controlled-trials.com/mrct/trial/CHRONIC FATIGUE SYNDROME/1042/40645.html>

On 2017 Nov 23, Tom Kindlon commented:

More data demonstrating why the SF-36 physical functioning threshold of 60+ is problematic

The PACE trial's principal investigators (PIs) argue that scores of 60 or higher on the SF-36 physical function subscale (SF-36 PF) fall within the "normal range" and use this threshold as one component of their revised definition of recovery from Chronic Fatigue Syndrome (CFS), as well as a post hoc measure in this paper[1,2].

Referring to the normal ranges for physical function and fatigue used in the PACE trial, one of the trial's PIs, Trudie Chalder, stated that “twice as many people on graded exercise therapy and cognitive behaviour therapy got back to normal”[3]. This same terminology, "back to normal", was also used by the PIs in a patient information leaflet[4].

The use of this phrase, which implies full restoration of health, merits closer scrutiny following publication of a new paper containing data from CFS patients assessed at one of the PACE trial's treatment centres, the Chronic Fatigue Research and Treatment Unit in London, UK, between November 2007 and January 2014[5].

The paper, whose corresponding author is Trudie Chalder, reports that 39.6% of the patients diagnosed with CFS (228/576) had SF-36 PF scores of more than 60; i.e, despite having a score within the normal range, they were judged as sufficiently disabled to be diagnosed with CFS. Note that the data given were for more than 60 on the SF-36 PF so the figure for 60 or more would likely be higher again.

Moreover, Dutch researchers recently reported that 39% of patients with CFS had SF-36 PF scores of 65 or higher[6], and in the PACE trial itself patients could start with a SF-36 PF score of 65 at baseline[7]. Also, as we reported in a reanalysis of the PACE Trial data, in a large British community sample 90% of people aged 18–59 without a long-term illness or disability actually score 90 or higher[8].

Taken together, these data suggest that the derived normal range threshold for physical function is too low to serve as a meaningful indicator of recovery and does not, in fact, represent getting "back to normal".

References:

1 White PD1, Goldsmith KA, Johnson AL, Potts L, Walwyn R, DeCesare JC, Baber HL, Burgess M, Clark LV, Cox DL, Bavinton J, Angus BJ, Murphy G, Murphy M, O'Dowd H, Wilks D, McCrone P, Chalder T, Sharpe M; PACE trial management group. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet. 2011; 377: 611–690

2 White PD, Goldsmith K, Johnson AL, Chalder T, Sharpe M. Recovery from chronic fatigue syndrome after treatments given in the PACE trial. Psychol Med. 2013;43(10):2227–2235.

3 Boseley, S. Study finds therapy and exercise best for ME. The Guardian. Feb 18, 2011 https://www.theguardian.com/society/2011/feb/18/study-exercise-therapy-me-treatment

4 PACE participants newsletter 4. February 2011. http://www.wolfson.qmul.ac.uk/images/pdfs/participantsnewsletter4.pdf

5 Ryan EG, Vitoratou S, Goldsmith KA, Chalder T. Psychometric properties and factor structure of a shortened version of the Cognitive Behavioural Responses Questionnaire (CBRQ). Psychosom Med. 2017 Oct 10. doi: 10.1097/PSY.0000000000000536. [Epub ahead of print]

6 Janse A, Nikolaus S, Wiborg JF, Heins M, van der Meer JWM, Bleijenberg G, Tummers M, Twisk J, Knoop H. Long-term follow-up after cognitive behaviour therapy for chronic fatigue syndrome. J Psychosom Res, 2017. doi: 10.1016/j.jpsychores.2017.03.016.

7 White, PD, Sharpe, MC, Chalder, T et al. 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; 7: 6

8 Wilshire CE, Kindlon T, Matthees A, et al. Can patients with chronic fatigue syndrome really recover after graded exercise or cognitive behavioural therapy? A critical commentary and preliminary re-analysis of the PACE trial. Fatigue. 2017;5:1–4.

On 2014 Mar 26, Gwinyai Masukume commented:

The authors write, “With respect to the concern that men might engage in riskier sexual behavior after circumcision, data from the three RCTs1–3 and a prospective cohort study8 found no overall increases in risk behavior following circumcision.”

In the abstract of the first RCT it is written, “When controlling for behavioural factors, including sexual behaviour that increased slightly in the intervention group, condom use, and health-seeking behaviour, the protection was of 61% (95% CI: 34%-77%).” Auvert B, 2005

In the abstract of a meta-analysis of the three RCTs it is written, “For the South African trial [the first RCT] the mean number of sexual contacts at the 12-month visit was 5.9 in the circumcision group versus 5 in the control group, which was a statistically significant difference (p < 0.001). This difference remained statistically significant at the 21-month visit (7.5 versus 6.4; p = 0.0015).” Siegfried N, 2009

One can then conclude that in the first RCT men engaged in riskier sexual behavior after circumcision. The authors appear to downplay risk compensation i.e. men engaging in riskier sexual behavior after circumcision.

In the abstract of the next paper that the authors cite (9), it is written, “In the context of a RCT [not the first RCT but one of the three], circumcision did not result in increased HIV risk behavior. Continued monitoring and evaluation of risk compensation associated with circumcision is needed as evidence supporting its' efficacy is disseminated and MC is widely promoted for HIV prevention.” Mattson CL, 2008

Apparently downplaying risk compensation seems curious since continued monitoring and evaluation is needed.

RCT - Randomized Controlled Trial

On 2014 Feb 06, Anastasia L Bodnar commented:

This comment focuses on the claim by Aris and Leblanc that CryAb1 toxin was detected. In short, they used an incorrect method and an incorrect standard.

The ELISA kit used by Aris and Leblanc to detect Bt was made by a company called Agdia (as described in section 2.4. of the paper). The kit was created and tested to detect Bt in plant tissues (Agdia doesn’t make any kits for animal tissues). This is potentially a problem because a kit that is not tested on mammalian tissues might cross-react with proteins found in mammals that aren’t found in plants, giving a false positive result. ELISA methods have been developed for Cry proteins in mammalian blood, but these methods have had varying success.

German researchers developed an ELISA method for cows’ blood, which was able to detect Cry proteins in blood that was spiked with the protein. They did not find any significant difference between cows that had been fed Bt and conventional maize for a two month period, and all values detected in all cows’ blood were less than 1.5 ng/mL. Paul V, 2008

Aris and Leblanc did cite a paper that showed fragments and intact Bt protein could be detected with ELISA in the gastrointestinal tract (not in blood). Aris and Leblanc did not mention that the researchers found that Bt was probably digested in cattle, and suggested that a different method besides ELISA should be used to confirm presence of Cry protein. Lutz B, 2005

Aris and Leblanc also cited a paper that used ELISA to detect Cry protein in pigs. ELISA, immunochromatography, and immunoblot were sucessful in detecting Cry protein fragments in the gastrointestinal tract. Aris and Leblanc did not mention that the researchers did not detect any Cry protein in blood with any of these methods. Chowdhury EH, 2003

In addition to using an incorrect method to detect Cry proteins in blood, Aris and Leblanc also used an incorrect standard. Aris and LeBlanc created Cry protein solutions of 0.1 to 10 ng/mL. In Table 2, they report that a a range of 0 to 1.50 ng/mL was detected in maternal blood and 0 to 0.14 was detected in fetal cord blood. The mean and SD for maternal was 0.19 ng/mL ± 0.30 and for fetal was 0.04 ± 0.04 ng/mL. Ideally, test values will be in the middle of a standard curve. Any values outside or at the edges of of the standard curve may be false positives. Aris and Leblanc could have confirmed their results with a Western blot or any number of other methods, but they did not.

On 2014 May 26, Ivan Oransky commented:

This is one of two retractions by Annemie Schuerwegh: http://retractionwatch.com/2014/05/23/second-paper-falls-for-ex-leiden-researcher-accused-of-fraud/

On 2014 Oct 23, Casey M Bergman commented:

Genomic DNA sequences for the Canton-S and w1 strains studied in this paper have not been deposited in the Short Read Archive. The GEO accession given in the paper (GSE25180 corresponding to SRA accession SRP004442) only contains RNA-seq data, but not DNA-seq data. DNA-seq data for these strains can be obtained from the authors' website at: http://www.eisenlab.org/dosage/data/Reads/Genomic/

Edit 28 Aug 2015 Genomic data for Canton-S from this study have now been deposited in SRA: http://www.ncbi.nlm.nih.gov/sra/?term=SRP061802

On 2015 Mar 05, Siddhartha Jonnalagadda commented:

The working link for BioSimplify is biosimplify.sourceforge.net

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 NCT001195663. We believe the correct ID, which we have found by hand searching, is NCT00195663.

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

* 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 Jan 10, Helmi BEN SAAD commented:

The second author name is "BEN SAAD H" not "SAAD HB".

On 2016 Apr 06, Daniel Tsin commented:

Correction in Reference 3. Tsin DA, Sequeria RJ, Giannikas G.Culdolaparoscopic cholecystectomy during vaginal hysterectomy.JSLS. 2003 Apr-Jun;7(2):171-2. PMID 12856851

On 2017 Feb 20, David Keller commented:

These editorialists actually favor a clinical trial of ibuprofen in patients with Parkinson disease

In 2011, Gao and colleagues published data from 2 large cohorts which demonstrated ibuprofen use was associated with a significant 38% reduction in risk of developing Parkinson disease (PD), with a significant dose response. In addition, they conducted a new meta-analysis including these plus 5 other similar studies, demonstrating a significant 27% reduction in the incidence of PD for persons taking ibuprofen [1]. The accompanying editorial was titled "Is the answer for Parkinson disease already in the medicine cabinet? Unfortunately not". This title seems to contradict the beneficial findings described in Gao's new study and meta-analysis, and the favorable assessment of the design and execution of the studies. The caveat is a familiar one: reduction of risk for PD has been associated with ibuprofen in observational studies only. Treatment cannot be based on observational evidence alone, which cannot eliminate bias and confounding. In the end, the editorialists do conclude that "a clinical trial of ibuprofen, or perhaps a safer PPAR-gamma agonist, may be warranted." A randomized, placebo-controlled clinical trial is necessary to prove that ibuprofen is beneficial before it can be recommended for prevention or treatment of PD.

However, why wait for a PPAR-gamma agonist other than ibuprofen, which is safe enough that millions of patients take it as a non-prescription medicine for pain? Its adverse effects are well-known and can be monitored for during a clinical trial, or prophylaxed. The call by Gao and colleagues for further research on ibuprofen, so well-supported by their findings, has gone unanswered since 2011. Millions of PD patients await proof that any medication can slow the progression of their disease, while a promising possibility may be, indeed, already in the medicine cabinet.

Reference

1: Gao X, Chen H, Schwarzschild MA, Ascherio A. Use of ibuprofen and risk of Parkinson disease. Neurology. 2011 Mar 8;76(10):863-9. doi: 10.1212/WNL.0b013e31820f2d79. PubMed PMID: 21368281; PubMed Central PMCID: PMC3059148.

On 2016 Nov 18, David Keller commented:

This study supports a controlled clinical trial of ibuprofen for treatment of Parkinson's disease

This study found that users of ibuprofen had a significant 38% reduction in their adjusted risk of Parkinson disease (PD) compared with nonusers of ibuprofen. Furthermore, a significant dose-response relationship was observed between the number of ibuprofen tablets taken per week and the reduction in PD risk. Further still, an accompanying meta-analysis found a significant 27% reduction in the risk of PD with ibuprofen use, but not with other NSAIDs.

The above three results [1] strongly support the authors' suggestion that "ibuprofen should be further investigated as a potential neuroprotective agent against PD". In particular, a randomized, placebo-controlled trial of ibuprofen in the setting of early PD seems justified, yet has not been reported in the years since the publication of this paper in 2011. Can anyone explain why?

Reference

1: Gao X, Chen H, Schwarzschild MA, Ascherio A. Use of ibuprofen and risk of Parkinson disease. Neurology. 2011 Mar 8;76(10):863-9. doi:10.1212/WNL.0b013e31820f2d79. PubMed PMID: 21368281; PubMed Central PMCID:PMC3059148.

On 2014 Mar 10, Madhusudana Girija Sanal commented:

You observed that significantly more CNVs are present in early-passage human iPS cells than intermediate passage human iPS cells or human ES cells. Can the reason for the observed improvements in genetic quality be a conscious selection by a trained eye for ideal hES cell morphology resulting in improvement of the quality of iPSC over passages-(although the investigators were not knowing that they are selecting for genetically/epigenetically normal cells)!

It has been observed by several groups that the genetic/epigenetic quality of iPSC improves over passages (1,2). The reasons could be DNA repair mechanisms acting over time, natural selection or human (artificial) selection over passages. Primary cells become adapted over time in culture conditions, short term adaptations due to changes in regulation and expression of various genes at transcription and translational levels and later by acquiring genetic changes including mutations, copy number variations, deletions and probably epigenetic changes (3-5). It is observed that cells will accumulate mutations under the ‘natural’ selection pressure which favor in-vitro growth and proliferation and most of the robust cell lines have mutations which make them successful for in-vitro growth. This is a contrast to iPSC which improves the genetic quality over passage. Morphology identified by human eye is very powerful in identifying subtle differences in phenotype which in turn reflects the changes in the genotype. This is why a trained person can identify types of cancer from a simple H&E stained section without going for genetic markers or one can distinguish between the identical twins. In case of iPSC, every time the investigator observes the culture dishes under microscope, he discards ‘bad looking’ colonies and selects ‘good-healthy’ colonies. In this process he unknowingly selects for genetically/epigenetically normal cells. It may be noted that all of the established human embryonic stem (hES) cell lines have undergone several passages and hence careful human selection and hence less genetic defects compared to relatively ‘fresh’ (low passage number) iPSC. Conscious selection by a trained eye for ideal hES cell morphology could be the prime reason for the observed improvement of the quality of iPSC over passages.

"majority of the cells, whether during the early or late passages, had the ideal hES morphology" The first author notes. But majority is a relative term. Anyway, the majority of the IPSC has normal genetics also.

Please see an extract from first and second page of your article : "A control probe was selected from a chromosome 1 location that showed normal copy number across all human iPS cell lines that were tested. During early passages, the test probe demonstrated a significantly higher fraction of cells with aberrant copy number state than the control probe. The fraction of aberrant cells was also significantly higher in early-passage human iPS cells (18%) than in fibroblasts (3%) or in later-passage human iPS cells (9%)".

"The median number of CNVs in human iPS cell lines was about twofold higher than in human ES cell lines and fibroblasts" This is expected because most of the established human ES lines have undergone several passages compared to relatively "freshly brewed iPSC" and hence more rounds of selection by an expert's eye!

It may be noted that morphology is one or the most important markers of ES cells, all others- alkaline PO4ase staining, expression of Nanog, TRAs are non-specific. They are present in several cancer cell lines also. In contrast, typical ES cell morphology is quite rare among non-ES cells.

A note on the methods: "consistently passaged the cells enzymatically (Collagenase or dispase), and as such this alleviates bias that may occur by manual passaging of ideal hESCs"

Suppose you have a dish of IPSC cells, say 40-60 colonies and you find one or two colonies looking "bad" or atypical or 'differentiated', then you will most likely discard the entire dish. You will not attempt an enzymatic splitting and passaging. This is what we do in our lab. Suppose the ES/IPSC line is precious, then we would do? We would manually pick good colonies by cutting them out using a pipette tip. In both cases we are doing the same.

You believe that "most of the selection pressure may actually occur through the fact that several of the mutations observed in early passage hiPSCs (as highlighted in your paper, supplementary table 8) carry the possibility of hindering hESC maintenance and self-renewal."

I will say several of the mutations which hinders with maintenance/self-renewal will not be selected because as soon as they show these phenotypic changes the experimenter will discard them!

"hiPSCs are genetically mosaic, more so in early passage than in later passages". Moreover, SNP arrays (as highlighted in your paper) would detect CNVs that are found in the majority of the cells.

I would explain this fact, this way: This can be because of inefficiency of the method -the positive predictive value versus negative predictive value of the test! Again, our key question why more defects in early passages? My answer is that with every passage genetically/epigenetically bad colonies were discarded by the experimenter. It is possible that mosaics are generated during enzyme treatment (collagenase/trypsin/dispase) when two or more monoclonal colonies gets mixed up. So these facts cannot be followed up without studying and following up iPSC clonal selection and proliferation.

It is possible that genetically defective cells, parasite on (or may be complementing!) the growth and maintenance of IPSC colonies which is facilitated by mosaic-ism.

References:

1. Mayshar Y et al. Identification and classification of chromosomal aberrations in human induced pluripotent stem cells. Cell Stem Cell. 7:521-31(2010).

2. Hussein, S. M. et al. Nature 471, 58–62 (2011).

3. http://www.sanger.ac.uk/genetics/CGP/CellLines/

4. Freshney, R.I. (2005) Culture of Animal Cells, a Manual of Basic Technique, 5th Ed. Hoboken NJ, John Wiley & Sons.

5. Chen J et al. Evaluation of x-inactivation status and cytogenetic stability of human dermal fibroblasts after long-term culture. Int J Cell Biol.2010:289653 (2010).

On 2014 May 26, Ivan Oransky commented:

This is the ninth retraction so far for Hiroaki Matsubara: http://retractionwatch.com/2014/05/26/ninth-retraction-appears-for-cardiology-researcher-matsubara/

On 2014 May 09, Madhusudana Girija Sanal commented:

A SIMPLER DEFINITION OF CANCER

The following two conditions needs to be satisfied to define a cancer:

1) Non physiological rate and duration of cell proliferation. Non physiological rate is defined as a growth rate which is a statistical outlier spatially and temporally for a given type of cell and organism. 2) A change, genetic or epigenetic with reference to the "healthy genome" The genetic or epigenetic 'change' is a statistical outlier, spatially and temporally, for a given cell type and organism. Healthy reference genome and epigenome may be defined as the 'consensus' genome of individuals which satisfy two conditions a) falling within the statistically defined normal range of anatomical and physiological parameters for a population b) demonstrated longevity above 99.9 percentile of the population of a given organism under optimal growth conditions and environment and excluding accidental deaths. Consensus may be reached through statistical or non-statistical approaches (functional,computational or even based on social and economic goals).

According to this definition an apparently "healthy" person having hundreds of cells with known cancer causing mutations do not have cancer because condition #1 is not met. So he will have cancer only when mutated cells start to proliferate at a non-physiological speed.

On 2015 Jul 15, Bill Cayley commented:

A good example of when "Less" is "more" - https://lessismoreebm.wordpress.com/2015/07/15/a-novel-cost-effective-approach-to-post-vasectomy-semen-analysis/

On 2014 Nov 23, Harri Hemila commented:

A comment on the paper is available at https://helda.helsinki.fi/handle/10138/228055.

On 2016 Dec 20, Alessandro Rasman commented:

Anatomical stenosis of the internal jugular veins : supportive evidence of chronic cerebrospinal venous insufficiency ?

Andrea Baiocchini, MD Raffaele Toscano, Wilfredo von Lorch and Franca Del Nonno National Institute for Infectious Diseases "L. Spallanzani", Via Portuense 292, 00149 Rome, Italy, +390655170277, Fax +390655170430

We write in relation to the editorial commentary from Khan et Tselis (1) who rightly suggest caution to consider chronic cerebrospinal venous insufficiency (CCSVI) as a pathological entity and cast serious doubt on its relevance to multiple sclerosis (MS); they forecast properly designed studies to investigate the relevance of CCSVI to MS, in order to carry out interventional procedures.

The absence of extracranial venous stenosis at the earliest stage of MS makes it an unlikely cause of the disease (2). The idea of venous congestion as a possible contributor to the pathogenesis of MS has been discussed for the past 40 years, but remained widely unappreciated by the scientific community.

In contrast with other authors, Zamboni et al (3) defined CCSVI as a vascular condition associated with MS; it is characterized by multiple intraluminal stenosing malformations of the principal pathways of extracranial venous drainage, particularly in the internal jugular veins (IJVs) and the azygous vein (AZY), that restrict the normal outflow of blood from the brain. In the study of Zamboni et al there was significant extracranial venous stenosis localised at the principal level of the cerebrospinal venous segments as detected by selective venography and anomalies of venous outflow at color Doppler high resolution examination. The pathological consequences of CCSVI have been hypothesised to emanate from chronic venous reflux and hypertension leading to increased iron deposition in the brain and subsequent MS pathology, including inflammation and neurodegeneration.

Other recent reports found no differences in cerebrospinal venous drainage using transcranial and extracranial Doppler imaging (4-5). The discrepancies in the results may be explained with the absence of standardized internationally accepted criteria for normal Doppler venous flow parameters (2).

We performed complete post-mortem examination of two patients with MS, died for different causes. One patient, a 74 year-old-woman, was hospitalized for acute respiratory illness and died because of bacterial pneumonia; the other one, a 35 year-old-woman, died for otogenic bacterial meningitis complicated with internal jugular thrombosis as demonstrated on MR venography.

Postmortem examination demonstrated in both patients a marked stenosis of left internal jugular vein at the apex of the angle formed by the two heads of the sternocleidomastoid muscle where the IJV overlie the carotid artery with ectasia and congestion of the intracranial veins. Venous flow slowing, caused by the stenosis, had predisposed to IJV thrombosis, histologically demonstrated in the second case.

Severe inflammatory disease may be a risk factor for deep venous thrombosis but also chronic cerebrospinal venous insufficiency. We demonstrate, for the first time as far as we are aware, the presence of anatomical alteration in the veins of the neck with impaired venous drainage from the central nervous system in two patients with multiple sclerosis who died from other causes.

We do not know the exact implications in MS pathology and certainly there is no doubt that this area warrants a great deal more study. Clinical trials for evaluating new therapeutic agents and other clinical experimental protocols may be required.

References: 1. Khan O, Tselis A. Chronic cerebrospinal venous insufficiency and multiple sclerosis: science or science fiction? J Neurol Neurosurg Psychiatry 2011;82:355. 2. Yamout B, Herlopian A, Issa Z Extracranial venous stenosis is an unlikely cause of multiple sclerosis Mult Scler 2010 16: 1341-9 3. Zamboni P, Galeotti R, Menegatti E, et al Chronic cerebrospinal venous insuffiency in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry 2009;80:392-9. 4. Doepp F, Paul F, Valdueza JM, et al No cerebrocervical venous congestion in patients with multiple sclerosis. Ann Neurol 2010, 68:173-183. 5. Sundstrom P, Wahlin A, Ambarki K, et al Venous and cerebrospinal fluid flow in multiple sclerosis: a case-control study. Ann Neurol 2010, 68:255-259.

Conflict of Interest: None declared

Published 28 April 2011

On 2014 May 04, Ivan Oransky commented:

This paper has been retracted: http://retractionwatch.com/2014/04/29/contaminated-cells-force-retraction-of-blood-paper/

On 2014 Dec 27, DAVID ALLISON commented:

Our paper contains one or more typographical errors which are corrected in this paper:

Cresswell L, Mander AP. How to use published complete case results from weight loss studies in a missing data sensitivity analysis. Obesity (Silver Spring). 2014 Apr;22(4):996-1001. doi: 10.1002/oby.20635. Epub 2013 Dec 5. PMID: 24124049.

On 2015 May 06, M Mangan commented:

In preparation for a blog post on TargetMine, I contacted the authors. They asked me to note that the URL to access TargetMine is now: http://targetmine.mizuguchilab.org

Blog post, in case you wish to see that: http://blog.openhelix.com/?p=21533

On 2015 Mar 09, Hilda Bastian commented:

This is an excellent and important review, and its conclusions are likely to generally still be valid. The authors' reply to a 2011 comment about missing trials by Steven Woloshin and Lisa Schwartz indicates a particularly key trial subsequent to the 2007 search is missing (Waters EA, 2006; Cuite CL, 2008; Woloshin S, 2011). There are likely to be many more. (Several are included in a post of mine on using NNTs, at PLOS Blogs.)

The relatively small amount of data in this review on some comparisons is, I believe, becoming a problem as the conclusions of the authors are being too readily dismissed. If the update of this review is not likely to be soon, it may be useful to add a comment about the currency of the review, and highlight studies awaiting assessment to counteract the current impression.

It would also be useful if the authors could clarify in their update the status of the "additional results" in Appendix 4. As these trials are also listed as excluded from the review, it is a little confusing. Indeed, at least some of those studies do seem to be eligible: the time-to-event measure, for example.

Although I can understand the reasoning for including medical students as lay people rather than health professionals, I think that is potentially problematic, and they require separate analysis as the quantity grows.

I look forward to the update of this important review. Thanks!

On 2015 Oct 08, Elie Akl commented:

Dear Hilda Thank you for the excellent and critical review. I agree that this review is due for updating, and its conclusions are not current. We are not aware of more recent studies besides the ones you pointed to, but there are likely few of them. We will consider in the update the points you make below about how to include studies of medical students. thank you again Elie

On 2014 May 21, Arnaud Chiolero MD PhD commented:

A fantastic paper, about a major issue in public health

On 2014 Jan 08, Tom Kindlon commented:

The criteria for CFS require 5 symptoms (fatigue plus 4 more) not 4 symptoms as were assessed

Bhui and colleagues [1] state: "We counted as CFS those individuals with all four of the above symptoms, each lasting for at least 6 months. Our definition of at least four symptoms meets the threshold criteria, as CFS is usually diagnosed on the basis of four of eight symptoms, including fatigue [2]." It is incorrect to say: "CFS is usually diagnosed on the basis of four of eight symptoms, including fatigue" One can either say: "CFS is usually diagnosed on the basis of five of nine symptoms, one of which must be fatigue" Or "CFS is usually diagnosed on the basis of four out of eight symptoms, plus fatigue".

This doesn't appear to be a typo: the questions used only involve 4 symptoms including fatigue: "The questions asked about the following symptoms: (1) getting tired and lacking energy and whether there were any reasons for this (such as physical illness), (2) having any problems with concentrating or noticing any problems with forgetting things, (3) having problems with falling asleep or with getting back to sleep, (4) any sort of ache or pain or being troubled by any sort of discomfort such as headache or indigestion." The symptoms that make up the referenced definition are: Fatigue Plus 4 out of 8 of the following: "post-exertional malaise lasting more than 24 hours; unrefreshing sleep; impaired short-term memory or concentration severe enough to cause substantial reduction in previous levels of occupational, educational, social, or personal activities; headaches of a new type, pattern, or severity; muscle pain; multi-joint pain without swelling or redness; sore throat; and tender cervical/axillary lymph nodes."

The authors explain that what they is discussed is CFS-like illness as the individuals were not assessed individually by a physician to check for exclusions. The authors state they “were able to identify diseases that might exclude a diagnosis of CFS (31 of 108 (28.7%) participants met the criteria for CFS): cancer, diabetes, epilepsy, arthritis or fibrositis and infectious or parasitic disease.” We probably do not have enough data from previous work to estimate the percentage who would have been excluded from a diagnosis of CFS following an individual assessment; however one large expensive US study conducted by the CDC [3] which used a comparable definition [4] to the 2003 definition[2] found that while 1.607% had a CFS-like illness, only 0.235% had CFS (or 14.62% of those with a CFS-like illness). If the figure was similar for the current study, only 16 out of the 108 would have CFS.

While not evidence per se about the validity of the CFS definition used, the fact that female gender was not a risk factor for the "diagnosis" in this study adds another level of doubt about the cohort of "CFS" patients used, given the consistent findings that CFS is more prevalent in female adults e.g. [4,5]. The NICE guidelines for "CFS/ME" say it affects "women at four times the rate of men"[6].

Finally, I think there is a risk that the "risk factors" mentioned in the abstract will be misread by some: an ongoing discussion in the CFS field is whether a certain level of activity predisposes one to CFS e.g. whether people with CFS were more or less active than the general population before becoming ill [7-13]. However, this study does not attempt to look at the period before individuals become ill; instead, it makes use of data collected close to when the symptoms were assessed, using a cross-sectional type of design; it is not thus not that surprising that such individuals [with CFS] were found to relatively inactive given the definition of CFS.

References:

[1] Bhui KS, Dinos S, Ashby D, Nazroo J, Wessely S, White PD. Chronic fatigue syndrome in an ethnically diverse population: the influence of psychosocial adversity and physical inactivity. BMC Med. 2011 Mar 21;9(1):26.

[2] Reeves WC, Lloyd A, Vernon SD, Klimas N, Jason LA, Bleijenberg G, Evengard B, White PD, Nisenbaum R, Unger ER, International Chronic Fatigue Syndrome Study Group: Identification of ambiguities in the 1994 chronic fatigue syndrome research case definition and recommendations for resolution. BMC Health Serv Res 2003, 3:25.

[3] Reyes M, Nisenbaum R, Hoaglin DC, Unger ER, Emmons C, Randall B, Stewart JA, Abbey S, Jones JF, Gantz N, Minden S, Reeves WC (2003). Prevalence and incidence of chronic fatigue syndrome in Wichita, Kansas. Archives of Internal Medicine 163, 1530–1536.

[4] Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff AL, and the International CFS Study Group (1994). The chronic fatigue syndrome: a comprehensive approach to its definition and study. Annals of Internal Medicine 121, 953–959.

[5] Jason LA, Richman JA, Rademaker AW, Jordan KM, Plioplys AV, Taylor RR, McCready W, Huang C-F, Plioplys S (1999). A community-based study of chronic fatigue syndrome. Archives of Internal Medicine 159, 2129–2137.

[6] Turnbull N, Shaw EJ, Baker R, Dunsdon S, Costin N, Britton G, Kuntze S and Norman R (2007). Chronic fatigue syndrome/myalgic encephalomyelitis (or encephalopathy): diagnosis and management of chronic fatigue syndrome/myalgic encephalomyelitis (or encephalopathy) in adults and children. London: Royal College of General Practitioners.

[7] 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, 6:53.

[8] Harvey SB, Wadsworth M, Wessely S, Hotopf M: Etiology of Chronic Fatigue Syndrome: Testing Popular Hypotheses Using a National Birth Cohort Study. Psychosom Med. 2008 Mar 31

[9] Viner R, Hotopf M: Childhood predictors of self reported chronic fatigue syndrome/myalgic encephalomyelitis in adults: national birth cohort study. BMJ 2004, 329:941.

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

[11] 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.

[12] MacDonald KL, Osterholm MT, LeDell KH, White KE, Schenck CH, Chao CC, Persing DH, Johnson RC, Barker JM, Peterson PK: A case-control study to assess possible triggers and cofactors in chronic fatigue syndrome. Am J Med 1996, 100:548-54.

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

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 NCT0102293. We believe the correct ID, which we have found by hand searching, is NCT01022931.

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 2016 Oct 05, Santosh Kondekar commented:

Though distal RTA is often related to urological disease or associated immune disease; we had a case of familial distal RTA. These cases often go unnoticed if the acidosis doesnot manifest with clinical symptoms. The cases may get missed as Rickets if proper workup is not done. I suggest to complete the RTA workup in all cases of rickets with deformities that appear slow responsive to vitamin D and calcium.

On 2013 Dec 24, Kenneth Witwer commented:

Following the link to the VMir download results in a "Seite nicht gefunden" (page not found) error. Is there a new site, or is there an error in the published URL?

On 2013 Oct 22, Jonathan Eisen commented:

I am the senior author of this paper and I wrote a detailed blog post about the "Story behind the paper" that may be of interest. See http://phylogenomics.blogspot.com/2011/03/story-behind-story-of-my-new-plosone.html.

On 2015 Aug 11, Lydia Maniatis commented:

The claim that this study controlled for shape is incorrect. The contour elements making up the "patterned rectangles" referred to in the abstract did have a shape, and this shape was perfectly confounded with the factor of "entropy." The elements in the "low entropy" figures had squared-off, rectangular, edges, while the elements in the "high-entropy" figures had non-rectangular, slanted edges. Inferring an occlusion allows their shape to be regularised.

On 2016 Apr 07, Dr. Kam Cheong Wong commented:

There are various methods that can be applied to generate inputs for an Ishikawa diagram such as focus group discussion, review of process-flow, survey, interview, literature review, brain storming, and failure mode and effects analysis (FMEA).

FMEA is an engineering methodology in origin. It can be modified and applied to provide inputs into an Ishikawa diagram via team work or self-directed learning. The human biliary system was used to illustrate a modified FMEA (in short, mFMEA) in an editorial paper which can be accessed via: http://jmedicalcasereports.biomedcentral.com/articles/10.1186/s13256-016-0850-6

On 2014 Jul 25, Jens Staal commented:

The VRPR experiment was unfortunately not the best verification that we could have done. In a later experiment, we silenced the uncleavable CYLD in our stable Jurkat cells with siRNA and could restore JNK activation to levels equal to that of normal Jurkats silenced for CYLD, providing further proof that the uncleavable CYLD is indeed causing the JNK inhibition and that it is not a clonal effect.

On the other hand, later results indicate that MALT1 protease activity is not required for JNK activation so the most likely explanation for our observations is that they are visible thanks to the overexpression of CYLD (both WT and R/A are overexpressed to the same extent so the difference is cleavage-dependent) whereas the effect is not visible when expressed at endogenous levels.

On 2015 Feb 19, Devon Ryan commented:

In the off-chance that someone else comes across this paper and wonders why exactly they chose a bonferroni-adjusted p-value threshold of 1.81e-6, it's presumably because that turns out to be a benjamini-hochberg adjusted p-value threshold of 0.05 for maternal age in their microarray dataset. I have no clue why they didn't just say that in their methods.

On 2014 Oct 10, Martin Turner commented:

Would the authors care to report the limits of agreement between the Tonosafe and standard Goldmann prisms? Thank you.

On 2014 May 05, Madhusudana Girija Sanal commented:

1) Provides evidence for the endosymbiotic theory on the origin of mitochondria 2) It says it is possible to make transgenic higher animals with photosynthetic ability (limited by the available body surface area) 3) It shows the adaptability of an organism to foreign genes and gene products through co-evolution 4) It shows the capability of embryonic cells to accept foreign genes and gene products and opens the possibility for wonderful 'compound organisms' Is there any evidence of genetic exchanges between the genomes of the salamander and the alga? It would be nice to do a whole genome sequencing of the salamander and alga and compare with the closest neighbors and relatives (species) to understand the depth of co-evolution.

On 2015 Jun 24, Spencer Bliven commented:

The URL for Mattbench has changed. The current (2015-06) URL is http://bcb.cs.tufts.edu/mattbench

On 2017 Oct 05, Jason Snyder commented:

Doesn't the majority of dentate granule cells express calbindin? And yet there are only ~20 calbindin+ cells per dentate gyrus slice (fig 4).

On 2017 Oct 11, Joe Herbert commented:

A recent paper (Hosp JA, Strüber M, Yanagawa Y, Obata K, Vida I, Jonas P, Bartos M.

Hippocampus. 2014 24:189-203.) says 24% . But I can't see this is very relevant to the major thrust of the paper.

On 2014 May 15, G L Francis commented:

In setting out to produce a simplified chemically defined culture medium for human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) the authors demonstrated removal of bovine serum albumin (BSA) and other constituents was possible. By judicious screening the resultant optimized medium (E8) was greatly simplified compared to the starting medium (TeSR) and provided comparable outcomes for long term undifferentiated proliferation of both human ESCs and iPSCs.

The authors appear to show quite convincingly that in the original TeSR medium BSA serves the purpose of neutralizing the potential toxicity of β-mercaptoethanol (BME) (see Fig 1 : Title. ‘’Albumin is not required for hESC culture’’). The only question I raise is about the veracity of the overall conclusion is that albumin presence in the absence of BME does not enhance the proliferation (I assume equals combined survival of plated ESCs and subsequent proliferation) measured at 120h after plating in TeSR-based medium, as depicted in Fig.1 panel (f).The first bar in Fig.1 panel (f) representing the activity for ‘’complete TeSR medium (with BSA & BME)’’, is stimulated a further two- fold in the ‘’without BME’’ medium (presumably with BSA!) represented in the last bar of that panel (f). If that is the case, does that not indicate that addition of albumin significantly improves the performance of the medium in the long term proliferation of hESCs – apparently at odds with the conclusions argued in the Discussion of the paper?

Moreover, in Figure 2 titled “Essential medium components for human ESC survival and proliferation” in panel (c) the improvement in proliferation at 129 h for plated hESCs over the starting TeSR medium by a number of additions to a base E8 medium was only 40% (compare this to the improvement of TeSR by TeSR –BME+BSA above in Fig.1). Admittedly the further addition of other components, and finally Nodal, led to incremental improvement over the base components of E8.

I understand the importance of eliminating an animal or human sera sourced component (also what about the transferrin?) This still prompts the question as what would have been the result if albumin was added to the final E8 medium in terms of long term proliferation of hESCs in this study. For the experimental evaluation of this question the best performing batch of BSA would have been most appropriate, however, to address the issues raised about the use of this xenobiotic material, a human recombinant source of albumin could have been evaluated. Human recombinant albumin is now produced at scale under GMP conditions and I believe the price has become more acceptable - I agree the final acceptance of that would rely on a cost benefit analysis at the process level.

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 NCT0094398. We believe the correct ID, which we have found by hand searching, is NCT00944398.

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 2015 Feb 04, Alberto Halabe Bucay commented:

In this article is cited in the references my work regarding treatment of cancer with citric acid (citrate) published in PubMed since March, 2007: PMID: 17368752.

On 2014 Jan 11, I-Chen Tsai commented:

Wow. PubMed now opens for comments!

On 2013 Oct 21, John Boothroyd commented:

I find this an extremely exciting paper and one of the most important in Toxoplasma epidemiology in the past decade. For years, there has been debate about what fraction of toxoplasmosis infections in humans stems from ingestion of oocysts (in drinking water or on soil-contaminated food) vs. tissue cysts (in under-cooked meat, etc.). But until this paper, there was no way to do more than guess. Here, the authors report very exciting data showing that antibodies to an oocyst (sporozoite) protein are elicited and detectable in oocyst-initiated infections in animals and humans. Further work will be needed to determine how reliable it is but all the indications are that it is, in fact, a good predictor of oocyst-initiated vs. tissue-cyst-initiated infections. The results to follow could alter the public health message in very important ways and allow advice to be targeted to the most risky activities.

On 2014 Jun 21, Ivan Oransky commented:

This paper has been retracted: http://retractionwatch.com/2014/06/20/if-it-smells-like-pig-sh-it-probably-is-pig-sh-a-stinky-retraction/

On 2014 Nov 23, Harri Hemila commented:

A comment is available at: https://helda.helsinki.fi/handle/10138/228058

On 2016 May 02, Riccardo Polosa commented:

Evidence that activation of the haemo-coagulative system occurs in COPD is accumulating with potential implications for cardiovascular disease (CVD)(1,2). Maclay and colleagues(3) have recently reported a significant but small increase in platelet activity by flow cytometric analysis of circulating platelet-monocyte aggregates in COPD patients. This does not seem to be strongly supportive of this view as the observed changes are well within test repeatability and mainly due to a handful of outliers. Moreover, no changes were reported for the well characterised platelet activation marker, P-selectin.

Although small sample size, co-morbidities and medications may have contributed to these largely negative findings, an important factor to be considered is smoking. Of note, the authors excluded active smokers from COPD patients and included a control group of smoking habit- (i.e. ≥10 pack/yrs; at least 6 months tobacco abstinence) and age-matched ex-smokers with no respiratory symptoms. However, as for several biomarkers of systemic inflammation (e.g. C-reactive protein)(4), airway inflammation (e.g. sputum neutrophilia)(5), and clotting activation (e.g. D-Dimer and prothrombin fragment 1+2)(6), elevation in markers of platelet activation may persist for many years after smoking cessation, reflecting that the underlying damage caused by smoking takes a protracted time to recover. Thus, the baseline level of platelet activation in the control group may not be truly representative. Future studies should recruit either lifetime non-smokers or ex-smokers who have been abstinent for 3-5 years as controls.

Assuming that platelet activation is significant in COPD, it is highly speculative to suggest that such mechanisms are associated with increased risk of CVD in COPD. Firstly, measurements of platelet activation in smoking-related conditions may not be that efficient in predicting cardiovascular mortality and morbidity. Secondly, platelet activation is not disease specific (can occur in degenerative, inflammatory and smoking-related diseases) and may be due to immobilization during hospitalization. A control group for this confounder was not included in the exacerbation study. Thirdly, although systemic inflammation may be responsible for platelet activation, we cannot discount a role for the underlying tissue/cellular injury that persists for many years after smoking cessation(4-6). Specifically, the source of systemic inflammation (± platelet activation) in COPD may not necessarily be associated with activation/injury of the airway epithelium. Alternatively, direct spill-over of pro-inflammatory mediators and potent platelet activators in the bloodstream can be traced to the vascular endothelium, which are metabolically activated on smoke exposure(7,8). Lastly, it is unclear whether the low-grade systemic inflammation reported in COPD has an independent causal role in cardiovascular co-morbidities(9). CVD is known to occur long before the onset of COPD and is known to be strongly associated with cigarette smoking. Conclusive evidence of systemic inflammation contributing to greater risk of CVD requires large well-controlled long-term prospective studies normalized for intensity and duration of smoking.

References

1. Wedzicha JA, Syndercombe-Court D, Tan KC. Increased platelet aggregate formation in patients with chronic airflow obstruction and hypoxaemia. Thorax. 1991;46(7):504-7.
2. Polosa R, Malerba M, Cacciola RR, Morjaria JB, Maugeri C, Prosperini G, et al. Effect of acute exacerbations on circulating endothelial, clotting and fibrinolytic markers in COPD patients. Intern Emerg Med. 2011. Epub 2011/06/11.
3. Maclay JD, McAllister DA, Johnston S, Raftis J, McGuinnes C, Deans A, et al. Increased platelet activation in patients with stable and acute exacerbation of COPD. Thorax. 2011;66(9):769-74.
4. Yanbaeva DG, Dentener MA, Creutzberg EC, Wesseling G, Wouters EF. Systemic effects of smoking. Chest. 2007;131(5):1557-66.
5. Willemse BW, ten Hacken NH, Rutgers B, Lesman-Leegte IG, Postma DS, Timens W. Effect of 1-year smoking cessation on airway inflammation in COPD and asymptomatic smokers. Eur Respir J. 2005;26(5):835-45.
6. Caponnetto P, Russo C, Di Maria A, Morjaria JB, Barton S, Guarino F, et al. Circulating endothelial-coagulative activation markers after smoking cessation: a 12-month observational study. Eur J Clin Invest. 2011;41(6):616-26.
7. Cacciola RR, Guarino F, Polosa R. Relevance of endothelial-haemostatic dysfunction in cigarette smoking. Curr Med Chem. 2007;14(17):1887-92.
8. Guarino F, Cantarella G, Caruso M, Russo C, Mancuso S, Arcidiacono G, et al. Endothelial activation and injury by cigarette smoke exposure. J Biol Regul Homeost Agents. 2011;25(2):259-68.
9. Morjaria JB, Polosa, R. The holistic perspective of chronic obstructive pulmonary disease: doubt some more. Ther Adv Chronic Dis. 2010;1(2):37-41.

On 2014 Feb 27, George W Hinkal commented:

The National Cancer Institute has been investing in the development of an online webportal of curated cancer nanotechnology data called caNanoLab. The numerical data, nanomaterial characterizations and composition information for the two nanoparticles related to this publication have been added to the database and can be found at:

https://cananolab.nci.nih.gov/caNanoLab/characterization.do?dispatch=summaryView&sampleId=37191682&page=0&tab=ALL

https://cananolab.nci.nih.gov/caNanoLab/characterization.do?dispatch=summaryView&sampleId=37191683&page=0&tab=ALL

The left navigation links on these pages provide information about each sample (under Navigation Tree).

For general information on how to use caNanoLab, please visit https://cananolab.nci.nih.gov/caNanoLab/home.jsp

On 2014 Mar 12, George W Hinkal commented:

None

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 NCT0083283. We believe the correct ID, which we have found by hand searching, is NCT00832832.

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 2013 Oct 31, John Cannell commented:

The authors stated that markers of oxidative stress are present in autism spectrum disorder (ASD). I wonder if the authors are aware that the genes for the antioxidants superoxide dismutase and thioredoxin reductase are directly up-regulated by the secosteroid 1,25 di-hydroxy vitamin D3 (calcitriol). I believe both genes also harbor a vitamin D response element.

Peehl DM, Shinghal R, Nonn L, Seto E, Krishnan AV, Brooks JD, Feldman D. Molecular activity of 1,25‐dihydroxyvitamin D3 in primary cultures of human prostatic epithelial cells revealed by cDNA microarray analysis. J. Steroid Biochem Mol. Biol 2004;92:131–141. PMID:15555907>

Calcitriol also directly up-regulates glutathione reductase and increases glutathione levels.

Jain SK, et alo. Vitamin D upregulates glutamate cysteine ligase and glutathione reductase, and GSH formation, and decreases ROS and MCP-1 and IL-8 secretion in high-glucose exposed U937 monocytes. Biochem Biophys Res Commun. 2013 Jul 19;437(1):7-11. doi: 10.1016/j.bbrc.2013.06.004. Jain SK, 2013

Also, supplemental vitamin D significantly reduces oxidative stress in humans.

Nikooyeh B, et al. Daily intake of vitamin D- or calcium-vitamin D-fortified Persian yogurt drink (doogh) attenuates diabetes-induced oxidative stress: evidence for antioxidative properties of vitamin D.J Hum Nutr Diet. 2013 Jul 5. doi: 10.1111/jhn.12142. Nikooyeh B, 2014

Asemi Z, et al. Vitamin D supplementation affects serum high-sensitivity C-reactive protein, insulin resistance, and biomarkers of oxidative stress in pregnant women. J Nutr. 2013 Sep;143(9):1432-8. doi: 10.3945/jn.113.177550. Asemi Z, 2013

Thus the vitamin D theory of ASD (vitamin D deficiency being the environmental risk factor for this highly heritable disorder) is consistent with the authors work. Three recent studies, using community controls, have found 25(OH)D levels are significantly lower in children with ASD. Two of the studies below (Mostafa et al and Gong et al) also found ASD severity, as rated on standard ASD rating scales, is inversely correlated with 25(OH)D levels. Mostafa et al found an R value of -.86 for the association of serum 25(OH)D with ASD severity.

Gong ZL, Luo CM, Wang L, Shen L, Wei F, Tong RJ, Liu Y. Serum 25-hydroxyvitamin D levels in Chinese children with autism spectrum disorders. Neuroreport. 2013 Oct 1. Gong ZL, 2014

Meguid NA, Hashish AF, Anwar M, Sidhom G. Reduced serum levels of 25-hydroxy and 1,25-dihydroxy vitamin D in Egyptian children with autism. J Altern Complement Med. 2010 Jun;16(6):641-5. Meguid NA, 2010

Mostafa GA, Al-Ayadhi LY.Reduced serum concentrations of 25-hydroxy vitamin D in children with autism: relation to autoimmunity. J Neuroinflammation. 2012 Aug 17;9:201. Mostafa GA, 2012

There is a plethora of basic science explaining why low gestational or early childhood 25(OH)D levels would adversely effect brain development.

Eyles DW, Feron F, Cui X, Kesby JP, Harms LH, Ko P, McGrath JJ, Burne TH. Developmental vitamin D deficiency causes abnormal brain development. Psychoneuroendocrinology. 2009 Dec;34 Suppl 1:S247-57. doi: 10.1016/j.psyneuen.2009.04.015. Epub . Review. Eyles DW, 2009

DeLuca GC, Kimball SM, Kolasinski J, Ramagopalan SV, Ebers GC. Review: the role of vitamin D in nervous system health and disease. Neuropathol Appl Neurobiol. 2013 Aug;39(5):458-84. doi: 10.1111/nan.12020. DeLuca GC, 2013

Eyles DW, Burne TH, McGrath JJ. Vitamin D, effects on brain development, adult brain function and the links between low levels of vitamin D and neuropsychiatric disease. Front Neuroendocrinol. 2013 Jan;34(1):47-64. doi: 10.1016/j.yfrne.2012.07.001. Epub 2012 Jul 11. Review. Eyles DW, 2013

Furthermore, the vitamin D theory of autism explains most of the epidemiological facts of ASD.

Cannell JJ. On the aetiology of autism. Acta Paediatr. 2010 Aug;99(8):1128-30. Cannell JJ, 2010

Cannell JJ. Autism and vitamin D. Med Hypotheses. 2008;70(4):750-9. Cannell JJ, 2008

70% of American toddlers do not take

On 2017 Jul 07, Wei Wang commented:

Several issues have been raised about this paper on PubPeer. Below are some of the comments:

Comment #1: "Jonathan Warner and colleagues failed to reproduce results reported in this paper. In their paper (PMID: 24860015), Warner et al. state:

"These results are at significant odds with the report that there can be 100-fold differences in the levels of the various RP mRNAs in several tissues of the developing mouse embryo (Kondrashov et al. 2011)."

Comment #3: "The authors wrote:

"Strikingly, we observed tremendous heterogeneity in RP expression among different RPs and within different tissues over a 250-fold range, expressed in log2 space (Figure 7D and Table S3)."

As Jon Warner and colleagues noted, this strikingly tremendous heterogeneity is at odds with any other dataset that we have seen. We downloaded the data from Table S3 and could not reproduce the 250-fold range either. Can the authors explain how they analyzed the data to find the 250-fold range ?

Hopefully, the authors can provide the raw data used for Figure 7D and Table S3.

Maybe some tissues express the mRNAs for all ribosomal proteins at higher levels because they need more ribosomes. Were the transcript data normalized for different global levels of ribosomal protein in different tissues ? "

Comment #4: "In addition to the mentioned issues with this paper, I would like to note some further points. I don't want to discredit the authors, they are certainly working on a very exciting topic, however, this paper makes conclusions and over interpretations, which are by no means proven by the data that they present. The authors claim to "uncover an important role for RPL38 in transcript-specific translational control". However, there are several important concerns with that claim:

(1) The authors don't provide any evidence that the ribosomes in the tissues/cells they are using are lacking RPL38, hence any assumptions about RPL38 specifically regulating the translation of these certain Hox mRNAs are purely speculative.

(2) As "evidence" that the translational defect of these mRNAs is specific to RPL38 deficiency, the authors present figure 4Q, where they are using additional mouse mutants. However, no data are provided to present how much the levels of the respectively affected ribosomal protein in the mutants are actually affected in the used tissues. Furthermore, out of the 8 Hox mRNAs, whose translation is impaired with RPL38 deficiency, the authors test the protein levels only for one (HoxA5) of these 8 transcripts in the additional mouse mutants, this seems like this was picked on purpose. And even for that 1 Hox protein, the data seem questionable. The RPS19 mutant seems to have also reduced HoxA5 protein levels when I look at the western, suggesting that the translational defect is not specific to RPL38 deficiency. The westerns for the other mutants seem to be slightly overloaded in the mutant samples compared to controls, hard to make a conclusion there.

(3) The polysome profiles in figure 3b are more than questionable. The polysomes are basically just a flat line, any quantitative data from RT-qPCR from isolated RNA of these polysomes don’t seem really reliable in terms of translation. Also, it appears hard to believe that the authors were able to dissect selectively the somites without including non-affected tissue material. "

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 NCT00314575. We believe the correct ID, which we have found by hand searching, is NCT00314574.

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 Jul 25, Prof.Dr.Jogenananda Pramanik commented:

The effects of noise on sleep and their potential harmful repercussions on cardiac patients in hospitals"

Invited Co-Authors: Dr.Saurabh Kole, MBBS.Dip Card.MD.Cardiologist,Belle Vue Clinic, Kolkata,India;and Tanu Pramanik, Lecturer (Clin.Psychology), Allianze University College of Medical Sciences, 13200-Penang, Malaysia.

The author of the current paper (1) deserve applause for timely evaluation of the effects of sound pollution on hospitalized cardiac patients. The World Health Organization guidelines say that for a good sleep, sound level should not exceed 30 dB(A) for continuous background noise, and 45 dB(A) for individual noise events.(2,3) The effect of noise on sleep, however, not only depends on the acoustical parameters of noise but also on the individual as there is large variance in the experience of a person with a particular noise. Personal characteristics such as personality traits, diurnal type, age and self-estimated sensitivity to noise are important individual factors.(4) These autonomic responses to noise during sleep can be obtained for much lower peak noise intensities as during wake states. These effects, mainly involving increased heart rate and vasoconstriction, have been found to habituate over successive noise-exposed nights as opposed to long exposure times. This could indicate an effect on cardiovascular response over the long term exposure. (5) During sleep, heart rate is related to changes in the parasympathetic-sympathetic balance with an increase in sympathetic tone associated with activation and with electroencephalogram (EEG) arousal. Catecholamine levels and sympathetic activity decrease during sleep. So, as one might assume that decreased sleep is associated with increased sympathetic activity and as a result increased blood pressure and heart rate. This association has been observed not only with sleep deprivation but also with regard to sleep disruption. Brief awakenings from sleep for only a few seconds are associated with temporary elevation in blood pressure and heart rate that results from an autonomic reflex.(6) Noise that prevents or interrupts sleep is a nearly universal complaint of patients who are hospitalized (1,2) However, no previous record of systematic research or published report from developing countries like ours is available till date.

The causal relationships between noise exposure, effects on sleep, and contribution to health disturbances, both behavioral and physical, are not firmly established yet. Therefore, we designed current research proposal with a well-defined objective to study noise induced repercussions on cardiac patients in a hospital setting. During our study, we will use EEG, EKG, polysomnogram and other monitoring systems for the patients selected under stringent criteria set by the clinical research committee and University ethical committee. Our research may reveal adequate experimental data to substantiate noise induced repercussions on cardiac patients which may enlighten hospital authorities to be more cautious to protect vulnerable patients from sound pollution.

References: 1. Babisch W.: Cardiovascular effect of noise :Noise Health. 2011 May-Jun;13(52):201-4. doi: 10.4103/1463-1741.80148.

2.Sleep Disruption due to Hospital Noises: Ann Intern Med. 7 August 2012;157(3):1-32 3. Berglund B, Lindvall T, Schwela DH. Guidelines for Community Noise. World Health Organization 1999. Available from: http://www.who.int/docstore/peh/noise/guidelines2.html . [Accessed on 2010 March 28].<br> 4.Muzet A, Weber LD, Di Nisi J, Ehrhart J. Comparison of cardiovascular reactivity to noise during waking and sleep. National Center for Scientific Research Center for Bioclimatic studies. Convention No 82243, 1985.

5.Muzet A, Ehrhart J, Eschenlauer R, Lienhard JP. Habituation and age differences of cardiovascular responses to noise during sleep. In Sleep 1980;212-5.<br> 6.Sforza E, Chapotot F, Lavoie S, Roche F, Pigeau R, Buguet A. Heart rate activation during spontaneous arousals from sleep: Effect of sleep deprivation. Clin Neurophysiol 2004;115:2442-51.

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 NCT0110743. We believe the correct ID, which we have found by hand searching, is NCT01107431.

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 2016 Sep 21, Morten Oksvold commented:

There is an interesting Brief Communication letter which is questioning the role of BID in NOD signaling (Nachbur U et al., 2012). Please see link:

http://www.nature.com/nature/journal/v488/n7412/full/nature11366.html

In the communications arising, Yeretssian et al., have a reply:

http://www.nature.com/nature/journal/v488/n7412/full/nature11367.html

Yeretssian et al. have even a correction to their reply, due to the fact that they removed several data points from a figure generated by the authors of the original Brief Communication (Nachbur U et al., 2012). Please see link:

http://www.nature.com/nature/journal/v491/n7426/full/nature11668.html

On 2015 Mar 30, University of Kansas School of Nursing Journal Club commented:

University of Kansas School of Nursing Undergraduate Program Team 12: Stacy Hanson, Chelsi Puskas, Shannan Orpin, Sami Johnson, Chandler Schoen, Jen Huynh, and Valerie Melin

Introduction:<br> The purpose of this Journal Club Literature Review was to take a closer look at shared governance by evaluating the functionality Unit Practice Councils through a study by Beverly Fray (2011). Not only did the article create a credible tool for rating this specific hospital’s system, it also obtained important qualitative data that the hospital can use to identify weaknesses in their Unit Practice Councils. This information is crucial for the hospital that this survey serves because this hospital system is on their Magnet journey. This survey is working to fill the gap in knowledge of a credible survey to access functionality of Unit Practice Councils. Our team chose this article after listening to two presentations about Shared Governance from the University of Kansas Hospital and Children’s Mercy Hospital, we were interested on how effectiveness of Shared Governance, specifically Unity Practice Councils, can be measured. We were also interested in this article because it was looking at a hospital system that had not yet achieved Magnet status, unlike the University of Kansas Hospital and Children’s Mercy Hospital. We were interested in a non-magnet status hospital because according to Clavelle, O’Grady, and Drenkard (2013), magnet hospitals have shown to have higher rates of shared governance, resulting in higher levels of nurse-physician relationships and greater positive work environments. Therefore, we were wondering how non-magnet status hospitals approached shared governance.

For this Journal Club Literature Review, we used ProQuest Nursing & Allied Health Source for search for the article. To retrieve this specific article, we typed “shared governance and nurse satisfaction” in the search bar, and then we restricted the search to only include articles that were peer reviewed and published in the last 5 years. This was a descriptive study, describing the Functionality of the Unity Practice Councils and testing the validity of the newly created survey. The target population is Jackson Health System, a health system attempting to achieve magnet status. While Jackson Health System wanted to identify strengths and weaknesses in Unit Practice Councils, they believe that this survey could be used in other hospitals to identify ways to strengthen Unit Practice Councils. This is important because Unit Practice Councils are one of the primary ways that voices are given to nurses, and if the Unit Practice Council is not functioning properly, some of the ideas brought by nurses may not be properly implemented. It is also important because this tool would be able to be used in other hospitals, and weak Unit Practice Council would be able to use strong Unit Practice Councils as resources. Data for the study was collected by surveys based on traits that were observed from highly functional and successful Unit Practice Councils. These surveys results were compared between the Unit Practice Council Coordinator and then the Center for Nursing Excellence.

Findings:<br> The Center for Nursing Excellence and the Unit Practice Council Coordinators reached a 78% concurrence level for functionality of Unit Practice Councils. The study found that 38% of the Unit Practice Councils were low functioning, 22% were middle functioning, and 40% were high functioning. It is also notable to look at what the Unit Practice Councils focus on: 96% focus on improving clinical practice or patient, staff, and physician satisfaction; 92% had invited management to their meetings; 64% use their communication network; and 68% reported being innovative in making tangible improvements at the bedside. While this study was not compared to other settings, the survey would be able to be implemented in other locations to compare the functionality of Unit Practice Councils. The limitations of this study included a low survey response rate and more research needs to be completed to establish reliability of the instrument. Implications: This study is important to nursing because it identifies the functionality of Unit Practice Councils. Because the importance of Shared Governance has been identified, it is important to look at the Unit Practice Council as a source for nursing ideas and empowerment. This survey can be used to identify strength and weaknesses of Unit Practice Councils. The tool is simple enough that it could also be used to measure improvement in Unit Practice Councils, and evaluate nursing practice outcomes. and can be used as objective tool to access quality of Unit Practice Councils. A functional Practice Council can leads to nurse-lead changes on the unit. These changes promote nurse satisfaction and patient-centered care, leading to a positive work environment. Any tool that can promote the higher functioning of Practice Councils is worth studying.

Reference: Clavelle, J., O’Grady, P., Drenkard, K. (2013). Structural empowerment and the nursing practice environment in Magnet organizations. The Journal of Nursing Administration. 43(11), 566-573.

On 2014 Mar 06, Christopher Southan commented:

There is a follow-on paper http://www.ncbi.nlm.nih.gov/pubmed/24204758 that analyses an update of the same data but sliced on a per-year basis

On 2015 Feb 08, Arnaud Chiolero MD PhD commented:

An elegant demonstration of how age could be the only element to consider for the individual primary prevention of CVD

On 2017 May 23, Egon Willighagen commented:

The link to the source code repository no longer exists and now points to this (currently active) repository: https://bitbucket.org/wwmm/chemicaltagger

On 2014 Nov 17, Peter H. Asdahl commented:

The study by Villani et al. addresses the issue of cancer surveillance among TP53 mutation carriers with Li-Fraumeni syndrome. The authors interpreted data from an institutionally-devised cancer surveillance program. Villani et al. concluded that their surveillance approach is feasible, and may lead to a reduction in mortality. In addition, the authors emphasized the importance of genetic testing for early detection. Nonetheless, certain results of the study warrant further discussion.

Villani et al. used an observational design to address their aim, where mutation carriers were given the option of participating in the surveillance or non-surveillance (i.e. standard clinical practice) groups, and were subsequently followed for incident cancers. Given the goal of systematic cancer surveillance, we would expect a higher yield of incident cancers in the surveillance group. Nevertheless, the result from the Villani et al. study contradicts expectation. Specifically, one or more tumors were detected among seven of the 18 (39%) participants who opted for surveillance in contrast to 10 of the 16 participants (63%) who opted for non-surveillance. Given insufficient data in the published report by Villani et al. to estimate person-time contribution for individuals in each group, we assume equivalent follow-up between groups for the purpose of our illustration. Consequently, a patient-level comparison of the two groups yields a 24% reduction in the absolute risk of incident cancers in the surveillance group (risk difference= -24%, 95% confidence interval: -56% to 9%). We would not expect a negative risk difference in this scenario, which raises concerns about potential biases such as healthy user bias or confounding by functional status [1].

Healthy user bias and confounding by functional status are often overlooked but legitimate problems in observational studies of screening effects. For example, if participants in the non-surveillance group had more functional impairments (e.g. related to underlying but undetected cancer) which resulted in opting for standard clinical care rather than systematic surveillance, then eventual detection of underlying cancer in this group may result in a higher yield compared with the surveillance group. Some evidence for this phenomenon may be apparent by the lower than expected survival among participants with incident cancers in the non-surveillance group. In particular, three-year survival among the non-surveillance group was 21%, which is low even for aggressive tumors.

An ideal screening program aims for early detection of cancer with subsequent reduction in cancer-related mortality. Although we do not reject the notion that the screening program in this study detected asymptomatic tumors, the interpretation that the authors’ surveillance program is superior to non-surveillance is not supported by the results. To investigate a possible effect of screening in this population, a more robust study design with random allocation to intervention may be less sensitive to bias.

REFERENCE 1. Shrank WH, Patrick AR, Brookhart MA. Healthy user and related biases in observational studies of preventive interventions: a primer for physicians. J Gen Intern Med. 2011 May;26(5):546-50.

On 2015 Feb 23, MELISSA DAVIS commented:

This cell line is also known as HCC1806

On 2015 Jun 23, Bill Cayley commented:

A great example of when "Less" can be "More": https://lessismoreebm.wordpress.com/2015/06/23/low-cost-mesh-for-inguinal-hernia-repair-in-resource-limited-settings/

On 2014 Feb 27, George W Hinkal commented:

The National Cancer Institute has been investing in the development of an online webportal of curated cancer nanotechnology data called caNanoLab. The numerical data, nanomaterial characterizations and composition information for the nanoparticle related to this publication have been added to the database and can be found at:

https://cananolab.nci.nih.gov/caNanoLab/characterization.do?dispatch=summaryView&sampleId=37191685&page=0&tab=ALL

The left navigation links on this page provide information about each sample (under Navigation Tree).

For general information on how to use caNanoLab, please visit https://cananolab.nci.nih.gov/caNanoLab/home.jsp

On 2014 Mar 12, George W Hinkal commented:

None

On 2016 May 02, Riccardo Polosa commented:

We read with great interest the recent article by Grainge and coll. (1) showing that experimental airway narrowing induced by serial bronchoprovocation testing in patients with asthma may in itself be a stimulus for the development of airway remodelling. These tissue changes were independent of the broncoprovocant used in the study, development of remodelling being equivalent either after allergen or methacholine challenge. Surprisingly, however, the occurrence the characteristic late asthmatic response associated with a progressive fall in FEV1 after allergen (but not methacholine) challenge, failed to produce additional effects in term of enhanced airway remodeling changes in this study.

As for the action of hemodynamic sheer stress in endothelial pathophysiology and atherosclerotic plaque formation (2), it is likely that adaptative wall remodelling in asthma occurs only in response to a brisk mechanical stimulus (as in the severe acute bronchoconstriction of the early asthmatic response), whereas a slow, more progressive fall in FEV1 (as in the late asthmatic response of the allergen challenge) is not able to induce a sufficient stress response for tissue remodeling. Given the wide variability in individual fall in FEV1 and remodelling responses reported in the study by Grainge and coll., it cold have been relevant to investigate a possible correlation between severity of bronchoconstriction and amplitude of remodelling changes. This is important to substantiate these authors speculations.

Remodelling changes in response to bronchoconstriction are not necessarily detrimental, and may have a protective role by stabilizing airway calibre and limiting further narrowing (3). However, in presence of an inflammatory infiltrate and of an intrinsically dysfunctional epithelium – as in asthma (4,5) - mechanotransduction may promote a more harmful form of airway remodelling. To test specificity of the observed effects in asthma, a further study group to control for a non specific effect of bronchoconstriction (by high dose inhaled methacholine) in non-asthmatic individuals would have been highly informative.

Given the relative insensitivity of inhaled corticosteroids in modulating airway remodelling and its progression (6), the search for novel therapies that can specifically reverse or prevent airway remodeling has become an active area for drug development. For the time being, as appropriately pointed out by Grainge and coll., sustained (and safe) bronchodilatation should be recommended more insistently in addition to classical means of disease exacerbation prevention. Unsurprisingly, these considerations may be also valid for patients with chronic obstructive pulmonary disease (COPD).

REFERENCES

1. Grainge CL, Lau LCK, Ward JA, Dulay V, Lahiff G, Wilson S, Holgate ST, Davies DE, Howarth PH. Effect of bronchoconstriction on airway remodeling in asthma. N Engl J Med 2011; 364: 2006-15.
2. Davies PF. Hemodynamic shear stress and the endothelium in cardiovascular pathophysiology. Nat Clin Pract Cardiovasc Med 2009; 6(1): 16-26.
3. McParland BE, Macklem PT, Pare PD. Airway wall remodelling: friend or foe? J Appl Physiol 2003; 95: 426-434.
4. Puddicombe SM, Polosa R, Richter A, Krishna MT, Howarth PH, Holgate ST, Davies DE. Involvement of the epidermal growth factor receptor in epithelial repair in asthma. FASEB J 2000;14: 1362-74.
5. Holgate ST, Polosa R. The mechanisms, diagnosis, and management of severe asthma in adults. Lancet. 2006 Aug 26;368(9537):780-93.
6. Royce RG, Tang ML. The effects of current therapies on airway remodelling in asthma and new possibilities for treatment and prevention. Curr Mol Pharmacol 2009; 2(2):169-81.

On 2015 Jan 30, Zhiyong Lu commented:

Check out our latest developments at: http://www.ncbi.nlm.nih.gov/CBBresearch/Lu/Demo/MeSHNow/

On 2017 Aug 04, Luis Mauricio T. R. Lima commented:

This is an interesting article showing human amylin and zinc interaction, and the role of His18 in zinc interaction.

We have recently reported that murine amylin can also interact with zinc, and this peptide has no His18, and interaction is mediated by several other contacts, and can result in modulation of the amyloid aggregation process. https://www.ncbi.nlm.nih.gov/pubmed/27693831 http://dx.doi.org/10.1016/j.bpc.2016.09.008

Collectively, these data suggest an universal amyloid behavior of amylin analogues and interaction with zinc, regardless of the presence of proline or His18.

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 NCT0078634. We believe the correct ID, which we have found by hand searching, is NCT00786344.

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 Jan 20, Tom Kindlon commented:

Things are not clear cut in the CFS field yet

I'm afraid I found the analysis in this paper to be somewhat superficial. In particular, it did not explore why positive statements might not predominate for GET and CBT.

Evidence-based medicine should not just be about efficacy measures but also adverse events. The reporting of harms in trials of CBT and GET for CFS has been recognised as being poor (2,3). As one systematic review pointed out: "There is limited evidence about adverse effects associated with behavioural interventions. Withdrawals from treatment in RCTs suggest that there may be an issue but the evidence is often difficult to interpret because of poor reporting."

A published survey of Norwegian ME/CFS patients found that of 620 who reported their experiences of graded exercise, 488 (78.7%) said that it had caused an overall deterioration (1). Surveys of patients in other countries have also found a high rate of adverse events associated with graded exercise regimes (2).

I am not that familiar with the Norwegian health system but in other countries central schemes to collate information on adverse events associated with interventions, such as the yellow card scheme, are not available for nonpharmacological interventions (such as CBT and GET), increasing the importance of survey data.

While some efficacy has been reported for CBT and GET, the measures used have generally been self-reported. Objective results are less impressive. For example, a review of three Dutch CBT studies found that no increase in activity levels, as measured by motion sensors, was recorded (above those in the control groups) despite improvements being reported in fatigue, as well as other subjective measures in the individual studies.

The recently published PACE Trial got a lot of positive media coverage. However, on the only measure that could be described as being an objective measure, the six-minute walking distance (6MWD), there was no difference between the CBT and control groups. The GET group did improve on the 6MWD. However, 379m is not a particularly impressive result at 12 months considering 644m is the distance reference equations would estimate for this cohort.

Anyone familiar with such evidence could justifiably be cautious in statements about CBT and GET.

A common threshold for interventions to be seen as evidence-based is at least two positive (high quality) RCTs. Most posited therapies in the field have not been subjected to two RCTs. Any comments on other therapies, including on the Lightning Process, should certainly be tempered in the meantime.

References:

[1]. Bjorkum T, Wang CE, Waterloo K. [Patients' experience with treatment of chronic fatigue syndrome.] Tidsskr Nor Laegeforen. 2009 Jun 11;129(12):1214-6

[2]. Kindlon T. Reporting of Harms Associated with Graded Exercise Therapy and Cognitive Behavioural Therapy in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Bulletin of the IACFS/ME. 2011;19(2):59-111. http://www.iacfsme.org/BULLETINFALL2011/Fall2011KindlonHarmsPaperABSTRACT/ tabid/501/Default.aspx

[3]. Chambers D, Bagnall AM, Hempel S, Forbes C. Interventions for the treatment, management and rehabilitation of patients with chronic fatigue syndrome/myalgic encephalomyelitis: an updated systematic review. J R Soc Med. 2006;99:506-20. Review.

[4]. 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 Aug;40(8):1281-7.

[5]. White PD, Goldsmith KA, Johnson AL, Potts L, Walwyn R, DeCesare JC, et al. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet. 2011;377:823-36.

Conflict of Interest: I am the Assistant Chairperson and Information Officer of the Irish ME/CFS Association. All my work for the Association is unpaid

On 2014 Sep 13, Vahid Rakhshan commented:

A detailed version of this review and the author's response can be found from this address (LINK).

Results

(1) In the methods, it was stated that ANOVA and Duncan post hoc test had been used to analyze the data. However, in the results, it was Tamhane post hoc test. These two completely differ.

(2) There was not even any mention of the name ANOVA or its P values.

(3) There were numerous pairwise comparisons in this study. However, most of them had not been reported and even many of comparisons that had been reported, lacked P values.

(4) Finally, it is stated that “For further elucidation of the reasons for ion release in the different solutions, the pH values of the 3 mouthwashes and distilled deionized water were measured.”… (A) The pH of mouthwashes should have been reported in the Methods section, not at the end of the Results. (B) A statistical test was needed for this purpose.

Discussion

(5) It is stated (p 732) that “all release is completed within 4 weeks”. The level of ion release reduces after sometime, but does not finish in the said period or even longer.^1,2

(6) This sentence (p 732) should have been stated very cautiously: “Chlorhexidine … caused not significantly higher release of copper than did Persica” A non-significant result is not of internal validity to be stated like something valuable.

(7) I could not understand the next sentence: “Since the pH values for mouthwashes had no significant difference in the acidity of the 3 mouthwashes, this could be attributed to the corrosiveness of chlorhexidine compared with the other 2 mouthwashes”… How did the authors find out that the pH values were not significantly different? This sentence was quite incorrect. Also the rest of the sentence was vague.

(8) I simply did not understand this sentence (after carefully reading the whole paper for some times): “We measured the means of ions released from every bracket in separate vials, but, on the basis of about 20 brackets in a patient’s mouth in clinical use, the results might become clinically significant.” What result might become significant? What are the authors talking about? There was no clue in the previous or later paragraphs.

Conclusion

Overall, conclusions were few and unsubstantiated. (9) The comparisons reported do not substantiate the first sentence of conclusions.

(10) The second sentence is not at all relevant to this study. It was not at all based on the findings or even the scope of this article.

Abstract

(11) Many of comparisons were done at a level of significance adjusted to 0.008. However, in the abstract “P < 0.05” or “P > 0.05” are introduced as indicators of statistical significance or lack of it.

References

1. Amini F, Rakhshan V, Mesgarzadeh N. Effects of long-term fixed orthodontic treatment on salivary nickel and chromium levels: a 1-year prospective cohort study. Biol Trace Elem Res 2012;150:15-20.

2. Amini F, Rakhshan V, Sadeghi P. Effect of fixed orthodontic therapy on urinary nickel levels: a long-term retrospective cohort study. Biol Trace Elem Res 2012;150:31-6.

On 2016 Aug 19, Lydia Maniatis commented:

Please find comments on PubPeer.

On 2014 Jan 08, Brett Snodgrass commented:

Dear Author,

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

http://bit.ly/Thebesius http://bit.ly/JTWearn

I am moved by Dr. Lurie's pleas for the scientific community to produce accurate medical nomenclature, and I ask that others consider his please. http://www.ncbi.nlm.nih.gov/pubmed/18505600 http://www.ncbi.nlm.nih.gov/pubmed/22176755 http://www.ncbi.nlm.nih.gov/pubmed/22704295 http://www.ncbi.nlm.nih.gov/pubmed/23332812

In 2013, it is unfortunate to note that many peer-reviewed articles refer to arterial connections as "veins”. There are several reasons that referring to arteries as veins is potentially harmful.<br> For additional commentary, please see https://twitter.com/BrettSnodgrass1/status/417897291404812288

Comments or suggestions are welcome.

Thank you very much.

On 2016 Sep 06, Morten Oksvold commented:

Please note that part of this study is not reliable due to report of falsified/fabricated data in figure 3C:

"...Respondent falsified and/or fabricated the results in Figure 3C by using the same gel images to represent expression of PLDN in fibroblasts and melanocytes".

A full report has been published by ORI:

http://ori.hhs.gov/content/case-summary-cullinane-andrew-r

On 2014 Feb 14, David Keller commented:

In response to the editorial “Opioids for Chronic Pain”:

1) The authors distinguish between patients with chronic pain, and patients whose painful condition has a “clear end point of cure or death” (e.g. cancer). They propose restricting or denying opioid prescriptions for chronic pain patients. I disagree. If a patient with severe chronic pain might obtain some relief from opioid therapy, it is wrong to deny the patient that choice.

2) The authors argue that opioids only reduced pain scores by approximately 30% in clinical trials. Why not let the patient decide whether a 30% reduction in pain is worth the side effects and risks of opioid therapy? The degree of pain reduction is subjective and varies between individuals.

3) Overdose deaths caused by opioid abuse are tragic, and we need to work harder to prevent them. At the same time, we are obligated to relieve suffering, and if opioids are required, then they should be an option. Doctors need to educate patients on the safe use of opioids, as with other drugs which can cause overdose deaths (e.g. warfarin, insulin). If a patient requires escalating doses of opioids, or if their physician is uncomfortable about their treatment for any reason, they should be referred to a pain specialist.

4) The authors argue that government regulations make it too burdensome for physicians to prescribe strong opioids, which require monthly visits and non-refillable scripts. We should work to reform those regulations, not use them as an excuse to under-treat pain patients.

5) The authors advocate trying NSAID's, anti-depressants, and physical therapy before prescribing opioids. However, some patients are in too much pain to tolerate physical therapy. Depression caused by unrelenting physical pain may not remit until the pain is treated. And NSAID's can worsen hypertension, coronary disease, renal insufficiency, peptic ulcer disease and congestive heart failure. Opioids can often be prescribed safely in these conditions when NSAID's cannot. Adjunctive treatments should supplement opioids which are required for severe pain, with the goal of tapering the opioids as tolerated.

It is true that physicians need to exercise greater care when prescribing strong opioids, but to deny or restrict opioids for chronic pain patients is not humane or sensible.

To facilitate discussion, I respectfully request the person who found this comment "not helpful" to state their reason

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 2013 Nov 04, Jamie Horder commented:

In keeping with these results, van Pelt et al van Pelt S, 2012 reported strong heritability of the peak frequency of visually-induced gamma band oscillations, in a MEG study of 80 healthy twins (20 DZ pairs and 20 MZ pairs).

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 Oct 29, Kenneth Witwer commented:

This paper describes an extremely well controlled study of the respiratory tract microbiome by high throughput sequencing. In addition to the interesting biological findings, the article (along with Charlson ES, 2012) has important technical implications. Nucleic acid contamination is widespread and will confound results if not controlled for carefully, as these authors have so elegantly done. Here, diverse sequences were obtained even from "microbiologically sterile" solutions and medical instruments. Users of sensitive sequencing techniques to investigate foreign sequences should take note.

On 2014 Jan 12, Brett Snodgrass commented:

Dear Authors,

Thank you very much for the excellent publication and acknowledging that the connections between the coronary arteries and left ventricle were not probably not veins.

These connections may represent the vessels of Wearn, which appear unusually prominent.

An applicable ICD9 code might be 746.85, coronary artery anomaly, as it may meet the clinical criteria for the definition of fistulae.

Referring to these arterial connections as Thebesian veins has caused me much confusion when I was trying to understand the simple relationship of pulmonary atresia with intact ventricular septum and the coronary arteriopathy seen in PAIVS. With the growth of social media, and electronic data storage, I think that we may now be able to address the diffuse distribution of ambiguous or misleading nomenclature that fills as least half of related publications.

Dr. Paul Lurie's plea for collaboration in this regard has motivated me to take several steps in an effort to try to help produce accurate, simple, precise anatomic nomenclature and include:

1. I collaborated with Elsevier to help get the article by Wearn et al. changed to open-access. http://bit.ly/JTWearn

2. I obtained the original article (through ArtRieve http://www.artrieve.com/) written by Thebesius and uploaded the first digital copy. http://bit.ly/Thebesius

3. I published or wrote in the American Journal of Cardiology, Cardiovascular Pathology, Twitter, Facebook, Google Plus, and directly E-mailed several authors that were publishing related content.

4. I have posted numerous PubMed Commons comments. I regret that they may not always be helpful to every user, but I echo Dr. Lurie’s plea for collaboration in this regard. The PubMed Commons commentary is a welcome means with significant potential to vastly improve the peer review process.

My aim is that researchers in the future will probably not need to read more than 30 articles before they realize that myocardial sinusoids indeed exist, they were defined by Wearn, and that Thebesian veins are not arteries.

Please see

1. http://bit.ly/JTWearn

2. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1933738/

3. http://bit.ly/vasaThebesii

4. http://bit.ly/ThebesianByPratt

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 2013 Jul 01, Joshua L Cherry commented:

This paper argues that protein evolution proceeds in a particular way: changes to the protein surface occur, and these enable changes to the core. Such a process would be non-time-reversible: fixation of the back-mutation(s) of the core, followed by the thus enabled backward change in the surface, is precluded, or at least less likely. This would be odd long-term behavior in the presence of fixed selective constraints. Furthermore, it is not clear how such irreversibility could be detected by the methods employed. This interpretation of Fig. 4A requires either that our observations start at some special time in the evolutionary process, or that the long-term process is somehow different from the sum of its parts. This is particularly strange-seeming because the longer evolutionary distances correspond to greater distances backward in time from contemporary species to common ancestors.

The phenomenon in Fig. 4A is in fact expected as an artifact of saturation effects. Rapidly changing positions become subject to such effects at shorter overall distances than slowly changing positions. Because surface positions are on average more rapidly evolving than core positions, the form of the nonlinearities in Fig. 4A is expected even in the complete absence of surface-core interactions.

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 NCT006895906. We believe the correct ID, which we have found by hand searching, is NCT00685906.

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 2016 Aug 17, Marco Galardini commented:

This software and server is no longer being actively maintained and supported (even though there might be occasional bugfixes and replies to simple requests). The recommended replacement is Medusa (http://combo.dbe.unifi.it/medusa and http://bioinformatics.oxfordjournals.org/content/31/15/2443)

On 2014 Aug 10, Matthew Katz commented:

CALGB 8433 proved the ability to improve cure rates in non-small cell lung cancer by combining chemotherapy with radiation. As of 2014, platinum-based regimens are still standard. The trend has been toward concurrent chemoradiation based on small increases in survival. But some patients still may benefit from a sequential approach to treatment.