On 2014 Aug 04, Samir Ounzain commented:

Overall a nice piece of work further extending the characterisation and identification of novel murine lncRNAs within the developing and adult heart post injury. However, sadly, a number of important publications predating the submission date of this manuscript were omitted.Specifically within introduction authors state ''Indeed, it is not yet known with certainty which lncRNAs are expressed in mouse hearts, nor have the identities of lncRNAs exhibiting 'cardiac-enriched' expression been defined''.

These points have been addressed in previous publications and I kindly refer the authors of this manuscript and readers here on PubMed to the following important publications which were published prior to this paper being submitted. Sadly the peer review process also missed these

1: Werber M, Wittler L, Timmermann B, Grote P, Herrmann BG. The tissue-specific transcriptomic landscape of the mid-gestational mouse embryo. Development. 2014 Jun;141(11):2325-30. doi: 10.1242/dev.105858. Epub 2014 May 6. PubMed PMID: 24803591.

1: Ounzain S, Micheletti R, Beckmann T, Schroen B, Alexanian M, Pezzuto I, Crippa S, Nemir M, Sarre A, Johnson R, Dauvillier J, Burdet F, Ibberson M, Guigó R, Xenarios I, Heymans S, Pedrazzini T. Genome-wide profiling of the cardiac transcriptome after myocardial infarction identifies novel heart-specific long non-coding RNAs. Eur Heart J. 2014 Apr 30. [Epub ahead of print] PubMed PMID: 24786300.

On 2015 Jun 22, Eileen Daly commented:

Dear Professor Bishop,

Thank you so much for inviting us, through PubMed Commons, to reply to your comments on our Brain paper Response inhibition and serotonin in autism: a functional MRI study using acute tryptophan depletion. Your comments highlighted the differences between our paper and that of Chantiluke et al.’s 2015 paper Inverse fluoxetine effects on inhibitory brain activation in non-comorbid boys with ADHD and with ASD.

From your comments, I sense your main issue is that our baseline data appears to differ from that of Chantiluke. This is of course a very interesting issue.

There were many differences between the two studies that should be taken into account when comparing the findings.

• The sample of Daly et al. was adults (mean age = 31) while that of Chantiluke et al. was pediatric (mean age = 15).

• It is not correct that both studies used a Go/No-Go (GNG) task. The tasks were not the same. The study of Chantiluke compared successful stop with failed stop trials, whereas the study of Daly compared successful No-Go with oddball trials. While both studies controlled for the oddball effect, the task demands are different - the stop task is more challenging and has a lower load on selective attention than the GNG task.

• The location of the right inferior frontal (R IFC) activation. The location of the R IFC underactivation in the study of Daly is in a more rostral and ventral location of ventrolateral prefrontal cortex at a z score between -12 and + 18 comprising BA 47, 10 and 46. It is hence a more ventral and rostral IFC region. In contrast the location of the IFC in the paper of Chantiluke only appears at + 30 to +40 and is in BA 44/9, - i.e. a far more dorsal and somewhat more caudal location. Therefore the two regions are not identical and the findings are consequently not inconsistent. Our most recent and yet unpublished (Lukito S, Carlisi C, Radua J, Simonoff E, Rubia K) meta-analysis of 13 inhibition fMRI datasets in 193 ASD children and adults shows in fact that the more dorsal location of IFC in BA 44/9 at a z-score of + 20 (comparable to IFC location in Chantiluke’s paper) is overactivated in ASD while a more ventral location in BA 47/46 at a z-score of 0 (comparable to the IFC location in Daly’s paper) is underactivated in ASD. The findings of the two papers are also in line with the findings of Kana et al., who found a more ventral location of IFC (BA 45) at + 10 to be underactivated in ASD, which corresponds to the IFC location of the study of our findings in Daly et al.

• It is very difficult to compare the two baseline conditions across studies. First, Chanktiluke’s baseline is a true “placebo” condition, in that an “inactive’’ substance was utilized, as the placebo was peppermint water. In our study, however, the baseline condition is actually a “sham” procedure with a drink containing many “active” (i.e. crosses blood-brain barrier) substances, which were amino acids in our case. Thus, peppermint water has no physiological effect on brain functioning while our amino acid drink includes molecules that will exert a direct effect upon the baseline. This important issue may hence explain why differences in baseline conditions were reported.

However, we would argue that the most consistent explanation for this apparent inconsistency and that is also in line with our recent meta-analysis of fMRI studies of inhibition in ASD is that there are two different IFC regions that are functionally abnormal in ASD during inhibition tasks. A more ventral and rostral region in BA 47/46 that is underactivated and a more ventral and caudal region in BA 44/9 that is overactivated. Serotonin modulation appears to normalize both deviant activations, in that it enhances the underactivated BA 47/46 cluster and it reduces the overactivated BA 44/9 cluster moving both activation patterns towards normality.

Last, we wholehearted agree that the reproducibility in neuroscience and pharmacological intervention studies are critical. We also fully agree that this is an initial proof-of-concept study (albeit one that involved over 60 separate imaging experiments) that requires replication. However, our paper fully acknowledged this issue and used state-of-the art statistical approaches for analysing small samples (e.g. non-parametric statistics). Furthermore, we correct for multiple comparisons using standard methods (e.g. clusterwise for fMRI data and FDR for correlations). We were very pleased to observe that the finding of BA 46/47 underactivation was replicated in our meta-analysis in a much larger sample of 193 ASD patients and are hence confident in the finding.

Again, we thank you for your invitation to reply to your comment and value your input.

Sincerely,

Dr Eileen Daly

On 2015 May 31, Dorothy V M Bishop commented:

I was searching for the original source of a claim about autism by Declan Murphy: "we have found this brain abnormality, and we’ve been able to show we can reverse it" http://alumni.kcl.ac.uk/pioneers-appeal-professor-declan-murphy, and I came across this paper. I'm not sure if it the source of the claims: there is another paper on a closely similar topic with overlapping authors by Chantiluke et al (2015).

I am puzzled, though, by the fact that these two papers seem to have inconsistent findings with regard to ASD, yet do not comment on this or cross-reference one another. Indeed, in the current paper, it is stated that: "to our knowledge, no one has investigated the modulatory effect of serotonin on inhibitory neural activity in individuals with ASD" (p 2601); the Chantiluke et al paper was not published at the time that Daly et al was submitted, but it was submitted two weeks later.

Both papers look at behavioural and brain responses to a Go-NoGo task in individuals with ASD, with a child sample in Chantiluke et al, and adults in Daly et al. Serotonin levels are modified by fluoxetine administration in Chantiluke et al, and by tryptophan depletion in Daly et al. There are some procedural differences in the Go-NoGo task, but my impression is that these were not so great that one would expect to see a major effect on results. Yet quite apart from any impact of serotonin manipulations, the studies find different results in the placebo conditions. Daly et al find that "after sham, subjects with autism relative to control subjects, showed reduced activation in right inferior frontal cortex". In contrast, Chantiluke et al reported "Under placebo, relative to controls, ASD boys showed overactivation in left and right inferior frontal cortex (IFC)." (p. 2071).

In the introduction to these papers, both cite prior work on inferior frontal cortex (IFC) and inhibition in autism. In particular, they make predictions based on another study by this group, by Schmitz et al, which also used fMRI to compare ASD and control groups during a Go-NoGo task. Schmitz et al reported significant increase in left middle/inferior (Brodmann area 10/46) and orbitofrontal gyrus during correct inhibition of NoGo trials, and no significant areas of decreased activation (p 11-12). Yet, Daly et al hypothesise that in the placebo conditions "subjects with ASD compared to controls would show decreased activation in right inferior frontal and increased activation in left inferior frontal cortices".

The importance of reproducibility of research findings in neuroscience is receiving increased attention (Pernet & Poline, 2015), with growing recognition that there is a major problem for neuroimaging studies with small samples (Button et al., 2013), especially when, as in this case, multiway Anovas and correlations are computed without correction for multiple comparisons. Pharmacological interventions that 'normalise' brain abnormalities are potentially of huge interest, but they are unlikely to reflect more than error of measurement and regression to the mean if baseline differences are not reproducible.

It may be that there is some simple explanation for these inconsistencies; it would be good to hear the authors' views on this.

References Button, K. S., Ioannidis, J. P. A., Mokrysz, C., Nosek, B. A., Flint, J., Robinson, E. S. J., & Munafo, M. R. (2013). Power failure: why small sample size undermines the reliability of neuroscience. Nature Reviews Neuroscience, 14, 365-376. doi: 10.1038/nrn3475

Chantiluke, K., Barrett, N., Giampietro, V., Santosh, P., Brammer, M., Simmons, A., Murphy, D., & Rubia, K. (2015). Inverse fluoxetine effects on inhibitory brain activation in non-comorbid boys with ADHD and with ASD. Psychopharmacology, 232(12), 2071-2082.

Pernet, C., & Poline, J.-B. (2015). Improving functional magnetic resonance imaging reproducibility. GigaScience, 4(15). doi: 10.1186/s13742-015-0055-8

Schmitz, N., Rubia, K., Daly, E., Smith, A., Williams, S., & Murphy, D. G. M. (2006). Neural Correlates of Executive Function in Autistic Spectrum Disorders. Biological Psychiatry, 59(1), 7-16

On 2014 Aug 13, Amanda Capes-Davis commented:

Zhao et al published a paper in 2011 (PMID 21868764) to show that ARO is not an appropriate model for anaplastic thyroid carcinoma. ARO is a misidentified cell line, meaning that it does not come from the original donor. ARO is actually HT-29, a colon carcinoma cell line. For a list of known misidentified cell lines, see http://iclac.org/databases/cross-contaminations/.

On 2014 Oct 08, David Keller commented:

Screening the Pap smear plus HPV status in parallel improves overall sensitivity

Dr. Feldman's recommendation to continue screening with the Pap test makes sense; the Pap smear directly detects malignancy and worrisome pre-cancerous cellular changes. High-risk HPV is an infection which can cause cervical cancer, but testing for HPV does not provide direct evidence of the presence or absence of cervical cancer and its precursor lesions. Women die of cervical cancer, they do not die from HPV infection. The HPV test and the Pap test provide complementary information, there is unique information learned from each test when they are both performed, and screening sensitivity is enhanced when 2 such tests are performed in parallel (1). Screening women for cervical cancer without any examination of cervical cytology does not seem prudent at this time.

Reference

1: Fletcher RH, Fletcher SW. Clinical Epidemiology: The Essentials Lippincott Williams & Wilkins, 2005: 4th ed

On 2014 Nov 06, Hugues Lefort commented:

I would ligke to know if it is possible to modify the last name of an autor in a publication such this one. The first author is "Lefort H". It's seem that Elsevier has send three times an email to pubmed, so did I... and no modification yet. Thank you for your lights.

On 2014 Nov 24, Guillaume Filion commented:

This article is one of the "CISCOM meta-analyses", which are very similar papers written by different authors. For more information about the CISCOM meta-analyses, check the blog post "A flurry of copycast on PubMed" at the following link http://blog.thegrandlocus.com/2014/10/a-flurry-of-copycats-on-pubmed

On 2014 Nov 17, Raphael Levy commented:

Comments by Philip Moriarty (Nottingham, UK) and Quanmin Guo (Birmingham, UK) are available at PubPeer. They raise questions on the interpretation of the images shown by Ong et al.

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

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

On 2014 Aug 09, Seyed Moayed Alavian commented:

Occult HCV infection is a new entity and we need to more studies for better clarification the issue

Hepatitis C is an important etiology for chronic liver disease and it is the most common cause in chronic renal failure patients. Recently, occult HCV infection has described with the absence of HCV-RNA and anti-HCV antibodies in serum in the presence of genomic HCV-RNA in the liver biopsy specimen, in patients who suffer from cryptogenic liver diseases. Furthermore, about 70% of patients with occult HCV infection also have HCVRNA in their peripheral blood mononuclear cells (PBMCs); the genomic and the antigenomic HCVRNA have also been detected in these cells. The detection of antigenomic HCV-RNA strand in PBMCs of subjects with occult HCV infection can be supported the hypothesis that HCV is able to replicate in these cells. Patients on hemodialysis are at higher risk for HCV infection and HCV infection has a bad impact on survival of patients after renal transplantation. The anti-HCV antibody can be negative in these patients and in sometimes we have some cases that are negative for HCV infection before renal transplantation and after it, the HCV infection appears and may be some cases had occult HCV infection and after using the immunosuppressive drugs HCV will appear. I suggest to be more sensitive regarding the occult HCV infection in hemodialysis patients. Ref: Bokharaei-Salim F, Keyvani H, Monavari SH, Alavian SM, Madjd Z, Toosi MN, et al. Occult hepatitis C virus infection in Iranian patients with cryptogenic liver disease. J Med Virol. 2011;83(6):989-95

On 2014 Aug 05, Sergio Uribe commented:

For anyone interested, here is the 1st clinical report about approximal therapeutic sealants (in spanish): http://j.mp/1QwmeAd

On 2014 Aug 12, Karim Asehnoune commented:

In the CRASH trial, mild to severe TBI patients (GCS<14) were included, and a short course of high-dose methlyprednisolone was used. In the CORTI-TC study, only severe TBI patients (GCS<8 and abnormalities on brain CT-scan) were included, and low dose of steroids (hydrocortisone)+fludrocortisone were used. When comparing these 2 studies, one could say: the population is different, the drugs used are different, the outcomes are different. One book is closed, the other one remains open.

On 2014 Aug 10, Ryan Radecki commented:

Post-publication commentary:

"A Moratorium on Steroids for TBI"

In 2004 the CRASH trial examining the efficacy of steroids for acute traumatic brain injury (TBI) was published in The Lancet. This massive trial included over 10,000 patients was stopped prematurely because of an increased mortality in the patients who received corticosteroids. This should have definitively closed the book on such a therapy. Despite this damning evidence, it appears all one has to do to make this question relevant again is to devise a disease-oriented endpoint with plausible clinical relevance and test it using a sample size too small to differentiate these harms from the surrounding noise of statistical chance.

http://www.emlitofnote.com/2014/08/a-moratorium-on-steroids-for-tbi.html

On 2015 Dec 11, Deborah Ritter commented:

It is ZNF444, not ZNF44. Throughout the article, they use ZNF444 and the referenced article uses ZNF444. I contacted to publisher to report the mistake and was told they cannot change it.

Dear Dr Ritter,

Thank you for your email.

We can no longer correct the article because it is already published in an issue.

Regards,

Production Editor On behalf of Wiley Manila

From: cs-author@wiley.com Sent: Thursday, December 03, 2015 10:33 AM To: Subject: URGENT --- correct ZNF44 in abstract to ZNF444 Your case 00636351 [ ref:00Dd0eeku.500d0f4DMy:ref ]

Dear Deb,

Histopathology - Vol 65, Iss 6, Dec 2014 "Myoepithelioma of bone with a novel FUS-POU5F1 fusion gene" DOI: 10.1111/his.12517

Thank you for your recent communication regarding a correction to the above article.

We understand your concern, hence, we have copied the journal's Production Editor into this email, as they are in the best position to assist you further. They will be contacting you shortly. Your patience in the meantime is much appreciated.

Arjane, we would greatly appreciate if you could please assist with the customer's inquiry regarding a typographical error as detailed in their email below. They are asking if this can possibly be corrected. Please respond to the customer directly at dritter@bcm.edu.

Kind regards,

Wiley Author Support

If you require further assistance with this matter or would like information on any of our other journals please visit Online Get Help to assist with many of your queries 24 hours a day, 7 days a week.

--------------- Original Message --------------- From: Sent: 12/2/2015 8:40 AM To: cs-journals@wiley.com Subject: correct ZNF44 in abstract to ZNF444 {500d000000f4DMyAAM.003d000002imvxXAAQ}

Hi,

I recently found an article from Genes Chromosomes Cancer on myoepithelioma of bone, and I was interested in ZNF44 gene, which is mentioned in the abstract. However, throughout the rest of the article (and in the referenced article about fusion with EWSR1) the gene is ZNF444. It looks like there is a typo in the abstract for ZNF44 instead of ZNF444, and I just wanted to send a quick note about it to be corrected if possible.

http://www.ncbi.nlm.nih.gov/pubmed/25066216

Thank you,

Deb

On 2016 Jun 24, Lily Chu commented:

The limitation with this study is that symptoms were only recorded within a 24-hour period. Many patients with ME/CFS suffer from post-exertional malaise. Post-exertional malaise can start after 24 hours have passed and can endure for longer than 24-hours. Patients are often able to perform activities once or for a short period but the difficulty is when they have to repeat it again the same day or over the next few days. Repeated cardiopulmonary testing shows drops in cardiometabolic parameters not during a first exercise test but during a repeated test the next day. One study, for example,

https://translational-medicine.biomedcentral.com/articles/10.1186/1479-5876-12-20

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4004422/

Similarly, see this study which follows symptoms for more than 24 hours.

http://www.ncbi.nlm.nih.gov/pubmed/20095909

Finally, clinicians should be careful about prescribing aerobic exercise. On average about 50% of patients report worsening of their health if exercise is prescribed without careful consideration of symptoms that flare up. http://www.ncf-net.org/library/Reporting of Harms.pdf

On 2016 Dec 30, Arturo Martí-Carvajal commented:

I would like to ask the following: How should figure 4 be understood? That funnel plot only has 6 trials.

On 2014 Nov 03, Christopher Southan commented:

Note that protein targets and ligands from the PDF or the HTML (on the Willey site http://onlinelibrary.wiley.com/doi/10.1111/bph.12848/full) are hyperlinked to http://www.guidetopharmacology.org

On 2014 Oct 14, Anders von Heijne commented:

The authors quite correctly identify that making prior imaging available to the current institution and formally summarizing their findings as one of the greatest opportunity to provide value to the health care system in order to avoid unnecessary repeat examinations. When patients are transferred between providers the referring physician commonly summarizes the case and its course in discharge notes. In radiology, however, the chore of collecting and compiling the performed radiology is usually done at the receiving hospital. It stands to reason that if the equivalent of radiological discharge notes instead are created at the department performing the examinations, the quality of the summaries must be improved, as well as the content of the transferred information, to the benefit of both clinicians and radiologists at the receiving hospital.

On 2014 Aug 10, Ryan Radecki commented:

Post-publication commentary:

"Get to the Choppa! Or ... Maybe Not?"

Helicopter transport is entrenched in our systematic management of trauma. It is glamorized on television, and retrospective National Trauma Data Bank studies seem to suggest survival improvement – and those with head injury seem to benefit most.

But, these NTDB studies encompass heterogenous populations and are challenged in creating truly equivalent control groups. This study, on the other hand, is a single-center experience, allowing greater consistency across divided cohorts. In a novel approach, these authors collected all HEMS trauma transfer requests to their facility across their 30-county catchement area – and specifically looked at occasions when weather precluded HEMS. This therefore created two cohorts of patients eligible for HEMS, with a subset that was transported by ALS due to chance events. The paramedic crews manning the HEMS and ALS transfers were staffed by the same company, and therefore had roughly equivalent training....

http://www.emlitofnote.com/2014/08/get-to-choppa-or-maybe-not.html

On 2015 Aug 17, Phyllis Mervine commented:

Why does PubMed include this 2004 review at the top of the list among studies published in 2014-15?

On 2015 Aug 17, Phyllis Mervine commented:

Why does PubMed include this 2003 review at the top of the list among studies published in 2014-15?

On 2015 Aug 07, Serge R Mordon commented:

Dr Liu and the co-authors of this article must be congratulated for this very interesting and important clinical study.

On 2014 Jul 30, Jim Woodgett commented:

The GSK-3beta inhibitor used here, SB216763, is equipotent towards GSK-3alpha, a highly related isoform that plays equivalent roles to GSK-3beta in regulation of Wnt (and other) responses.

On 2015 Jun 18, Elsamma Chacko commented:

This is about very intense pre-meal exercise is not good for glucose control; There can be post exertion glucose elevation.

On 2014 Jul 25, Ryan Radecki commented:

Post-publication commentary:

"The Scandal of Dabigatran – A Summary"

We’ve been desperate for a more elegant solution to anticoagulation than rat poison for seemingly an eternity. Now, we have them: direct thrombin and factor Xa inhibitors. The studies supporting their use seem favorable.

But, as the old story goes – and as previously reported on this blog many times – Boehringer Ingelheim has been selectively reporting only the most favorable aspects of their flagship drug, dabigatran. Increased cardiovascular events have been downplayed through study design not powered to detect a difference. Issues with fixed dose therapy – and lack of a range of options for patients with renal impairment – rear their ugly head in multiple case reports....

http://www.emlitofnote.com/2014/07/the-scandal-of-dabigatran-summary.html

On 2014 Oct 04, Quentin Hill commented:

In the section on guidelines, the authors have stated that the current British Committee for Standards in Haematology guidelines Davies JM, 2011 recommend lifelong penicillin prophylaxis for all persons with surgical asplenia. Although this was true in previous guidelines Working Party of the British Committee for Standards in Haematology Clinical Haematology Task Force., 1996, Davies et al recommend a risk adapted approach to antibiotic prophylaxis. They recommend antibiotic prophylaxis "at least" in the immediate post-operative period following splenectomy for trauma. Otherwise, long term prophylaxis is recommended for those considered to be high risk of pneumococcal infection: age <16 years or >50 years, inadequate serological response to pneumococcal vaccination, previous invasive pneumococcal disease and splenectomy for underlying haematological malignancy.

Additionally, the authors do not discuss the meningitis serogroup B vaccine (MenB). A MenB vaccine was licensed by the European Medicines Agency in January 2013. Although not yet FDA licensed, it has been used to control several outbreaks in the United States http://www.cdc.gov/meningococcal/outbreaks/vaccine-serogroupb.html. In England, over 80% of Neisseria meningitidis cases are due to capsular group B strains and it has been recommended in England for children and adults with asplenia, splenic dysfunction and complement disorders https://www.gov.uk/government/collections/immunisation-against-infectious-disease-the-green-book.

On 2014 Jul 31, Amanda Capes-Davis commented:

Please be aware when choosing cell line models that some are misidentified and do not correspond to the expected tissue or disease. The KB cell line is one example of a misidentified cell line. It is cross-contaminated with HeLa and is actually cervical adenocarcinoma, not oral squamous cell carcinoma. For a list of known misidentified cell lines, see http://iclac.org/databases/cross-contaminations/.

On 2015 Apr 14, RheumJC - Rheumatology Twitter-Based Journal Club commented:

This article was discussed on March 3rd, 2015 by participants of #RheumJC, an international Twitter-based Rheumatology Journal Club. An engaging discussion on the science of the topic as well as the methodology of the study was had over 2 different one hour live "chats" as well as a full 24hr of asynchronous participation. Included in the second live session was the participation of the study lead author, Dr. Miloslavsky (@emilosla). Overall (combined sessions and time between and after) there were 46 total participants from 17 different countries. For the full 24 hours, there were 518 total tweets – 387 unique tweets and 117 RTs

A slide-show summary of the sessions was compiled by Lois Wingerson (@RheumatologyNet) and can be seen at http://www.rheumatologynetwork.com/vasculitis/rheumatology-journal-club-2-rituximab-aav-relapse

We would like to thank Wiley and A&R for making this manuscript open access leading up to this journal club.

Interested individuals can track and join in future journal clubs by following @RheumJC or #RheumJC, or visit the webpage at http://www.rheumjc.com and sign up for announcements.

On 2014 Dec 02, Ross Mounce commented:

If you're not blind or visually-impaired you can read the full-text of this article here: http://www.readcube.com/articles/10.1038/nature13486?shared_access_token=GH9dxN6_GINpp00ym9QgKtRgN0jAjWel9jnR3ZoTv0NJL5Ba9SPYgfBBM3JISgmQbOFfLVcenfRgy6F0G2tPq9nBuN11D1sSl53wYJfmrZ0HEH_S-gneWSynRkUGS6OikZSpC7jsfYG96cJiO43y7lxkIJbPGJgnNSDiF9u9A6CJfe5z9kjiOxxl7NjTqzfylw2CJ21w2YearebvIunnIuXNdBMreS2kWGjfLZj9dDo=

On 2014 Dec 02, Ross Mounce commented:

If you're not blind or visually-impaired you can read the full-text of this article here: http://www.readcube.com/articles/10.1038/nature13577?shared_access_token=0hsoe2K_j4JC7fkDgoB-etRgN0jAjWel9jnR3ZoTv0M17NVrl8gamM_mUsXL3BNMorSZLyFIXX3MGNarjp3Fl6k60DXrPWQFDZur_WvG8JEBKrvoO9rSi9uXNXmqpkDqQ3GWvjs8EkjQK-CPuv2l_6H0v0zM8vbpSBFGhXKo2Hw5bio1Q7iN0_FaxDPW_bned2u45EoZpGiIa-nZqlLhTw0JAZ2WCQKjf65dMqklVfk=

On 2014 Dec 02, Ross Mounce commented:

If you're not blind or visually-impaired you can read the full-text of this article here: http://www.readcube.com/articles/10.1038/nature13490?shared_access_token=ep_eOGZIHxbfO_8iU4iHNdRgN0jAjWel9jnR3ZoTv0PuT8rMiA03ZJrz7RKsB-for30Ie0i5VesbJmO6Kg58Quugicv4BZg9tEFe9URJsN3p4ZnL0A8j6Qu40Dc11_P9YUrafzKrcAmc0054LIedZ0KXg2AyjLzHf3M-xMd2a73IGf9Fq_AMcvYVEkoCbzr2YNBmwBirHdSRluaNW2h8NMVe4T1qdTKd3SQw3hcQ1SE=

On 2014 Aug 22, Attila Csordas commented:

3 associated proteomics datasets are available via PRIDE/ProteomeXchange with identifiers PXD000692, PXD000693 and PXD000956:

http://www.ebi.ac.uk/pride/archive/projects/PXD000692 http://www.ebi.ac.uk/pride/archive/projects/PXD000693 http://www.ebi.ac.uk/pride/archive/projects/PXD000956

On 2014 Dec 02, Ross Mounce commented:

If you're not blind or visually-impaired you can read the full-text of this article here: http://www.readcube.com/articles/10.1038/nature13495?shared_access_token=Df0ohGBobOoGWMJqyk8ZhNRgN0jAjWel9jnR3ZoTv0Pa5-Z-FelOCUQDAHmluI4E4S7gSEYpUVROjNUI40rhFVdZa7GUyjQiyr4bjWaGowObAQREYa22FeJiPylgxCSF06-Iz3sOgAH4h_qlLyl1cbMQG1CU-hh5PfqCxGZ7jJNlI9gIbWG1WkZaLgQEG-ro6-gtHnBpr25glbMqlnRqY0FgnDQgfxEmiDH8qFIkHXM=

On 2016 Mar 04, Andrea Margulis commented:

Diabetes progression and the consequent need for intensification of treatment occur in stages over time, with feedback loops and several influences including those from diabetes complications, comorbid conditions, and concomitant medications. The resulting web of prognosis, prescription, and disease progression over time creates methodological challenges for research on the effect of diabetes treatments [1,2]. Patients under different diabetes therapies may have very different baseline characteristics that may be only partially amenable to standard observational research techniques for confounding control. As patients pass through different stages of diabetes, treatment escalates or changes, and these updated therapeutic schemes may become indicators for a more severe stage of diabetes with a more guarded prognosis. In addition, each medication carries its own risks. In this situation, it becomes unclear how to validly assess exposure to earlier medications such as metformin, since continuing follow-up under a new therapeutic scheme mixes exposure effects and disease progression together, while stopping follow-up to isolate exposure to earlier therapeutics may create a bias similar to the differential loss to follow-up than can affect randomised controlled trials (informative censoring).

Challenges increase in the context of a comparison between treated diabetic patients and non-diabetic patients, as Bannister and colleagues [3] did with regard to the assessment of all-cause mortality. The authors report a 15% survival benefit in patients with diabetes on metformin monotherapy relative to patients without diabetes who were not on metformin, even though patients with diabetes were sicker at baseline. Results were consistent across subgroups, and a similar benefit was not observed for sulfonylurea treatment. This study addresses an important question, as previous research on metformin has produced promising findings, such as the ability to prolong lifespan and improve healthful aging in mice [4].

Although the results from Bannister et al. [3] are intriguing, we wonder whether study design features might have created a cohort of patients with diabetes that selectively retained healthier individuals, while the same was not true for the cohort without diabetes to which they were compared. To identify the effect of metformin or sulfonylurea monotherapy, follow-up of treated patients with diabetes was censored after any modification to the initial treatment. Thus, as patients with diabetes progressed to the point they needed treatment intensification, they left the cohort. In contrast, the patients without diabetes would not have the chance to be excluded from the cohort in a similar manner with any progression from a starting point of good health. This censoring is tied to the mortality outcome since if a patient with diabetes dies, the matched comparator patient cannot leave the cohort until he or she dies. On the other hand, if the comparator without diabetes dies first, the matched patient with diabetes can still leave the cohort upon treatment modification. This creates a different opportunity for mortality to be observed in the two cohorts.

Furthermore, the requirement of patients with diabetes to stay on glucose-lowering therapy for 180 days to be eligible (while comparators without diabetes are only required to survive for the 180 days) may have created an additional opportunity to selectively retain healthier individuals, i.e., adherent patients. Good adherence by itself has been shown to reduce mortality [5]. In subgroup analyses where patients with and without diabetes received cardiovascular prophylaxis (making them more similar in terms of adherence) the survival benefit decreases or disappears.

While the authors have posed an interesting and relevant research question, it is accompanied by many difficulties from a methodological perspective. It may be worth considering an alternative comparison cohort comprised of non-diabetic persons with treatment for some other chronic condition, for which an analogous run-in period and censoring upon treatment intensification could be applied. Such an approach would enhance comparability of the cohorts at baseline and provide similar opportunity for follow-up to stop when patients in either cohort change treatment; all of which would mitigate the healthy adherer effect in the comparison group. The validity of this approach would depend on the possibility for both arms to follow similar patterns of treatment modification in relation to the risk of death. This proposed alternative approach has the drawback of answering a somewhat different research question, but one that may be more amenable to observational investigation.

Andrea V Margulis, MD, ScD ¹

Manel Pladevall, MD, PhD ¹

Nuria Riera-Guardia, PhD ¹

John Seeger, PharmD, DrPH ² ³

Elisabetta Patorno MD, DrPH ²

Cristina Varas-Lorenzo, MD, PhD ¹

¹ RTI Health Solutions

² Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham & Women’s Hospital/Harvard Medical School

³ Optum Epidemiology

REFERENCES

1 Patorno E, Patrick AR, Garry EM, et al. Observational studies of the association between glucose-lowering medications and cardiovascular outcomes: addressing methodological limitations. Diabetologia. 2014 Nov;57(11):2237-50.

2 Suissa S, Azoulay L. Metformin and the risk of cancer: time-related biases in observational studies. Diabetes Care. 2012 Dec;35(12):2665-73.

3 Bannister CA, Holden SE, Jenkins-Jones S, et al. Can people with type 2 diabetes live longer than those without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non-diabetic controls. Diabetes Obes Metab. 2014 Nov;16(11):1165-73.

4 Martin-Montalvo A, Mercken EM, Mitchell SJ, et al. Metformin improves healthspan and lifespan in mice. Nat Commun. 2013;4:2192.

5 Granger BB, Swedberg K, Ekman I, et al. Adherence to candesartan and placebo and outcomes in chronic heart failure in the CHARM programme: double-blind, randomised, controlled clinical trial. Lancet. 2005 Dec 10;366(9502):2005-11.

On 2014 Aug 16, M P M Hensgens commented:

Dear Peter English, It is indeed correct that we did not study the cost effectiveness of increased testing for C. difficile. In this manuscript we showed that C. difficile occurs in a fair amount in general practitioners practice, although many still consider the disease as nosocomial. Now that we know that the bacterium occurs in this setting, a study concerning the cost effectiveness is an aim for future reseach. Thank you for your interest and kind regards, Marjolein Hensgens

On 2014 Aug 15, Peter English commented:

I didn't spot anything about the costs and benefits of dramatically increasing the amount of testing that this paper is recommending.

If you do a lot more tests for C diff infection, the costs to laboratories and health systems of doing the tests and acting on the results will be considerable. Most health systems have limited resources: money spent on this will have to be taken from something else. That might be worth while; but to be sure, we have to know if the value of doing this (in terms of e.g. reduced years of life lost, QALYs, reduced costs of treatment, reduced sickness/carers' absenteeism and resulting lost revenues etc.) are sufficient to justify the additional costs.

Perhaps I missed this in the paper; but I don't think this was done.

On 2014 Jul 24, Ryan Radecki commented:

"You Can Use Absorbable Sutures Anywhere"

Although, can and should are entirely different interpretations of these data.

There have been many studies showing facial lacerations can be repaired with absorbable sutures with similar cosmetic and adverse outcomes compared with non-absorable sutures. The same principles, presumably, hold for the trunk and extremities – although, there are significant differences in blood supply and healing time....

http://www.emlitofnote.com/2014/07/you-can-use-absorbable-sutures-anywhere.html

On 2015 Jun 04, Christina Niederstadt commented:

The authors tell us their “data on overall survival appeared interesting” - especially concerning "Overall survival from date of diagnosis of metastatic disease". They fail, however, to say anything about possible influences of "later Treatment for Metastases" on overall survival.<br> The only two patients who were, apparently, still alive at the end of the trial did receive either two times surgery (patient I-C14) or treatment with a protein kinase C inhibitor (patient VIII-A4).

The sustained survival of those two patients could well be attributable to the method of "later Treatment for Metastases" - as might be the case with part or all of the other patients, too.

On 2014 Aug 05, Attila Csordas commented:

associated dataset available via PRIDE/ProteomeXchange: http://www.ebi.ac.uk/pride/archive/projects/PXD001185

On 2014 Aug 05, Peter English commented:

Given the apparent success of vaccination of pregnant women at 29+ weeks gestation, is there any point in trying to achieve something as difficult as coccooning? It's next to impossible to do, systematically. Is there evidence that it is significantly more effective than vaccination of pregnant women?

On 2016 Dec 16, Laura Williams commented:

Our online journal club discussed this paper on March 19, 2015. https://www.youtube.com/watch?v=fiMyf48vkp8

On 2017 Mar 16, KEVIN BLACK commented:

This report gives some useful information but I interpret the results quite differently. The authors start with the assumption that the trough level is what one wants. I disagree. What one wants is to be able to compare a patient's lithium dosing to the large body of published knowledge about lithium treatment. Almost all of that data comes from standard 12-hour blood draws with plain (immediate-release) lithium carbonate or citrate. So the real question of interest is, with extended-release lithium formulations, at what time point do I draw the lithium level to compare most accurately with a standard 12-hour blood draw with plain lithium carbonate? The answer is not obvious because extended-release formulations affect only the absorption and not the excretion of lithium. Their primary benefit is reducing the transient peak lithium serum concentration, not delaying the (already relatively slow) elimination of lithium.

Emami J, 2004 provide the needed data. They show, first, that 90% of the administered dose of a commercial extended-release formulation (Eskalith CR®) is absorbed by 4 hours after a dose, and ~100% is absorbed by 8 hours (Fig. 2A). Second, they show that at 12 hours after a dose, the blood levels for immediate and extended release formulations are essentially identical (Fig. 3). Thus 12 hours after the last dose is the ideal time for drawing blood levels for extended-release lithium tablets.

On 2014 Sep 23, Samir Ounzain commented:

The potential for lncRNAs to serve as biomarkers in cardiovascular disease is very exciting and warrants further investigation. In an editorial associated with this interesting study from Vausort et al, Skroblin and Mayr raise a couple of very interesting points that need further investigation and discussion.

They state ''All selected lncRNAs have been identified in noncardiac tissues. This lack of cardiac specificity questions their usefulness as predictors of cardiac dysfunction. At best, measuring lncRNA expression in full blood might reflect inflammation at the site of MI''.

We agree strongly with this statement and would like to emphasise that cardiac specific/restricted lncRNAs likely represent the most important candidates both as biomarkers but also as highly specific therapeutic targets for future manipulation. Indeed, we recently demonstrated that through utilising very deep RNA-sequencing coupled with ab initio transcript reconstructions it is possible to identify 1000s of novel heart specific lncRNAs. Importantly we feel sequencing to a high depth, in a very specific context (we sequenced to a depth of 400x106 PE-reads per sample in isolated border zones post myocardial infarction, as compared to 50x106 PE-reads used in most comparable studies)is critical for the idenfication of highly cell/tissue and context specific lncRNAs, that ultimately we believe will represent the most attractive biomarkers and therapeutic targets.

It is worth noting that when utilising this approach, we found that novel previously unknown lncRNAs were both a) much more cardiac specific than mRNAs and annotated lncRNAs (indeed many exhibit cell type specificity within the heart, b) were better correlated with cardiac physiological traits vs cannonical biomarker mRNAs and annotated lncRNAs, supporting the notion novel heart enriched lncRNAs could represent very attractive biomarkers, c) were highly associated with unique heart specific chromatin signatures linked to active -cis control enhancers, again has implications in therapeutic settings as enhancer reprogramming post stress underpins the fetal activation of gene program that is implicated in pathological remodelling and finally d) using a novel approach to infer lncRNA functions based on developmental chromatin state transitions, we found that novel lncRNAs were highly enriched in functional clusters linked to very specific cardiac functional processes including contractility etc.

Many of the novel lncRNAs we identified in this study were conserved in human, and we hope future studies will leverage our data for the identificaiton of novel heart specific biomarkers that may be circulating in the blood. The excellent cohort described here and assesed by the Devaux group could represent a great starting point to asses these heart specific lncRNAs. Most studies to date have only assesed the annotated long non-coding transcriptome in this setting, and we believe our paper demonstrates that novel cardiac enriched lncRNAs are likely much more interesting candidates for analysis.

For those interesting in these novel heart specific lncRNAs, and their potential utility as a biomarker, please refer to..

Ounzain S, Micheletti R, Beckmann T, Schroen B, Alexanian M, Pezzuto I, Crippa S, Nemir M, Sarre A, Johnson R, Dauvillier J, Burdet F, Ibberson M, Guigó R, Xenarios I, Heymans S, Pedrazzini T. Genome-wide profiling of the cardiac transcriptome after myocardial infarction identifies novel heart-specific long non-coding RNAs. Eur Heart J. 2014 Apr 30. [Epub ahead of print] PubMed PMID: 24786300.

On 2015 Apr 29, Andrew Brown commented:

Our letter discussing concerns about the conclusions of this article can be found here Bohan Brown MM, 2015, and the authors' responses here Kiecolt-Glaser JK, 2015.

On 2014 Sep 27, David Keller commented:

Pembrolizumab first-line for metastatic melanoma & preexisting autoimmune disease?

Patients with preexisting autoimmune diseases were excluded from the landmark trials of ipilimumab and pembrolizumab, which therefore cannot provide high-quality safety data for these patients. The grade 4 (life-threatening) and grade 5 (fatal) adverse events for both medications were primarily autoimmune in nature, in trial patients with no history of autoimmune disease. Pembrolizumab appears to have a somewhat lower rate of severe-to-fatal adverse events than ipilimumab, although no head-to-head comparison is available.

Pembrolizumab was recently approved by the FDA for treating metastatic melanoma patients who have disease progression following ipilimumab. Medicare and private insurers are quite strict about not paying for off-label use of pembrolizumab, even for patients with active autoimmune disease. I have personally corresponded with two authors of this paper who advocate first-line treatment using pembrolizumab in selected clinical scenarios, for enhanced patient safety. Although there is controversy on this question in the immuno-oncology community, it seems reasonable to let treating oncologists decide when pembrolizumab should be used first-line and off-label for selected high-risk patients, pending their inclusion in randomized trials. As matters now stand, the wealthy who can pay cash for pembrolizumab effectively have access to a treatment option not available to less-wealthy melanoma patients. The FDA should reconsider their narrow prescribing indication for pembrolizumab, the adverse effects this may have on melanoma patients with preexisting autoimmune diseases, and the disparity caused by expensive off-label treatment options which are available only to patients who can pay the very large cash price in advance.

On 2014 Dec 18, CREBP Journal Club commented:

The new plain language summary (PLS) evaluated was substantially revised from the current one in the Cochrane systematic review, although it maintained the narrative format. We would have preferred a three-arm RCT (new PLS format vs. revised current PLS vs. current PLS). The group discussed what proportion of correct responses is realistic for the public (or indeed health professionals) to attain? Also, how might people or health professionals be taught to assist their understanding of this format? More respondents exposed to the new PLS format strongly disagreed with the statement “The information is reliable" (Figure 4, pg. 8) and poses the question whether improving understanding of the quality of evidence paradoxically introduces a level of uncertainty. We also wondered whether the wording of questions may have introduced bias – for example, the question on the comprehension of the purpose of the summary (ie. “This summary is about the results of a large study”; Yes/No/I’m not sure) might be correctly interpreted as a single study or a systematic review and meta-analysis. The evaluation of ‘creative language’ used in standardised qualitative statements about treatment effects might also introduce bias. Despite carefully defining standardised qualitative statements in relation to distinct levels of evidence (eg. ‘will’=high level of evidence; ‘probably’=moderate level of evidence) they were combined on one occasion which was counter-intuitive (eg. “Probably will not decrease how long a cold lasts…”). See CREBP Journal Club Page for more

On 2014 Dec 10, Kath Wright commented:

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

On 2014 Jul 30, Jung Weon Lee commented:

The coauthor Kim S should be affiliated with "5 Therapeutic Antibody Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejon, Republic of Korea", rather than "Department of Biological Sciences, Kangwon National University".

On 2014 Jul 31, Amanda Capes-Davis commented:

Thank you for your reply. Yes, it is important to use a range of cell line models. It is also important to spread the word that Chang cells are not an appropriate model for liver. Authentication testing using a method such as short tandem repeat (STR) profiling will help to confirm that cell lines used in experimental work are not misidentified.

On 2014 Jul 30, Jung Weon Lee commented:

In this study, many different liver cells in addition to HCC827 (NSCLC) and Chang cells were used in parallel.

On 2014 Jul 29, Amanda Capes-Davis commented:

Although they carry the name "Chang liver", these cells are not from normal liver. The Chang liver cell line is cross-contaminated with HeLa and is actually cervical adenocarcinoma. For a list of known cross-contaminated cell lines, see http://iclac.org/databases/cross-contaminations/.

On 2014 Aug 01, Torsten Seemann commented:

I found the software at https://code.google.com/p/axxa76/wiki/SFannotation

On 2014 Jul 20, Annie De Groot MD commented:

By the way there is already concern that H7N9 is immmune-modulating on its own. Would immune-modulating drugs help, or hinder protection against severe disease?

On 2014 Jul 21, Thomas Crouzier commented:

Very interesting to learn that lubricin has such an effect.

In a recent study (Crouzier T, 2013), we also showed that mucins can effectively prevent the adhesion of mammalian cells. The effect was dependent on mucins and mucin source as well as the surface chemistry.

On 2014 Sep 08, Jonathan Eisen commented:

I wrote a blog post about this paper: A very important paper for any interested in microbial ecology: importance of rare taxa

On 2014 Sep 06, Ryan Radecki commented:

Post-publication commentary:

"Still Adrift in Ignorance Over Blood Cultures"

While supervising residents, one of the frequent diagnostic suggestions in undifferentiated febrile patients is: blood cultures. As an Emergency Physician, the utility of blood cultures – short of diagnosing endocarditis or another primary hematogenous source – is vanishingly small. After all, the source of infection is nearly universally somewhere else – lung, urine, CSF, skin & soft tissue – and relying on the blood to give you the answer two days later is an unreliable and impractical proposition.

This study is yet another attempt at identifying patients with high likelihood of bacteremia, retrospectively analyzing 5,499 patients at Odense University Hospital for whom blood cultures were drawn....

http://www.emlitofnote.com/2014/09/still-adrift-in-ignorance-over-blood.html

On 2014 Nov 18, Helen E Benson commented:

Ligands and proteins specified in this paper are linked to the corresponding IUPHAR/BPS Guide to Pharmacology database entries via this blog post.

On 2014 Jul 29, Amanda Capes-Davis commented:

Please be aware that "Chang liver" cells are actually not from liver. The Chang liver cell line is known to be cross-contaminated with HeLa and comes from cervical adenocarcinoma. For a list of known cross-contaminated cell lines, see http://iclac.org/databases/cross-contaminations/.

On 2015 Sep 16, M Mangan commented:

An MD has taken a look at the claims in this paper. You can see that discussion here: https://www.sciencebasedmedicine.org/seneff-claims-gmos-cause-concussions/

On 2014 Oct 29, Roman Stilling commented:

Thank you for the comment. We realized that the paper is not associated with the search term "Gcn5" in Pubmed, hence I posted this comment. I had hoped that if the term appears in the comments it would appear in the search results, but it doesn't, as you pointed out correctly. While personally I'm all for "rationalizing" gene names, since today most genes are associated with a lot more functions than the name would suggest, I think databases should be able to deal with synonyms, i.e. Pubmed should show results for Gcn5 when Kat2a was searched and vice versa. It works well in the NCBI Gene database, so why not in Pubmed?

On 2014 Oct 22, L Charles Murtaugh commented:

A good example of the unintended consequences of "rationalizing" gene names - rendering opaque almost 30 years of literature! Note that if one searches Pubmed for "Gcn5," this paper does not appear among the hits.

On 2014 Oct 18, Roman Stilling commented:

For clarification of this abstract, it may be worth noting that K-Lysine acetyltransferase 2a (Kat2a) is more widely known by its former name General control of amino-acid synthesis 5 (Gcn5) or General control of amino-acid synthesis 5 like 2 (Gcn5l2). http://www.ncbi.nlm.nih.gov/gene/14534

On 2014 Aug 13, David Keller commented:

Smoking reduces risk of PD, but increases risk of COPD and of vascular Parkinsonism

It is well established that smoking is a major risk factor for COPD. Smoking has also been shown to reduce the risk of Parkinson disease (1), thought to be due to neuroprotection by nicotine (2). Therefore, based on the prior observed associations with smoking, one would expect the risk of PD to be lower in COPD patients than in patients with no smoking history. I propose that the unexpected association between COPD and PD may be due to misdiagnosis of vascular Parkinsonism as PD.

Smoking is a major risk factor for COPD and for atherosclerotic vascular disease (ASVD). Parkinsonism can be caused by ASVD, in which case it is categorized as vascular Parkinsonism (VP), a disease distinct from classic neurodegenerative PD. VP would be expected to correlate directly with COPD, while PD should be inversely correlated with COPD, based on the known association of smoking with ASVD, and its inverse association with PD.

COPD is expected to be associated with vascular Parkinsonism, but not with Parkinson's disease, based on the known relationships of these diseases with smoking. The results of this study would be consistent with these known associations if enough VP patients were misdiagnosed as having PD. I suggest that the data be re-examined to consider this possibility.

Lastly, the authors refer to dementia as a neurodegenerative disease. Dementia is actually a symptom which can be caused by neurodegenerative diseases (such as Alzheimer's disease or dementia with Lewy bodies), atherosclerotic disease (as in multi-infarct vascular dementia), other disorders, or a combination thereof. It is incorrect to categorize dementia due to atherosclerotic infarctions as a "neurodegenerative disorder".

References

1: van der Mark M, Nijssen PC, Vlaanderen J, Huss A, Mulleners WM, Sas AM, van Laar T, Kromhout H, Vermeulen R. A case-control study of the protective effect of alcohol, coffee, and cigarette consumption on Parkinson disease risk: time-since-cessation modifies the effect of tobacco smoking. PLoS One. 2014 Apr 30;9(4):e95297. doi: 10.1371/journal.pone.0095297. eCollection 2014. PubMed PMID: 24788751; PubMed Central PMCID: PMC4005732.

2: Ross GW, Petrovitch H. Current evidence for neuroprotective effects of nicotine and caffeine against Parkinson's disease. Drugs Aging. 2001;18(11):797-806. Review. PubMed PMID: 11772120.

On 2016 Dec 05, Anne Carpenter commented:

Please note that there is a typo for the microscope's TexasRed filter, which is mentioned in the Supplemental Materials. It is listed as excitation/emission (562/642 nm) when it is actually (562/624 nm). This was confirmed with the screening center that performed the microscopy described in the paper.

On 2016 Dec 05, Anne Carpenter commented:

As one of the senior authors on this paper, I report an error on page 14 of the Supporting Materials and Methods: the words "after cell fixation with 16% paraformaldehyde" should be replaced by "after cell fixation with 3.2% formaldehyde".

On 2016 Jan 06, Lydia Maniatis commented:

This article finally clarified what the authors of this and similar papers mean by “biologically-generated” or “evolved” stimuli. Here are the relevant statements:

The visual system achieves its goals on the basis of “the creation of light energy patterns whose frequency of occurrence tracks reproductive success...these patterns are “stimuli” ...Photon energy in the environment causes receptor cells in the retina to respond...It is only after the evolved apparatus of the eye collects, focuses, and selects a particular fraction of this energy into a biologically determined pattern that a stimulus exists...light stimuli are determined by a collaboration between physics and evolved biology.”

Thus, Purves et al “stimulus” is simply the physiological state of the retina, which is contingent on incoming light that is focussed. I don't think anyone would argue with that. It acknowledges that the “stimulus” is connected with the physics of the world around us, specifically, the light impinging on the retina.

However, this description of the visual stimulus does not in any way justify or explain the notion that the “frequency of occurrence” of these stimuli "tracks reproductive success.” The pattern of retinal stimulation changes with each movement of the eye, and the patterns, depending as they do on the chance arrangements of the environment and on the line of sight, on the time of day, etc, could fairly be described as “random.” Even if we could somehow define, categorise and track particular “patterns,” why should their frequency of occurrence track reproductive success? Also, since the slate, insofar as the frequency of occurrence of these light patterns is concerned, is wiped clean with every generation, how are these frequency distributions preserved?

The repeated claims that the visual system can't use the stimulus to infer features of the physical world is contrdicted by the authors, who say that “the visual system does not take the measure of physical reality...that we readily assess with the instruments of physics.” In fact, we readily assess using our perception of the physical properties of the instruments of physics. In addition, the fact that focussing of light achieves a point to point correspondence between points on the retina and points in the world that reflected the light is suggestive of an attempt to infer the shapes and locations of actual physical objects.

The claims about the inability of the v.s. to access properties of the physical world is made based on our perception of pictorial mimics of projections from real-world scenes. If I compare my perceptions of the color of objects in a naturally-lit real-life scene under inhomogeneous illumination, then my perception of the intrinsic surface properties of objects (e.g. reflectance, chromaticity) will appear quite reliable. If I then take a photo of that scene, and compare my perceptions of its surface properties to the actual properties of the photo surface, then, of course, errors all around. This doesn't justify denying the veridical outcome in the natural scene, or discounting it in accounts of how perception works.

The methods are oddly weak. "Three hundred and eight high-resolution natural red–green–blue (RGB) images from The University of Texas at Austin “set 1” database (7) served as a proxy for human spectral experience.” [The sampling problem should speak for itself. The sample was collected by a different team with different priorities. We are not given a description of the images, or of the rationale with which they were collected. The lighting conditions are not controlled for before or after the fact. Perceptual effects are not tested. The claim that it is a proxy for human evolutionary experience is to be taken on faith. The argument of this paper hinges on this database.]

On 2014 Nov 24, Guillaume Filion commented:

This article is one of the "CISCOM meta-analyses", which are very similar papers written by different authors. For more information about the CISCOM meta-analyses, check the blog post "A flurry of copycast on PubMed" at the following link http://blog.thegrandlocus.com/2014/10/a-flurry-of-copycats-on-pubmed

On 2014 Aug 04, MARK VRABEL commented:

Good to see this article. My (librarian) contributions have been acknowledged on www.guidelines.gov; for example, "With the assistance of the Oncology Nursing Society (ONS) librarian" at http://www.guideline.gov/content.aspx?id=15702

Mark Vrabel, MLS, AHIP, ELS Oncology Nursing Society twitter.com/ONSmark

On 2015 Mar 28, Edward Archer commented:

Hébert et al.’s defense of the status quo is an impediment to both scientific progress and empirically supported public nutrition policy.

For details please see the following:

"Implausible data, false memories, and the status quo in dietary assessment." Archer, E., Blair, S.N. Adv Nutr. 2015 Mar 13;6(2):229-30. doi: 10.3945/an.114.007799.

and

"Validity of U.S. nutritional surveillance: National Health and Nutrition Examination Survey caloric energy intake data, 1971-2010." Archer et al., PLoS One. 2013 Oct 9;8(10):e76632. doi: 10.1371/journal.pone.0076632.

Link: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0076632

On 2014 Aug 30, Michelle Lin commented:

Excellent article on this relatively unrecognized epidemic. Week-long discussion on ALiEM blog with webcast discussion with authors.

http://www.aliem.com/opioid-prescription-epidemic-annals-em-resident-perspectives-article/

On 2014 Jul 28, Changting Liu commented:

Hi Willem, thanks for your attention on our manuscript. Some of your questions are really important and here is my answering. Firstly, the large differences on genome size. We noticed that the assembly results of these two strains were not good and some genome sequences were not obtained. But it was shown that the sequences of repeats and plasmids were much longer in strain LCT-KP289 and the some of the results were exhibited in Table1 and Table2. And the assembly results of repeats and plasmids can be affected by the sequencing data size and software parameters distinctively. On the other hand, the strains with special phenotypes were sequenced after space-travelling and laboratory-culturing, so there could be some mutations laid in the genome of LCT-KP289. Secondly, the acquisition of several antibiotic resistance genes and plasmids (some of enterococcal origin) in strain LCT-KP289. The manuscript has illustrated that the gene sul1 was multi-copy gene in Klebsiella pneumonia and there was one more copy exhibited in LCT-KP289. And other drug resistance genes which contained in integron were found both in LCT-KP214 and LCT-KP289, so it only explained the multiple drug resistances of Klebsiella pneumonia. As for the enterococcal plasmids, we should notice that it exist both in LCT-KP214 and LCT-KP289, so the plasmid should be captured by Klebsiella pneumonia before space traveling and it was not acquired from the medium or sequencing contaminant. Thirdly, the manuscript contains several errors (including a reported %GC of 84.42% for one of the strains). I apologize for this writing error, and the GC% of LCT-KP289 should be 56.78% and we are contacting the editor of BMC for the typo correction. Thanks again for your question. And if you have any more problems, please don't be hesitated to contact us. Thank you.

On 2014 Jul 15, Willem Schaik commented:

This paper attempts to show genomic differences between a Klebsiella pneumoniae strain that was incubated in the Shenzhou VIII unmanned spacecraft for 17 days and a control that remained on Earth. The reported differences between the two strains are large and include a 200 kbp difference in genome size and the acquisition of several antibiotic resistance genes and plasmids (some of enterococcal origin). These data are highly unlikely because when strains are grown in isolation, they should not be able to acquire foreign DNA from the medium. The authors do not explain these observations and simply claim that this is a result of spaceflight. In my opinion it is more likely that strains have been mixed-up or a contaminant has been sequenced. I also note that the manuscript contains several errors (including a reported %GC of 84.42% for one of the strains) and unsubstantiated claims.

On 2016 Aug 07, Nidal Jaradat commented:

Hard work

On 2017 Oct 05, ROBERT HURST commented:

Unfortunately the significance of these findings for bladder cancer is unclear because KU7 cells have been shown to be HeLa cells. PMC3805942

On 2014 Jul 15, T Eugene Day commented:

This is a very high quality paper. The validation metrics are appropriate and statistically validated. The data collection is high quality, and the model supports the conclusions the authors assert. The incorporation of patient punctuality, and separating it by new and follow-up distributions, is a particularly elegant piece.

And then, finally, they showed what happened when a simulated strategy was implemented in the real world, which is missing in a lot of the literature. One quibble there is that the table showing the results isn't completely clear. I'd like to see something along the lines of {Pre-implementation Real World, Simulated Performance Prediction, Post-Implementation Real World, Statistical test of Sim to Post-I Real, Statistical test of Pre-I real to Post-I real}. This would make it very clear how well the prediction fared in a single table.

All around extremely important work.

On 2014 Jul 18, William Cawthorn commented:

Several thoughts about this very interesting study:

1. Larger adipocytes are often taken as a surrogate for impaired adipogenesis, whereas smaller adipocytes are seen as indicative of enhanced adipogenesis. But lipogenesis, leading to adipocyte hypertrophy, also contributes to adipose tissue expandability (perhaps more so than adipogenesis). Therefore, I wonder if the smaller adipocytes at baseline actually represent impaired lipogenesis, and therefore impaired adipose tissue expandability?

2. Was there any association between adipocyte size at baseline, and changes in circulating lipids? I.e. the subjects with larger adipocytes had smaller change in SAT, VAT, and total fat mass, without accumulating more lipid in liver or SkM; therefore, is the excess lipid circulating instead?

3. The adipocyte size measurements are for subcutaneous WAT. It would be interesting to see if there were similar associations for the sizes of adipocytes in visceral WAT, which tends to be more inflamed.

4. The authors here find no association between SAT adipocyte size and expression of markers of inflammation. Another study in humans found that smaller SAT adipocytes were associated with increased inflammation (McLaughlin et al, 2010; PMID 19816674). Each of these studies are in contrast to the concept that adipocyte hypertrophy is associated with increased inflammation (e.g. Gustafson et al, 2009; PMID 19622783). Clearly, further studies in humans, both in subcutaneous and visceral WAT, are needed to determine if adipocyte hypertrophy is associated with increased WAT inflammation.

On 2014 Dec 03, MARY PATTI commented:

Thank you very much for your interest in our study. We agree that genetic variation is an important consideration when conducting comparative epigenetic studies. However, we would like to clarify that we used samples of sperm from a total of 8 control (C) and 8 undernutrition (UN) mice for MeDIP-seq analysis. We prepared 2 pools for each condition, each comprising 4 individuals from 4 independent litters. These pools were used for 2 independent analyses (C pool 1 vs. UN pool 1, and C pool 2 vs. UN pool 2); differentially methylated loci common to both analyses were identified comprising clusters of CGs behaving similarly, not single site differences. Subsequent validation of these loci was very important. Pyrosequencing validation of differential methylation was performed on unpooled sperm using 12 individual control males from 5 litters and 11 individual UN males from 4 litters. This approach minimized outcomes potentially linked to inter-individual genetic differences.

On 2014 Oct 17, Andrew Sharp commented:

Readers should note that the whole genome-profiling in this study used outbred mice, with a sample size of n=4 per group. In my opinion, this is a very serious limitation, as it will result in the identification of many differences between groups that are simply due to the underlying genetic variation of the mice being tested, and are unrelated to nutrition status.

On 2014 Aug 24, David Keller commented:

Please see the response posted on the BMJ website by Dr. Yedy Israel, who explains why caution must be used in projecting the results of this study to persons with wild-type genes for alcohol dehydrogenase. The effects of ethanol consumption on normals can only be determined by studying normals. The consistently-observed minimum risk for cardiovascular disease in normals occurs with a chronic daily ingestion of about 1 to 2 ounces of ethanol per day (1), the so-called "J-shaped curve".

Reference

1: O'Keefe JH, Bhatti SK, Bajwa A, DiNicolantonio JJ, Lavie CJ. Alcohol and cardiovascular health: the dose makes the poison…or the remedy. Mayo Clin Proc. 2014 Mar;89(3):382-93. doi: 10.1016/j.mayocp.2013.11.005. Review. PubMed PMID: 24582196.

On 2014 Jul 14, Dale D O Martin commented:

Once again, the myristoylation site 'predicted' in this paper is unlikely. N-myristoylation occurs on N-terminal Glycines hence the name N-myristoylation. It can only happen on internal glycine residues following proteolysis of the protein before the Glycine. As this protein has no cleavage site, it is unlikely to be myristoylated. I have pointed this out to one of the authors who agreed with this assessment and yet continues to publish this data.

Also, as far as I can tell, they do not reference what prediction tool they used for myristoylation.

On 2014 Jul 31, Amanda Capes-Davis commented:

The authors use HeLa, KB and MCF-7 as examples of human cancer cell lines. However, KB is known to be cross-contaminated with HeLa and so is cervical, not oral. For a list of cross-contaminated or otherwise misidentified cell lines, see http://iclac.org/databases/cross-contaminations/.

On 2014 Nov 24, Guillaume Filion commented:

This article is one of the "CISCOM meta-analyses", which are very similar papers written by different authors. For more information about the CISCOM meta-analyses, check the blog post "A flurry of copycast on PubMed" at the following link http://blog.thegrandlocus.com/2014/10/a-flurry-of-copycats-on-pubmed

On 2015 Feb 07, Airton Stein commented:

very interesting article.

On 2016 Dec 06, Pan Pantziarka commented:

Concerns about the validity of this review have been raised in the South African Medical Journal by Z. Harcombe and T. Noakes: "The universities of Stellenbosch/Cape Town low carbohydrate diet review: Mistake or mischief?", (S Afr Med J 2016;106(12):1179-1182. DOI:10.7196/SAMJ.2016.v106i12.12072. http://www.samj.org.za/index.php/samj/article/view/11605/7753.

On 2016 Jun 17, David C. Norris commented:

Four deficiencies in Dr Kessler's reply may be noted:

• Kessler describes as a "strong statement" my assertion that "a unitary PTSD construct cannot be presumed to support meaningful comparisons of prevalence across environments differing in ambient violence." Aside from his merely technical error (properly speaking, it is such a presumption and not its negation that is logically the 'strong' statement^1§15 ), by labeling my assertion as 'strong' Kessler overlooks its sharp qualification by "unitary" and "meaningful" -- words that point the way to an opportunity for productive critical discourse.

• Kessler asserts that my negating this presumption "dismisses psychiatric epidemiological research on PTSD, which is based [on it]". In so doing, he seems to employ no fewer than 3 logical fallacies² : He advances an argument from authority [of said research programme], and employs the fallacy of the excluded middle to produce a straw man caricature of my point. Far from 'dismissing' such epidemiologic research, my sharply qualified caution indicates how such research may be improved. From a point of view in which the meaning in "meaningful" is to be sought not in the tabulation of p-values but in the critical examination of open concepts³ , a PTSD epidemiologist may readily acknowledge a "unitary" PTSD construct -- ungraded as to severity and undifferentiated as to causation -- as worthy of critical appraisal.

• To my question, unmistakably cast in terms of construct validity, Kessler then responds in terms of criterion validity, ignoring a distinction that was articulated even at the very birth⁴ of construct validity 60 years ago. The phrase "construct validity" appears twice in my Letter; each time, I speak of the "construct validity of the instruments used" relative to "mental health" as (unmistakably) the target construct. Dr Kessler's discussion of "concordance" in para. 3 of his reply is completely irrelevant to this issue.

• When at last, in para. 4 of his reply, Kessler does begin to address a point of construct validity, he does so only from a perspective that is "primarily concerned with the adequacy of tests as measures of a construct rather than with the adequacy of a construct"^5p100 . Indeed, even then, only a convergent validity argument is pursued, with no effort at an exploration of discriminant validity (such as I solicited in the 2nd paragraph of my letter), which might have gone some way toward addressing my criticism.

[1] Popper, Karl. The Logic of Scientific Discovery. 2 edition. New Delhi: Routledge, 2002.

[2] Sagan, Carl. “Chapter 13: The Fine Art of Baloney Detection.” In The Demon-Haunted World: Science as a Candle in the Dark, 1996. See pp. 212-216.

[3] Meehl, Paul E. “Theoretical Risks and Tabular Asterisks: Sir Karl, Sir Ronald, and the Slow Progress of Soft Psychology.” Journal of Consulting and Clinical Psychiatry 46 (1978): 806–34. Full text

[4] CRONBACH LJ, 1955 Full text

[5] CAMPBELL DT, 1959 Full text

On 2014 Jul 31, Paul Glasziou commented:

We agree with Bastian's comments, but getting authors to do this will not occur soon! However, journals could potentially use automated tools to assist with extraction of trial details and provision of UTNs. Manual extraction, whether by author, journal, or reviewer, should become a thing of the past.

On 2014 Jul 26, Hilda Bastian commented:

A thorough and valuable breakdown of what could and should be automated in systematic reviewing. One additional important strategy lies in the hands of everyone doing (and publishing) clinical trials and systematic reviews: following the IJCME recommendation to include the clinical trial registry identification number of every trial at the end of abstracts. This needs to be done using the specific, unaltered formats for each registry in which a study is included, so that IDs are easily retrievable - and the IDs should be with every cited study inside the systematic review, too. Using the WHO's Universal Trial Number (UTN) would also help with the critical, and time-consuming, task of study de-duplication.

The issue raised in this article of some databases of manually extracted trial data not being publicly available is an important one. It's worth noting, though, that this is not because it's not possible: systematic reviewers have the option of using the open and collaborative public infrastructure of the SRDR (Systematic Review Data Repository) (Ip S, 2012).

Another option to add to the list of ways of improving the snowballing technique for identifying studies: using the related articles function in PubMed. That's been found to be useful in empirical studies of techniques for updating systematic reviews (Shojania KG, 2007).

(Disclosure: I work on projects related to systematic reviews at the NCBI (National Center for Biotechnology Information, U.S. National Library of Medicine), which is also responsible for ClinicalTrials.gov.)

On 2015 May 30, Torsten Seemann commented:

The software is available at: https://sourceforge.net/projects/simulatepcr/

On 2014 Jul 15, Elisabeth Bik commented:

There seems to be a typo in the title: "Escherchia".

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 NCT00602603. We believe the correct ID, which we have found by hand searching, is NCT00603603.

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 20, Neven Patrick commented:

Although results from ongoing prospective trials looking into the predictive value of multigene signatures (MGS) for chemotherapy benefit are pending, many use them for prognostic purposes. In general, this leads to less adjuvant chemotherapy. This paper reported on how a multidisciplinary team (MDT) changed treatment decisions studying 75 patients with a grade 1-2 cT1-2N0 ER-positive, HER2-negative breast cancer. Clinical risk by MDT based on (St Gallen criteria) pathological tumor size, grade, nodal stage, steroid receptors and Ki-67 was compared with MammaPrint® (MP) risk. There was discordance between clinical and MP-risk in 29 out of 75 patients; 21 had a clinical high, MP low and 8 a clinical low, MP high risk. In this group of 29, 4 out of 8 with a clinical low, MP high risk did and 10 out of 21 in the clinical high, MP low risk did not get chemotherapy. All together, based on clinical risk alone, 31 of 75 women would have received adjuvant chemotherapy while this changed to 25 of 75 when incorporating the MP-risk. The use of MGS in this cohort was cost effective. The paper however, lacks some important details that are relevant and will help understand the use of MGS in this MDT. First, the discordance rates between clinical and MGS-risk in this paper are much higher for the clinical high risk patients (67%)compared with other experiences with MGS, like MP in RASTER or MINDACT (Bueno-de-Mesquita et al., 2007; Rutgers et al., 2011). This might be related to an overestimation of the clinical or underestimation of the MGS-risk. The definition they used for clinical risk is lacking and suggests an overestimation of clinical risk as 41% of women with a low to intermediate risk were stratified by the MDT as high risk. Otherwise, MGS might underestimate relapse risk. It would be interesting to know from the patients’ demographics whether some of the patients stopped exogenous hormones prior to breast cancer surgery. Short term changes in the hormonal environment following an ER-positive breast cancer diagnosis on core needle biopsy might confound MGS results. This has been shown for proliferation markers other than MGS for example with hormone replacement therapy withdrawal. Second, the authors state why they decided to give adjuvant chemotherapy in 11 out of 21 women with a clinical high, MP low risk, but they did not indicate why adjuvant chemotherapy was or was not given to half of the patients with a clinical low, MP high risk.

On 2014 Jul 12, David Keller commented:

The USPSTF statement confuses sensitivity and specificity

The following error appears in the USPSTF Recommendation statement posted on their own website (1) as well as in the identical document published online by Annals of Internal Medicine (2):

"Although screening with ultrasonography has few direct harms, all screening strategies, including those with or without confirmatory tests (that is, digital subtraction or magnetic resonance angiography), have imperfect sensitivity and could lead to unnecessary surgery and result in serious harms, including death, stroke, and myocardial infarction."

Correction: The author meant to write that these screening tests "have imperfect specificity, and could lead to unnecessary surgery..."

Rationale: Imperfect specificity is defined as a rate of false-positive test results greater than zero, which can lead to a diagnosis of disease which does not exist, and hence to unnecessary surgery. In contrast, imperfect sensitivity is defined as a rate of true-positive test results less than 100%, which does not lead to unnecessary surgery - but it can lead to the opposite kind of harm, which is a missed diagnosis, which can lead to the failure to perform necessary surgery.

The correct use of these terms, and the distinction between their definitions, is important in any discussion of public health measures.

The erroneous word was bolded by this commentator.

9/22/2014: As of today, the above error remains uncorrected on both the USPSTF and Annals websites. I have notified the editor of Annals by email. I encourage readers to submit their comments regarding this error to USPSTF, Annals, and PubMed Commons.

11/9/2014: As of today, the above error remains uncorrected on the Annals of Internal Medicine website. However, it has been corrected on the USPSTF website, at the following new web address:

http://www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/carotid-artery-stenosis-screening

I will again attempt to have it corrected by the editors of Annals.

12/26/2014: I exchange emails with the editor-in-chief of Annals, who assures me that the matter will be looked into.

1/21/2015: A recheck of the Annals website discloses that the error has been corrected, and now reads "Although screening with ultrasonography has few direct harms, all screening strategies, including those with or without confirmatory tests (that is, digital subtraction or magnetic resonance angiography), have imperfect sensitivity and specificity and could lead to unnecessary surgery and result in serious harms, including death, stroke and MI".

To date, I have received no acknowledgement or thanks for pointing out the above error, from either the USPSTF or from Annals. This is the typical response I have received when correcting errors, including other, more serious errors in JAMA and the NEJM, which were eventually corrected after I expended almost preposterous efforts. Errors in the scientific literature can propagate unless corrected, leading to further errors. The NIH should establish an impartial board of experts, to whom outstanding errors in PubMed-indexed publications can be appealed, in cases where readers have spotted significant errors and the responsible editors refuse to correct them.

References

1: U.S. Preventative Services Task Force website, accessed on 7/12/2014, search for the second instance of "imperfect sensitivity" http://www.uspreventiveservicestaskforce.org/uspstf13/cas/casfinalrs.htm

2: Annals of Internal Medicine website, accessed on 7/12/2014, search for the second instance of "imperfect sensitivity" http://annals.org/article.aspx?articleid=1886690

On 2014 Jul 12, David Keller commented:

This USPSTF statement contains two different recommendations, which must be discussed separately

1) The USPSTF recommends against screening for asymptomatic carotid artery stenosis in the general adult population. Grade D

2) The USPSTF recommends against invasive mechanical treatment (ie: surgery or angioplasty) for asymptomatic carotid artery stenosis in the general adult population. Grade D.

The USPSTF statement convinced me that their grade of "D" is valid for recommendation #2 above; invasive treatments of asymptomatic carotid stenosis probably do more harm than good.

However, the USPSTF is clearly wrong on recommendation #1 above. Their statement admits that there is insufficient data to determine whether high-dose statin therapy will prove to be as beneficial for carotid atherosclerotic disease as it has proven for coronary atherosclerotic disease. Therefore, by their own grading standards, recommendation #1 should be classified as Grade "I" for indeterminate.

Further, many experts maintain that atherosclerotic stenoses, whether discovered in a carotid artery or a coronary artery, are manifestations of the same underlying disease entity, systemic atherosclerosis, which if present in a significant degree, should be treated with high-dose statin therapy. For those who hold this view, screening asymptomatic patients for carotid stenosis should be given a grade of "C", meaning each individual should discuss with their physician whether they should get screened, based on their risk profile.

I screen asymptomatic patients who have a reasonable risk of atherosclerosis, to identify systemic atherosclerosis in a convenient artery which is accessible to ultrasonic evaluation. If carotid stenosis is present, I treat is as a coronary artery disease risk equivalent, and initiate treatment with high-dose statin therapy. This strategy is reasonable, based on extrapolation of the findings of benefit in every cardiac statin trial.

The arguments supporting carotid screening for the purpose of risk-stratification are biologically plausible and lead to active changes in therapy for patients without known coronary artery disease, who are found to have asymptomatic carotid stenosis.

The USPSTF should rewrite this statement to narrowly focus on recommending against invasive treatment of carotid stenosis, and encourage physicians to continue screening appropriate patients for asymptomatic carotid atherosclerosis as a way to identify additional patients who can benefit from the use of high dose statin therapy.

On 2016 Mar 18, ZHONGMING ZHAO commented:

My lab recently moved to the University of Texas Health Science Center at Houston. The dataset now available at https://bioinfo.uth.edu/kinomenetworkX/.

On 2014 Sep 19, Ian Dworkin commented:

In addition to all of the data and scripts being on Dryad, we also have them in a repository on github.

https://github.com/DworkinLab/Pitchers_PTRS2014

On 2014 Nov 22, Ruchira Engel commented:

We recently discussed this article in our journal club. Our comments can be found on our journal-club blog Sanquin Digests.

On 2014 Jul 24, Ryan Radecki commented:

Post-publication commentary:

"ED Hocus POCUS ... or Just a Hoax?"

A landmark paper recently published in Lancet Respiratory Medicine is certainly destined to send the ED Ultrasound world into a tizzy. This is the first RCT examining the utility of Emergency Department based Point of Care ultrasound (POCUS) for patients presenting with undifferentiated respiratory complaints. Authors randomized patients presenting to the ED with signs or symptoms concerning for a respiratory etiology to either a standard work up as determined by the treating physician or the addition of POCUS performed by a single experienced operator. The US protocol consisted of sonographic examination of the heart, lungs and lower extremity deep veins to identify possible causes of patients' symptoms. The authors' primary outcome was the percentage of patients with a correct presumptive diagnosis 4 hours after presentation to the Emergency Department as determined by two physicians blinded to ED POCUS findings, but with access to the records of the entire hospital stay....

http://www.emlitofnote.com/2014/07/ed-hocus-pocus-or-just-hoax.html

On 2014 Jul 28, Amanda Capes-Davis commented:

Please be aware that HEp-2 is not a laryngeal squamous carcinoma cell line. HEp-2 is known to be cross-contaminated with HeLa and is actually cervical adenocarcinoma. For a database of known cross-contaminated cell lines, please see http://iclac.org/databases/cross-contaminations/.

On 2014 Aug 07, Madhusudana Girija Sanal commented:

This is an interesting observation. There is another aspect. It is known that platelets carry serotonin and they play an important role in distributing extra-neural serotonin.Platelet depletion impairs liver regeneration. Lesurtel M et al reported in 2006 that platelet-derived serotonin mediates liver regeneration (Science. 2006 Apr 7;312(5770):104-7.). Another paper by Paulose and others, back in 1998 reported increased mitotic activity in liver cells in-vitro in response to serotonin. (Hepatology. 1998 Jan;27(1):62-6.). It is therefore possible that platelets may play a role in hepatocellular carcinoma-proliferation and metastasis. Thus, serotonin may have an additional role different from the growth factors such as PDGF in liver cancer secreted by platelets. However, I doubt if this has some direct clinical implication in the management of this cancer considering its extremely dynamic nature.

On 2014 Jul 09, Ryan Radecki commented:

Post-publication commentary:

"Build a New EDIS, Advertise it in Annals for Free"

As everyone who has switched from paper to electronic charting and ordering has witnessed, despite some improvements, many processes became greatly more inefficient. And – it doesn’t matter which Emergency Department information system you use. Each vendor has its own special liabilities. Standalone vendors have interoperability issues. Integrated systems appear to have been designed as an afterthought to the inpatient system. We have, begrudgingly, learned to tolerate our new electronic masters....

http://www.emlitofnote.com/2014/07/build-new-edis-advertise-it-in-annals.html

On 2014 Dec 30, William Grant commented:

Geographical variations in solar ultraviolet-B doses may explain some of the spatial-temporal excess mortality patterns of the 1918-1919 influenza pandemic in Spain

Disclosure I receive funding from Bio-Tech Pharmacal (Fayetteville, AR), the Sunlight Research Forum (Veldhoven), and Medi-Sun Engineering, LLC (Highland Park, IL).

The paper by Chowell and colleagues presents maps of excess respiratory death rates during the 1918-1919 influenza pandemic in Spain 1. The summer and winter peak rates are in the center and south of Spain, while the fall peak rates are predominantly in the north. The authors suggested that colder temperatures and lower humidity in the north and in fall-winter might explain the observed patterns. I agree that this suggestion is generally correct. However, there is another factor that should also be considered - the role of solar UVB irradiance and vitamin D production. In an ecological study of the 1918-1919 influenza pandemic in the United States, it was reported that both summertime and wintertime solar UVB doses were inversely correlated with case-fatality rates for a dozen communities 2. Most of the deaths associated with the influenza were due to pneumonia, and occurred about ten days after the start of influenza. The mechanisms suggested were induction of cathelicidin, which has antibiotic properties, and reduction of the cytokine storm due to the body fighting influenza. The UVB-vitamin D-influenza hypothesis was proposed in 2006 by John Cannell and colleagues 3. This hypothesis has gained further support from vitamin D randomized controlled trials involving people with low 25-hydroxyvitamin D-25OHD concentrations at the time of enrollment in the trials 4-6.

Broadband solar UVB doses have been measured for 14 locations in Spain 7. In summer, values at solar noon ranged from 1234 to 1726 units but do not follow a strict latitude gradient. In winter, the values ranged from 160 to 348 and showed a strong latitudinal gradient. Based on these values, the higher mortality rates in winter and in the north may be due in part to lower UVB doses in winter. The higher rates in south and central Spain in summer may be related to where influenza was first introduced into Spain. A related paper found that cancer mortality rates were often inversely correlated with latitude and directly correlated with nonmelanoma skin cancer 8.

This analysis suggests that 25OHD concentrations be raised by vitamin D supplementation in winter in Europe to reduce the risk of respiratory infections. Optimal 25OHD concentrations are between 75 and 125 nmol per L 9, which can be achieved with 800-2000 IU per day vitamin D3 for most people 10. There are also many other beneficial effects of higher 25OHD concentrations 9, 11.

References 1. Chowell G, Erkoreka A, Viboud C, Echeverri-Dávila B. Spatial-temporal excess mortality patterns of the 1918-1919 influenza pandemic in Spain. BMC Infect Dis. 2014;14:371. 2. Grant WB, Giovannucci E. The possible roles of solar ultraviolet-B radiation and vitamin D in reducing case-fatality rates from the 1918–1919 influenza pandemic in the United States. Dermatoendocrinol. 2009;1:215-9. 3. Cannell JJ, Vieth R, Umhau JC, Holick MF, Grant WB, Madronich S, Garland CF, Giovannucci E. Epidemic influenza and vitamin D. Epidemiol Infect. 2006;134:1129-40.<br> 4. Aloia JF, Li-Ng M. Re: epidemic influenza and vitamin D. Epidemiol Infect. 2007 Oct;135:1095-6; author reply 1097-8. 5. Urashima M, Segawa T, Okazaki M, Kurihara M, Wada Y, Ida H. Randomized trial of vitamin D supplementation to prevent seasonal influenza A in schoolchildren. Am J Clin Nutr. 2010;91:1255-60. 6. Camargo CA Jr, Ganmaa D, Frazier AL, Kirchberg FF, Stuart JJ, Kleinman K, Sumberzul N, Rich-Edwards JW. Randomized trial of vitamin D supplementation and risk of acute respiratory infection in Mongolia. Pediatrics. 2012;130:e561-7. 7. Martínez-Lozano JA, Utrillas, MP, Nunez JA, Esteve AR, Gomea-Amo JL, Estelles V, Pedros R. Measurement and Analysis of Broadband UVB Solar Radiation in Spain. Photochemistry and Photobiology, 2012;88:1489–96 8. Grant WB. An ecologic study of cancer mortality rates in Spain with respect to indices of solar UV irradiance and smoking. Int J Cancer. 2007;120:1123-7. 9. Pludowski P, Holick MF, Pilz S, Wagner CL, Hollis BW, Grant WB, Shoenfeld Y, Lerchbaum E, Llewellyn DJ, Kienreich K, Soni M. Vitamin D effects on musculoskeletal health, immunity, autoimmunity, cardiovascular disease, cancer, fertility, pregnancy, dementia and mortality- a review of recent evidence. Autoimmun Rev. 2013;12:976-89. 10. Pludowski P, Karczmarewicz E, Bayer M, Carter G, Chlebna-Sokół D, Czech-Kowalska J, Dębski R, Decsi T, Dobrzańska A, Franek E, Głuszko P, Grant WB, Holick MF, Yankovskaya L, Konstantynowicz J, Książyk JB, Księżopolska-Orłowska K, Lewiński A, Litwin M, Lohner S, Lorenc RS, Lukaszkiewicz J, Marcinowska-Suchowierska E, Milewicz A, Misiorowski W, Nowicki M, Povoroznyuk V, Rozentryt P, Rudenka E, Shoenfeld Y, Socha P, Solnica B, Szalecki M, Tałałaj M, Varbiro S, Zmijewski MA. Practical guidelines for the supplementation of vitamin D and the treatment of deficits in Central Europe - recommended vitamin D intakes in the general population and groups at risk of vitamin D deficiency. Endokrynol Pol. 2013;64:319-27. 11. Hossein-Nezhad A, Holick MF. Vitamin D for Health: A Global Perspective. Mayo Clin Proc. 2013;88:720-55.

On 2016 May 09, Attila Becskei commented:

Keung et al write that “An interesting result that emerged from our CR [chromatin regulator] library screens is that transcription can be repressed but not activated from downstream of a gene. Furthermore, activators do not appear to display the long-range properties that some repressors do”. This result confirms the conclusion of an earlier work (1). At the same time, Keung et al implicitly re-classified some repressors as activators (2).

(1) Basic mechanisms of transcription are conserved among eukaryotes; however, there are interesting quantitative differences. While genes can be activated from distant sites in higher eukaryotes, yeast genes can be controlled only from nearby sites in wild-type cells (Dobi KC, 2007). Only the Sir (silent information regulator) proteins have been known to display long-range (> 1kb) repression in yeast, which have a strong effect on chromatin structure(Nasmyth KA, 1982). Later, our study revealed that even classical repressors, such as Ssn6, can repress genes from distant sites provided they are positioned downstream of a gene (Ratna P, 2009,Kelemen JZ, 2010). An activator recruited to these downstream sites did not affect gene expression. In a set of synthetic gene reporters, three regulators (Ssn6, Sum1 and Sir3) had similar ranges of repression (Figure 3A in Becskei A, 2011). The range of repression from upstream (U) of a gene was considerably shorter than that from downstream (D) of the gene.

Using similar set of synthetic gene reporters, Keung et al recruited all known regulators to downstream sites. Interestingly, the our above conclusion was found to be true for all regulators: genes can be repressed but not activated from downstream sites.

(2) This uniform behavior of the repressors at the downstream sites is also interesting because a variable, non-uniform, behavior was observed by the authors at the upstream sites, i.e. at the promoter. For example, the classical yeast repressors, Ssn6, Tup1 and Ume6 did not repress expression when recruited to the promoter. Instead, they turned out to be the most potent activators of all regulators: they activated gene expression around 100 times (Figure 2B) (< PMID: 24995982>). Previous studies indicate that they are potent repressors both in wild-type and synthetic contexts (Keleher CA, 1992,Smith RL, 2000,Kadosh D, 1997).

On 2015 Feb 27, Geriatric Medicine Journal Club commented:

This cross sectional and longitudinal analysis of a prospective cohort of osteoporosis in men was critically appraised at the November 2014 Geriatric Medicine Journal Club (follow #GeriMedJC on Twitter). Full details of the discussion can be found at: http://gerimedjc.blogspot.com/2014/11/gerimedjc-november-28-2014.html?spref=tw One of the highlights was the concern that the Multicenter Osteoporotic Fractures in Men (MrOS) cohort did not include many people on steroids.

On 2014 Jul 17, Alexander Weiss commented:

Wilson et al. tested how participants reacted to doing no more than thinking. They couched this research question in the human ability to engage in “directed conscious thought” and asked whether this activity was pleasant. It was not. In fact, many participants self-administered electric shocks when given the opportunity to do so during the thinking task. Discussing their findings, the authors stress the “thinking” aspect of their tasks and concluded that “people prefer doing to thinking”.

I question this interpretation. Removal of stimuli individuals find pleasing (“doing”), is a means of shaping behavior and is as aversive to chimpanzees and pigeons (Ferster, 1958) as it was, presumably, to the participants of this study. The importance of “doing” for animals by providing environmental enrichment in the form of puzzles, games, and social contact is enshrined in animal welfare regulation (see the 1985 amendment to the 1966 United States Animal Welfare Act) based on decades of research showing, for example, that a lack of enrichment is associated with self-injurious behavior (Lutz & Novak 2005).

Engaging in “directed conscious thought” is thus either common across a range of different species or it is not the aversive stimuli in question. The over-interpretation of well-known phenomena, however, is probably unique to humans and most definitely aversive.

References

C. B. Ferster, Control of behavior in chimpanzees and pigeons by time out from positive reinforcement. Psychological Monographs: General and Applied 72, 1-38 (1958).

C. K. Lutz, M. A. Novak, Environmental enrichment for nonhuman primates: Theory and application. ILAR J. 46, 178-191 (2005).

On 2015 Aug 06, David Keller commented:

Possible bias in the reporting of test results for this weight-loss product

The main author of this study reports conflicts of interest with regard to the green-plant membrane weight-loss product being tested, which is sold under the brand name "Appethyl" [1]. Her positions as scientific adviser, part-owner and member of the board of directors of companies that produce Appethyl could bias her evaluation of its efficacy. Results from her research are presented in promotional materials for Appethyl [2] and quoted in the popular media [3].

An example of possible bias involves two subjects who dropped out of this study after they were randomized to the control group. Their weight data was simply deleted, yielding an average weight loss in the control group of 3.5 kg. Intention-to-treat analysis, performed by carrying forward the starting weight in Table 1 for each of the control group drop-outs, yields an average weight loss in the control group of 3.9 kg. A smaller weight loss in the control group makes the Appethyl-treated group's average weight loss appear larger and more significant, by comparison to placebo. The U.S. Food and Drug Administration requires intention-to-treat analysis in studies of products submitted for their approval [4], which would be required if Appethyl is to be offered in the U.S.

The NIH suggests the following measures be taken to ameliorate financial conflicts of interest [5]:

"Change of personnel or personnel responsibilities, or disqualification of personnel from participation in all or a portion of the research;

"Reduction or elimination of the financial interest (e.g., sale of an equity interest); or

"Severance of relationships that create financial conflicts."

A safe and effective weight loss product derived entirely from natural green plant sources is a welcome possibility. The existence of significant conflicts of interest requires great care to prevent bias in the reporting of experimental results for Appethyl.

References:

1: Science Direct website, accessed on 8/6/2015, at the following URL: http://www.sciencedirect.com/science/article/pii/S0195666314003493

2: Online press release published 3/10/2014, "New Clinical [sic] Shows That Greenleaf Medical's Appethyl(TM) Decreases Urge to Eat Sweet Foods", SOURCE: Greenleaf Medical AB, accessed on 8/20/2015 at http://www.marketwatch.com/story/new-clinical-shows-that-greenleaf-medicals-appethyltm-decreases-urge-to-eat-sweet-foods-2014-03-10

3: Commercial sale of Appethyl on Amazon.com, accessed on 9/12/2015, at: http://www.amazon.com/Appethyl-30-ct/dp/B00RM5KY48/ref=cm_cr_pr_product_top?ie=UTF8

4: Guideline for the Format and Content of the Clinical and Statistical Sections of Applications, Center for Drug Evaluation and Research, Food and Drug Administration, Department of Health and Human Services, 5600 Fishers Lane Rockville, Maryland 20857 (301) 443-4330. 1988 Jul 24

5: ELECTRONIC CODE OF FEDERAL REGULATIONS, Subpart F—Promoting Objectivity in Research, accessed on 8/20/2015 at http://www.ecfr.gov/cgi-bin/text-idx?c=ecfr&SID=992817854207767214895b1fa023755d&rgn=div5&view=text&node=42:1.0.1.4.23&idno=42#sp42.1.50.f

On 2015 Sep 14, David Keller commented:

Blinding of study subjects was not assessed, and likely failed, causing Pygmalion effect

In this study, the control group subjects were given a beverage containing 2.8 grams of rapeseed oil and 50 grams of blueberry "soup". The active intervention group subjects were given the same beverage, with the addition of 5 grams of a commercial green spinach extract powder called "Appethyl". No assessment was made of whether the subjects remained blinded after seeing and tasting these beverages, which must have differed markedly in appearance and taste. It is difficult to imagine that the study subjects would not quickly figure out who was getting the placebo beverage, and who was getting the active intervention beverage. Once this was known, uncontrolled Pygmalion effect [1] is likely in a weight loss clinical trial. The Pygmalion effect is defined as enhanced benefit that occurs when a subject becomes aware that she is receiving the active experimental intervention. Pygmalion effect is closely related to placebo effect; in the limit, if the product being studied is actually ineffective, then the Pygmalion effect becomes equal to the placebo effect.

Clinical studies should evaluate the quality of the blinding achieved and maintained throughout the study, in order to exclude or quantify the biases and and confounding factors introduced when subjects know whether they received placebo or the experimental therapy. Assessment of blinding quality could have been obtained by asking the subjects to provide their best guess as to whether they received the placebo beverage with or without added Appethyl, and tracking those results over time. With perfect blinding, all subjects should guess with the random accuracy of a fairly flipped coin, on the average (50%). With complete unblinding, all subjects guess correctly whether they received placebo or the therapy being studied.

Perhaps Higgs and Geary can reveal further heretofore unpublished data to settle this question.

References:

1: Draper,S.W. The Hawthorne, Pygmalion, Placebo and other effects of expectation, published on 5/14/2002, and visited on 5/14/2015, at:<br> http://www.psy.gla.ac.uk/~steve/hawth.html#Hawthorne overall

2: Bang H, Ni L, Davis CE. Assessment of blinding in clinical trials. Control Clin Trials. 2004 Apr;25(2):143-56. PubMed PMID: 15020033.

On 2015 Aug 04, David Keller commented:

The data in Table 1 contain important discrepancies, which require discussion & correction

Table 1 states that the average starting weight for the 19 control subjects who began the trial was 80.2 kg, and the average ending weight was 76.3 kg for the 17 control subjects who finished the trial. Given this data, one can calculate the average weight loss of 3.9 kg by intention-to-treat analysis using the "last data point carried forward" technique. The authors of this paper chose to report the per-protocol average weight loss, which is impossible to calculate from Table 1, because it is missing the average starting weight of the 17 control patients who completed the study. None of this was disclosed anywhere in the paper, nor was it disclosed that the weight loss results were not analyzed by intention-to-treat analysis, which preserves the statistical qualities of the original randomization. Deleting control patients from a study degrades its statistical randomness and increases the effect of confounding factors. That is why intention-to-treat analysis is the scientific standard for analyzing data from clinical trials.

Further, there is no way for readers to check these calculations or the integrity of the paper's conclusions, due to the data missing from Table 1. This is an important point, because dropping the data from the 2 control patients decreased the average weight loss by control group subjects from 3.9 kg to 3.5 kg. This, in turn, increased the apparent average net weight loss among subjects treated with Appethyl.

The editors of Appetite should encourage readers to report published errors, because such reports are the last line of defense of the truth in scientific publishing. False counter-charges of error made against such readers, such as in their reply to me, will only discourage readers from pointing out published errors in the future.

On 2015 Aug 04, David Keller commented:

The authors DID specify the data variability as SEM, not SD, as falsely claimed by Higgs and Geary

The following quote is taken from the last paragraph of the Materials and Methods section of this paper: "In figures and text, data are expressed as the mean,  plus or minus the standard error". There is no other statement in this paper defining the data format. Interpreted using the data format specified by the authors, the study's reported weight loss with Appethyl is not significantly better than achieved with placebo, which I reported in an earlier comment. In their reply above, Higgs & Geary, the co-editors of Appetite, state that the study's final results are actually reported in the format of the mean plus or minus the standard deviation, a format not specified anywhere in the paper. It is only by substituting the use of the undocumented SD variability format that the weight loss with Appethyl is made to appear significantly better than with placebo. If, indeed, the authors decided to change data formats, that should have been documented in the paper. Rather than thanking me for identifying this important error in the paper, the editors of Appetite attack my conclusion that Appethyl is statistically ineffective, which is the only possible interpretation of the data using the format specified by the authors. My observations exposed an important error in this paper, which they should be grateful to have corrected by a reader.