14,839 Matching Annotations
  1. Jul 2018
    1. On 2015 Mar 17, Alan Taylor commented:

      This confirms work done to determine causes of OA in elderly patients. Aromatase deficiency is a key contributor to OA. Not only is it responsible for the final step in the synthesis of estrogen from androstendione but also converts testosterone to estrogen in males. The estrogen acts on two E receptors in female bone cells/ in males there is one androgen receptor and one estrogen receptor. These are a essential for bone health and maintenance. In the genome wide study under expression of CYP19 gene that codes for aromatase was evident in most cases. Severe OA in a male has been successfully treated for 15 years using a low dose of transdermal estrogen. This effect has been shown to be reversible It takes 6 to 8 weeks for the treatment to reverse the OA. Discontinuation causes OA to redevelop after 6-8 weeks. Recommencement again reverses the OA to give no symptoms whatsoever. Aromatase inhibitors will obviously prevent the two E receptors in the osteocytes from working. In males testosterone deficiency also will prevent the aromatase from catalysing the formation of estrogen.


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    1. On 2015 Apr 12, James Tsung commented:

      Video of Right Ventricular Puncture During Pericardiocentesis for Cardiac Tamponade: https://youtu.be/WflPJCDl34I


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    1. On 2015 Feb 05, G Gasim commented:

      Dear Dr.Yousif congratulations for the great efforts

      do you have an explanation for the variation in genotypes between monoinfected Sudanese patients and those coinfected with HIV?


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    1. On 2015 Apr 26, Geriatric Medicine Journal Club commented:

      This is a systematic review of non-pharmacologic interventions for orthostatic hypotension including exercise, FES, compression, physical countermaneuvers, head of bed up, water intake, and meal strategies. This article was critically appraised at the April 2015 Geriatric Medicine Journal Club (follow #GeriMedJC on Twitter). The full discussion can be found at: http://gerimedjc.blogspot.com/2015/04/april-2015-gerimedjc.html?spref=tw An interesting finding was that an acute bout of exercise may exacerbate orthostatic hypotension in short term. This review did not cover interventions like salt intake.


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    1. On 2015 Feb 09, David Keller commented:

      Dr. Lee,

      Your arguments against prescribing ezetimibe at this time are very persuasive, especially with regard to the cost of preventing cardiovascular events with this drug, even if the recent reports of such efficacy are eventually verified. This kind of perspective from a cardiovascular scientist is most beneficial to general internists like me.

      Your comments regarding rosiglitazone form a sort of inverse analogy to ezetimibe; if physicians who prescribed rosiglitazone are not to be condemned for "guessing wrong" in advance of the data proving that drug was harmful, then physicians who prescribed ezetimibe should not be congratulated for "guessing right" if this drug is proven to be beneficial. Good point.

      However, I chose never to prescribe rosiglitazone, even before its harmful outcomes were known. My decision was not due to luck or clairvoyance, but to the simple fact that rosiglitazone raises LDL cholesterol, and a very similar alternative drug (pioglitazone) exists which lowers LDL cholesterol instead. Knowing that every point of LDL increase in a diabetic is correlated with increased cardiovascular risk, I thought it would be folly to choose an agent which worsened LDL, even if it was only a surrogate marker.

      So, all of these examples get back to the question of the strength of LDL-lowering as a surrogate marker for reduction of cardiovascular events. The example of rosiglitazone versus pioglitazone seems to strengthen LDL as a valid surrogate marker for events. It appears that the new data for ezetimibe will also do so, if it confirms that this weak LDL-lowering drug also weakly improves cardiovascular event rates. Of course, ezetimibe still may not be worth its cost, as you point out, and that appears to be the bottom line, at least until ezetimibe is available as a cheap generic medication.


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    2. On 2015 Feb 03, Todd Lee commented:

      Dr. Keller,

      You do make a very interesting point about hindsight.

      It is a fact that billions of dollars have been spent in North America on a drug that, to date, does not have any high quality published evidence of efficacy in terms of clinical endpoints. This drug was thus used on the basis of theoretical arguments and a belief that lower LDL means lower events. The findings of IMPROVE-IT may suggest that some patients that have received this drug all of this time did derive benefit. However, based on the effect size in the trial and the patients enrolled, this may be the minority -- and at a considerable health care cost for each benefit.

      I'm really not sure what to infer about physicians who believed in the drug all this time. Are they to be commended for being correct?

      I'm not certain that money could not have been used for greater benefit with another intervention -- that is a question for health care economists; however, at $1,000,000 per event prevented (earlier post) it seems likely there may have been a more cost effective option.

      Let me contrast that with another example as I believe the case for ezetimibe and LDL is analogous to what people believed about hemoglobin A1c and the complications of diabetes. ROSIGLITAZONE was an extremely popular drug in 2006 -- to the tune of US prescriptions exceeding 2 billion dollars. This was because people inferred that lower A1c meant improved outcomes. Later, after the landmark paper showed that ROSIGLITAZONE might have been associated with increased cardiovascular risks, the sales plummeted to less than 15 million dollars in 2012. Thousands of lawsuits were settled and billion dollar fines were paid (for ROSIGLITAZONE and issues around other drugs) by the manufacturer. Furthermore, that drug was withdrawn from numerous European markets.

      I'm not sure what to infer about all of the physicians who believed in that drug. Are they all to be condemned? The answer is no. Physicians do the best they can for their patients within the limits of current medical knowledge. They had no a priori way of knowing that this intervention may actually harm patients more than help them.

      That said, it is not an accident that both agents were billion dollar winners for their prospective companies and that they were heavily marketed.

      Our group incidentally received a marketing pamphlet on ezetimibe in the mail today extolling the IMPROVE-IT trial. The jist of it: the lipid hypothesis is reaffirmed and ezetimibe has been proven effective in patients at risk of coronary artery disease. Does it matter that the paper hasn't been peer reviewed or put in the context of all of the negative papers before it? Not at all. That wouldn't be very good marketing.


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    3. On 2015 Jan 24, David Keller commented:

      Thank you, Dr. Lee, for that thorough, informative and excellent reply to my comment. For many years, I avoided prescribing ezetimibe (either alone or with a statin) due to the lack of data documenting improved outcomes. Prior to IMPROVE-IT, I would not have questioned the need for your study, and I would have been curious to learn why other clinicians were prescribing ezetimibe despite its interesting ability to improve lipids but not outcomes. Other non-statins which improve lipids - such as niacin, fibrates and bile acid sequestrants - had been able to demonstrate improved cardiovascular outcomes, at least in certain populations or under certain circumstances. The reports of improved outcomes from IMPROVE-IT seemed to reaffirm the importance of lowering LDL and to remove the major obstacle which had prevented me from adding ezetimibe when patients failed to achieve their LDL goal on a tolerable dose of statin. Based on the reservations you have expressed regarding IMPROVE-IT, I will hold back from prescribing it until the questions you raised are answered.

      For the sake of discussion, assume that cardiovascular outcome benefits of ezetimibe are eventually proved to your satisfaction. How, then, would that affect the utility of your investigation of why physicians were prescribing a drug which lacked outcome data, if their patients were thereby benefiting from lower event rates? These physicians may have prescribed ezetimibe based on their anecdotal experience with the drug, their knowledge of lipid physiology and pharmacology, or other factors, making them guilty of nothing more than being ahead of the randomized trial data, correctly predicting the outcome benefits of ezetimibe, and benefiting their patients with better outcomes sooner than more conservative physicians like me. Should we be trying to "correct" that kind of "mistake"?


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    4. On 2015 Jan 24, Todd Lee commented:

      As stated in our paper, we need the data from IMPROVE-IT to better inform us on the use of ezetimibe. However, rather than relying on a conference presentation and press releases we will also need to await the peer-reviewed and sponsor-independent analysis of the IMPROVE-IT trial to judge the quality of the results and evaluate their impact on general practice. Given interim analysis was performed (and the study was subsequently re-sized) any multiple comparisons performed will require expert statistical review.

      Furthermore, given no other positive studies exist, it may be prudent to perform an independent individual patient data analysis of all similar studies to better refine or confirm the estimate of effect prior to making any final conclusions from one trial.

      The net conclusion of this study, if the presented data is taken at face value, is a number needed to treat (NNT) of 50 over 7 years for the composite outcome. Overall mortality was not reduced. At generic Canadian prices it would cost approximately $58,765 to prevent 1 event over 7 years (Ontario formulary price as of January 2015). However, at US brand name prices of approximately $8.50 per day (Lexicomp 2015) the cost of preventing one composite outcome would be more than $1,000,000.

      It is also important to note that IMPROVE-IT was a secondary prevention study (acute event within 10 days) and not primary prevention. In primary prevention, the NNT is likely much higher and the corresponding costs per event prevented would increase proportionately and likely be substantial even at generic prices. In our cohort 6/17 (35%) were receiving ezetimibe for primary prevention.

      Whether the drug lowers event rates in the absence of a statin remains unproven and cannot be inferred from this study. Nonetheless, it will be interesting to see the effects on monotherapy uptake given the publicity around this study and also when IMPROVE-IT is ultimately published.

      The impact of this study on the uptake of other drugs approved on the basis of LDL as a surrogate marker is also not to be underestimated. The issue of treating to specific LDL targets is currently being debated amongst experts after recent changes to the guidelines. It would be somewhat naive to think that there isn't a substantial market pressure behind bringing back targets to be measured and obtained through additional medications.


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    5. On 2015 Jan 23, David Keller commented:

      Recent evidence of ezetimibe outcome benefits undermines the premise of this study

      The underlying premise of this study of ezetimibe prescribing patterns is that there is “a lack of evidence supporting its efficacy” in reducing adverse cardiovascular outcomes, despite its demonstrated efficacy in improving lipids and other surrogate endpoints (1).

      In the recently reported “IMPROVE-IT” study, patients taking ezetimibe plus simvastatin experienced significantly fewer major cardiovascular events (as measured by a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, rehospitalization for unstable angina or coronary revascularization occurring at least 30 days after randomization) than patients treated with simvastatin alone (2).

      Now that there is evidence that ezetimibe improves cardiovascular outcomes, the question of why clinicians prescribed it inappropriately in the past seems moot. Perhaps their clinical experiences using ezetimibe convinced them that evidence of beneficial outcomes would emerge over time. If ezetimibe was improving outcomes all along, then studies based on the premise that it should not have been used seem less relevant.

      References:

      1: McDonald EG, Saleh RR, Lee TC. Ezetimibe use remains common amongst medical inpatients. Am J Med. 2014 Oct 19. pii: S0002-9343(14)00917-6. doi: 10.1016/j.amjmed.2014.10.016. [Epub ahead of print] PubMed PMID: 25448168.

      2: Kohno T. Report of the American Heart Association (AHA) Scientific Sessions 2014, Chicago. Circ J. 2014 Dec 15. [Epub ahead of print] PubMed PMID: 25502168.


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    1. On 2017 May 21, Misha Koksharov commented:

      This paper provides interesting insights on the role of the 471–481 and 487–495 flexible regions in P. pyralis luciferase and on their utility in improving its thermostability.

      For those interested to investigate this topic further, I suggest to look also at the substitution D475P. As can be seen in the alignments below, this substitution occurs naturally in Luciola and in many other beetle luciferases:

      D476: http://forumbgz.ru/user/upload/file33577.gif

      D489: http://forumbgz.ru/user/upload/file33578.gif

      Moreover, in the available structures of L. cruciata luciferase the region 471–481 is not flexible - in contrast to P. pyralis enzyme - so I expect that this mutation should work (where the mutations D476P (Yu H, 2015) and D476N (Amini-Bayat Z, 2012) were inefficient). Interestingly, the successful substitution H489P also naturally occurs in many pH-insensitive luciferases (as shown in the alignments above).


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    1. On 2015 May 26, Paul Brookes commented:

      Portions of Figure 4 and Figure 5 from this paper appear more similar than would be expected by chance, when compared to portions of Figure 3 and Figure 8, from Zhao ZQ, 2012 Br J Pharmacol. 167, 1550-1562, PMID: 22823335

      Relevant information is available in the following two images... http://imgur.com/0DI1G78 http://imgur.com/u47Fdr8

      Usual disclaimers apply - i.e. go look for yourself at the originals and decide if they're similar, don't take my word for it, no implications about motives or underlying causes of this apparent similarity should be taken from this comment.

      That being said, the lead author has had two papers retracted for similar matters... http://retractionwatch.com/2015/05/26/heart-repair-study-retraction-marks-second-for-mercer-unviersity-researcher/


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    1. On 2016 Aug 24, 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 NCT097115. We believe the correct ID, which we have found by hand searching, is NCT01857388.

      This comment is being posted as part of the OpenTrials.net project<sup>[1]</sup> , 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


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    1. On 2015 Jul 24, Md. Shahidul Islam commented:

      The 2015 Islet Society Meeting took place in Sydney during 19-21 July, 2015. This meeting, organised by Anand Hardikar was also of high scientific quality. The 2016 Islet Society meeting will be in Istanbul (15-17 July, 2016). The organizer of 2016 meeting is Erdal Karaoz


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    1. On 2015 Mar 05, Anders Prior commented:

      High effect sizes and immortal person-time

      In a paper published in Medicine, Wang et al. presented this cohort study of 47,225 stroke patients.<sup>1</sup> (Wang JY, 2014) They concluded that the 30-day mortality after stroke was significantly reduced if treatment with antipsychotic drugs was initiated before or after the stroke.

      The reported effect sizes were very large; the mortality rate in stroke patients decreased by 73% in those who received antipsychotic treatment before the stroke and by 87% in those who received antipsychotic treatment shortly after the stroke. Effects of this size are rarely seen in such studies.

      The study was based on a nested case-control design. Included cases were stroke patients who died within 30 days after having a stroke, while controls (matched on age, gender and stroke date) were stroke patients who survived at least 30 days after their stroke. The main exposure was antipsychotic drugs given at any time within 30 days after the stroke date. Multivariate logistic regression was used to calculate odds ratios of mortality.

      We are concerned that the results may be substantially biased because the definition of the antipsychotic user group conditions on the future; in order to receive the antipsychotic treatment and become a member of the antipsychotic user group, study participants need to survive until the drug is prescribed. In other words, study participants in the antipsychotic user group are ‘immortal’ until the day of treatment (immortal person-time).<sup>2</sup> The authors do not describe any analytical measures taken to counteract this conditioning. If they have not taken this into account, this would pose a very serious problem as also described numerous times in the epidemiological literature.<sup>3</sup> (Hanley JA, 2014) Immortal time bias will generate an illusion of treatment effectiveness and is frequently found in observational studies that compare with non-users.<sup>4</sup> (Suissa S, 2007)

      In general, suspicion for immortal time bias should be raised when exposure groups are assigned with no regard to exposure time in a longitudinal study. Furthermore, the reported effect sizes are surprisingly high, especially when considering the fragility of the population in question. This group consists of stroke patients with complications; they may suffer from e.g. post-stroke delirium and may need antipsychotic treatment. They would most likely have more adverse outcomes, not the opposite.<sup>5,6</sup> (Shi Q, 2012, Prior A, 2014)

      Dr. Anders Prior, MD

      Research Unit for General Practice and Section for General Medical Practice, Department of Public Health, Aarhus University, Denmark

      Dr. Thomas Munk Laursen, PhD

      National Centre for Register-based Research, Department of Economics and Business, Aarhus University, Denmark

      Prof. Mogens Vestergaard, PhD

      Research Unit for General Practice and Section for General Medical Practice, Department of Public Health, Aarhus University, Denmark

      References

      1 Wang JY, Wang CY, Tan CH, Chao TT, Huang YS, Lee CC. Effect of different antipsychotic drugs on short-term mortality in stroke patients. Medicine (Baltimore). 2014;93(25):e170.

      2 Rothman KJ, Greenland S, Lash TL. Modern Epidemiology. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2008.

      3 Hanley JA, Foster BJ. Avoiding blunders involving 'immortal time'. Int J Epidemiol. 2014;43(3):949-961.

      4 Suissa S. Immortal time bias in observational studies of drug effects. Pharmacoepidemiol Drug Saf. 2007;16(3):241-249.

      5 Shi Q, Presutti R, Selchen D, Saposnik G. Delirium in acute stroke: A systematic review and meta-analysis. Stroke. 2012;43(3):645-649.

      6 Prior A, Laursen TM, Larsen KK, et al. Post-stroke mortality, stroke severity, and preadmission antipsychotic medicine use--a population-based cohort study. PLoS One. 2014;9(1):e84103.


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    1. On 2015 Jan 12, Larry Parnell commented:

      This paper was my selection for Paper of the Week for 1-5 Dec 2014.

      This is highly important work and the conclusions drawn are valuable and applicable to many areas of genetic research into complex phenotypes. It is great to see scientists of this stature adding important insight into the role of GxEs, especially in terms of influence on gene expression.

      I don't feel that the relationship described in this paper for ADIPOQ is so meaningful as the variant described is not in high LD in most populations with the ADIPOQ variants that support known GxE interactions for cardiometabolic phenotypes. See http://www.biodatamining.org/content/7/1/21 Nonetheless, there is also in the BioData Mining article a list of GxEs described for UCP2, which does have evidence in this report above.


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    1. 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 NCT0093283. We believe the correct ID, which we have found by hand searching, is NCT00932893.

      This comment is being posted as part of the OpenTrials.net project<sup>[1]</sup> , 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


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    1. On 2015 Jan 07, Mohammad Salman commented:

      I'm surprised by the findings of this paper since several authors have reported antiinflammatory effects of Thymoquinone and inhibition of COX-2 and PGE2 via Thymoquinone. See:

      1: Kundu JK, Liu L, Shin JW, Surh YJ. Thymoquinone inhibits phorbol ester-induced activation of NF-κB and expression of COX-2, and induces expression of cytoprotective enzymes in mouse skin in vivo. Biochem Biophys Res Commun. 2013 Sep 6;438(4):721-7. doi: 10.1016/j.bbrc.2013.07.110. Epub 2013 Aug 1. PubMed PMID: 23911786.

      2: Al Wafai RJ. Nigella sativa and thymoquinone suppress cyclooxygenase-2 and oxidative stress in pancreatic tissue of streptozotocin-induced diabetic rats. Pancreas. 2013 Jul;42(5):841-9. doi: 10.1097/MPA.0b013e318279ac1c. PubMed PMID: 23429494.

      3: El Mezayen R, El Gazzar M, Nicolls MR, Marecki JC, Dreskin SC, Nomiyama H. Effect of thymoquinone on cyclooxygenase expression and prostaglandin production in a mouse model of allergic airway inflammation. Immunol Lett. 2006 Jul 15;106(1):72-81. Epub 2006 May 22. PubMed PMID: 16762422.

      4: Marsik P, Kokoska L, Landa P, Nepovim A, Soudek P, Vanek T. In vitro inhibitory effects of thymol and quinones of Nigella sativa seeds on cyclooxygenase-1- and -2-catalyzed prostaglandin E2 biosyntheses. Planta Med. 2005 Aug;71(8):739-42. PubMed PMID: 16142638.


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    1. On 2014 Dec 06, Yannis Karamanos commented:

      This was not a "happy" idea to use ENGase for endoglucanase... This abreviation is in use, for many years, for endo-N-acetyl glucosaminidase


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    1. On 2015 Aug 17, Anders von Heijne commented:

      It is so interesting to compare the workings of our different healthcare systems. The type of order/referral for overread of outside radiological stuies described in this paper have been used in swedish radiology for at least as long as I have been in practice - ie at least for three decades. In addition to the obvious advantages described by the authors, the clinican that places the overread order can add relevant facts and queries in the new order. One easy way of documenting the outside report is to add it as a DICOM image to the study and save it in the PACS, rather than transfering it between different RIS.


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    1. On 2016 Feb 18, Kristina Hanspers commented:

      The pathway in figure 2 is available in the "Open Access Publication" collection at WikiPathways: http://www.wikipathways.org/index.php/Pathway:WP3297. This pathway can be downloaded for use in network analysis tools such as Cytoscape and PathVisio.


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    1. On 2015 Oct 22, Horacio Rivera commented:

      A de novo inv dup(1) turns out to be a rea(1)dup q chromosome I remark that the de novo mosaic 1q32→qter duplication onto 1pter (concomitant with a normal clone) described by Levy et al. [2015] is not an inverted duplication because direct and inverted duplications are officially defined as “a gain of a chromosomal segment observed at the original chromosome location” [Shaffer et al., 2013], not to mention that the orientation of the extra segment was indeed a direct one. It is significant that in their discussion, Lévy et al. [2015] refer to three other similar chromosome-1 rearrangements entailing an 1q duplication (although none with interstitial telomeric repeats) and visualize them as “recombinants” from an hypothetical pericentric inversion. In this regard, a compilation of 104 recombinant-like chromosomes of de novo or sporadic occurrence [Rivera et al., 2013] lists 11 other comparable chromosome-1 composites entailing dup q/del p but without an interstitial telomere. To avoid a nonsensical “der vs rec” controversy, we have designated such rearranged chromosomes with the official term rea coupled with the lengthy description of the novel composite [Rivera et al., 2013]. In that paper, we pointed out that “this formula makes no causal assumptions, unambiguously describes the rearranged chromosome, allows for a meiotic or mitotic origin, and is consistent with the involvement of 1 or 2 homologs”. Moreover, the term rea had already been used for this purpose [Thomas et al., 2006] and properly describes a rearranged unbalanced chromosome mimicking a recombinant ensued from a pericentric inversion as it is epitomized by the rea(1)(qter→q32::pter→qter) here alluded to. It goes without saying that inv dup is also improperly used to designate mirror structures such as isodicentrics and neocentric isofragments [e.g., Warburton et al., 2000]. Although Lévy et al. [2015] recognized that “[T]he recurrent nature of all these similar recombinants, including our dup(1q), suggests an identical mechanism of formation”, they failed to identify it. According to D’Angelo et al. [2009], who analyzed in fine detail two dup q/del p and two other comparable chromosome-1 rearrangements, the DNA repair mechanism of non-homologous end joining (NHEJ) appears to be “the pathway in the formation of these de novo nonreciprocal translocations, because of the lack of evidence to support a homology-based recombination mechanism”. Yet, the location in unique, non-repetitive DNA sequences of all the breakpoints in the four chromosome-1 rearrangements above mentioned [D’Angelo et al., 2009] may call into question the NHEJ mechanism for rearranged chromosomes with an interstitial telomere alike to the exceptional rea(1) documented by Lévy et al. [2015]. Because Lévy et al. [2015] also omitted some relevant references on other rearrangements with interstitial telomeres, I reiterate here the academic and moral duty that authors, reviewers, editors, and readers have to improve the current citation practices [Rivera, 2014]. Finally, I stress that seven months ago a Letter to the Editor with these comments was judged unacceptable by the concerned journal because “the conclusions of Dr. Levy's paper are really not about terminology and nomenclature”. REFERENCES D’Angelo CS, Gajecka M, Kim CA, Gentles AJ, Glotzbach CD, Shaffer LG, Koiffmann CP. 2009. Further delineation of nonhomologous-based recombination and evidence for subtelomeric segmental duplications in 1p36 rearrangements. Hum Genet 125:551-563. Lévy J, Receveur A, Jedraszak G, Chantot-Bastaraud S, Renaldo F, Gondry J, Andrieux J, Copin H, Siffroi J-P, Portnoï M-F. 2015. Involvement of interstitial telomeric sequences in two new cases of mosaicism for autosomal structural rearrangements. Am J Med Genet Part A 167A:428-433. Rivera H. Commentary: peer review and incomplete reference lists. 2014. Account Res 21:138-141. Rivera H, Domínguez MG, Vásquez-Velásquez AI, Lurie IW. 2013. De novo dup p/del q or dup q/del p rearranged chromosomes: review of 104 cases of a distinct chromosomal mutation. Cytogenet Genome Res 141: 58-63. Shaffer LG, McGowan-Jordan J, Schmid M. 2013. ISCN 2013: an international system for human cytogenetic nomenclature (2013), Basel, S Karger. p. 69. Thomas NS, Durkie M, Van Zyl B, Sanford R, Potts G, Youings S, Dennis N, Jacobs P. 2006. Parental and chromosomal origin of unbalanced de novo structural chromosome abnormalities in man. Hum Genet 119: 444-450. Warburton PE, Dolled M, Mahmood R, Alonso A, Li S, Naritomi K, Tohma T, Nagai T, Hasegawa T, Ohashi H, Govaerts LC, Eussen BH, Van Hemel JO, Lozzio C, Schwartz S, Dowhanick-Morrissette JJ, Spinner NB, Rivera H, Crolla JA, Yu C, Warburton D. 2000. Molecular cytogenetic analysis of eight inversion duplications of human chromosome 13q that each contain a neocentromere. Am J Hum Genet 66:1794-1806.


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    1. On 2015 Jan 26, Vojtech Huser commented:

      This is a report on a clinical trial and it is mentioned in the abstract (NCT02231866). Ideally, the identifier would be within the PubMed [SI] field. This results in this result article not displaying as linked on ClinicalTrials.gov


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    1. On 2014 Nov 27, Jürgen Hänggi commented:

      Dear community

      this new study shows that a recently published "apparent" sex effect in the form of "increased interhemispheric connectivity in women and increased intrahemispheric connectivity in men" (see http://www.ncbi.nlm.nih.gov/pubmed/24297904) is driven by brain size and not by sex per se.


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    1. On 2015 Sep 03, Lydia Maniatis commented:

      It seems generally to be the case that when a darkish-looking surface grows in area, it appears to lighten. There is no doubt that this occurs, and also no doubt that the effect is subject to a large degree of variability between experiments and between individuals. Boyaci et al (2014) report, as their main finding, that the effect occurs in the context of "computer-rendered scenes" (their stimuli) as well as in the context of "real scenes" (referring to the rarefied laboratory set-up of Radonjic and Gilchrist (2014)).

      As a way of describing experimental conditions - whose results, moreover, were subjected to technical analyses to determine which datasets fit a linear model, a quadratic model, a one-phase model, a two-phase model, and used to form hypotheses about the neurophysiological underpinnings of performance and to judge conceptual models - the crude distinction between "computer-rendered" and "real" seems rather insufficient. Indeed, when it comes anything more specific than the general consistency with the "larger gets lighter" effect, all bets are off. Noting that their results were different from those of Radonjic and Gilchrist (2014), the authors speculate simply that: "The disagreement between our studies is likely to be because of differences between the stimuli." More specifically: "Whereas their stimuli (Radonji砦 Gilchrist, 2014) were real and as simple as possible, ours were computer generated and relatively more complex." Like the unqualifed "real" vs "computer-generated" distinction, the "simple vs complex" distinction is too vague for the purpose. Very subtle and neurophysically complex perceptual operations can be triggered by geometrically simple stimuli. Surely, mathematical modelling and theoretical/neurophysiological extrapolations should follow, not precede, qualitative understanding of a phenomenon and the effects of conditions. Otherwise, such speculation is strictly ad hoc.

      The "area rule" as originally proposed said more than that the darker of two areas will lighten with area. It said that this lightening of the darker area will "anchor" cause the appearance of the lighter area such that it brightens and eventually becomes luminous. The proposal was made in order to rationalize the luminosity observed in the disc in classic disc/annulus experiments, without having to ascribe a role to figure-ground organization. The predicted changes in the lightness of the lighter area qua area apparently haven't been corroborated and are no longer referred to or tested for. As an isolated phenomenon not affecting surrounding surfaces, it's hard to see the theoretical importance of a highly-variable and condition-sensitive tendency toward lightening of relatively darker surface with increases in area, or the value of making fussy models of this tendency, tailored to particular stimuli.

      I would also like to take issue with the choice of references the authors chose to support their opening assertion that "The lightness of a surface depends not only on its luminance but also on its geometry and the context within which it is viewed (Boyaci, Doerschner, Snyder, & Maloney, 2006; Gilchrist, 2006; Kingdom, 2011; Maloney, Boyaci, & Doerschner, 2005; Maloney, Gerhard, Boyaci, & Doerschner, 2010)." The case for this was made in classic literature and experiments well before 2006. The assertion is so fundamental and uncontroversial that references are not even necessary.


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    1. On 2015 Nov 04, Lydia Maniatis commented:

      Continuation of "area rule" story: Avoiding acknowledging the role of figure-ground in contrast effects also allowed advocates of "anchoring theory" to claim that "the debate seems to revolve around layer models and framework models" (Gilchrist, 2015), frameworks being adjacent "like countries on a map." Figure-ground structure means layers, and so would complicate this presentation.


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    2. On 2015 Sep 20, Lydia Maniatis commented:

      In line with the earlier point about avoiding figure/ground issues, the "multi-sector" stimuli used here are of the sort used by Gestalt psychologists to demonstrate and study figure-ground effects (e.g. the role of sector color, size, orientation; bistability). But such effects and their potential lightness consequences are not acknowledged.


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    3. On 2015 Sep 17, Lydia Maniatis commented:

      "Simple" vs "complex" stimulus is not a meaningful distinction, because there is no objective criterion for making it. Geometric simplicity may or may not produce complexity in the percept, of different kinds.

      Which is more simple: a. the three pacmen of a Kanizsa triangle, that produce subjective contours/ contrast/amodal completion; b. the simultaneous contrast effect that produces contrast and amodal completion? c. the de Valois checkerboard that produces assimilation; d. a random array of variously shaped, overlapping white, grey, black shapes? e. the checkerboard used here, which produces transparency/inhomogenous illumination effects; f.a black shape that produces the impression of two overlapping black shapes; g. etc.

      The authors offer their own “clear distinction” of simple vs complex. Not only is this proposed distinction unclear, it lacks theoretical content. The authors subsequently seem to ignore it, and use the terms in a loose and undefined way. The proposed distinction, attributed to “anchoring theory” is: “A simple image is one in which all the surfaces lie within a single illumination level (a single framework) whereas complex images contain multiple adjacent fields of illumination (multiple frameworks).” This distinction is theoretically hollow, because it references actual (actual level of illumination) and not perceived (perceived illumination) image features. By this definition, a photograph of sunlight and shadow should count as a single framework, provided it is being viewed under a homogeneous illumination. Even if we take the authors' distinction to refer to perceived illumination (which begs the question the “frameworks” argument is supposed to answer, i.e. how do we parse the scene into separate illumination “frameworks”), they don't stick to it. A little later, for example, we are told that the stimuli of Boyaci et al (2014) “are still fairly simple, [but] qualify [] as complex as they consist of more than one framework” (the distinction is invoked to explain discrepancies between those authors findings and the findings of R and G (2014). But Boyaci et al's stimuli are neither under inhomogeneous illumination nor are they designed to create such an impression. So the definition of “framework,” which wasn't explanatory to begin with, has shifted in the space of a few paragraphs, from “framework of illumination” to something else (what?). We are similarly told that “a dozen previous experiments...used images that qualify as complex images;” but many (perhaps all) of these studies did not involve inhomogeneous illumination, real or perceived.


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    4. On 2015 Sep 17, Lydia Maniatis commented:

      A short, instructive history of the “area rule”

      The “area rule” was born in an attempt to deny the role of figure-ground structure in lightness. This is its original sin, and has led to interesting distortions in theory and practice.

      Classic disc-annulus experiments, which demonstrated the dependence of lightness on luminance ratios, also showed an asymmetrical influence of disc and annulus. The annulus would always look white, and push a lighter disc towards luminosity. In other words, raising the luminance of the annulus would lighten the disc, but not vice versa. The disc appeared to lie on top of an amodally-completed larger disc, so an easy provisional conclusion would be to assign different influences to figure and ground in mediating lightness perception of a surface (the same asymmetry applies to figure-ground contrast in general).

      Gilchrist et al (1999) did not like this solution because it interfered with their preferred theoretical assumption that the highest luminance in a (vaguely-defined) “framework” would be white. Clearly, in the very simple, disc-annulus situation, the highest luminance was not necessarily white. Instead of acknowledging a role for figure-ground, Gilchrist et al (1999) created a new rule, stating that if the darker area was more than 50% larger than the smaller, then it would lighten, and progressively push the smaller, lighter area toward luminosity. They presented a speculative function, reprinted in Gilchrist and Radonjic (2009), that has never been corroborated, despite a number of attempts.

      The Gilchrist group's own results constantly cried out for a figure-ground explanation. Tellingly, they were forced to modify their area claim to include “amodally-completed” area – thus in effect making the area rule indistinguishable from a figure-ground claim. Later, Economou et al (2007) acknowledged a similar, figure-ground-related asymmetry in the simultaneous contrast display. The team acknowledged the asymmetry but did not explore it further.

      Preserving the highest-luminance-white rule was not the only or even most important incentive for rejecting a possible figure-ground role. Another fundamental claim of Gilchrist et al (1999) was that the classic simultaneous contrast demonstration is due to a process which, at a certain stage, treats each square and its interior as a separate “framework” and evaluates its contents based on the ratio principle and highest-luminance rule. The idea that the lightness of the targets is actually mediated by local luminance contrast between the apparent figure and its background was not compatible with this assumption. However, it is easy to show (Maniatis, 2015), by adding surfaces within each putative “framework” that border contrast between figure and ground, not the ratios with all surfaces contained in the background square, mediates this effect.

      The commitment to avoiding acknowledging a role for figure-ground explains, I believe, the preference manifested by investigators with these theoretical commitments for stimuli which either did not produce figure-ground effects, or in which the contrast effects would average out. Specifically, they adopted the use of checkerboards or Mondrians, and random or semi-random selection of luminances. Such stimuli and choices muddy rather than clarify the role of structure in lightness. Thus, proponents of a “Gestalt” theory, were, paradoxically forced by their commitments to prefer stimuli in which image structuring could be ignored.

      There was a second reason that this “Gestalt” theory needed to avoid confronting the role of structure in lightness, and this was that it did not/could not address the fact that we sometimes perceive surfaces as lying beneath transparent layers with their own lightness. As in the case of figure-ground/amodal completion effects, such layers arise when contours showing good continuation intersect, with the added proviso that the luminance structure is compatible with such a solution. Checkerboards, lacking such cues, avoid such effects.

      Well, actually, they don't. They often produce multiple such effects, as well as luminosity. This latter result arose in Radonjic et al (2011). It was awkward and they tried to explain it away by selectively attributing inconvenient results to presentation on an “emissive” screen. Allred et al (2012) tentatively acknowledged, after much highly technical wrestling with very low-resolution data, the self-evident yet apparently unplanned-for fact that checkerboards do produce differential lightness impressions. So restricting the class of allowable stimuli (rationalized on the basis that they were “simple” and that results would carry over to more “complex” situations – a view codified in the oft-repeated “applicability assumption”) in order to avoid confronting figure-ground and transparency effects has nevertheless led researchers back to these same, unavoidable issues.

      It is interesting that the checks on a checkerboard can coalesce into transparent overlays/underlying surfaces despite the absence of apparent overlap. It is surely not unrelated to the fact that checkerboards produce assimilation rather than contrast when we replace a black or white check with a grey one (the de Valois and de Valois checkerboard contrast demonstration). It would be worth analyzing.


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    5. On 2015 Aug 12, Lydia Maniatis commented:

      This article is a bit misleading. The authors seem to be claiming to have corroborated the area rule, at least for the case where the darker area fills more than half the visual field.

      As defined and illustrated by Gilchrist et al (1999) and Gilchrist and Radonjic (2009), the area rule predicts the onset of luminosity when the darker area exceeds half the display. But this prediction has never been corroborated, even for far, far larger darker area coverage, nor has the description of the rule changed. In addition, lightening of the darker are has never been shown to start until the latter covers far more than 50% of total area. So the claim that this study has corroborated the "area rule" needs to be qualified by the introduction of a new description of the area rule.


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    1. On 2013 Oct 25, DAVID SANDERS commented:

      From the abstract of Ueda T, 1989

      "Two proteins stimulating the GTPase activity of the smg-21 GTP-binding protein (smg p21) having the same effector domain as the ras proteins (ras p21s) are partially purified from the cytosol fraction of human platelets. These proteins, designated as smg p21 GTPase activating protein (GAP) 1 and 2, do not stimulate the GTPase activity of c-Ha-ras p21. smg p21 GAP1 and 2 are separated from c-Ha-ras p21 GAP by column chromatographies. The activity of smg p21 GAP1 and 2 is killed by tryptic digestion or heat boiling. The Mr values of smg p21 GAP1 and 2 are similar and are estimated to be 2.5-3.5 x 10(5) by gel filtration analysis. These results indicate that there are two GAPs for smg p21 in addition to a GAP for c-Ha-ras p21 in human platelets."


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    1. On 2014 Dec 10, Alberto Zambrano commented:

      Dear Ilya, The Ab used was initially described by Dr. Sonenberg (Mol Cell Biol. 1998 Jan;18(1):334-42, A novel functional human eukaryotic translation initiation factor 4G.) and was kindly donated by Dr. Cesar de Haro (CBM, Madrid, Spain) There you can see that the size of the recombinant form of EIF4G2 (His-tagged) (Figure 3) recognized by the Ab is a little bit lower than 206 KDa. You can also see another prominent band higher than 117KDa, recognized by the Ab. In a another article from the same author (J Neurosci. 2012 Apr 18;32(16):5620-30. doi: 10.1523/JNEUROSCI.0030-12.2012. Regulation of neuronal mRNA translation by CaM-kinase I phosphorylation of eIF4GII) the same Ab was also used but, unfortunately the protein markers were not indicated. In our blots, the Ab reactivity shows either a prominent, discrete band or a doublet at size indicated. We don't observe any other significant reactivity in the full blots. In addition, those bands were sensitive to specific specific siRNA downregulation (figure 5). We don't have a clue about the origin of such differential electroforetic mobility differencies, described in the original paper or in ours (in MEFs, with respect to the predicted size but with the evidences we had, we assumed that protein identity.


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    2. On 2014 Dec 01, Ilya M Terenin commented:

      Ghm... Guys, why your eIF4G2 is heavier than 150 kDa on blots? The protein is ~100 kDa.


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    1. On 2014 Dec 03, Rafael Najmanovich commented:

      We predicted back in 2012 (Chartier M, 2012) as part of a large scale analysis of rare codon cluster that such clusters may play a role in the molecular recognition of the nascent protein for intracellular targeting and membrane insertion. It is unfortunate that the authors were not aware of our publication.


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    1. On 2015 Jan 03, William Grant commented:

      Here are some papers not included in this review showing benefits of vitamin D testing. Peiris AN, Bailey BA, Grant WB, Mascitelli L. Vitamin D testing. Lancet 2012 May 5;379:1699-1701.

      Der T, Bailey BA, Youssef D, Manning T, Grant WB, Peiris AN.,Vitamin D and prostate cancer survival in veterans. Military Med. 2014;179 (1) :81–84.

      Peiris AN, Bailey BA, Manning T. Relationship of vitamin D monitoring and status to bladder cancer survival in veterans. South Med J. 2013 Feb;106(2):126-30.

      Bailey BA, Manning T, Peiris AN. Vitamin D testing patterns among six Veterans Medical Centers in the Southeastern United States: links with medical costs. Mil Med. 2012 Jan;177(1):70-6.

      Of course some may have been published after your literature search was completed. However, they do support the benefits of vitamin D testing among hospital patients.

      Also, this paper is supportive in that it found that patients in the ICU with very low 25OHD concentrations benefited from vitamin D supplementation. Amrein K, Schnedl C, Holl A, Riedl R, Christopher KB, Pachler C, Urbanic Purkart T, Waltensdorfer A, Münch A, Warnkross H, Stojakovic T, Bisping E, Toller W, Smolle KH, Berghold A, Pieber TR, Dobnig H. Effect of High-Dose Vitamin D3 on Hospital Length of Stay in Critically Ill Patients With Vitamin D Deficiency: The VITdAL-ICU Randomized Clinical Trial. JAMA. 2014 Oct 15;312(15):1520-30.

      One of the impediments to acceptance of vitamin D seems to be the lack of supportive trials. The trials have not supported the ecological and observational studies largely because the trials have not been properly designed. Too often, people with normal to high 25OHD concentrations are enrolled and given a small amount of vitamin D. The proper way to conduct such trials was outlined recently in this paper: Heaney RP. Guidelines for optimizing design and analysis of clinical studies of nutrient effects. Nutr Rev. 2014 Jan;72(1):48-54.

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


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    1. On 2014 Nov 25, Robert Eibl commented:

      Sounds like a very good step forward in understanding these cells.


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    1. On 2015 Jan 12, Larry Parnell commented:

      This paper was my selection for Paper of the Week for 10-14 Nov 2014.


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    1. On 2015 Mar 22, Sean Ekins commented:

      And here is a post on the letter from editor http://www.collabchem.com/2015/03/22/what-warrants-an-erratum-and-why-the-old-publishing-model-must-change/


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    2. On 2015 Mar 22, Sean Ekins commented:

      Here is the letter CAS sent to J Med Chem Editor (which was forwarded to me) regarding this paper http://figshare.com/articles/jm_2014_011308_CAS_report_of_error_2_pdf/1348274 alerting us to 20 document records for one patent which were not visible to us when the analysis was done in 2014.


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    3. On 2015 Feb 11, Christopher Southan commented:

      None


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    4. On 2014 Dec 17, Sean Ekins commented:

      Here are some slides on this work http://www.slideshare.net/ekinssean/medicinal-chemistry-due-diligence-computational-predictions-of-an-experts-evaluation-of-the-nih-chemical-probes


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    5. On 2014 Dec 17, Sean Ekins commented:

      Here is a link to a post discussing this paper and also link to in the pipeline mention https://www.collaborativedrug.com/buzz/2014/12/16/beware-researchers-challenges-navigating-commercial-and-public-databases/


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    6. On 2014 Dec 15, Sean Ekins commented:

      Also added in my summary of 2014 papers http://www.collabchem.com/2014/12/15/a-year-in-publications-2014/


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    7. On 2014 Dec 04, Sean Ekins commented:

      Here is a link to a discussion of the peer review of this paper and it includes all reviewer comments http://www.collabchem.com/2014/12/04/chemical-probes-and-parallel-database-worlds-who-wants-to-know-more-publishing-fun/


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    8. On 2014 Dec 02, Nadia Litterman commented:

      Here is a link to the related paper on using maching learning to model an expert's evaluations and due diligence: http://www.ncbi.nlm.nih.gov/pubmed/25244007


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    9. On 2014 Nov 29, Christopher Southan commented:

      Comparative statistics updated and live links added at http://cdsouthan.blogspot.se/2014/11/pmid-25415348-back-story-on-bioactivity.html


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    1. On 2014 Nov 28, Paolo Tieri commented:

      This article is one of the "Multi-omic Data Integration" Research Topic in Frontiers, which focuses on data integration approaches and methods of any type and extent, their application in understanding the pathogenesis of specific diseases or in identifying candidate biomarkers, in order to exploit the full benefit of multi-omic datasets and their intrinsic information content. For more information about multi-omic data integration check http://journal.frontiersin.org/ResearchTopic/2280


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    1. On 2015 Jan 29, Christopher Southan commented:

      Please make the separate molecular classes (the numbers of which are specified in the abstact) available for download. This should have been a condition for publication. I cant even open the CFAM seed file.


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    1. 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 NCT0160325. We believe the correct ID, which we have found by hand searching, is NCT01603251.

      This comment is being posted as part of the OpenTrials.net project<sup>[1]</sup> , 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


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    1. On 2015 Apr 06, Jeffrey Ross-Ibarra commented:

      Muñoz-Fuentes et al. offer an interesting look at the relationship between domestication and recombination rate in animals. A quick correction worth mentioning: while they cite my 2004 paper on recombination and domestication in plants (PMID: 14767840) several times, it's done somewhat out of context. They quote me as saying

      '"recombination rate is likely of little importance" in relation to plant domestication (Ross-Ibarra 2004)'

      whereas the actual quote from my paper clearly referred specifically to preadaptation:

      "Other hypothesized genetic preadaptations, such as polyploidy (Hilu 1993), have been shown to be unimportant in determining the successful domestication of plant species, and the present analysis suggests that recombination rate is likewise of little importance."

      and the abstract is fairly unambiguous:

      "The results support the hypothesis that domestication selects for an increase in recombination..."


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    1. On 2014 Nov 30, Hilda Bastian commented:

      Thanks for the helpful and informative reply, Tetyana.

      While modeling can take account of some known variables, it can't overcome the limitations of measures based on these traditional theories. Other mechanisms that could explain the results remain. There are assumptions used to explain the results of these data simulations (such as that hiring and firing exposes people to conflict and hostility, but pay decisions do not) that remain open to question.

      The results do not exclude the possibility that the women did not have enough authority in comparison with the men with whom they were compared, or other associated (in)tangible benefits that the men could take for granted with the "hire/fire/influence pay" status. Having equal status may indeed have brought similar benefits. Adequate markers for a particular status attainment for the original in-group from whom the measures were derived, may lack the power to discriminate unequal status for others. If so, then like is not necessarily being compared with like. It wasn't possible to "take all other job characteristics into account," because they weren't measured.

      Using unreported modifications of measurement tools for the key outcome makes it difficult for others to be able to assess the validity of the data and its interpretation. It would be helpful if that were done within the larger project, and linked here. Depression implies an adverse mental health condition (both in the community and clinically), and the study's conclusions refer to health benefits, not happiness. The CESD has cut-offs for symptomatology that has no clinical relevance.

      While there's no doubt that workplace circumstances for women and other traditional "out groups" must change, I don't believe on the basis of this data that people should believe that workplace authority over others per se makes women depressed. But the data are enormously valuable, and this work is indeed an important contribution to addressing an important social issue. Thank you for that, as well as the additional information in your reply.


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    2. On 2014 Nov 30, Tetyana Pudrovska commented:

      Dear Hilda, thank you for your thoughtful and insightful comments and for engaging in this dialogue. It was a pleasure to ponder over the points you made and to consider our methodology, data, and findings from another perspective. Below are some of my thoughts.

      1. The measure of depression does not have a clear clinical relevance. Different terms are used interchangeably. Each item is coded 0 or 1.

      The most widely used term for the CES-D scale is depressive symptoms. We also use depression because it is a very general term that doesn’t refer to a clinical diagnosis. Depression is not a disease in the DSM, “major depressive disorder” is.

      The CES-D items (like almost all other measures of self-reported physical and mental health) are highly skewed because most people report no depressive symptoms. Hence, the dichotomization of each item. We conducted a variety of sensitivity analyses using different coding approaches for the outcome, such as averaging all items and taking a natural log to reduce the positive skew, and the findings were remarkably similar.

      The issue of using continuous scales vs binary diagnoses has received a lot of attention in sociology of mental health. Both approaches have strengths and weaknesses. Our findings hold in a variety of alternative models when we use a binary measure with a cutoff at the 75th percentile or at 10+ symptoms.

      Sociologists typically prefer continuous scales because they are better for capturing the stressful consequences of social inequality. Unlike clinicians, sociologists are interested in the full spectrum of mental health, not only its negative extremes. To uncover the effects of social structures and social relationships on individual mental health, we need a continuum from mild to very severe that enables us to compare social groups on this scale. Binary diagnoses can obscure important differences because people who have, for example, 5 symptoms are in the same category as people who have no symptoms.

      Because the effects documented in our study are large in magnitude and statistically significant after adjustment for many factors that are traditionally used to explain women’s higher depression, our findings provide important insights into the psychological consequences of social arrangements.

      Ultimately, clinical relevance is not consistent with the brunt of our argument. One of the major implications of our study is that a higher level of depression among women in authority positions is not a clinical issue that can be addressed by diagnosing and treating specific individuals. It’s a social issue that should be addressed at the macro-level of society and the meso-level of organizations.

      2. The observed differences in depression may reflect not the effect of job authority itself but the effects of many other job characteristics that differ between men and women with job authority.

      The workplace situation is certainly not equal between men and women in authority positions. It is well-documented that in the same occupations and at the same levels of human capital characteristics, women have lower earnings, lower autonomy, and lower levels of many other desirable workplace characteristics than men.

      Yet, the gender difference in depression documented in our study is not due to the differences in other job characteristics between men and women. Our models control for all these variables, and the effects of job authority are observed after we take all other job characteristics into account.

      In addition to multiple regression, we use counterfactual approach to improve causal inference. It’s also called a “quasi-experimental” design because it simulates random assignment in an experiment. Our approach matches people with job authority (the “treatment” group) and people without job authority (the “control” group) in 1993 on many characteristics, including baseline depression, education, occupation, earnings, weekly hours, job characteristics and job satisfaction, marriage, parenthood, and early-life characteristics, especially parents’ socioeconomic resources. By matching people, we make the two groups as similar as possible with the exception of job authority and then see how depression changes over time based on people’s authority status in 1993.

      It is also important that we conduct not only between-gender comparisons but also within-gender comparisons. Women with job authority have more depressive symptoms compared to women without job authority. In contrast, men with job authority have lower depression than men without job authority. What’s striking is that women with job authority in our study are socially advantaged in terms of most socioeconomic characteristics that are strong predictors of positive mental health. These women have more education, higher income, more prestigious occupations, and higher levels of job satisfaction and job autonomy than women without job authority. By all traditional models of socioeconomic status and health women with job authority should fare better than lower-status women. Yet we find the opposite.

      3. Absence of direct measures of interpersonal stress, harassment, and prejudice.

      Ideally we’d certainly like to have all possible measures of interpersonal stress and discrimination. But such a data set simply does not exist. The Wisconsin Longitudinal Study (WLS) that we use is currently among the best for our purposes. We are doing more work with other data sets, including the National Longitudinal Surveys, but all data have their advantages and limitations. So we are launching our own data collection. The current study, by documenting these patterns and providing a theoretically and empirically grounded interpretation, makes an important contribution and one of the first steps to address an important social issue.

      The WLS has very rich array of measures of job characteristics. We include all variables that are considered main stressors in traditional theories of work stress. Yet, the effect of job authority persists net of these traditional explanations, which bolsters the indirect evidence for the mechanisms we propose.

      The WLS started in 1957 and is still ongoing. We have information about our participants’ employment histories for the last 55 years. Job authority (but not depression) was measured for the first time in 1975 when our participants were 36 years old. We used this earlier measure of job authority in related articles that are all components of a larger project.


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    3. On 2014 Nov 29, Hilda Bastian commented:

      This paper uses the terms "depressive symptoms" and "depression" interchangeably. However, the relationship between the screening questions asked and the "clinical" condition of depression is unclear. A modified form of an unspecified version of the CESD screening tool was used. It included an unspecified 10 of the 16 CESD questions, applied only for the last week. In a further variation to the CESD, answers were scored with only a dichotomous outcome.

      The cut-off for determining "depression" was also not explained and the "clinical" relevance of the measure (and associated increase) is unclear. If there has been a validation of an association between the scores used here and depression, it was not referred to in the paper. More details on this would be helpful to people interested in interpreting the results of this study.

      The workplace situation was not equal between the men and women bracketed in the same job authority categories in this sample. The women worked fewer hours per week, earned less than the men of the same age, and were supervised more often. It's women's job authority with less pay and less freedom than men's job authority that is being compared. That would also be a function of the gender inequality the authors identify as a clear problem here. But it raises a question about the level of emphasis given to the psychological impact of having supervisory authority, and, therefore, to know what to do about it.

      The range of workplace factors addressed by this study include the traditional ones related to autonomy. Those questions don't address the kinds of gender-related issues the authors point to in the literature as constituting psychological workplace adversity for women in management: such as endemic social exclusion by peers and supervisors, frequent slights from all directions, being judged more frequently as socially disruptive, unequal opportunity and status attainment, and harassment. More sensitive tools (and relevant data from before the age of 54) would have been needed to unpack what made that generation of women unhappier than the men. The underlying point these authors show, though - that psychological aspects of the workplace experience have serious bearing on women's happiness - is a critical one.

      The full text of this article is available here.


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    1. On 2015 May 31, Shin Lin commented:

      This response discusses the manuscript submitted by Gilad and Mizrahi-Man at F1000Reseach, as well as our two responses at that journal. For details, we encourage interested individuals to read those various pieces.

      The batch effect that Gilad and Mizrahi-Man present as confounders of our findings are not the result of experimental protocols. Our sequencing libraries were largely prepared in one sitting by the same person, and we used matched primer indices/barcodes to minimize variation as observed in 't Hoen PA, 2013. The potential batch effect to which Gilad and Mizrahi-Man are referring is from sequencing on different lanes/flow cells/sequencing machines. In our experience, these effects are small (also found in 't Hoen PA, 2013), and we did not observe any such effects in the original published data. However, to further settle the issue, we reconstructed the sequencing libraries under a different multiplexing scheme to address their concerns, and we found the same clustering pattern as originally presented by Lin et al. Thus, we emphatically disagree with the conclusion from Gilad and Mizrahi-Man that our conclusions are “not warranted,” but rather, we argue that objective normalization procedures allow the discovery of the clustering of transcriptomes by species.

      Gilad and Mizrahi-Man found clustering by tissue after normalization, because in their attempt to account for lane/flow cell/sequencing machine effect, they normalized away the species effect. In that set of experiments, tissues of the same species were multiplexed on the same sequencing lane; accounting for primer indices would not have been possible otherwise. That normalization of the data by each species separately causes clustering by tissue was known to authors of Lin S, 2014, as this observation was presented in the Mouse ENCODE main paper Yue F, 2014.

      Gilad and Mizrahi-Man's work focused on one particular dataset in Lin S, 2014. However, that paper contains a principal component analysis (PCA) on data from multiple sources: Stanford (human, mouse), Salk (human), HBM (human), LICR (mouse), and CSHL (mouse). There are undoubtedly many technical differences between the various sources. Yet, the clustering by species was seen in higher order principal components (PCs) (see Figure 1A Lin S, 2014); clustering by tissues, in lower components (Figure 1B in Lin S, 2014) or by normalizing species separately (Extended Data Fig. 1C of Yue F, 2014). The same behavior is seen in the Stanford-only data—both in Lin S, 2014, which minimizes primer index effect (Figure 1C & 1D) and now the newly generated results that account for lane effect. The latter are consistent with our earlier observation that experimental batch did not drive the species-specific clustering.

      As for the latest criticisms concerning sample collection, these are issues outside the scope of the manuscript by Gilad and Mizrahi-Man. We state that our procurement practices are consistent with what other investigators have done and continue to do. When we limit our analyses to the small number of tissues examined by recent studies showing tissue specific-clustering (i.e. those with a large number of tissue-specific genes), we also find tissue specific clustering (see Figure 1F in Lin S, 2014). Thus, there are no inherent biases in our data which account for species-specific clustering. Rather, it is our complete dataset with many additional tissue types which results in the different clustering pattern. This evaluation of a broad tissue set is the critical difference which led to our finding of species-specific clustering. Indeed, when we examine the broad dataset of mouse and human CAGE expression data from the Riken Fantom 5 project (FANTOM Consortium and the RIKEN PMI and CLST (DGT)., 2014), we confirm species-specific clustering.

      Finally, as stated in the F1000 comment, we reiterate our enthusiasm of the mouse as a vital model system for experimental research, because of its many similarities to humans, which we show in our PNAS paper. However, an appreciation of the differences which exist between human and mouse will allow investigators to better interpret the disparities which are encountered when applying findings in the mouse model to humans.

      ***New data mentioned herein is available for download at the Mouse ENCODE website.

      Shin Lin<sup>1,2</sup> , Yiing Lin<sup>3</sup> , Michael A. Beer<sup>4</sup> , Thomas R. Gingeras<sup>5</sup> , Joseph R. Ecker<sup>6,7</sup> , Michael Snyder<sup>1</sup>

      <sup>1</sup> Department of Genetics, Stanford University, 300 Pasteur Drive, M-344 Stanford, California 94305; <sup>2</sup> Division of Cardiovascular Medicine, Stanford University, Falk Building, 870 Quarry Road Stanford, California 94304; <sup>3</sup> Department of Surgery, Washington University School of Medicine, 660 S. Euclid Ave., Campus Box 8109, St. Louis, Missouri 63110; <sup>4</sup> McKusick-Nathans Institute of Genetic Medicine and the Department of Biomedical Engineering, Johns Hopkins University, 733 N. Broadway, BRB 573 Baltimore, Maryland 21205; <sup>5</sup> Cold Spring Harbor Laboratory, Functional Genomics, 1 Bungtown Road, Cold Spring Harbor, New York 11742;<sup>6</sup> Genomic Analysis Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037; and <sup>7</sup> Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA 92037.

      Acknowledgement: We thank the other members of the Mouse ENCODE consortium in formulating this response.


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    2. On 2015 May 26, Steven Salzberg commented:

      Serious technical questions have been raised about the main conclusion of this paper. Specifically, Yoav Gilad and Orna Mizrahi-Man described how the human and mouse samples were processed separately in several ways, any of which could lead to a significant "batch effect." They published some of their findings in F1000 Research, at http://f1000research.com/articles/4-121/v1. They showed that after removing the batch effects, the finding that human and mouse genes cluster separately completely disappeared. In the discussion of that paper on the F1000 site, further sources of batch effects were identified. Thus it appears that the main finding of this paper cannot be supported by the data, because the samples from human and mouse were handled and processed in distinct ways, confounding the batch effect and any possible biological effect.


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    1. On 2015 Jan 24, Wichor Bramer commented:

      I think this article is a rathor open door article, in that its conclusions can be drawn beforehand, wihout executing the experiments. If you consider PICOS as PICO + S, surely then of course PICO will retrieve more relevant articles and PICOS sarches will be more specific. The searches used for testing PICOS were the exact searches for PICO, with an added element of S, which in this case was very basic (two or three tersm), compared to the exhaustive translation of the other elements (more than 10 terms). PICO, PICOS and SPIDER should not be used in the creation of search strategies. Not every element in those methods is necessary in a search query. Including specific outcomes and controls can introduce bias in the search results. For a good thorough systematic review, only P and I are used, and when necessary combined with a sensitive filter on study design, that consists of more than three terms and is verified (when possible). PICO, PICOS ad SPIDER can be useful in the process of evaluating the retrieved full text references for inclusion, but should not direct the search strategy.


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    1. 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 NCT00696414. We believe the correct ID, which we have found by hand searching, is NCT00696514.

      This comment is being posted as part of the OpenTrials.net project<sup>[1]</sup> , 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


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    1. On 2016 Sep 14, Peter Hajek commented:

      There exists a simple test of whether the 'gateway effect' applies to humans. Over the past 60 years, the prevalence of smoking among young men in the US and UK declined about 4-fold. If nicotine use leads to increased use of cocaine and other drugs, the use of other drugs should decline as well. There is no sign of that.


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    1. On 2017 Jul 07, Wei Wang commented:

      Several other problems have been reported: https://pubpeer.com/publications/DAA39CA8966C9B4DAB38EDAA343B4C


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    2. On 2014 Dec 15, Ivan Shatsky commented:

      General comment: The phenomenon studied in this paper is very exciting. I read the article with a great interest. Unfortunately, I regret to say that the underlying mechanism remained uncovered. Although I agree that the authors identified some curious structures within the 5’UTRs of HOXA mRNAs which might be implicated in the regulation of these mRNAs by RPL38, I did not find sufficient evidence for existence of IRES-elements in these mRNAs. As in numerous other similar investigations, to identify IRES-elements the authors employed the method of DNA bicistronic constructs, the approach that had been repeatedly shown to be associated with almost unavoidable artifacts (see Jackson Cold Spring Harb Perspect Biol. 2013 Feb 1;5(2); Lemp et al. Nucleic Acids Res. 2012 Aug;40(15):7280-90.). And I suspect this paper is not free of those artifacts either (see below). Several crucial control experiments necessary to support or to exclude the IRES-mediated mechanism have been recently described (for references see Shatsky et al. Mol Cells. 2010 Oct; 30(4):285-93). One of them, for instance, is the ratio of translational activities for m7G capped versus uncapped (A-capped) monocistronic constructs. This value estimates contribution of the cap to the translational potential of a 5’UTR under selected conditions. If this contribution is very high (as is the case of cap-dependent mRNAs) one may exclude the presence of a true IRES. I think that this and other obligatory controls are feasible to perform with cells C3H10T1/2 used in this paper but they were not done.

      Some specific points:

      1. The authors regard the cap-independent and IRES-dependent modes of translation initiation as synonymous mechanisms and support this notion with reference 21. I should stress that not all specialists in eukaryotic translation would share this opinion since nobody has ever shown that a 5’end dependent translation initiation cannot be regulated by specific structures within the respective 5' UTR. The opposite has recently been demonstrated (Terenin et al. Nucleic Acids Res. 2013 Feb 1;41(3):1807-16.)
      2. When listing examples of cellular IRESs identified to date (second paragraph), the authors mention c-myc, Apaf-1, XIAP. To the best of my knowledge, these cellular IRESs have been disproved (Andreev et al. Nucleic Acids Res. 2009 Oct;37(18):6135-47; Bert et al. RNA. 2006 Jun;12(6):1074-83; Baranick et al. Proc Natl Acad Sci U S A. 2008 Mar 25;105(12):4733-8; van Eden et al. RNA. 2004 Apr;10(4):720-30); Lemp et al. Nucleic Acids Res. 2012 Aug;40(15):7280-90. )
      3. “Extended data Figure 1a” raises a great concern: the HCV IRES should not be used as a normalizing construct for testing bicistronic DNAs since the HCV IRES has been reported to harbor a cryptic promoter (Dumas, E. et al. 2003 Nucleic Acids Res. 31 (4): 1275-1281) and hence may produce capped monocistronic mRNAs . By the way, among viral IRESs characterized to date the HCV IRES is regarded as one of the weakest.
      4. The control test with Rluc shRNA (Extended data Figure 1 b,c) strongly suggests that some significant amount of monocistronic (and therefore capped) Fluc mRNAs is present in transfected cells since the residual Fluc activity after RNA interference is too high. This may also be the case for the control bicistronic mRNA containing the HCV IRES (see point 3). Otherwise, the pictures 1b and 1c must be similar. At least, in the analogous test performed in our lab, the Rluc and Fluc activities fall down to the similar background levels (Fig. 2D in Dmitriev et al. Mol Cell Biol. 2007 Jul;27(13):4685-97).
      5. The authors suggest that the IRES elements are mostly confined within ~300 nts proximal to the start codon. As a support to this conclusion, they note that some of HOXA mRNAs possess a 5’ UTR of that size. If so, why the activity of HOXA9 construct 944-1266 is much lower than that for the full length 5’UTR (Fig. 1d)?<br>
      6. “Extended Figure 1d”. This control is useless. It only shows that the bicistronic mRNA of the expected size is present in transfected cells but unable to show the presence of monocistronic mRNAs starting within the intercistronic region. The corresponding bands won’t be seen.
      7. On the base of pull-down experiments the authors claim that 80S ribosomes are specifically formed on their IRES-elements. The problem is that they use 10mM of magnesium in these expts, i.e. the concentration at which the assembly of translation initiation complexes in mammalian systems should not occur.
      8. The mode of action of TIE element looks absolutely puzzling. It is even difficult to imagine any mechanism for its operation. My question: is it specific to these particular cells?


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    1. On 2015 Jan 12, Larry Parnell commented:

      This paper was my selection for Paper of the Week for 15-19 Dec 2014.


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    1. On 2015 Feb 06, Ryan Radecki commented:

      Post-publication commentary: "Social Media in Medicine – Useless!"

      Or, might it be how you use it that matters?

      This is a brief report from the journal Circulation, regarding a self-assessment of their social media strategy. The editors of the journal performed a prospective, block-randomization of published articles to either social media promotion on Facebook and Twitter, or no promotion, and compared 30-day website page views for each article. 121 articles were randomized to social media and 122 to control, and were generally evenly balanced between article types.

      And, the answer – unfortunately, for their 3-person associate editor team – is: no difference....

      http://www.emlitofnote.com/2014/11/social-media-in-medicine-useless.html


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    1. On 2015 Nov 25, S A Ostroumov commented:

      This article is exploring new links between issues of ecology (trophic web, trophic chains) and medicine (malaria control). It is very interesting.


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    1. On 2014 Dec 30, Kausik Datta commented:

      To add to Hilda Bastian's informative comment, the press release mentions the misleading statement not only in the title, but also in the first paragraph - stating definitively: "The study, published Nov. 17 by Proceedings of the National Academy of Sciences, shows that triclosan causes liver fibrosis and cancer in laboratory mice through molecular mechanisms that are also relevant in humans." (Emphasis mine.)

      This is, at best, irresponsible journalism (and at worst, a terrible disservice to people living with cancer). What seems particularly galling is the fact that this sacrifice of scientific accuracy at the altar of needless sensationalism in the press release was perpetrated by none other than the University (UCSD) at which the work was done. This brings to mind once again the age-old tussle in science communication, between science and journalism.

      At the same time, the authors cannot deflect the blame completely, especially since the lead author, quoted in the Press Release, didn't seem to emphasize at all the dosage effect of Triclosan administration and exposure route - which is rather odd, given that the Triclosan was either fed to the mice or injected directly into their peritoneal cavity at a high enough amount, none of which would apply to humans.

      I hope the authors pay heed to the most germane points raised by Hilda about the further inclusion of the data; I'd be most interested in the actual experimental outcomes.


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    2. On 2014 Nov 21, Hilda Bastian commented:

      The title and abstract of this article focuses on the positive finding in tumor promotion, without emphasizing that the findings were negative on causation, in a way that is clearly accessible for non-specialist readers. This is of particular importance, as a university press release issued for this study was headed with this misleading statement: "The dirty side of soap: Triclosan, a common antimicrobial in personal hygiene products, causes liver fibrosis and cancer in mice." This encouraged unwarranted alarm in the community (which I discuss further in this blog post).

      A 2010 inventory of animal and clinical studies of triclosan safety (Rodricks JV, 2010) found that oncogenicity studies to that point had not found cancer-related increases in any species, except for liver cancer in mice. Without pre-registration of studies on this question, we are unaware of what the outcomes have been for all oncogenicity studies on this substance, and thus whether there is publication bias.

      Further areas of uncertainty relate to the experiments here. The article does not report sufficient data and methodological information to enable adequate assessment of the level of uncertainty associated with the experiments (see the NIH's Proposed Principles and Guidelines for Reporting Preclinical Research). It would be helpful if the authors took the opportunity to include key data here, specifically:

      • how the sample size was determined;
      • the inclusion/exclusion criteria;
      • exact data on the experiments' results (including confidence intervals);
      • whether or not allocation of mice to the groups was random, and if so, details of the method of randomization (including whether or not there was blinding);
      • whether there was blinding in outcome assessment.


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    1. On 2014 Nov 20, Neven Patrick commented:

      Looks like estrogen removal reduced the proliferation significantly and probably the tumor has high ER mRNA score and very sensitive to estrogen deprivation. My thought is to regard this tumor as luminal A. Also important would be to check the probability of the class assignment by PAM50. Some cases surely will have lower probability than others and this case might be one of those. Because I presume single case PAM50 algorithm based on distance from centroid of model cases of intrinsic subtype will be forcing the class assignment for the cases which in the clustering would be gray zone cases. Does Prosigna report provide such QC measure? Soon Paik

      Truly fascinating (and not so simple) questions! To my knowledge this has not been studied, and I agree that removal of estrogen could potentially alter the proliferative rate of the tumor (and proliferation is a dominant aspect of most MGS to date). For this patient I would base treatment on the higher risk result. Kathy Albain

      If one measures Ki67 on the core it will be higher because pt is on E but if you measure it again 2 wks later on the surgical specimen it will be lower and won't agree with that done on the core. I would be surprised if that is not true. C.Kent Osborne

      Just saw a patient with an ER+ cancer, ki67 30% on core biopsy. Stopped HRT. Had surgery for T2N0 IDC and oncotype 14. Oncologist recommended chemo due to Ki67. Repeated ki67 on surgical sample and it was less than 5%. There is clearly an education opportunity here. Presumably the lower ki67 after stopping HRT is predicative of outcome and impact of hormone therapy. Interesting.<br> Hope S. Rugo


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    1. On 2015 Feb 18, Christophe Dessimoz commented:

      Note that this article was published as open access and is thus freely available from the publisher's website.


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    1. On 2015 Jan 05, NephJC - Nephrology Journal Club commented:

      This study was discussed on Dec 2nd 2014 in the open online nephrology journal club, #NephJC, on twitter (along with a related article).

      Introductory comments, written by Eoin O'Sullivan, are available at the NephJC website and cross-posted at the Renal Fellow Network blog.

      The discussion was quite intense, with more than 50 participants, including nephrologists, emergency medicine physicians, fellows and residents as also two of the authors, Bhupinder Singh and Edgar Lerma.

      A transcript and a curated (i.e. Storified) version of the tweetchat are available from the NephJC website.

      The highlights of the tweetchat were:

      • There is considerable interest in a drug such as ZS-9, given the incidence of hyperkalemia, both acute and chronic, sometimes resulting in the need to stop ACE-inhibitors and ARBs in CKD patients.

      • There was considerable discussion about the choice of placebo (as against sodium polystyrene sultanate, or diuretics and/or low potassium diet) as a comparator; the authors provided insight that this was mainly to comply with FDA requirements.

      • Though the results of the trial show that ZS-9 as studied was effective in lowering potassium levels, more information about the differential incidence of edema as also the details of diuretic use in both groups was sought.

      Overall, though there is considerable enthusiasm about the availability of new agents for management of hyperkalemia, considerations of safety, cost and data from more studies will determine how widely this drug will be used once licensed.

      Interested individuals can track and join in the conversation by following @NephJC or #NephJC, or visit the webpage at NephJC.com.


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    1. On 2016 Apr 20, Jennifer S Walsh commented:

      It wasn't possible to get perfect matching for all the factors, so it was done in order of: gender, age, height, postcode and smoking. Because smoking was the lowest priority, there were a few pairs who were matched on the other factors but not on smoking. The number of smokers was low overall, and we don't think the imperfect matches for smoking had any influence on the study results.


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    2. On 2016 Apr 15, Jose M. Moran commented:

      There is an issue that needs to be addressed. Controls were recruited to be individually matched to an obese participant by sex, age (±3 years), height (±5 cm), postcode and smoking status (current smoker or nonsmoker). If controls were matched 1:1 by the smoking status, how it is possible that the percentage of current smokers differs between normal and obese subjects across all the age groups (except in men aged 25-45 years n=6)?


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    1. On 2016 Oct 03, Morten Oksvold commented:

      Please note that after an investigation at the University of Cologne, six articles where T. Wenz figures as first or senior author were found to contain questionable data due to scientific misconduct. This article is one of these six articles.

      The conclusion from the report was ready June 28, 2016, please see the link (in German):

      http://www.portal.uni-koeln.de/9015.html?&tx_news_pi1[news]=4335&tx_news_pi1[controller]=News&tx_news_pi1[action]=detail&cHash=1deb8399d7f796d65ca9f6ae4764a1ce


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    1. On 2014 Dec 04, David Keller commented:

      Cause and effect cannot be distinguished in the observed associations

      Dopamine levels are reduced in the brains of patients with Parkinson's disease (PD). Dopamine inhibits the secretion of prolactin, and prolactin, in turn, reduces the activity of the steroid sex hormones (estrogen, testosterone, etc.) Thus, untreated PD patients should have low brain dopamine levels, high prolactin levels and thus low sex steroid hormone levels. These hormone actions are well-documented in physiology texts.

      The next clinical scenario to consider is the effect of treating PD with levodopa, which is metabolized to dopamine in the brain. Clearly, brain dopamine levels will rise, driving down prolactin levels, which, in turn, allows an increase in sex steroid levels, ameliorating, to a variable degree, the hypogonadism caused by untreated PD.

      To what degree does the dose of levodopa, taken in amounts sufficient to control the movement disorder symptoms of PD, also treat the hypogonadism caused by PD? This question is not addressed in the abstract.

      The authors conclude that lower sex steroid levels and higher prolactin levels "may result in a bigger susceptibility to the disease in men." This observational study cannot possibly prove the cause-and-effect mechanism implied in that statement. The observed associations are explained equally well by the opposite conclusion: that PD causes men to have lower dopamine levels, higher prolactin levels and consequently lower sex steroid levels (hypogonadism), in other words, that hypogonadism is an effect of PD, not a cause. It would require a randomized, controlled interventional study in which hypogonadal PD patients were repleted with administered exogenous sex steroids to prove that hypogonadism is a cause, rather than just an effect, of PD.


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    1. On 2015 Jan 12, Larry Parnell commented:

      This paper was my selection for Paper of the Week for 17-21 Nov 2014.


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    1. On 2014 Dec 19, Scott Federhen commented:

      I am Scott Federhen, author of this article, and would like to report some aspects of our genomes from type that were discovered too late to include in the manuscript. A visual inspection of our k-mer tree revealed two genomes from type for Bacillus subtilis subsp. spizizenii that are placed quite distantly from each other.

      The average nucleotide identity (ANI) statistics from the alignments of the type genomes from the relevant subspecies of Bacillus subtilis are as follows:

      96.7997 CP002905 ADGS01 89.7316 94.8698 – spizizenii vs. spizizenii

      94.6427 CP002905 AMXN01 89.4248 86.6265 – spizizenii vs. inaquosorum

      93.2854 CP002905 AL009126 88.7053 88.4756 – spizizenii vs. subtilis

      89.7% of CP002905 aligns with 94.9% of ADGS01, and the parts that align share 96.8% average nucleotide identity. These two genomes a likely to be from the same species, but probably not from the same subspecies - and certainly not from co-identical strains.

      To examine this problem systematically, we looked for all of the cases where we had more then one genome from type from the same species (or subspecies) and sorted them by pairwise ANI. These were usually from different culture collections and often sequenced in different labs. 274 pairwise combinations break down like this:

      4 pairs of genomes < 90% identical.

      5 pairs of genomes 96% - 99% identical.

      8 pairs of genomes 99% - 99.9% identical.

      112 pairs of genomes 99.9% - 99.99% identical.

      135 pairs of genomes 99.99% - 99.999% identical.

      10 pairs of genomes > 99.999% identical

      This is a wide range for genomes from strains that are supposed to be co-identical. The four most diverse pairs are likely to be from different species. The problem could lie in many places - the annotation in the sequence entries, a strain mixup in the sequencing lab, or a contamination, misannotation or misidentification in the culture collection. We are working with submitters and culture collections to resolve the most egregious discrepancies and improve the reliability of our subset of genomes and sequences from type. At some point the community is going to have to come to a consensus as to what constitutes identity between co-identical strains.

      We look forward to the day when every described species of prokaryote has a complete genome sequence, and a genome is included with every new species description. At that point it would be useful for each culture collection holding strains from type to sequence at least a low-coverage genome to verify the identity of the strain.


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    1. On 2017 Jul 13, Randi Pechacek commented:

      Sean Gibbons, first author of this paper, provided some background information on microBEnet.


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    1. On 2015 Feb 26, Harri Hemila commented:

      Missing contradictory findings and other problems in Curtis AJ, 2014

      Curtis AJ, 2014 state in their abstract that “The evidence from pooled analysis of 18 randomised controlled trials undertaken in apparently healthy people shows no effect of vitamin E supplementation at a dose of 23-800 IU/day on all-cause mortality.” This conclusion was based on the pooling of results from 18 RCTs that obtained RR = 1.01 (95% CI: 0.97 to 1.05).

      In their calculation of the average effect of vitamin E from the 18 studies, Curtis (2014) assume that there exists an overall uniform effect for all of those 18 RCTs, which can be estimated by pooling their findings. However, a subgroup analysis of the ATBC Study (1994) refutes the notion that the effect of vitamin E is uniform for all people. The combination of age and dietary vitamin C in the subgroup analysis modified the effect of vitamin E, which provides very strong evidence of heterogeneity over 6 subgroups (P = 0.0005) Hemilä H, 2009. Such heterogeneity refutes the assumption of a uniform effect in pooling the findings of the 18 RCTs by Curtis (2014).

      Curtis AJ, 2014 also state “Subgroup analyses by ... duration of exposure ... showed no association with all-cause mortality.” However, the effect of time should not be analyzed by comparing RCTs at the study level, some of the RCTs being long in duration while the others being short in duration. In the ATBC Study, harm from vitamin E in the young participants was seen after 3.3 years of supplementation. Longer vitamin E supplementation increased mortality by 38% (17% to 63%), whereas vitamin E had no effect on mortality over the earlier period, see Hemilä H, 2009. This finding of a time-dependent effect modification refutes the claim that the duration of vitamin E supplementation does not modify the effects of the vitamin with regard to all-cause mortality. Comparing RCTs on vitamin E by the mean durations of the RCTs, ie study-level analysis, cannot capture changes in the vitamin E effect after lag periods. Instead the analysis of time-dependent effect modification requires individual-level analysis.

      Ecological fallacy occurs when mean data about a group is used to impute identical values for all individuals of the group. Thus, the assumption by Curtis AJ, 2014 that the calculated average effect of vitamin E on mortality for the 18 RCTs (ie RR = 1.01) is valid for all participants in these 18 studies, or for other individuals in the community, is an example of ecological fallacy. The conclusion by Curtis AJ, 2014 that “duration of exposure ... showed no association with all-cause mortality” is another example of ecological fallacy.

      We do not know how far the heterogeneity of the ATBC Study can be generalized. The participants in that study were middle-aged males, who were aged 50-69 years at the start of the trial in the 1980s, which indicates that they were born before WW-II. In addition, all were smokers and lived in Finland. We do not know if similar effect modification occurs in other populations. Nevertheless, the heterogeneity found in this particular cohort refutes the notion that there might be a universal vitamin E effect on mortality that would be valid for all groups of people. Highly significant heterogeneity was also found in the effect of vitamin E on pneumonia incidence in Hemilä H, 2011 and on the incidence of the common cold in Hemilä H, 2006. Thus the evidence of heterogeneity of the vitamin E effect is not restricted to overall mortality but exists to other outcomes as well.

      Furthermore, in the Table 1 of Curtis AJ, 2014 it is stated that the “study quality” of the ATBC Study (1994) was “medium”. As a justification for this classification, in Appendix 2 (“quality of included studies”) Curtis AJ, 2014 inserted question marks next to “blinding of personnel” and “blinding of participants” and a cross (to indicate high risk of bias) to “blinding of outcome assessment”.

      The ATBC Study (1994), Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group., 1994, reported that “Participants and all study staff involved in the ascertainment of end points and the assignment of final diagnoses remained blinded to the participants' treatment assignments throughout the trial” (p. 1030). The same report also stated that “Deaths (n=3570) were identified from the National Death Registry, a branch of Statistics Finland” (p. 1030), which clearly indicates that the deaths in the ATBC study were recorded by an organization that had nothing to do with the administration of the tablets. Thus, the claims by Curtis (2014) about the blinding of participants and personnel in their Appendix 2 are inconsistent with the ATBC Study (1994) report.

      Transparency in systematic reviews is important, so that the reader is correctly informed what the basis for the quality assessments is. Curtis AJ, 2014 do not give any explanations about why they dismiss the descriptions about blinding in the ATBC Study (1994) report. Therefore the readers are misled about the quality of the study that has the greatest weight in Fig. 2 of Curtis (2014).

      Finally, the ATBC Study (1994) is wrongly cited in Curtis AJ, 2014. They write Virtamo (1998) in Fig. 2 ,Virtamo (2006) in Appendix 2, and Virtamo (2003) in the reference section. All of these three years are wrong. The ATBC Study was actually published in 1994, with the PubMed record Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group., 1994 (the correct year and reference). Virtamo (2003), which is listed in the reference section, does exist but it is a post-intervention follow-up report of the trial and not the correct reference for the main results of the ATBC Study (1994).


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    1. On 2017 Jan 09, Kausik Datta commented:

      I came to this paper after reading about Dr. Hadiyah-Nicole Green on Social Media. Much plaudits to Dr. Green and her team. The principle - conversion of near Infra Red light to thermal energy by Gold nanorods - is exciting and full of possibilities, and the proof-of-concept is well-demonstrated both in vitro and in vivo. The question that I had about the AuNR-only group in Figure 2D is answered in the discussion, although I'd have loved to see confirmation of the visible light PTE hypothesis: because if visible light is able to show similar effects on AuNRs, it might make their therapeutic spectrum broader - but bring in problems of specificity as well. In cancer therapeutics, specificity/focus of treatment is an important issue in respect of preserving good cells and destroying rogue, tumorous ones. Ideally, visible or any other light should have minimal effect, while NIR should have maximal on rousing the AuNRs, so to speak.

      Also in that respect, while intratumoral delivery of AuNRs takes care of stationary tumors, perhaps an antibody/ligand-based mechanism in conjunction with AuNRs may in future be able to target metastatic tumors as well? This is excellent work that I shall be much interested to follow. (I note that this paper is from 2014. Perhaps Dr. Green would be kind enough to provide a status update?)


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    1. On 2015 Mar 03, Dita Gratzinger commented:

      We congratulate the authors on a comprehensive overview of this very complex and evolving field of research. Many of the crucial studies represent in vitro and mouse model research; we are characterizing the state of the intact bone marrow stroma in myelodysplastic syndromes. The authors state that

      "Multiple data have shown that osteoprogenitors—MSPCs—exhibit normal morphology and frequency in the bone marrow of MDS patients, as well as undisturbed osteoblastic, adipocytic and chondrocytic differentiation potential in vitro."

      We have recently published data, not available at the time this review was written, regarding the architecture and extent of the CD271+ mesenchymal stromal cell compartment in intact human bone marrow core biopsies Johnson RC, 2014, and in fact demonstrate an increase in the density of this compartment in higher grade MDS as compared to lower grade MDS and marrow from similarly aged cytopenic patients. We also found an association of high CD271+ mesenchymal stromal cell density with shorter overall survival among patients with MDS, independent of IPSS-R and history of transfusion. We acknowledge that it is not clear whether functionally described osteoprogenitors correspond to all or a subset of CD271+ mesenchymal stromal cells; however, as cited in your review, we have previously shown Flores-Figueroa E, 2012 that CD271+ mesenchymal stromal cells express CXCL12 and arborize extensively within marrow, in association with marrow vasculature, and are intimately associated with the majority of CD34+ hematopoietic stem/progenitor cells in intact human marrow, and are thus good candidates to represent a key functional component of the human bone marrow hematopoietic progenitor/stem cell niche.


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    1. On 2014 Nov 14, Hilda Bastian commented:

      Very useful data on an important issue, given the high proportion of the population using contact lenses (Swanson MW, 2012). On the issue of the level of individual risk, readers might find a review of large-scale epidemiological studies helpful (Stapleton F, 2013).

      The authors stress the importance of good lens hygiene to reduce the risk of infection. That's a critical issue, and people may well over-estimate the adequacy of their own lens care (Bui TH, 2010). Given the increased risk of extended wear (rising from 2-4 per 10,000 for daily use to about 20 for extended wear Stapleton F, 2013), users being better informed about reduced wear as a way of lessening risks may also help (covered along with social and historical aspects in this blog post.)


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    1. On 2014 Nov 24, Alexis Clapin commented:

      Congratulation for your important work. In table 1, you state that the first approache to addressing attrition bias is intend-to treat analysis. Intend to treat analysis includes all data but when a clinical trial suffers from attrition bias, patients followed up for a longer duration are favouring one of the compared product. For a lot of outcome criteria, a longer duration means a more important impact on the criteria. Consequently, the intend to treat analysis is a biased evaluation of the difference between groups. An example of the impact of attrition bias on the intend-to-treat analysis is given in this article http://www.ncbi.nlm.nih.gov/pubmed/23662092. Without complete data, the best way to evaluate attrition bias is the comparison of intend-to-treat analysis and per-protocol analysis. If the per-protocol analysis provides us with a "better" result than intend-to-treat analysis, it means that patients followed up for the longer duration are favouring one of the compared product. This comparison should be done for all truncated trials. Unfortunately, it is not the case and a lot of clinical trials are truncated ; almost all based on survival analysis. To conclude, if intend-to-treat analysis is the only performed analysis, it is a good way to mask an attrition bias.

      For french readers : a more complete evaluation of the advantages of performing both analysis : http://www.etudes-et-biais.com/per-protocole-ou-intention-de-traiter-les-deux-svp/


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    1. On 2014 Dec 31, Dennis Eckmeier commented:

      We deposited an earlier version of the manuscript on the free pre-print repository bioRXiv: http://biorxiv.org/content/early/2014/08/12/002550


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    1. On 2013 Oct 25, DAVID SANDERS commented:

      From abstract from Kikuchi A, 1989

      "In this paper, two proteins stimulating the GTPase activity of smg p21 are partially purified from bovine brain cytosol. These proteins, designated as smg p21 GTPase-activating protein (GAP) 1 and 2, are separated from a c-ras p21 GAP described previously by column chromatographies. smg p21 GAP1 and -2 stimulate the GTPase activity of only smg p21 but not that of c-Ha-ras p21 or the rho and smg-25A GTP-binding proteins. The Mr values of smg p21 GAP1 and -2 are estimated to be 250-400 x 10(3) and 80-100 x 10(3) by gel filtration and sucrose density gradient ultracentrifugation, respectively. The activity of smg p21 GAP1 and -2 is killed by tryptic digestion or heat boiling. These results indicate that bovine brain contains two smg p21 GAPs in addition to c-ras p21 GAP.


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    1. 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


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    1. On 2017 Apr 05, Misha Koksharov commented:

      None


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    2. On 2017 Apr 04, Misha Koksharov commented:

      Great! Thank you! Apparently, in your field people normally don't describe the mutagenesis part much (in contrast to protein engineering field per se) and focus on characterization of the final version as I see from various papers.


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    3. On 2017 Mar 30, Yi Shen commented:

      Thanks Misha for your interest in our work! We are happy to provide further detailed information regarding the experimental procedures. Please email me at yshen3@ualberta.ca.


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    4. On 2017 Mar 20, Misha Koksharov commented:

      The developed FPs are nice. However, the experimental details (and intermediate results) of mutagenesis procedures are very limited and insufficient. It's impossible to understand what exactly you were doing at this part of the study.


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    1. On 2015 Jul 23, thomas samaras commented:

      Over 80 diverse populations show that weight increases as the cube of height increase. For example, the publication Advancedata, US Department of health, education, and welfare, Nov 19, 1976, Table 7 provided data for 18-24 year olds which allowed the following calculations.

      Males: 1971 vs. 1960: (69.7"/68.7")cubed x 158 lb = 165 lb (predicted by cubed law) Actual weight given for taller cohort = 165 lb

      For females, the results were 130 lb predicted and 132 lb actual.

      Another publication, Secular growth and its harmful ramifications, 2002, confirmed the height cubed law (not height squared or BMI law)for five populations (Table 1):

      Harvard male entrants (1958 vs. 1930) Wellesley female entrants (1958 vs. 1930) Malina's child data (1958 vs. 1934) Swedish males (n= 488,732) (1971 vs. 1960) US population (18-74 years)(1971 vs. 1960)

      A number of more recent studies provide data that support the Ponderal Index or height cubed law.


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    1. On 2015 Mar 11, IRWIN FEINBERG commented:

      Crawley et al 1 state that there have been few longitudinal studies of sleep/wake timing across adolescence. They fail to take note of our findings in a ten-year longitudinal study of 93 subjects aged 6-18 years. Sleep EEG was recorded twice yearly on habitual school-night schedules in subjects aged 6-18 years. In addition, weekend recordings with extended time in bed and a follow-up night, were obtained from subjects 9-18 years. Results published thus far could have added perspective to the findings of Cowley et al. In addition to defining the trajectories of NREM delta and theta EEG power 2, 3, their within-night dynamics 4, and their relations to puberty 5 and daytime sleepiness 6, we documented changes in NREM and REM bed schedules and sleep durations 7 that bear directly on the findings of Crowley et al. Our study demonstrated that school-night time in bed decreased by 13 min/year between ages 9-18 yrs (p<0.0001). From an average bedtime of 9:15 PM at age 9 yrs, bedtimes advanced by 13 min/year (p<0.0001), whereas rise times did not change (p=0.11). Sleep latency did not change (p=0.70), but sleep efficiency increased over this age range (p<0.0001). The net result was that total sleep time (TST) decreased by 10 min/yr from 515 min at age 9 to xx min at age 18 (p<0.0001). This TST reduction was not produced by shorter REM and NREM durations, as would be expected if it was the result of sleep deprivation due to restricted time in bed. Instead, TST declined because of a selective reduction of NREM sleep, which declined by 12 min/yr (p<0.0001). REM sleep durations actually increased significantly by 2 min/yr (p<0.0001). This pattern of change cannot be attributed to a phase advance. We interpret it, along with the massive decline in slow wave EEG power, as a manifestation of brain maturation driven by synaptic elimination. In our model, synaptic elimination during adolescence decreases the intensity of waking brain activity (shown also by declining cerebral metabolic rate 8) which decreases the need for NREM dependent recuperation of plastic neuronal systems.

      1. Crowley SJ, Van Reen E, LeBourgeois MK, et al. A longitudinal assessment of sleep timing, circadian phase, and phase angle of entrainment across human adolescence. PLoS One 2014;9:e112199.
      2. Campbell IG, Feinberg I. Longitudinal trajectories of non-rapid eye movement delta and theta EEG as indicators of adolescent brain maturation. Proc Natl Acad Sci U S A 2009;106:5177-80.
      3. Feinberg I, Campbell IG. Longitudinal sleep EEG trajectories indicate complex patterns of adolescent brain maturation. Am J Physiol Regul Integr Comp Physiol 2013;304:R296-303.
      4. Campbell IG, Darchia N, Higgins LM, et al. Adolescent changes in homeostatic regulation of EEG activity in the delta and theta frequency bands during non-rapid eye movement sleep. Sleep 2011;34:83-91.
      5. Campbell IG, Grimm KJ, de Bie E, Feinberg I. Sex, puberty, and the timing of sleep EEG measured adolescent brain maturation. Proc Natl Acad Sci U S A 2012;109:5740-3.
      6. Campbell IG, Higgins LM, Trinidad JM, Richardson P, Feinberg I. The increase in longitudinally measured sleepiness across adolescence is related to the maturational decline in low-frequency EEG power. Sleep 2007;30:1677-87.
      7. Feinberg I, Davis NM, de Bie E, Grimm KJ, Campbell IG. The maturational trajectories of NREM and REM sleep durations differ across adolescence on both school-night and extended sleep. Am J Physiol Regul Integr Comp Physiol 2012;302:R533-R40.
      8. Chugani HT, Phelps ME, Mazziotta JC. Positron emission tomography study of human brain functional development. Ann Neurol 1987;22:487-97.


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    1. 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 NCT0150177. We believe the correct ID, which we have found by hand searching, is NCT01501773.

      This comment is being posted as part of the OpenTrials.net project<sup>[1]</sup> , 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


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    1. On 2015 Jan 02, Meenakshisundaram Ananthanarayanan commented:

      I would like to clarify that the title of our paper is misleading since what we are describing in this study is the post-transcriptional regulation of type 3 InsP3R3 by miR-506 at the mRNA level and not at the protein level.


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    1. On 2015 Feb 10, Pieter-Jan Volders commented:

      At the time of submission, we were unaware of a specific RefSeq lncRNA subset. As a result, we initially used the NR_* records larger than 200 nucleotides. When dr. Kim D. Pruitt contacted us regarding this issue, we repeated the analysis for the suggested RefSeq subset. This subset contains 4774 transcripts and was obtained through the UCSC table browser. As expected, the percentage of transcripts passing the PhyloCSF cutoff has decreased from 48% to 14% of the RefSeq subset. The online manuscript was updated and the current Figure 3 (online as of January 15, 2015) represents these new results. Additionally, LNCipedia.org was updated as well, and the RefSeq records that do not represent lncRNAs were removed from the database version 3.1.

      It is worth noting that we could not find any information on the keyword that was used in the query suggested by dr. Kimm D. Pruit (biomolncrnalncrna), neither on the RefSeq website, nor in the cited manuscript. It is unclear to us how many researchers are aware of this and we would like to suggest to RefSeq to indicate this subset on their website as it is of great value to the lncRNA research community.


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    2. On 2014 Dec 03, Kim D Pruitt commented:

      The RefSeq results that are presented in Figure 3 do not accurately reflect the high quality of the RefSeq lncRNA dataset.

      The article does not describe how this dataset was defined but the authors kindly provided this information as well as a file listing all of the RefSeq accessions and PhyloCSF results. The authors’ definition of RefSeq lncRNA was too simple as it was primarily based on the RefSeq accession prefix (‘NR_’). However, this accession prefix is used by the RefSeq project for several types of noncoding transcripts (PMID:18927115). Roughly 50% of the RefSeq dataset analyzed represent transcribed pseudogenes or noncoding transcripts for protein-coding genes.


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    1. On 2016 Feb 05, Kristina Hanspers commented:

      Figure 8 is available as a pathway in the "Open Access Publication" Collection at WikiPathways: http://wikipathways.org/index.php/Pathway:WP2886. This pathway can be used for data visualization and network analysis in tools like Cytoscape and PathVisio.


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    1. On 2015 Sep 08, CREBP Journal Club commented:

      This study gives an excellent insight into GPs’ experiences of two contrasting interventions – training in communication skills (including use of a patient booklet) and the use of a point of care test (CRP). We found it encouraging that the clinicians reported gaining new knowledge from the interventions. Information, such as expected duration of illness and the benefits and harms of antibiotic treatment of acute respiratory infections should preferably be part of any intervention aimed at either GPs or patients. Both interventions achieved important reductions in antibiotic prescribing for acute respiratory infections – and combining the interventions was associated with an even greater reduction(1). The group discussed if future interventions should be multi-faceted. Anthierens et al. found that the GPs reported that the two interventions were complementary and often used for different situations, i.e. the CRP test when there was uncertainty about the severity of the infection, and the communication skills/booklet when an explanation was required. However, it was mentioned that in some countries, such as Australia, the CRP test is still not routinely used as a point of care test in general practice. The group found the information in the booklet very useful. However, the sections about “Helping your immune system fight infection” and “How you can care for your cough” were debated. E.g. a Cochrane Review on Echinacea products did not find any benefits for treating colds(2) and also in the booklet it is stated that the advice on fluids, rest and stress is based on evidence about how the immune system works. Preferably, information used in interventions to enhance the quality of antibiotic prescribing for acute respiratory infections should be based on solid evidence about the group of patients being examined – i.e. in this case patients with acute respiratory infections. In addition, high quality, primary care-based studies are needed to further explore alternatives such as probiotics, zinc and vitamin C and to develop and test new non-antibiotic treatments. See CREBP Journal Club for more information.

      References: (1) Little P, Stuart B, Francis N, et al. Effects of internet-based training on antibiotic prescribing rates for acute respiratory-tract infections: a multinational, cluster, randomised, factorial, controlled trial. Lancet 2013; 382(9899): 1175-82. (2) Karsch-Volk M, Barrett B, Kiefer D, Bauer R, Ardjomand-Woelkart K, Linde K. Echinacea for preventing and treating the common cold. The Cochrane database of systematic reviews 2014; 2: Cd000530.


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    1. On 2015 Feb 27, Geriatric Medicine Journal Club commented:

      This clinical trial of of Problem Adaptation Therapy (PATH) was critically appraised at the January 2015 Geriatric Medicine Journal Club (follow #GeriMedJC on Twitter). A transcript of the discussion can be found here: http://gerimedjc.blogspot.com/2015/01/gerimedjc-january-30-2015.html?spref=tw Highlights include the question of how feasible it is to deliver this type intervention in our current health care climate.


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    1. On 2015 Jan 05, NephJC - Nephrology Journal Club commented:

      This trial was discussed on Dec 16th and Dec 18th (in the first transatlantic version) in the open online nephrology journal club, #NephJC, on twitter. Introductory explanatory comments, written by Rheumatologist, Dr Paul Sufka, are available at the NephJC website, and Dr Sufka’s blog. It had more than 50 participants, including nephrologists, rheumatologists and nephrology and rheumatology fellows. Transcripts and curated (i.e. Storified) versions of the tweetchats are available from the NephJC website.

      The salient highlights of the discussion included:

      • The authors and the funding agency (the French Ministry of Health) should be commended for performing this trial to find better ways of minimizing relapses in ANCA associated vasculitis.

      • There was significant discussion around the Azathioprine dose chosen (tapered down to levels below that used in the CYCAZAREM trial in later part of this trial); as also the finding of early separation between arms, suggesting some patients in the control arm were azathioprine non-responders.

      • The Rituximab dosing strategy seemed quite astute, and was quite successful in reducing relapses without an increase in adverse events. The discussants looked forward to publication of more data from this trial, especially on B cell populations and ANCA titres, that could shed more light for a deeper understanding of the results.

      Overall, there was significant enthusiasm for using Rituximab in this setting, though the results of more trials, especially RITAZAREM and MAINRITSAN-2 are now keenly awaited.

      Interested individuals can track and join in the conversation by following @NephJC or #NephJC, or visit the webpage at NephJC.com.


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    1. On 2014 Nov 12, KEVIN BLACK commented:

      I think the effects of levodopa itself on brain activity may be of interest when interpreting the effects of levodopa on movement-related brain activity. Examples from my colleagues include the 4 following articles: PubMed Central IDs PMC21757 and PMC1738560, doi: 10.1038/sj.npp.1300632, and doi: 10.1006/exnr.2000.7522 .


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    1. On 2014 Nov 19, David Keller commented:

      A landmark paper with important implications for melanoma patients

      The results obtained by combining high-dose ipilimumab (10 mg/kg) with GM-CSF (sargramostim) are remarkable. The combination increased median overall survival by 4.8 months compared with high-dose ipilimumab alone, an increase of over 37%, and the combination also reduced the rate of serious adverse events significantly compared with high-dose ipilimumab monotherapy. Patients with advanced melanoma and poor response to existing treatments will want to discuss these results with their oncologists, particularly since GM-CSF is currently available in the U.S.

      Since GM-CSF is already approved for other indications, there will be great pressure on oncologists to prescribe ipilimumab in combination with GM-CSF on the basis of this study, particularly for patients whose tumor burden worsens despite approved therapy. Questions which will be encountered include:

      1) Would the pairing of GM-CSF with the approved dose of ipilimumab (3 mg/kg) have similar benefits, despite the fact that the ipilimumab dose used in the study was more than 3 times larger than the approved dose?

      2) Given the reduction in toxicity of the combination compared with ipilimumab monotherapy, can the approved dose of ipilimumab be safely tripled to 10 mg/kg if used in combination with GM-CSF?

      3) Is there any reason to believe that PD-1 checkpoint inhibitors, such as pembrolizumab, given in combination with GM-CSF, would not afford similar improvements in survival and adverse events?

      Patients with advanced melanoma who do not respond to currently approved treatments have little to lose. There is no reason to force these patients to wait for the results of confirmatory studies which they may have little hope of surviving to see published. Those that can be accommodated into clinical trials should be encouraged to participate, while the others should be offered the option of adding GM-CSF to their checkpoint inhibitor, if the latter fails to control their disease.


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    1. On 2014 Nov 17, Alexandre Chigaev commented:

      After the Nobel Prize in Physiology or Medicine in 1998 nitric oxide became a widely accepted signaling messenger. Studies of carbon monoxide are still largely limited to the fields of pollution, carbon monoxide poisoning, and vascular biology. This paper provides insight into possible role of carbon monoxide in the rapid regulation of cell adhesion that is crucial for cell mobilization and migration, ischemia-reperfusion injury and transplantation, immune response modulation and evasion of host defence employed by haemolytic pathogens.


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    1. On 2014 Nov 10, Serge Ahmed commented:

      This is an interesting series of experiments on choice between nicotine and sucrose in rats. In experiments 1, 3, 4 & 5, hungry rats were first trained to respond for sucrose or nicotine on alternate days before being provided with a choice between the two options. Overall, virtually all rats responded more for sucrose than for nicotine under a variety of choice conditions. Thus, all else being (approximately) equal, sucrose surpasses nicotine reward in rats!

      In experiment 2, rats were first trained to respond for nicotine before being provided with a choice between nicotine and sucrose. In this condition, about 50% of the rats responded more for nicotine than for sucrose, suggesting that “nicotine self-administration does not only occur in the absence of alternative reinforcement options”, at least in some rats.

      Though the results of experiment 2 are promising, they are difficult to interpret univocally. Experiment 2 lacks an important control group that controls for the difficulty in learning to respond for sucrose during choice testing. Briefly, rats were asked to respond on a novel lever under a random ratio 4 schedule of sucrose reinforcement, WITHOUT ANY PRIOR PROGRESSIVE TRAINING on this lever and after a long period of operant extinction. It is likely that many rats will fail to learn to respond for sucrose under these specific conditions, even in the absence of the opportunity to self-administer nicotine! Future research should resolve this important issue.


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    1. On 2014 Nov 07, Stephen Strum commented:

      I have looked at the full article in JCO and will re-read it, but it seems to me that the issue of salvage RT in the context of men with persistent PC after a local or local-regional therapy could be focused on additional key issues along with stronger advice. Issues that come to mind are the many papers that demonstrate that the first PSA post-RP taken at about 5-6 weeks post-op should use an ultrasensitive PSA. Papers by Doherty et al, Witherspoon and others showed that those with ultrasensitive values ≤ 0.01 had outstanding prognoses e.g., Only 2 patients with an undetectable prostate-specific antigen after radical retropubic prostatectomy biochemically relapsed (3%),compared to 47 relapses out of 61 patients (75%) who did not reach this level. More importantly, in 31 years of focused work caring for men with PC at all stages of illness, I rarely (< 1%) of the time see any diligence regarding use of nomograms and/or ANNs(artificial neural nets)done prior to initial therapy or at the time of so-called PSAR. Nomograms using PSAV + pathologic findings at RP are very helpful in risk assessment for men likely to be helped by salvage IMRT vs not.

      Another key issue not discussed in this paper is the RT treatment field and again, the use of nomograms, and ANNs to get a risk assessment for which patients are at risk for nodal spread. Too many men are being treated with RT fields that are not inclusive of where the disease is.

      To this end, I will say that ODAC blew it badly when they rejected a simple iron contrast nanoparticle (Combidex) to identify nodal mets at a level of sensitivity and specificity that is dramatically superior to the lousy sensitivity of CT abdomen and pelvis exams. The latter studies involve a half billion dollars globally on an annual basis but even more importantly MISdirect the use of RT and give the RadOnc and patient a false sense of where the active PC is.

      We have some wonderful tools that remain in the proverbial Al Gore "lockbox", often discussed in academic meetings but rarely used in the day in and day out care of men faced with prostate cancer.

      Stephen B. Strum, MD, FACP Member ASCO since 1973, AUA since 1998, ASTRO since 2002 PCRI (Prostate Cancer Research Institute) First Medical Director and Co-Founder 1997


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    1. On 2015 Jun 18, NephJC - Nephrology Journal Club commented:

      This guideline document was discussed on June 9th and 10th 2015 in the open online nephrology journal club, #NephJC, on twitter.

      Introductory comments are available at the NephJC website and blog. The discussion was very detailed, with more than 50 participants, including nephrologists, urologists and residents. Notable were nephrolithiasis experts, David Goldfarb and John Asplin.

      A transcript and a curated (i.e. Storified) version of the tweetchat are available at the NephJC website.

      The highlights of the tweetchat were:

      • Though the ACP follows stringent guideline development process, the absence of high quality data made the end result not quite useful for practical use, especially when compared to other competing publications, such as from the American Urological Association and the European Association of Urology. There was also concern that these guidelines may be (mis)used by third party payers to deny coverage for tests not endorsed in these guidelines.

      • From a physiological rationale, there was near unanimity that testing for stone composition is essential, especially in recurrent stone-formers. There was concern that the guideline developers were interpreting absence of evidence of benefit as evidence of absence of benefit.

      • Additional online comments that were thought to provide useful context to the discussion, written by Drs Coe, Goldfarb and Topf, are available here, here, here and here.

      Interested individuals can track and join in the conversation by following @NephJC or #NephJC, or visit the webpage at NephJC.com.


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    1. On 2014 Nov 28, Paolo Tieri commented:

      This article is one of the "Multi-omic Data Integration" Research Topic in Frontiers, which focuses on data integration approaches and methods of any type and extent, their application in understanding the pathogenesis of specific diseases or in identifying candidate biomarkers, in order to exploit the full benefit of multi-omic datasets and their intrinsic information content. For more information about multi-omic data integration check http://journal.frontiersin.org/ResearchTopic/2280


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    1. On 2014 Nov 28, Paolo Tieri commented:

      This article is part of the "Multi-omic Data Integration" Research Topic in Frontiers, which focuses on data integration approaches and methods of any type and extent, their application in understanding the pathogenesis of specific diseases or in identifying candidate biomarkers, in order to exploit the full benefit of multi-omic datasets and their intrinsic information content. For more information about multi-omic data integration check http://journal.frontiersin.org/ResearchTopic/2280


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    1. On 2014 Nov 28, Paolo Tieri commented:

      This article is part of the "Multi-omic Data Integration" Research Topic in Frontiers, which focuses on data integration approaches and methods of any type and extent, their application in understanding the pathogenesis of specific diseases or in identifying candidate biomarkers, in order to exploit the full benefit of multi-omic datasets and their intrinsic information content. For more information about multi-omic data integration check http://journal.frontiersin.org/ResearchTopic/2280


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    1. On 2014 Nov 28, Paolo Tieri commented:

      This article is part of the "Multi-omic Data Integration" Research Topic in Frontiers, which focuses on data integration approaches and methods of any type and extent, their application in understanding the pathogenesis of specific diseases or in identifying candidate biomarkers, in order to exploit the full benefit of multi-omic datasets and their intrinsic information content. For more information about multi-omic data integration check http://journal.frontiersin.org/ResearchTopic/2280


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    1. On 2014 Nov 28, Paolo Tieri commented:

      This article is one of the "Multi-omic Data Integration" Research Topic in Frontiers, which focuses on data integration approaches and methods of any type and extent, their application in understanding the pathogenesis of specific diseases or in identifying candidate biomarkers, in order to exploit the full benefit of multi-omic datasets and their intrinsic information content. For more information about multi-omic data integration check http://journal.frontiersin.org/ResearchTopic/2280


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    1. On 2014 Nov 10, Klaas Vandepoele commented:

      A dedicated supplementary data page incl. a pre-configured GenomeView browser is available at http://bioinformatics.psb.ugent.be/cig_data/RegNet/.


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    1. On 2015 Jan 05, NephJC - Nephrology Journal Club commented:

      This study was discussed on Dec 2nd 2014 in the open online nephrology journal club, #NephJC, on twitter (along with a related article: the HARMONIZE trial).

      Introductory comments, written by Eoin O'Sullivan, are available at the NephJC website and cross-posted at the Renal Fellow Network blog.

      The discussion was quite detailed, with more than 50 participants, including nephrologists,emergency medicine physicians, fellows and residents, with great insight provided by the senior author, David Juurlink.

      A transcript and a curated (i.e. Storified) version of the tweetchat are available from the NephJC website.

      The highlights of the tweetchat were:

      • The authors have leveraged administrative datasets to undertake numerous drug-interaction studies in the real world setting with important clinical outcomes.

      • The study reports a robust association between use of co-trimoxazole and sudden death amongst elderly patients already using a renin-angiotensin system blocker. While this remains an association, and causation is elusive in observational studies such as these, the consensus was that this is quite likely to be a true effect given the physiological basis, and prior work from this group reporting greater hospitalization for hyperkalemia from the same combination.

      • The final takeaway message was to be careful and prescribe co-trimoxazole specifically, and indeed all antibiotics generally, only when truly necessary.

      Interested individuals can track and join in the conversation by following @NephJC or #NephJC, or visit the webpage at NephJC.com.


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    1. On 2015 Mar 13, Gerhard Nebe-von-Caron commented:

      treat with care. Unless sample data are either submitted as supplimentary data or idealy at the flow repository to be checked, they data presented do not give confidence with regards to their relevance as the discriminator settings and gates used cannot be verified.


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    1. On 2014 Nov 07, Wenxian Sun commented:

      THank you for your interest in this work and reminding me to cite the preprinted paper. I will communicate with the editor and try to add the citation in the official publication.


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    2. On 2014 Nov 04, Benjamin Schwessinger commented:

      An interesting paper about the transfer of the dicot immune receptor EFR into the monocot crop rice. The authors demonstrate full functionality of the immune receptor in rice and its ability to contribute to bacterial immunity. For readers interested in the topic I would suggest to also read up on the following pre-print EFR in rice leads to ligand dependent activation of immune responses, which was posted June 11th 2014 well before initial submission of this manuscript. We regret that the author's did not cite our pre-print in their here presented work.


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    1. On 2015 Dec 03, Joshua L Cherry commented:

      None


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    2. On 2015 Nov 30, John P A Ioannidis commented:

      Dear Joshua,

      thank you again for your comments. I am worried that you continue to cut and paste to distort my sentences.

      1. The headline over my text was written by the Nature editors as their introduction to the paper, so perhaps you should blame them and ask them to replace it with "Here follows a horrible paper by Ioannidis". Yet, I think you would still be unfair to blame them, because their headline says "most innovative and influential", not just "most innovative". The terms "influential", "influence", "major influence" pervade my paper multiple times, but you pick one sentence with "innovative" instead, and interpret it entirely out of its context.<br>
      2. The phrases "the most important" and "very important" are not identical. Very important papers may not necessarily be THE most important. But they are very important - and influential. [As an aside, honestly, this repeated cross-examining quotation-comment style makes me feel as if I am answering the Spanish Inquisition. Am I going to be burnt at the stake now (please!) or there is one more round of torture?]
      3. We agree we need evidence, more evidence - evidence is good, on everything, including the current NIH funding system, which has practically no evidence that it better than other options, but still distributes tens of billions of dollars per year. Wisely, I am sure.<br>
      4. "your list contains...". This is not my list. This is the Scopus list. Right or wrong, I preferred not to manipulate it. Your colleagues did manipulate it and did not even share the data on how exactly they manipulated it.
      5. You continue to use the term "innovative thinker" out of its context. I scanned again carefully my paper and I can't find the word "excellent". In my mind, a student who has authored as first author a paper that got over 1000 citations (and the paper is not wrong/refuted) is already worthy to be given a shot as a principal investigator. If you disagree, what can I say, feel free not to fund him/her. And please don't worry, most of these guys are not funded anyhow currently, many of them even quit science. Hundreds of principal investigators who publish absolutely nothing or publish nothing with any substantial impact get funded again and again. Hurray!<br>

      I am afraid it is unlikely there will be more convergence in our views at this point. A million thanks once again, I have learnt a lot from your comments.

      John


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    3. On 2015 Nov 03, Joshua L Cherry commented:

      John,

      I, too, am wary of an endless discussion. In my view, my straightforward original point remains unscathed by our exchange. Your latest reply does compel me to make or repeat a few points.

      1) It is perplexing that you seemingly deny that your earlier work "claimed that NIH does a poor job of funding innovators, based on the assumption that the highly cited authors that you identified were innovators". Nicholson and Ioannidis say of these authors that

      Such innovative thinkers should not have so much trouble obtaining funding as principal investigators.

      The claim that the papers are highly innovative even appears in a headline above your text. This has nothing to do with how I might interpret "innovative"; you unambiguously asserted that these authors were highly innovative, according to your own meaning, based solely on their authorship of a very highly cited article.

      2) As already noted, the two publications are at odds with each other even if we consider "importance" rather than innovativeness. The discrepancy is reflected in your reply, where you confirm your belief that

      It is an open question whether “the most highly cited papers are the most important ones”

      and yet you write that

      My assumption was that papers with over 1000 citations (i.e. in the top 0.01% of citations) are very important

      I would add that one may rationally believe that there is a correlation between citation and importance while doubting that every primary author of every one of these papers should be funded as a principal investigator. (I add this because of your subtle replacement of "whether" with "the exact extent to which".)

      3) Again, I have not asserted, much less insisted, that anybody should not be funded. I have merely questioned whether a certain criterion is a reliable indicator that a scientist is among those most worthy of funding. Those who assert that it is bear the burden of proof.

      4) Much of your latest reply is an attack on others that has nothing to do with my comments here or with anything that I have written or done. I speak only for myself. I will note as a bystander that the letter to the editor that you criticize clearly does not say what you claim it does. Among other things, it characterizes only 11% of the papers as unrelated to human health. (I imagine that you have noticed that your list of "life sciences" papers includes some that clearly appear to belong to other disciplines.)

      5)

      Let us please collect more empirical evidence and fewer opinions.

      Indeed. Let us also acknowledge that the leap from "author of a very highly cited paper" to "innovative thinker", "excellent scientist", or "person who should certainly be a principal investigator" is based largely on opinion rather than empirical evidence, as your later statements about what we do not know would suggest.


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    4. On 2015 Oct 31, John P A Ioannidis commented:

      Dear Joshua,

      Thank you for your additional insights, I suspect this topic can be hotly debated ad infinitum. Let me please try again to convey what I think:

      You claim that my earlier paper was “based on the assumption that the highly cited authors identified were innovators.” I think that either your interpretation of my assumption is misleading and/or we understand the term “innovators” differently. My assumption was that papers with over 1000 citations (i.e. in the top 0.01% of citations) are very important and thus typically their leading authors merit support (unless the papers were wrong). Importance could include disruptive innovation narrowly defined, but also other equally major qualities that merit recognition and funding. I certainly do not believe that NIH should fund only “disruptive innovators” if the definition of “disruptive innovators” excludes influential experimental studies, randomized trials, other forms of evidence-based research, and interdisciplinary research – the types of work that were excluded by the letter-to-the-editor which was coauthored by David Lipman from your team whom I greatly admire but who threw out of the NIH-relevant agenda almost all health research that is important and almost everything that matters for health. I should also confess that I am disappointed by the stance of the authors of that letter. Their lead author had asked for my raw data and I had shared everything with him within 10 minutes of his request. Then, when I saw in his re-analysis that he had excluded two-thirds of the most extremely-cited papers with the excuse that they are not within the remit of NIH (even though they are objectively categorized by Scopus as belonging to life and health sciences), I asked him to share his raw data to understand his subjective arbitrations. I was very curious to see how leading NIH officials determined that the majority of the most influential medical and health-relevant research is not within the remit of NIH. Almost three years later, I still have not had the pleasure to see their raw data. Perhaps they did not want to reveal that their re-analysis was embarrassing: the re-analysis was based on the untenable assumption that the National Institutes of Health have almost nothing to do with health and with the majority of the most influential health-related research!

      I think our inability to converge in our views lies in our difficulty to agree on what is “innovative” and “important”. For example, I argue that randomized trials and other experimental studies, meta-analyses, guidelines, implementation research, team science, and interdisciplinary science can be extremely innovative and important to fund by NIH, while probably much/most of the funded R01 type of bench work and so-called “mechanistic” research currently funded by NIH is neither "innovative" nor "important", no matter how you want to define these terms within the confines of common sense.

      The exact extent to which “the most highly cited papers are the most important ones” is indeed an open question and the 2014 Nature paper tried to contribute towards answering this question. I hope that other scientists will revisit this question and improve on what we did. I do not expect a perfect correlation between citations and importance, but this does not mean that we know nothing about citations or that they have no value. When selecting papers in the top 0.01% of citations, it is hard to claim that they would not typically be even in the top 10-15% of importance so as to be worth funding. As I said already in my previous response, the papers assessed in the 2014 Nature analysis were less cited than the ones analyzed in the 2012 Nature analysis. The median number of citations in the papers analyzed in the 2014 Nature paper was 180. Only 39 of these papers (3%) had over 1000 citations, i.e. in the same range as the extremely cited papers evaluated in the 2012 Nature analysis. All of these 39 papers actually scored well in at least one of the 5 dimensions of importance assessed (excluding publication difficulty), with an average maximum score of 83/100. This means that practically all of these papers were considered to be important; thus it is fair to assume that the work would be worth funding by NIH. Nevertheless, if you still insist that NIH should not fund the people behind papers that are so extremely influential (provided they are not wrong), I am afraid I have run out of arguments and there is no way that I will ever convince you.

      I trust both you and me and the previous letter writers, we all want to support science and celebrate the best science possible. It is fine to disagree on how to achieve this noble goal. Let us please collect more empirical evidence and fewer opinions. I would cherish to have more robust evidence, even if it were to prove me wrong. Thank you for giving me an opportunity to discuss again this interesting topic.


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    5. On 2015 Oct 28, Joshua L Cherry commented:

      Thank you, John, for your response. As I see it, the apparent inconsistencies between the two publications remain unresolved.

      The earlier work claimed that NIH does a poor job of funding innovators, based on the assumption that the highly cited authors that you identified were innovators. The later work not only provides evidence suggesting otherwise, but explicitly states that the relationship between citations and innovation is unknown. Would you agree, then, that the earlier claim about funding of innovators is unfounded? I am asking about the particular case presented there, not about other arguments or claims that might or might not involve innovativeness.

      I would note, since it seems to be necessary, that the emphasis on innovativeness does not originate with me, but with your earlier publication. Your reply warns against a focus on disruptive innovativeness, but Nicholson and Ioannidis (2012) focused on innovativeness. I am merely responding to your argument. We can certainly consider whether highly cited authors necessarily have other qualities, but the shift in argument should be acknowledged.

      What, then, of the argument that your list of highly cited authors can be assumed to be among the best of the best on grounds other than innovativeness? According to your later piece there is much that we do not know about citation patterns and it is an open question whether "the most highly cited papers [are] the most important ones". How, then, can you be so certain that these authors are all exceptionally good scientists who should undoubtedly have been funded as principal investigators?

      The final paragraph of your response seems to suggest that by pointing out inconsistencies between these two publications I have laid the groundwork for an argument against funding of biomedical research. If this were correct, it is not clear how it would be relevant. (Surely you, of all people, are not suggesting self-censorship on those grounds.) But it is incorrect, and in fact backwards. I have never suggested, any more than you have, that anybody is unworthy of funding. Rather, we are discussing how to identify those most worthy of funding. Your remarks rely on the very point that we are debating: your conviction that your list of highly cited authors reliably identifies extraordinarily good scientists. Unlike my comment, your Conform and Be Funded piece, which claimed to have demonstrated empirically that NIH spends its funds unwisely, might make it difficult to argue for greater NIH funding. By pointing out that this claim was based on an unfounded assumption, I do, if anything, the opposite.

      Thank you again for engaging in this discussion.


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    6. On 2015 Oct 25, John P A Ioannidis commented:

      Dear Joshua,

      thank you for trying to make a connection between these two papers. I welcome further brainstorming and investigation on these topics. My interpretation of our results in the current paper is that highly-cited papers may be important for various reasons. Disruptive innovation is one of them, but continued progress, broader interest, and greater synthesis are more prominent features of these influential papers. This does not mean that extremely highly-cited papers are not important (even if some are more important than others), or that I would feel happy if the largest biomedical funding agency in the world does not have sufficient funds to support even the leading authors of extremely highly-cited papers. Also of note, the articles evaluated in the 2012 Nature analysis were far more cited, on average, than the papers evaluated in the 2014 Nature analysis and the sampling was very different, so the connection between the two analyses is even more tenuous.

      I continue to think that if someone has been a leader in a paper that has reached the top 0.01% of citation impact in the scientific literature (as in the articles in the 2012 analysis), that person warrants to have his/her research funded, unless this research has been clearly proven wrong and a dead end in the meanwhile. I never argued that the authors of the top-0.01% of cited papers should be the only researchers to be funded, that only disruptive innovative research should be supported, or that all great work is extremely highly-cited. I believe that it is important to support research that is innovative, but it is also important to support research that achieves continued progress, broader interest, and greater synthesis. Scientific excellence has many faces, and focusing only on disruptive innovation may even limit scientific progress and may lead to exaggerated expectations and exaggerated claims by researchers and funders who try to justify their existence in a societal environment that is unfortunately not very supportive of science.

      There is also a wider issue to be discussed in your criticism. I have always tried to make the strongest case for public support for science, I never tire to say that science is the best thing that has happened to human beings. In my humble opinion, the 2012 analysis should have offered strong support that the funding budget of NIH should be increased, since currently funds are so limited that NIH cannot even fund many of the people standing behind papers with the utmost extreme citation impact. I really do not see how it helps to make a case for more support for science, when one claims that even people behind the top-0.01% of cited work in the biomedical literature do not merit funding because their extremely high-impact work is unimportant or not relevant to NIH.

      Thank you again for your comments.


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    7. On 2015 Oct 16, Joshua L Cherry commented:

      This piece is quite astounding in light of earlier claims made by the first author in the pages of the same periodical. In the earlier piece, Nicholson and Ioannidis (Nicholson JM, 2012) based a harsh indictment of NIH funding decisions, along with a recommendation for a new policy, on a questionable assumption: that a scientist's authorship of a very highly cited article is a reliable indicator of excellence or innovativeness. This more recent work by Ioannidis et al. suggests that this assumption is false, or at best unsubstantiated, seemingly undermining the earlier work, while creating the impression that the authors never had any definite opinion on the matter.

      In a piece with the provocative title "Research grants: Conform and be funded", Nicholson and Ioannidis (Nicholson JM, 2012) analyzed the pattern of subsequent NIH funding of the primary authors (first, last, or sole authors) of very highly cited articles. Because the fraction funded as NIH principal investigators was lower than they believed it should be, they concluded that NIH does a poor job of funding innovative research. They also suggested that such authors, whom they regarded as having demonstrated exceptional innovativeness or excellence, be automatically funded as principal investigators. Several people, myself among them, argued that such authors are not necessarily innovative or exceptional scientists, but Nicholson and Ioannidis staunchly maintained their position (http://tinyurl.com/npojxk2; http://tinyurl.com/ozme26j).

      This more recent piece paints a very different picture. It begins by telling us how little we know about the meaning of citation patterns, posing such questions as "Are the most highly cited papers the most important ones?" If, as Ioannidis et al. have it, these were open questions, what basis could there have been for the conclusions of Nicholson and Ioannidis? Furthermore, to the extent that the evidence presented here tells us anything about what citation patterns actually mean, it tells us that very highly cited publications do not tend to be highly innovative, contrary to the assertions of Nicholson and Ioannidis. Strikingly, in the concluding section Ioannidis et al. tell us that

      It would be particularly useful to know whether successful out-of-the-box ideas are generated and defended largely by the most influential scientists or by colleagues lower on the citation rankings.

      Such knowledge would, indeed, be useful. It would, in fact, seem to be a prerequisite for the arguments of Nicholson and Ioannidis, a prerequisite that Ioannidis et al. tell us was unfulfilled.

      This piece makes no mention of the earlier arguments that it appears to undermine. This leaves one wondering whether Ioannidis maintains his earlier conclusions. If so, it is not clear how this can be reconciled with the present publication. If not, an indication of the change in position would be helpful.


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    1. On 2015 Jan 14, William Grant commented:

      Differences in 25-hydroxyvitamin D concentrations may explain some of the racial disparities in noncardia gastric cancer incidence rates

      The recent paper by Bautista and colleagues presented findings regarding risk modifying factors for noncardia gastric cancer related to racial disparities [1]. When averaged over the period 2000-2010, rates were highest for blacks, intermediate for Asians and Hispanics, and lowest for whites. However, median survival times were highest for Asians, followed by blacks, Hispanics, then whites. This letter proposes two factors to explain some of the findings.

      First, it is noted that gastric cancer incidence and/or mortality rates have been found significantly inversely correlated with solar UVB doses in ecological studies in Australia, China, Japan, Nordic countries, Spain, and the United States [2]. The most likely explanation for these findings is that UVB raises 25-hydroxyvitamin D [25(OH)D] concentrations [2]. 25(OH)D concentrations are correlated with skin pigmentation in the United States, with whites having the highest mean concentrations, Hispanics intermediate concentrations, and blacks the lowest concentrations [3]. Based on this information as well as many black-white health disparities that cannot be explained by socioeconomic status, stage or condition at time of diagnosis, and treatment, it has been proposed that black-white health disparities and cancer survival rates in the United States are related to the disparities in 25(OH)D concentrations [4,5]. Thus, disparities in 25(OH)D concentrations may explain the disparities in noncardia gastric cancer incidence rates reported in Ref. 1. They may also explain the higher rate of diabetes mellitus in blacks and Hispanics compared to whites, and hypertension in blacks compared to whites [4]. They may also help explain why blacks are diagnosed at younger ages than whites. In addition, Asians, blacks, and Hispanics had higher Heliocobacter pylori infection rates than whites, which would also contribute to risk of developing noncardia gastric cancer at a younger age.

      Second, age at time of diagnosis seems to affect survival rates. The data in Table 1 of Ref. 1 show that there are significant disparities in age at time of diagnosis, with whites having the highest fraction diagnosed after the age of 70 years and Asians and Hispanics the lowest fractions. A plot of median survival as a function of the percentage diagnosed after the age of 70 years yields a slope of -6.5 days/percent with r = 0.77, p = 0.23. While this regression is not significant at the 95% confidence level due to the large difference in survival times for Asians and Hispanics for similar fraction diagnosed over the age of 70 years, which could be due to differences in other factors such as diet, it does suggest that age is an important factor affecting survival rate.

      Thus, if blood samples from near or before the time of diagnosis are available, 25(OH)D concentrations could be measured to evaluate the role of vitamin D in noncardia incidence and survival rates. The effect of age at time of diagnosis can be studied using the existing data.

      References 1. Bautista MC, Jiang SF, Armstrong MA, Kakar S, Postlethwaite D, Li D. Significant racial disparities exist in noncardia gastric cancer outcomes among Kaiser Permanente's patient population. Dig Dis Sci. 2014 Oct 30. [Epub ahead of print] 2. Moukayed M, Grant WB. Molecular link between vitamin D and cancer prevention. Nutrients. 2013;5:3993-4023. 3. Ginde AA, Liu MC, Camargo CA Jr. Demographic differences and trends of vitamin D insufficiency in the US population, 1988-2004. Arch Intern Med. 2009;169:626-632. 4. Grant WB, Peiris AN. Possible role of serum 25-hydroxyvitamin D in Black–White health disparities in the United States. J Am Med Directors Assoc. 2010;11:617-628. 5. Grant WB, Peiris AN. Differences in vitamin D status may account for unexplained disparities in cancer survival rates between African and White Americans. Dermatoendocrinol. 2012;4:85-94.

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


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    1. On 2015 Jan 01, Prashant Sharma, MD, DM commented:

      The most interesting part of this case was realizing that co-inheritance of an alpha as-well-as a beta globin chain variant results in three abnormal hemoglobins on HPLC. One each corresponds to the variants as they combine with the corresponding normal chains (i.e. abnormal alpha with normal beta, normal alpha with abnormal beta), and a third when they combine with each other (abnormal alpha with abnormal beta).

      The other learning point was that abnormal alpha globin chains will result in not just a variant adult (A0) hemoglobin, but also a tiny peak of a variant HbA2 as they will combine with normal delta chains. This little spike is useful in hinting towards the fact that we are dealing with an alpha chain variant.

      Would be happy to share the full paper with anyone who requires it for personal reading.


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    1. On 2015 Nov 04, Carl de Boer commented:

      After publication, we found that our proposed mechanism was unclear, so we have published on figshare [1] a detailed model describing how a poly-dA:dT can be asymmetrically read by chromatin remodelers (http://dx.doi.org/10.6084/m9.figshare.1515926). Further, motivated by recent work by the Kornberg group, which showed that RSC can further decrease the nucleosome occupancy at poly-dA:dT sites [2], and unpublished results from Frank Pugh’s group [3], we checked for enrichment of chromatin modifiers surrounding poly-dA:dT tracts. RSC was specifically enriched in the 5’ offset NFR relative to the poly-dA:dT (http://dx.doi.org/10.6084/m9.figshare.1515927) [4], consistent with RSC recognizing and becoming stalled specifically at poly-dA:dT sequences in a strand-specific manner.

      [1] de Boer, C; Hughes, TR (2015): Model for how poly-dA:dT sites act as nucleosome turnstiles. figshare. http://dx.doi.org/10.6084/m9.figshare.1515926 Retrieved 18:47, Aug 28, 2015 (GMT)

      [2] Lorch Y, Maier-Davis B, Kornberg RD. Role of DNA sequence in chromatin remodeling and the formation of nucleosome-free regions. Genes Dev. 2014 Nov 15;28(22):2492-7. doi: 10.1101/gad.250704.114.

      [3] Wal M, Krietenstein N, Watanabe S, Peterson CL, Korber P, Pugh BF. Unpublished results.

      [4] de Boer, C; Hughes, TR (2015): The RSC complex may be the poly-A nucleosome turnstile mechanism. figshare. http://dx.doi.org/10.6084/m9.figshare.1515927 Retrieved 18:47, Aug 28, 2015 (GMT)


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    1. On 2014 Dec 02, Alison Harrill commented:

      This is a much-needed review of mechanisms of acetaminophen toxicity as they relate to pediatric populations. Thank you for citing our paper in which we first identified a pharmacogenetic risk allele in CD44 in a genetically diverse mouse population and then subsequently validated the finding in two independent clinical trial cohorts. In those studies, sensitive subjects exhibited sub-acute elevations in ALT due to acetaminophen exposure at the maximum recommended therapeutic dose (which has since been lowered). Court et al. examined acetaminophen-induced acute liver failure cases and found indications that the same polymorphism in CD44 was enriched in cases of chronic acetaminophen use versus controls (PMID:24104197). To my knowledge, enrichment of this polymorphism in pediatric cases has not been evaluated.


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    1. On 2014 Nov 20, Daniel J Simons commented:

      This paper reports data from the same training study that was previously reported in PLoS One: http://www.plosone.org/article/info:doi/10.1371/journal.pone.0092269#pone-0092269-g002. It reports results from different outcome measures, but it also reports the results from the earlier paper (including the same statistics and the same data figure: Figure 3b is nearly identical to Figure 2b in the PLoS paper). The paper does not acknowledge that these data were previously published. The training data and results also are presented in both places without acknowledgment of the overlap. The paper does not explicitly state that these are results from the same intervention that was published previously.

      I have posted this comment on the Frontiers website as well, and I have written about these issues in more depth at http://blog.dansimons.com/2014/11/hi-bar-more-benefits-of-lumosity.html. I also wrote about problems with the PLoS paper in an earlier post-publication review (which is why I noticed the overlap): http://blog.dansimons.com/2014/04/hi-bar-benefits-of-lumosity-training.html. The Frontiers paper suffers from the same problems as the earlier paper, given that it was the same intervention.


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    1. 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


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    1. On 2016 Aug 22, Anthony Jorm commented:

      The Royal Australian and New Zealand College of Psychiatrists (RANZCP) has recently published clinical practice guidelines on eating disorders Hay P, 2014, mood disorders Malhi GS, 2015 and schizophrenia Galletly C, 2016. These guidelines contain a mixture of evidence-based recommendations where there were relevant intervention studies, and consensus-based recommendations where relevant studies did not exist. The consensus-based recommendations comprised a substantial proportion of the guidelines for mood disorders (59%) and schizophrenia (46%), but less so for eating disorders (10%), indicating that expert consensus is an important source of guidance on best practice in psychiatry.

      Given the substantial contribution of expert consensus to these guidelines, it is important that the methods for establishing this consensus are adequate. The Australian National Health and Medical Research Council (NHMRC) has published requirements for development of clinical practice guidelines, but these do not give much guidance on how this should be done, simply mandating that “The method used to arrive at consensus-based recommendations or points (e.g. voting or formal methods, such as Delphi) is documented”. (National Health and Medical Research Council. Procedures and requirements for meeting the 2011 NHMRC standard for clinical practice guidelines. Melbourne: National Health and Medical Research Council; 2011.)

      Another potential source of criteria for evaluating the quality of methods for developing consensus-based recommendations comes from research on ‘wisdom of crowds’ Lorenz J, 2011 Kattan MW, 2016 Baumeister RF, 2016. Based on such research, Surowiecki has proposed four conditions necessary for a group to make good decisions (Surowiecki J. The wisdom of crowds: why the many are smarter than the few. London: Abacus; 2004.): 1. Diversity of expertise. A heterogeneous group of experts will produce better quality decisions than a homogeneous one. For guidelines developers, this may mean that the experts should come from a range of relevant disciplines, including consumer experts where appropriate. 2. Independence. The experts must be able to make their decisions independently, so that they are not influenced by others. For guidelines developers, this means that voting on consensus-based recommendations is carried out privately so that strong individuals cannot dominate the group. 3. Decentralization. Expertise is held by autonomous individuals working in a decentralized way. For guidelines developers, it is important to specify what sources of information the experts had available to them. 4. Aggregation. There is a mechanism for coordinating and aggregating the group’s expertise. For guideline developers, this could involve an independent person who runs the voting and gives feedback to the group.

      If we take these four conditions as appropriate for judging the quality of methods for developing consensus-based recommendations, how well do the RANZCP guidelines meet them?

      An indication of diversity of expertise is the disciplinary composition of the guideline working groups. There was limited diversity for all working groups, with non-psychiatrists comprising 3 of the 8 members for eating disorders, 4 out of the 12 members for mood disorders and 2 out of the 10 members for schizophrenia working group. There were no consumer or carer members of any of the working groups. While the mood disorder and schizophrenia guidelines included consensus-based recommendations s for indigenous peoples, it is not stated whether any of the working groups included indigenous members.

      The mood disorders and schizophrenia working groups did not appear to involve independent decision making. Both groups had discussions until consensus was reached. The eating disorders guidelines did not give relevant information about whether there was independence.

      All three guidelines state that consensus-based recommendations were based on collective clinical and research knowledge and experience. The eating disorder guidelines additionally state that level IV articles were considered where higher-level evidence was lacking and this informed the consensus-based recommendations.

      After drafting, all guidelines had input from a broader group of expert advisers with a wide diversity of expertise. However, it is not clear whether these advisers had the potential to persuade working group members to change consensus-based recommendations.

      Where the guidelines included consensus-based recommendations relevant to indigenous peoples, it is not clear what sources of cultural expertise these were based on.

      None of the guidelines state how judgements were aggregated to determine consensus. The mood disorders guidelines state that agreement on consensus-based recommendations was “in most cases unanimous but allowed one committee member to abstain”. The other guidelines did not define what constituted consensus.

      In conclusion, there are major weaknesses in the procedures used to determine consensus-based recommendations for all three guidelines. These are lack of independence in decision making by experts, a lack of a formal mechanism for aggregating judgments, and a lack of diversity of expertise, particular in areas where consumers and carers could contribute and where cultural expertise is relevant.

      While NHMRC gives quite detailed guidance on how to develop evidence-based recommendations, there is little guidance on best practice for developing consensus-based recommendations. While many of these weaknesses would be overcome by using formal consensus methods such as the Delphi process, there is a need for NHMRC and similar agencies to produce more rigorous quality standards for development of consensus-based recommendations.


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    1. On 2014 Oct 31, Wayne Butler commented:

      The ABS does not recommend that the CTV be defined as prostate only. The consensus guidelines specify a target volume margin of 5 mm in all directions about the prostate except posteriorly. Refer to the second paragraph on page 10 of the paper by BJ Davis et al., "American Brachytherapy Society consensus guidelines for transrectal ultrasound-guided permanent prostate brachytherapy." Brachytherapy, 11:6-19, 2012.


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    1. On 2016 Sep 19, Saurabh Gupta commented:

      More than 100 cases and variety of clinical presentation.

      But developmental biologists & embryologists are having tough time to match these numbers.

      Where are all fifth arteries in the human or mouse embryos?


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    1. On 2015 Jan 12, Larry Parnell commented:

      This paper was my selection for Paper of the Week for 3-7 Nov 2014.


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    1. On 2014 Nov 17, Mick Watson commented:

      Hi Robert, and thanks for the response. The results from your qPCR are inconclusive, really the only way to rule out contamination is to sequence the negative control, which has ideally been prepared using the same batch of kits and reagents. Also, the fact that the virus has an effect in mice is negated if the virus is a contaminant, as it may never get into mice in a natural environment.

      May I ask why you didn't sequence the negative controls?


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    2. On 2014 Nov 06, Robert H Yolken commented:

      We actively considered contamination as the source of the sequences we obtained since these viruses may be common in the environment. However, we believe that contamination is rendered unlikely by the fact that, in many cases, we were able to document the presence of DNA homologous to ATCV-1 by 2 independent methods, library generation and quantitative PCR. In the quantitative PCR the reagent controls gave consistently negative results. We also believe that the plausibility of our findings in humans is supported by the mouse experiments presented in the publication.


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    3. On 2014 Nov 04, Mick Watson commented:

      I'd like to politely suggest that the authors need to rule out contamination from reagents and kits used in the experiments (e.g. see http://biorxiv.org/content/early/2014/07/16/007187)


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    1. On 2015 Feb 09, Peter Csermely commented:

      Authors of the paper are happy to highlight the available additional information regarding the localization tree, manual mapping and revision, as well as the updates of the ComPPI database http://comppi.linkgroup.hu.

      Localization tree: ComPPI uses the GeneOntology (GO) cellular component terms for standardizing the different subcellular localization nomenclature in the source databases. The localization tree was needed for the unambiguous classification of minor localizations to the major subcellular compartments. Mappings of the original subcellular localization names to the relevant GO cellular component term for all input sources are available on our GitHub repository https://github.com/erenon/ComPPI/wiki/LOC-databases, while the whole localization tree and the mapping of minor localizations to major cellular components is accessible via our respective Help page http://comppi.linkgroup.hu/help/subcell_locs#structure, and was included in the Supplement of the paper http://nar.oxfordjournals.org/content/43/D1/D485/suppl/DC1 as Figure S2 and Table S4.

      Manual mapping of proteins: As we described it in our published paper (Figure 1) we manually built a mapping table to map 30% of proteins in ComPPI when 1.) the original gene ID (e.g. HGNC gene symbol, EnsemblGeneId etc.) was translated to more than one UniProt accessions (~20% of proteins total, e.g. "HTT" gene symbol could be mapped to both P31645 and P42858 UniProt accessions, where our manual decision of P42858 was based on the name description, "Huntingtin" found in the source dataset of OrganelleDB); or 2.) the original gene ID had no automatic translation to UniProt ID (~10% of proteins total, e.g. manual mapping of the OrganelleDB source dataset "p53AIP1" gene name to Q9HCN2 UniProt accession having the official gene ID "TP53AIP1"). We note that the process was not entirely manual, as we used online ID cross-reference tools (such as PICR http://www.ebi.ac.uk/Tools/picr/) and the UniProt ID mapping http://www.uniprot.org/uploadlists/ as gold standard validation of gene ID to UniProt mappings.

      Manual revision: Our manual revision process besides the construction of the localization tree and the ID mapping included 1.) the manual testing of the interfaces connecting the source databases to the ComPPI dataset during the database building process including the check for false-entries (e.g. non-existing UniProt accessions) and data content errors (e.g. minor subcellular localizations without GO terms) for randomly chosen 200 proteins, and 2.) six experts tested the integrated dataset for false-entries, data inconsistency and protein name mapping errors. Additionally, two of the six experts tested randomly chosen 200 proteins for exact matches between the entries in the source databases compared to the ComPPI dataset (this manual revision process is described in Figure 1 of the paper and in Supplementary Table S3). In Supplementary Table S3 of the publication we showed how many proteins, subcellular localizations and interactions were included from the source databases to the ComPPI dataset. The amount of data 'missing' in ComPPI compared to the sources is due to mapping differences between different namespaces (e.g. the integrated CCSB dataset contained 3,881 interactions, while only 3,733 interactions were included to the ComPPI dataset due to the removal of non-protein coding genes), data inconsistencies, or protein name mapping errors.

      Database updates: The manual steps, such as the inclusion of new GO terms to the localization tree, or mapping of missing IDs, can and will be included to all future ComPPI updates. In these updates we will document our manual curation process in more detail. We schedule the release of ComPPI 2.0 before May 2016. The new version will include the update of the source databases (such as the 2014 update of the CCSB dataset), the revision of our mapping system with the update of the UniProt dataset based on the latest release, the inclusion of new input sources, such as LocDB, as well as an upgraded network visualization and extended export options (such as SIF or PSI-MI).


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    2. On 2015 Jan 27, Robert M Flight commented:

      Commended because the issues they raise are valid. It makes sense that protein-protein interactions (PPI's) should be localization specific, and that many false PPI may be removed by considering localization information.

      However, the solution implemented by ComPPI is not an ideal solution. This is largely due to the "manual" curation steps required in its construction. These manual steps are described below, followed by a comment on why this is such a problem for this type of resource.

      Localization tree: the authors' state that 1600 of the ~3600 gene ontology (GO) cellular compartment (CC) terms were used to "manually" construct a localization tree whereby each GO term has a single path to one of the six defined compartments of Cytosol, Nucleus, Mitochondrion, Secretory-Pathway, Membrane, and Extracellular. There is no justification for the requirement of a tree with single paths to root compartments beyond the multi-parent nature of the directed-acyclic-graph of the normal GO. The description in the paper implies that the generation of the tree from the GO terms was done fully by hand. No description of how terms are assigned to compartments are provided, or if any attempts at automated assignment methods were made.

      Manual mapping of proteins: The authors state that 30% of protein IDs were un-mappable to UniProt IDs using databases, and had to be mapped manually. Although protein-protein ID mapping across databases is known to be a difficult problem (I will point to one possible solution: http://bioinformatics.louisville.edu/abid/), this seems like a rather large percentage to map by hand.

      Manual revision of database: 200 entries were checked by six experts, and based on their findings, revisions of the database made. No description of the type of checks made is provided, nor numbers on the rates for true, false / positives / negatives, and what the corrective efforts involved.

      Each of these manual steps is a possible point of introducing bias that is hard to quantify and replicate, and in fact makes it highly unlikely that the database will be updated at regular intervals in the future or expanded to other model organisms beyond yeast, c elegans, drosophila and human. This severely limits the reliability and future utility of the database in my opinion.


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    1. On 2015 Aug 12, Jim Woodgett commented:

      This manuscript would be improved by systematic removal of "beta" throughout as the inhibitor primarily used, GIN, is not selective for GSK-3beta vs the related isoform, GSK-3alpha. A direct quote from reference 17 (referring to the source of the GIN inhibitor used here):

      "A similar assay measuring inhibition of GSK3-alpha was also routinely run, but 7-12 showed no significant ability to discriminate between the two isoforms of GSK3 (data not shown). To the best of our knowledge, no isoform specific inhibitors of GSK3 have been reported, probably due to their high sequence homology (vida supra)."

      This inhibitor (GIN) acts equally on both isoforms of GSK-3 (alpha and beta) and should not be referred to as a GSK-3beta selective inhibitor. This makes sense given that inhibition of GSK-3beta alone is insufficient for deregulation of beta-catenin (PMID: 17543867).


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    1. On 2014 Dec 02, Mikkel Wallentin commented:

      On the behavioral effects, the authors write: "Compared with the low-flavanol intervention, subjects who received the high-flavanol intervention showed a mean improved cognitive performance of 630 ms." However, visual inspection of the supplementary figure 3 clearly shows that the 630 ms difference at follow up is due to a modest improvement of approx. 200 ms between baseline and follow up and a much more pronounced DECLINE in the control group (approx. 400ms). Needless to say, such a difference cannot be interpreted as "a mean improved cognitive performance of 630 ms", if it can be interpreted at all.


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    2. On 2014 Oct 27, David Colquhoun commented:

      For all the reasons given by Hilda Bastian (and a few more, like P = 0.04 provides lousy evidence) it astonishes me that this study should have been trumpeted as though it represented a great advance. That's the responsibility of Nature Neuroscience (and, ultimately, of the authors).

      I wonder whether what happens is as follows. Authors do big fMRI study. Glamour journal refuses to publish without functional information. Authors tag on a small human study. Paper gets published. Hyped up press releases issued that refer mostly to the add on. Journal and authors are happy. But science is not advanced.

      I certainly got this impression in another recent fMRI paper in Science. Brain stimulation was claimed to improve memory (P = 0.043)

      I guess these examples are quite encouraging for those who think that expensive glamour journals have had their day. Open access and open comments are the way forward.


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    3. On 2014 Oct 27, Hilda Bastian commented:

      This report of a very small, short-term trial in healthy adults does not meet the CONSORT standards for trial reporting in several key respects. It does not provide sufficient data on the cognitive outcomes assessed, nor an adequate flow chart of outcomes (despite considerable attrition). There is also very little detail provided in the record of this trial at ClinicalTrials.gov.

      The abstract does not make it clear that this is a dietary supplement and exercise trial (partially funded by a manufacturer). There were apparently two cognitive outcome measures on a ModBent task (an adapted test not elsewhere validated): immediate matching and delayed retention. Both relate to very specific functions, not an overall rating of cognitive abilities.

      No effect was found for the exercise component in the trial, and out of the two cognitive measures, some effect was found for one, but not the other. That this is a chance finding surely can't be ruled out.

      This report describes low vs high supplement groups. The study in ClinicalTrials.gov for the trial number they provide, however, was for a supplement and a placebo comparator.

      Despite the major limitations of this single trial to address the question, the "Newsroom" report for the trial claims that it shows that "dietary flavanols reverse age-related memory decline."

      It's good to see claims about dietary supplements tested. However, the results here rely on a chain of yet-to-be-validated assumptions that are still weakly supported at each point. In my opinion, the immodest title of this paper is not supported by its contents.


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    1. On 2015 Jul 12, Guo-Liang Jiang commented:

      Evaluation of the value of ENI in radiotherapy for cervical and upper thoracic esophageal cancer: a retrospective analysis (Radiat Oncol. 2014 Oct 25;9:232.) We correct the first author Liu M's affiliation as the following: 1. Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China; 2.Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Current address: Department of Radiation Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, China


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    1. On 2017 May 02, Zvi Herzig commented:

      The authors note, "Observed trends require confirmation in a larger nationally representative sample". This has become possible with Poland's Social Diagnosis data (http://diagnoza.com/index-en.html).

      The national data indicates that sharp declines in youth smoking have occurred during the present study's duration.

      Below are the are smoking rates for ages 16-24, as reported in the 2013 (p. 249) and the 2015 (p. 284) Social Diagnosis reports:

      year: smoking (%)

      2000: 22.7

      2003: 23.3

      2005: 21.4

      2007: 22.7

      2009: 21.6

      2011: 19.4

      2013: 18.1

      2015: 15.5

      The differences between this local study and the national trend may reflect the fact that only 13 of the 25 schools surveyed have participated in both the 2010-11 and the 2013-14 surveys.


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    1. On 2015 Mar 16, David Ayoub commented:

      That Contreras et al1 failed to report an association between vitamin D deficiency (VDD) and fracture risk is surprising in light of nearly a century of research linking vitamin D to bone health. We would like to suggest that study design limitations might have obscured such a potential relationship.

      While fractures are a well-known complication of rickets/osteomalacia their association with subclinical forms of deficiency is less well established. The prevalence of fractures in rickets varies but typically found in a minority of individuals suffering from the disease. In a review of vitamin D and skeletal health in children, Moon et al recently summarized 17 modern studies of rickets. Fractures were observed in 13 of these studies among 1,177 children. The average fracture prevalence was 6% with a range between 0% and 20%. Only 2 studies involved a similar aged subset as reported by Contreras. Agarwal and Gulati reported a 6% fracture prevalence in 10-13 y/o children in India. Narchi et al reported no fractures among 10-15 year olds with rickets in Saudi Arabia. A comparison of fracture rates among vitamin D sufficient vs. deficient individuals would therefore require an adequately large sample size ideally in prospective studies. Contreras’ alternative approach that compared VDD rates among those with fractures and non-injured cohorts introduces several potential confounders.

      Bone failure, especially with minor trauma, is considered to be a stochastic event – one associated with probabilities – caused by the interplay of various extrinsic (force/load) and intrinsic (bone strength) factors. Intrinsic factors put genetically susceptible individuals at risk for fractures when exposed to the random forces of trauma. The genetic component has been reported to be the most important intrinsic factor associated with bone failure. Other risk factors include, but are not limited to decreased bone loading, illness, various endocrine and nutritional conditions, medications, physiologic alterations associated with bone turnover, and growth spurts. Designing a population-based study to isolate the role of VDD in fractures would be nearly impossible unless other major determinants that effect bone quality and fracture risk are controlled.

      Contreras provides little detail of the nature of forces applied to the 100 fracture cases. Even if vitamin D deficiency was the major contributor to diminished bone strength, a force is still required to produce a fracture. Contreras’ fracture group could have had other confounding conditions that affected bone strength, including familial predispositions that adversely influenced bone quality. Since forces vary considerably it is certain that some fractures would occur regardless of bone strength. The fact that 63% of cases with fractures following “minor” trauma had inadequate vitamin D levels would raise concern that diminished bone strength may have contributed to injury in some children.

      It is possible that Contreras’ control population, similarly suffering from VDD ubiquitous to the general population, also had compromised bone strength and differed only from controls by having the good fortune of avoiding a significant accident. It would have been more ideal to choose a control group strictly comprised of children suffering traumatic injuries but without fractures instead of a group that included various acute medical conditions. In this scenario, all subjects of both groups would have been exposed to physical forces that would have challenged bone integrity. It is possible that their control group of emergency room patients without fractures suffered from conditions associated with higher rates of VDD and thus neutralizing any potential difference in vitamin D status from the fracture group.

      In addition to Ryan, there are several more studies that did report an association between vitamin D and fractures. Ruohola et al reported a strong association between lower vitamin D levels and stress fractures among 800 randomly selected and prospectively followed young military recruits. Leboff et al reported lower mean vitamin D levels in women with postmenopausal hip fractures compared to two groups of postmenopausal women prior to elective hip replacements. In a nested case-control study of 1200 female Naval recruits Burgi et al reported increased risk of stress fractures among those who were vitamin D deficient. There was approximately half the risk of stress fractures in women in the top vs. the bottom quintile of vitamin D concentration. While we agree that one cannot say that vitamin D status alone could predict who will fracture, these alternatively designed studies suggest that it can identify an at-risk population.

      Lastly, but perhaps of greater importance is the extraordinary rate (63%) of inadequate vitamin D status among Contreras’ emergency room-attended population. This observation alone deserves the full attention of local physicians and public health officials and goes far beyond the original mission of their study.

      REFERENCES 1. Contreras JJ, Hiestand B, O'Neill JC, Schwartz R, Nadkarni M. Vitamin D deficiency in children with fractures. Pediatr Emerg Care. 2014;30(11):777-781. 2. Moon RJ, Harvey NC, Davies JH, Cooper C. Vitamin D and skeletal health in infancy and childhood. Osteoporos Int. 2014;25(12):2673-2684. 3. Agarwal A, Gulati D. Early adolescent nutritional rickets. J Orthop Surg (Hong Kong). 2009;17(3):340-345. 4. Narchi H, El Jamil M, Kulaylat N. Symptomatic rickets in adolescence. Arch Dis Child. 2001;84(6):501-503. 5. Ferrari S, Chevalley T, Bonjour JP, Rizzoli R. Genetic determinants of bone microstructure and fracture risk in childhood. Bone. 2007;40(3)(suppl 1):S12. 6. Melamed ML, Kumar J. Low levels of 25-hydroxyvitamin D in the pediatric populations: prevalence and clinical outcomes. Ped Health. 2010;4(1):89-97. 7. Ryan LM. Forearm fractures in children and bone health. Curr Opin Endocrinol Diabetes Obes. 2010;17(6):530-534. 8. Ruohola JP, Laaksi I, Ylikomi T, et al. Association between serum 25(OH)D concentrations and bone stress fractures in Finnish young men. J Bone Miner Res. 2006;21(9):1483-1488. 9. LeBoff MS, Kohlmeier L, Hurwitz S, Franklin J, Wright J, Glowacki J. Occult vitamin D deficiency in postmenopausal US women with acute hip fracture. JAMA. 1999;281(16):1505-1511. 10. Burgi AA, Gorham ED, Garland CF, et al. High serum 25-hydroxyvitamin D is associated with a low incidence of stress fractures. J Bone Miner Res. 2011;26(10):2371-2377.


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    1. On 2014 Dec 30, William Grant commented:

      The review by Bonifazi and colleagues found that those with sarcoidosis have an increased risk of many types of cancer.1 The role of inflammation in explaining the link between sarcoidosis and cancer was discussed. However, no firm conclusion was reached regarding the link.

      A factor not considered was vitamin D. Those with sarcoidosis often have low 25-hydroxyvitamin D [25(OH)D] concentrations due to concerns about hypercalcemia.2 There is evidence that low solar UVB doses and serum 25(OH)D concentrations are a risk factor for sarcoidosis. A summary of the geographical and temporal mortality rates for sarcoidosis in the United States for the period 2000-2007 found higher mortality rates for non-Hispanic black and white decedents in the higher latitude states, which have lower solar UVB doses, as well as moderately higher trends of mortality rates for non-Hispanic males and females from 1989 to 2007.3 Serum 25(OH)D concentrations decreased during that period due to a number of factors.

      Low solar UVB exposure and 25(OH)D concentrations are an important risk factor for many types of cancer.4 Of the types of cancer with significant relative risks related to sarcoidosis, seven are significantly inversely related to solar UVB doses in ecological studies: colorectal, kidney, leukemia, liver, and upper digestive tract cancer, Hodgkin's lymphoma, and non-Hodgkin's lymphoma. However, eight types of cancer inversely correlated with solar UVB doses in ecological studies were not found directly linked to sarcoidosis: bladder, breast, cervix/uterus, lung, ovary, pancreas, prostate, and stomach cancer. Of these types, only bladder and breast cancer are strongly linked to low UVB doses and/or 25(OH)D concentrations. As noted in Ref. 1, smoking may affect the sarcoidosis-cancer link, and four of these types of cancer are strongly linked to smoking: bladder, crevix/uterus, lung, and pancreas cancer.

      Twelve of the 16 studies included in Ref. 1 were from Nordic countries. A study of cancer incidence rates with respect to a solar UVB exposure index in Nordic countries based on 54 occupational categories found much the same for males as summarized in Ref. 4.5 In addition, the melanoma incidence rate for males was inversely correlated with the UVB exposure index at the p=0.02 level, and the non-melanoma skin cancer rate was significantly inversely correlated with both the UVB index and lung cancer incidence rates in a multiple-linear regression analysis. Both melanoma and basal cell carcinoma are more frequent among people with limited solar UV exposure than those with chronic UV exposure.

      References 1. Bonifazi M, Bravi F, Gasparini S, et al. Sarcoidosis and cancer risk: systematic review and meta-analysis of observational studies. Chest. 2014 Oct 23. doi: 10.1378/chest.14-1475. [Epub ahead of print] 2. Bolland MJ, Wilsher ML, Grey A, et al. Randomised controlled trial of vitamin D supplementation in sarcoidosis. BMJ Open. 2013;3:e003562. 3. Swigris JJ, Olson AL, Huie TJ, et al. Sarcoidosis-related mortality in the United States from 1988 to 2007. Am J Respir Crit Care Med. 2011;183:1524-1530. 4. Moukayed M, Grant WB. Molecular link between vitamin D and cancer prevention. Nutrients. 2013;5:3993-4023 5. Grant WB. Role of solar UV irradiance and smoking in cancer as inferred from cancer incidence rates by occupation in Nordic countries. Dermatoendocrinol. 2012;4:203-211.

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


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    1. On 2014 Oct 24, Fernando Castro-Chavez commented:

      To All,

      When I was comparing the relative position of the 64 codons of the Genetic Code between two x-y 2-D Tables, i.e., while keeping the axis Y constant with the C-Rings of the DNA Nucleotides and changing the axis X from having their H-bonds in one Table to their Tautomerism in the other Table, what resulted of this comparison, as my article demonstrates, were the directional arrows of the ancient Chinese representation of the Yin and the Yang (external long arrows at opposite directions annealed to the two internal shorter arrows per each of the long ones). When I added the third Table with the third possible comparison of these DNA-Nucleotide properties (i.e., H-bonds in axis X and Tautomerism in axis Y), what I had was the half of a Cube, and by adding the remaining three reciprocal Tables, I was able to complete a Cube. From here, it was not difficult to Spherize such Cube in order to obtain the Spherical representation of the genetic code!

      This is my graphic representation of one of the Spherized sides of the Cube: Spherical Genetic Code

      Attentively,

      Fernando Castro-Chavez. 10/24/2014 Houston, TX


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    1. On 2014 Nov 30, Harri Hemila commented:

      Musher DM, 2014 conclude their paper by stating that RCTs are needed to determine whether the antiinflammatory activity of macrolides or statins is beneficial in treating CAP.

      I would like to propose that RCTs are also needed to determine whether vitamin C is beneficial in treating CAP. In dozens of animal studies, vitamin C protected against infections by various viruses and bacteria, implying that the vitamin may influence incidence and severity of some infections Hemilä 2006, pp. 5-9, 105-21.

      In the early 20th century, Alfred Hess carried out extensive studies of scurvy and summarized a large series of autopsy findings as follows: “pneumonia, lobular or lobar, is one of the most frequent complications [of scurvy] and causes of death” and “secondary pneumonias, usually broncho-pneumonic in type, are of common occurrence, and in many [scurvy] epidemics constitute the prevailing cause of death”, see Hemilä H, 2007. In this journal, Hess 1932 commented that in “infantile scurvy … a lack of the antiscorbutic factor which leads to scurvy, at the same time predisposes to infections [particularly of the respiratory tract]. … Similar susceptibility to infections goes hand in hand with adult scurvy.” Thus, deficiency of vitamin C and pneumonia may be associated. Deficiency of vitamin C is not rare even nowadays Schleicher RL, 2009.

      Furthermore, vitamin C has reduced the duration and severity of the common cold in well-nourished people suggesting that the vitamin may have effects on the respiratory system even in the absence of frank deficiency Hemilä H, 2013.

      Hemilä H, 2013 carried out a Cochrane review and found 3 controlled trials that looked at whether vitamin C prevents pneumonia and 2 that looked at whether it might help in curing pneumonia. Each of the 5 studies found that vitamin C supplementation was significantly beneficial against pneumonia. Two of them were placebo-controlled RCTs.

      Pitt HA, 1979 administered vitamin C to US marine recruits and reported 7 cases of pneumonia in the placebo-group compared with 1 case in the vitamin C group. Hunt C, 1994 administered vitamin C to elderly people who were admitted to hospital in the UK because of bronchopneumonia or acute exacerbation of chronic bronchitis. They reported a significant decrease in the “total respiratory score” by vitamin C administration, and 5 deaths in the placebo group compared with 1 death in the vitamin C group. Hunt et al. tested the effect of vitamin C “over and above those of normal medication (mainly antibiotics and cough medicines) to which all participants were exposed” so that all their patients received antibiotics and vitamin C was not an alternative to them.

      The prophylactic use of vitamin C to prevent pneumonia should be further investigated in populations who have a high incidence of pneumonia, especially if dietary vitamin C intake is low. Similarly, the therapeutic effects of vitamin C should be studied, especially in pneumonia patients with low plasma vitamin C levels.


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    1. On 2014 Oct 24, Gwinyai Masukume commented:

      The authors write, "Only two cases of an abdominal pregnancy combined with an intrauterine pregnancy has been reported [11, 12]."

      Zacchè MM, 2011 is an additional recent case that the authors did not cite. In addition Reece EA, 1983 is a review of 589 cases of combined intrauterine and extrauterine gestations. A Chinese article Wu X, 1999 also tackles similar cases.


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    1. On 2015 Jul 15, Raphael Levy commented:

      Thanks Harald for commenting on my blog post about SmartFlares / Nanoflares with reference to this paper.

      I reproduce the conversation below. I hope it continues and others join in.

      Raphael


      "Hi everybody, as the correspending author of a Stem Cell paper in which we have used the SmartFlares on different pluripotent cells of human, murine and porcine origin I want to reply to two of the above mentioned questions.

      Why do we see a signal at all in the scramble control? I think one cannot expect a negative control which does not produce a fluorescent signal at all. The fluorophore may not be quenched by 100% and may be subject to degradation, especially when applied for a longer time (two days or more). Nevertheless, within 16 to 24 hours after the application of the nanoparticles we see a clear-cut difference of fluorescence intensity when comparing scramble control and gene-specifc Smart Flares. http://www.ncbi.nlm.nih.gov/pubmed/25335772

      We believe that this difference is reliable and specific. We have selected freshly reprogrammed murine iPS cells based on their Nanog-specific fluorescence intensity in situ. In downstream experiments we could confirm that only colonies with a high fluorescence intensity expressed higher amounts of endogenous pluripotency factors and showed a superior capacity to differentiate. Therefore, we belive that these functional data strongly support the idea that the fluorescence intensity was indeed correlated to a specific interaction with the Nanog mRNA in these clones.

      Why do different cells take up varying amounts of SmartFlares? I think this difference is not surprising as the nanoparticles are engulfed by endocytosis. This process is influenced by the cell type, the differentiation status and the cellular ability to perform phago- and macropinocytosis. Therefore, we think that a uniform uptake rate cannot be expected."

      I replied "Hi Harald

      Thanks again for commenting here and sorry for the delay in replying. It is interesting that you see some differences but the big question that remains is how could the technology possibly work?

      It can only work if the particles escape endosomes, but: 1) there is no reason why they should, 2) this problem is not discussed in the original publication introducing the technology, 3) there is no direct evidence in the literature that it happens, and, 4) all the data we are accumulating indicates that the particles are indeed in vesicular compartments (more on this soon on the open notebook as we have just had our cell electron microscopy results this week).

      The images shown in your articles are low mag overviews of many cells and therefore the resolution does not allow to discuss any cellular localization. Do you have any higher resolution images that you could share? Do you have any (direct) evidence and/or proposed mechanism for endosomal escape?

      The unequal distribution of uptake (cell to cell variability) is also a big concern. I don鴠believe that it relates to differences between rate of uptake of different cells. Such differences would average over an 18 hour period and they should also be seen in the dextran uptake. A possible interpretation would be some degree of nanoparticle association/aggregation before interaction with the cells (this is to be tested experimentally).

      Raphael"


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    1. On 2017 Jun 22, Nathaniel Huebsch commented:

      The original url for downloading the software is no longer active. The correct website for downloading this software is:

      https://gladstone.org/46749d811

      We appreciate everyone who let us know about the weblink being down.


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    1. On 2014 Dec 14, Jeffrey Beall commented:

      I would like to express some concerns regarding this article. Examining the publisher's PDF version of the article, one finds this statement after the abstract: "Submitted Apr 19, 2014. Accepted for publication Apr 22, 2014." Based on this three-day period between submission and acceptance, it is fair to conclude, I think, that no bona fide peer review was carried out.

      Moreover, it appears that the article is being posted to online patient forums, perhaps by one of the authors, as a way of advertising and marketing the surgical technique described in the article.


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    1. On 2015 May 04, Andrew Brown commented:

      See our letter about this article here Brown AW, 2015; and the authors' response here http://jn.nutrition.org/content/145/5/1029 (not yet indexed in PubMed).


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    1. On 2016 Apr 27, Nadav Sorek commented:

      After the paper was published, we became aware of anomalies in the ITC plot in figure 2, and in the gel blot presented in figure 3. I performed the experiment and prepared the figure, and was not aware of these anomalies, as they can be seen only when the contrast of the blot has been changed dramatically. The anomalies in the ITC plot were determined to have been caused by a failure in the graphics card. The reason for the anomalies in the gel blot remains unknown, although they may have occurred as a result of image compression into JPEG format. I did not retain the original uncompressed images, so this was impossible for me to resolve without repeating the experiment. I was able to demonstrate that the results reported were reproducible, however due to the anomalies, JBC insisted that we retract the paper. To remove any doubt about the reliability of the data, we asked an independent researcher to repeat the experiment, and the results from these experiments were consistent with our published results. The report with all the details can be found in bioRxiv (http://biorxiv.org/content/early/2016/04/26/050427). Please don’t hesitate to contact me with question or further clarifications.<br> Nadav Sorek (Nadav.sore.il@gmail.com)


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    1. On 2015 Jan 12, Larry Parnell commented:

      This paper was my selection for an alternate Paper of the Week for 3-7 Nov 2014.


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    1. On 2016 Dec 10, Wen-Long Hu commented:

      Laser acupuncture (LA) is defined as the stimulation of traditional acupuncture points with low-intensity, non-thermal laser irradiation. LA combines the positive effects of traditional acupuncture with LLLT. http://dx.doi.org/10.5772/55092


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    2. On 2016 Dec 01, Jan Tunér commented:

      In the study by Hu et al., three acu points and 2-4 ashi points were irradiated, all but one (Hegu, LI4) were in the area of the masticatory muscles. So in fact, laser acupuncture and traditional LLLT for TMD was used. Let us look at the laser parameters: The laser was a 810 nm 150 mW laser, “chopped” at 50%, so actually 75 mW. Reason for chopping is not presented. Two acu points were in the TMD area: ST7 = condyle, ST6 = mandibular corner = muscle masseter. 5 s per acu point = 0.375 J. Two points in the TMD area = 0.750 J. 40 s per ashi/tender point = 3 J. For two points 6 J, for four points 12 J. Maximum total 12.750 J. Several studies on TMD and LLLT have used energy ranges between 3 and 6 J per point, or even less, and targeting tender points. Therefore, this study is a traditional LLLT study and the contribution of the acu points cannot be evaluated. Future studies should not mix local LLLT with laser acupuncture.


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    1. On 2015 Apr 02, Alasdair MacLullich commented:

      Thank you for the clarification. This is a very important issue because low arousal states of acute onset (excluding coma) are considered as indicating "severe inattention" in DSM-5: see the DSM-5 guidance notes.

      Many patients with low arousal states (of acute onset) are not testable by conventional cognitive tests, and yet these patients mostly have delirium. Because of this, there is an explicit 'untestable' category in the 4AT, a rapid assessment test for delirium designed for use in routine clinical practice (see www.the4AT.com; http://www.ncbi.nlm.nih.gov/pubmed/24590568; http://www.ncbi.nlm.nih.gov/pubmed/23988641).

      The issue of low arousal states and delirium diagnosis was covered in a consensus statement by the European Delirium Association and the American Delirium Society: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4177077/

      See also these two relevant papers: http://www.ncbi.nlm.nih.gov/pubmed/24080383; http://www.ncbi.nlm.nih.gov/pubmed/22173963


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    2. On 2015 Mar 15, Geriatric Medicine Journal Club commented:

      Thank you so much. We will share this comment with a link to the followers of #GeriMedJC on Twitter.


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    3. On 2015 Mar 09, Edward R Marcantonio commented:

      A recent Geriatric Medicine Journal Club commented on the limitations of the 3D-CAM in low arousal states. Note that for each 3D-CAM question, "no response" is considered the equivalent of "incorrect" and can trigger the presence of a CAM Feature. Therefore, the 3D-CAM should work equally well, and be even quicker, in patients with low arousal states. While we had relatively few patients with low arousal states in our validation study, the 3D-CAM correctly identified 100% of the delirium cases in this subgroup.


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    4. On 2015 Feb 27, Geriatric Medicine Journal Club commented:

      This study of the 3D-CAM, a 3-minute diagnostic assessment for CAM-defined delirium, was critically appraised at the November 2014 Geriatric Medicine Journal Club (follow #GeriMedJC on Twitter). Much discussion was generated between researchers and clinicians from around the world. See the full transcript of the discussion here: http://gerimedjc.blogspot.com/2014/11/gerimedjc-november-28-2014.html?spref=tw Highlights included limitations of assessment in patients with low-arousal states.


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    1. On 2015 May 31, Marc Girard commented:

      In accordance with my previous criticism regarding the methodological reliability of most studies presented as confirming the safety of vaccines, this investigation raises a number of serious concerns.

      Case ascertainment – Whereas the study title makes special emphasis on multiple sclerosis (MS: ICD code 340), case identification includes no less than nine ICD codes, some of which (optic neuritis or acute disseminated encephalomyelitis being sometimes difficult to differentiate from genuine MS, whereas others [transverse myelitis] are generally considered as distinct). The most expected result of such a diagnosis blending is to weaken statistical power and to blur epidemiological evidence.

      Vaccination assessment – Only 4.0% of the 3885 controls were exposed to hepatitis B vaccine in the 3 years before the index rate; this may be compared with the study by Hernán MA, 2004 (the design of which was fairly similar), where 2,4% of the 1565 controls were exposed to a recombinant hepatitis B vaccine. The trouble is that this immunization was highly selective in the latter population (UK), whereas it was massive in the former (USA). In spite of this major discrepancy in the vaccine policy between the two countries, the surprisingly small difference between these two percentages raises the hypothesis that, for one reason or another, vaccination recording was incomplete in the American sample. Although duly pointed out as remarkable by Langer-Gould et al., low vaccine exposure in their sample was not seriously discussed by the authors.

      Control selection – Although a black ethnicity was the most prominent risk factor identified by the authors in their previous study on the incidence of demyelinating syndromes (quoted as reference 17 in their current paper), one may wonder why their control selection did not include race in their matching method. As it happens, imbalance in the distribution of black race between cases and controls was the most striking feature of the baseline samples characteristics.

      Index date – Although the timing of symptoms appearance is generally a crucial argument for causality in drug monitoring (there may be exceptions to this rule), this parameter is never properly considered in investigations devoted to post-vaccine MS. Actually, as the disease may remain clinically silent for years, the relevant parameter is neither the date of diagnosis nor that of the late symptoms which lead to the investigations leading to positive diagnosis. In spite of this, what investigators mean by “symptoms onset date” is never clearly defined: which symptoms? For example, in their abovementioned reference 17 (Table 1), Langer-Gould et al. estimated at 0.9 month the median time from symptom onset to diagnosis, after having stipulated that, defining MS required two or more episodes of MS “separated in time”: is unlikely that 0.9 month is a sufficient time interval to separate two distinct MS episodes… At the opposite side of the clinical spectrum, the very first symptoms of a MS are often an unexplained fatigue, mild paresthesia, etc. the onset of which may be quite close to the time of vaccine injection (a few days or weeks), but which may last for years before onset of more significant symptoms: thus, if one focus on the late significant symptoms, this very long time lag is almost always interpreted as speaking against a vaccine role whereas, when considering the whole of symptoms sequence from its very beginning (i.e. from the time of quite discrete symptoms just after injection), it is on the contrary highly suggestive of a vaccine causality. I have never seen this crucial problem properly taken into account in any database, so that most investigations about the time between vaccination and the onset of MS symptoms are essentially misleading.

      Regarding MS and in spite of their denials, the authors ended up to a result very close to that of Hernan et al.’s., namely an overrepresentation of cases (4.2%) as compared to the controls (3.1%) within a time windows of 3 years. Of course, this difference just failed to reach statistical significance but: i) as documented above, the methodological tendency of the authors contributed to decrease the power of their results; ii) amongst the published case/control studies supposed to exclude a post-vaccine risk of MS (by means of like strategies of dilution of the cases or of insufficient observation period), the number of those suggesting (even in a nonsignificant way) an overrepresentation of cases in vaccinated subjects is clearly higher than those suggesting an underrepresentation, and the difference between the two groups of studies is clearly significant from a statistical point of view.

      Finally and as with most papers devoted to the safety of hepatitis B vaccines, the authors cannot refrain from concluding that no “change in vaccine policy” is warranted: yet, their investigation is totally devoid of the slightest element likely to validate any vaccine policy, whose potential shortcomings (included issues of cost, of resources allocation, of individual and collective efficacy, of nonneurological risks, etc.) go far beyond the sole issue of MS. In psychoanalysis, such optimism (going far beyond the available evidence from a given investigation) is called “the return of the repressed”…


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    1. On 2015 May 28, Andrew Brown commented:

      See our comment about the analysis of this cRCT in our letter to the editor published by the journal: "Ignoring the potential similarity among individuals in the same cluster (school) can ... increase the type I error rates and jeopardize the validity of conclusions from cRCTs." http://www.hindawi.com/journals/jobe/2015/708181/


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    1. On 2014 Oct 21, Carl L von Baeyer commented:

      Potentially a very important finding. However, it should be read with caution. Table 2 indicates a range of 6-8 for VAS. This is problematic in four ways: (a) VAS is not listed among the measures, which were a faces scale and a numerical rating scale. (b) Perhaps what is meant by "VAS" is actually a combination of scores on the faces scale and the numerical rating scale. But these different scales cannot be combined as if they were the same thing. They should be reported separately unless a rationale is provided for treating them as the same. (c) The idea that ALL 82 subjects with a chronic illness used only the scores 6, 7 or 8 (out of the 11 scores available on the self-report scale) is not plausible: this would represent an extraordinarily unlikely restriction of range on the 0-10 metric, or else there was some bias in the way the question was asked. (d) If all scores were 6, 7 or 8, then the mean could not have been greater than 8 as reported in the abstract. I'd invite the authors to check this line of Table 2 before the paper is finalized. Thank you.


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    1. On 2014 Oct 18, David Keller commented:

      Restricted entry of travelers from affected regions is a valid means of pandemic control

      Past pandemics have taught us that "travel restriction is an immediate and non-pharmaceutical means of retarding incidence growth. It extends the time frame of effective mitigation, especially when the characteristics of the emerging virus are unknown."(1)

      During the 2014 ebola virus pandemic, the oft-repeated objection that travel restrictions would "exacerbate the West African epidemic by impeding the flow of aid workers and supplies" (2) could have been addressed by allowing aid workers to enter the ebola zones, and then return to the U.S. after appropriate observation or quarantine measures. Fortunately, the ebola pandemic did not break out into the U.S. population, despite transmission of the virus to hospital personnel.

      Travel restrictions and quarantines are a valid means of slowing the spread of infection, and should be considered during the next deadly pandemic which lacks effective treatment.

      References

      1: Chong KC, Ying Zee BC. Modeling the impact of air, sea, and land travel restrictions supplemented by other interventions on the emergence of a new influenza pandemic virus. BMC Infect Dis. 2012 Nov 19;12:309. doi:10.1186/1471-2334-12-309. PubMed PMID: 23157818; PubMed Central PMCID: PMC3577649.

      2: Gostin LO, Hodge JG Jr, Burris S. Is the United States Prepared for Ebola? JAMA. 2014 Oct 17. doi: 10.1001/jama.2014.15041. [Epub ahead of print] PubMed PMID: 25325877.


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    1. On 2015 Mar 24, Amanda Capes-Davis commented:

      Thank you Radoslaw - I very much appreciate this clarification from you and the other authors of the article.


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    2. On 2015 Mar 23, Radosław Stachowiak commented:

      Thank you for your vigillance and comments. To correct this important issue we have published Erratum to the article: http://link.springer.com/article/10.1007/s00284-015-0803-0?sa_campaign=email/event/articleAuthor/onlineFirst


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    3. On 2015 Feb 26, Amanda Capes-Davis commented:

      Thank you to the authors for commenting on this paper in a feature article published in Science at http://www.sciencemag.org/content/347/6225/938.full. I appreciate the authors' comments in clarifying why these cell lines were used.


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    4. On 2015 Feb 13, Amanda Capes-Davis commented:

      The three cell lines used here - INT-407, HEp-2 and HeLa - are all HeLa. INT-407 and HEp-2 were clearly shown to be cross-contaminated by HeLa in the 1960s and 1970s. INT-407 and HEp-2 continue to be used widely today, by scientists who may not be not aware that these cell lines are misidentified.

      In my view, three cell lines are used here to indicate that the effect of Lmo0171 on cell morphology has broad impact across different cell types. But the results described here may be specific to HeLa cells and have no impact beyond that culture and cell type (human cervical adenocarcinoma).

      I would urge authors to be more transparent regarding the cell line information that they provide to readers. The authors here list cell bank catalogue numbers in their Materials and Methods section. When you look at the catalogue entry for each cell line, the entries clearly state that INT-407 and HEp-2 are HeLa. The authors of this paper are therefore aware of that information.

      In a letter to Nature back in 2000 (http://www.ncbi.nlm.nih.gov/pubmed/10667765), Stacey and other authors urged the research community to take action to improve our approach to misidentified cell lines. They recommend that all misidentified cell lines should be listed with the contaminant in brackets - for example, INT-407 (HeLa) and HEp-2 (HeLa). Taking that approach would make it much clearer to the reader that these three cell lines are all HeLa.

      The International Cell Line Authentication Committee (ICLAC) curates a database of known misidentified cell lines. Readers are welcome to refer to the database as a resource when naming or using cell lines. The database can be found at http://iclac.org/databases/cross-contaminations/.


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    1. On 2014 Nov 12, Musharraf Jelani commented:

      Before becoming Martin et al (2014) article online we had submitted an eletter to J Med Genet, however we did not receive any response for it publishing it online. We want to share our comments as follows.

      "PLK4: A novel candidate for primordial dwarfism?"

      Letter to Editor Shaheen et al. 1 recently reported a homozygous 5 bps deletion mutation (c.12991303delTAAG; p.Phe433Leufs*6) in the human polo-like kinase 4 (PLK4,MIM 605031) gene and proposed that it is a compelling candidate for primordial dwarfism (PD). Autozygosity mapping and LOD score, method of estimating linkage distances, are adopted for the novel locus identification. Candidate gene hunting among 144 in the region is based on filtering through ToppGene suite 2. Mutation screening through Sanger sequencing of PLK4 gene is only based on ToppGene suite ranking. In this study authors have not mentioned how many and which samples were selected for genotyping and linkage analysis so the predicted maximum LOD score cannot be calculated. Maximum multipoint LOD score (2.5) obtained by the authors is quite lower than the established threshold values (3.0). In article it has been stated that all PD genes in training set in comparison to all 144 genes of the locus in test set were enrolled in ToppGene candidate prioritization. These genes lists must be provided along with test parameters. In our opinion these informations are essential for data reproducibility and validation. Only PLK4 gene has been selected for Sanger sequencing but The candidate region (Chr4:112904466-129392060, GRCh37/hg19) includes some of the well- known syndromes characterized by autosomal recessive intellectual disabilities, microcephaly, short stature, and overlapping phenotypes. Alazami syndrome caused by mutations in LARP7, autosomal recessive type 1 mental retardation caused by mutations in PRSS12, Bardet-Biedl syndrome caused by mutations in BBS7 and BBS12, Van Maldergem syndrome 2 caused by mutations in FAT4, neuronal ceroid lipofuscinosis 7 caused by mutations in MFSD8, a multisystem disorder including brain function caused by mutation in SCLT1, as well as genes involved in mitosis and brain development e.g. MAD2L1, FGF2, INTU, have not been discussed throughout the manuscript. Furthermore, chromatograms for obligate carriers have not been presented nor the Saudi population screening for minor allele frequency has been performed. Similarly a homozygous variant (NM014264.4, c.1556G>C; p.Trp519Ser) reported in ESP6500 (http://evs.gs.washington.edu/EVS/) alters a highly conserved amino acid of PLK4 however it has not been assigned to any of primordial dwarfism phenotype and not discussed by the authors. In fact, phenotypic overlaps among the study mutants and the above syndromes would be of far more value instead of paying an exaggerated attention to PLK4 biology. References

      1 Shaheen R, Al Tala S, Almoisheer A et al. Mutation in PLK4, encoding a master regulator of centriole formation, defines a novel locus for primordial dwarfism. Journal of medical genetics 2014. 2 Chen J, Bardes EE, Aronow BJ et al. ToppGene Suite for gene list enrichment analysis and candidate gene prioritization. Nucleic acids research 2009; 37: W305-11.

      "conflict-of-interest" No conflict


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    1. On 2014 Oct 29, Benoit Kornmann commented:

      This paper presents some spectacular features of membrane chemistry. If you are not into the topic, watching some of the featured movies will likely pique your interest.

      It has long been known that different lipid species can have different affinity for each other, such that they may segregate into different phases, which can be visualized as subdomains on artificial membranes such as giant unilamellar vesicles (GUVs). Because a phase-separated membrane has a much lower entropy than a mixed one, phase separation can be achieved by lowering the temperature or increasing order in the membrane by stretching it.

      In this paper, the authors bathed GUVs in a hypotonic solution. Because these GUVs are semi-permeable to water, they swell until they eventually rupture, causing a catastrophic leak that re-equilibrates pression. After the GUVs recover from rupture, they start swelling again, and go through several cycles of swelling-rupture until reaching osmotic equilibrium.

      Here, the authors observe that, while in relaxed GUVs lipids are perfectly mixed, swelled GUVs show lipid phase separation. Mixing occurs right after each membrane rupture event; therefore, a cycle of separation-mixing follows the cycle of swelling-rupture of the GUV.

      It was previously known that vesicles underwent cycles of swelling-rupture. It was also previously known that membrane tension favored lipid phase separation. It is also not clear whether these phenomena are relevant in the case of biological systems. Nonetheless, the movies presented here are spectacular and unveil unexpected and very complex dynamic behaviors of seemingly very simple chemical systems.


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    1. On 2015 Dec 01, Bastien Boussau commented:

      My colleagues and I have published an article (Groussin M, 2016) in which we contest the results reported in the above study.


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    1. On 2014 Nov 22, Arturo Casadevall commented:

      There is little that has not been said before in the most recent post by Joshua L. Cherry and thus we do not see the need for additional responses. Interested readers are referred to the original article and the comments above.


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    2. On 2014 Nov 20, Joshua L Cherry commented:

      The reply above continues with the tactic that I criticized. It embraces and gives the benefit of the doubt to every argument in favor of the GOF experiments, ignores well-known counterarguments, and on this basis declares the other side's rhetoric to be misleading as though this were an additional pro-GOF argument rather than a corollary of the pro-GOF position. I will refrain from engaging in a rehash of arguments that should be familiar, but two specific points deserve brief mention. First, the reply glosses over the differences between laboratory engineered/selected transmission in ferrets and naturally-occurring human pandemic. Second, it makes a logical leap from somebody's intent to act on information to that information having value, as though nobody ever acted on valueless information.


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    3. On 2014 Nov 11, Arturo Casadevall commented:

      We fear that our position has been mischaracterized in Joshua L. Cherry’s latest comment. For example, nowhere in our article or response do we say or imply that “GOF advocates are right and GOF opponents are wrong”. Although we believe that everyone is entitled to their own opinion, we also think that Joshua L. Cherry most recent comments merit an additional response.

      First, we note that the correspondent is in fact invoking the ‘apocalyptic fallacy’ in his opposition to GOF experiments, something that we cautioned against in our editorial. The ‘apocalyptic fallacy’ arises when one side uses the apocalypse to inspire fear without factual data in the hope of convincing others of the correctness of their position. In our prior comment we chided both sides for using apocalyptic arguments but noted that that fallacy applied primarily to the anti-GOF camp because their appeals to fear were based on hypothetical accidents and scenarios, while the pro-GOF camp appeals to risk were based on known past epidemics. In his response Joshua L. Cherry mentions ‘reports of frequent laboratory accidents with infectious agents’ and ‘the return of H1N1 influenza from the laboratory in 1977’ to argue that anti-GOF proponents were in fact justified in their use of apocalyptic arguments. However, there is a problem here. First, while we are the first to agree that there is a need for utmost safety in these experiments, we note that it is guilt by association to aggregate GOF experiments with recent disparate laboratory accidents that range from a shipping error with H5N1 samples to incompletely sterilizing Bacillus anthracis spores. Second, the return of H1N1 1977 has been presumed by some to reflect the escape of that strain from a laboratory, but this has not been proven: that explanation for the reemergence of H1N1 remains a presumption that is not universally accepted among influenza experts. Thus, it is not reasonable to argue that these recent accidents should lead us to fear accidental pandemics from GOF experiments, whereas it is reasonable to worry that naturally occurring mutations in the H5N1 virus could lead to a global pandemic based upon historical evidence of similar such occurrences. Determining the possibility of precisely such events is the point of GOF experiments.

      Second, Joshua L. Cherry also states that some ‘would question the likelihood of a natural H5N1 pandemic, and whether GOF experiments tell us much about this likelihood’. I think we can all agree that GOF experiments have shown that H5N1 has the potential to become mammalian transmissible and that that information is new. Since prior to those experiments there was debate among experts in the field as to whether this was even possible, then we must disagree with the statement that GOF do not tell us ‘much about this likelihood’. In fact, those experiments have shown unequivocally that the H5N1 has the biological potential to become mammalian transmissible and that fact alone implies a greater threat from a natural pandemic that we knew previously. At the recent meeting of the National Science Advisory Board for Biosecurity (http://osp.od.nih.gov/office-biotechnology-activities/biosecurity/nsabb), evidence was presented that information obtained from GOF experiments was in fact being used in strain surveillance and vaccine development. Hence, the argument from the pro-GOF camp that this information is in fact useful for preventing a pandemic is more than ‘purely theoretical’.

      We agree with Joshua L. Cherry in his concerns about safety. In an earlier essay we took both sides to task for framing the debate in simplistic terms (PMID: 25085113) and we urge the need for careful analysis, rigorous thought and the avoidance of extrapolation and interpretation in framing arguments for and against this type of experimental work during the ongoing debate.


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    4. On 2014 Nov 04, Joshua L Cherry commented:

      The response above seeks to justify criticizing "apocalyptic rhetoric" from one side of the debate while ignoring the same sort of rhetoric from the other side. The justification offered is, more or less, that GOF advocates are right and GOF opponents are wrong, so that this rhetoric is justifiable from one side but fallacious when used by the other. A more specific case is, of course, presented, but it is an uncritical summary of pro-GOF arguments that ignores the well-known arguments of critics. The response and the editorial are of no help in deciding which side is right. The editorial misleadingly presents a view that depends logically on a pro-GOF position as though it is an argument that supports a pro-GOF position.

      As alluded to in my original comment, much of the GOF debate is about whether the experiments are more likely to cause a pandemic than prevent one. Casadavall appears to have reached a particular conclusion, but critics of GOF experiments would obviously dispute it. They would question the likelihood of a natural H5N1 pandemic, and whether GOF experiments tell us much about this likelihood. Critically, they would question the value of GOF experiments for prevention of such a pandemic, a value that remains purely hypothetical. (In contrast, refraining from performing a GOF experiment assures that this experiment produces no pandemic.) They would point to the return of H1N1 influenza from the laboratory in 1977, and to reports of frequent laboratory accidents with infectious agents, to refute the claim that their fear is purely theoretical.

      Would the viruses produced by the H5N1 GOF experiments, if released, be capable of causing human pandemics? If so, then there is a real danger to consider. If not, then these experiments do not provide strong evidence for the likelihood of a natural pandemic, and their general relevance to human pandemics is dubious.


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    5. On 2014 Oct 29, Arturo Casadevall commented:

      We agree with Joshua L. Cherry that both the pro- and anti-GOF camps have invoked the apocalypse. While pro- and anti-GOF camps invoke the apocalypse in their arguments and emphasize the benefits and risk of such work, respectively, both appeal to fear. However, when it comes to fear there are some significant differences. The fear of naturally caused pandemic comparable to 1918 finds support in the historical record and the available scientific information on influenza virus, including that generated by GOF experiments showing that it has the capacity for mammalian transmissibility. In contrast, fears of a pandemic from resulting from a mishap with a GOF-type of experiment remain a theoretical possibility. We note that such experiments are currently done with a high level of bio-containment and biosafety. Hence, the ‘apocalyptic fallacy’ applies only to use of the apocalypse as a rhetorical device by the anti-GOF camp for the apocalypse is invoked with a vacuum of evidence for this presumed catastrophic event. Given the differences in historically- and theoretically-based fears we do not feel that the use of the apocalypse by pro- and anti-GOF camps as a rhetorical device is comparable.


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    6. On 2014 Oct 27, Joshua L Cherry commented:

      From the title of this editorial I expected a critique of proponents of controversial gain-of-function (GOF) experiments. Perversely, it levels criticism only at the other side of the debate. According to the editorial, opponents of these experiments have used the possibility of a global pandemic (caused by laboratory-produced virus) as a rhetorical device that is so frightening that it trumps reason. It ignores the fact that proponents of these experiments have always invoked the dangers of a deadly (natural) global pandemic to argue that the experiments are critical for human health.

      "In the GOF debate," the editorial states, "the repeated mention of the likelihood of a pandemic is an apocalyptic rhetorical device." Perhaps it is, but who in the debate uses this device? The proponents of GOF experiments clearly do. The specter of a devastating pandemic is central, for example, to Yoshihiro Kawaoka's defense of his experiments. He tells us of the frighteningly high rate of death among confirmed H5N1 infections, and writes that

      "Within the past century, 'Spanish' influenza, which stemmed from a virus of avian origin, killed between 20 million and 50 million people. Because H5N1 mutations that confer transmissibility in mammals may emerge in nature, I believe that it would be irresponsible not to study the underlying mechanisms."

      Similarly, an Erasmus Medical Center press release about work by Ron Fouchier and colleagues bears the headline "Avian influenza could evolve into dangerous human virus", tells us that "The discovery is important as it could prevent a severe pandemic from occurring", and suggests a 60% death rate for H5N1 infection. A piece by Fouchier and others cites the same death rate data and suggests that the toll of an H5N1 pandemic would exceed that of the H1N1 pandemic of 1918. Many additional examples could be mentioned. This side of the debate repeatedly invokes the danger of a deadly pandemic, and presents GOF experiments as necessary for our rescue from this danger.

      (It should be noted that the high death rate for H5N1 infection has been called into question. Some defenders of GOF experiments have used diminished estimates of lethality to downplay the danger of the laboratory-produced viruses, usually failing to note that they would also weaken the original argument for the importance of the experiments.)

      It was quite reasonable for critics to ask whether GOF experiments are more likely to cause a global pandemic than prevent one. The critics' discussions of pandemics have generally been no more apocalyptic than those of the proponents, such as those referred to above. The editorial's accusations concerning misleading rhetoric are at best one-sided, and arguably are pointed in exactly the wrong direction.


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    1. On 2015 Feb 25, Gerard Ridgway commented:

      This work is generally very thorough, but the investigation of discriminant analysis seems rather limited. Only linear and quadratic discriminant analysis are considered, and there is little detail about the methods (for example, no mention of dimensionality reduction or regularisation terms). With up to 180 features, regularised and/or kernel variants of LDA, or other methods such as support vector machines (used in e.g. Ecker C, 2010) might well perform considerably better.

      It could be an interesting exercise if the authors would be willing to share their features (to save other researchers from the time-consuming process of running FreeSurfer on many subjects) along with labels for a randomly selected half of the subjects. Other researchers could then submit their predictions for the unlabelled half to Haar et al. for evaluation of the accuracy. I believe the numbers here would be sufficient for a split-half validation to provide meaningful results.


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    1. On 2017 Mar 24, Leonid Schneider commented:

      I was invited by the journal to submit a letter to the editor to point out some factual inconsistencies in this publication (e.g. patient is dead since 2011, but presented as apparently still alive). Unfortunately, my letter failed peer review. Here it is, together with reviewer reports: https://forbetterscience.com/2017/03/03/my-walles-trachea-transplant-reporting-fails-peer-review/


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    1. 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 NCT0042012. We believe the correct ID, which we have found by hand searching, is NCT00420212.

      This comment is being posted as part of the OpenTrials.net project<sup>[1]</sup> , 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


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    1. On 2014 Nov 13, Robert Eibl commented:

      Dear Readers,

      Here is a link to my critical comment on a paper, to which the authors published the above mentioned response: http://scitation.aip.org/content/aip/journal/apl/104/23/10.1063/1.4882182 In my view the authors do not address my fundamental critique very well; a cross-linker just binds any membrane protein covalently to the cantilever, but not all proteins in a membrane are related to cell adhesion. I recommend including a specific cell adhesion receptor, then bound to the cross-linker and repeat the experiment to start measuring real cell adhesion. Pubmed does not include my comment as a reference, although it recently added this response to my comment. This seems to be due to the publisher who only recommends NIH-funded comments and replies to be listed in Pubmed. In contrast, my comment is accurately mentioned in other scientific libraries, for example IEEE Xplore. For those interested in my research field of specific cell adhesion of living cells measured by nanotech methods and on a single-molecule level, I include a list of references; some of my book chapters are also not included in Pubmed.

      Best regards, Dr. Robert Eibl

      REFERENCES

      1. Moy VT et al. , Science (1994)

      2. Eibl RH and Moy VT, Atomic force microscopy measurements of protein-ligand interactions on living cells. In: Protein-Ligand Interactions, (Editor: G.Ulrich Nienhaus), Humana Press, Totowa, NJ, U.S.A., pp. 437-448 (2005)

      3. Benoit M et al. Nature Cell Biology (2000)

      4. Eibl RH and Benoit M, Molecular resolution of cell adhesion forces. IEE - Nanobiotechnology 151(3):128-132 (2004)

      5. Eibl RH, Direct force measurements of receptor-ligand interactions on living cells. In: Applied Scanning Probe Methods XII - Characterization. Bhushan B, Fuchs H (Editors), Springer, pp. 1-31, (2009)

      6. Eibl RH, Cell adhesion receptors studied by AFM-based single-molecule force spectroscopy. In: Scanning Probe Microscopy in Nanoscience and Nanotechnology 2, Bhushan B. (Editor), Springer, pp.197-215, (2011)

      7. Eibl RH, Single-molecule studies of integrins by AFM-based force spectroscopy on living cells. In: Scanning Probe Microscopy in Nanoscience and Nanotechnology 3, Bhushan B. (Editor), Springer, pp.137-169, (2013)

      8. Eibl RH, Comment on “A method to measure cellular adhesion utilizing a polymer micro-cantilever” [Appl. Phys. Lett. 103, 123702 (2013)]. Applied Physics Letters, 104, 236103 (2014)


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    1. On 2014 Oct 16, Michael Cariaso commented:

      The abstract uses 2 nearly identical rs#s, one of which is an error. rs1059111 appears to be correct, rs105911 appears to be a typo


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    1. On 2014 Oct 21, George McNamara commented:

      This is a nice paper. The abstract refers to using 24 epitope tags (24mer), much of the paper uses a 10mer. Just doing GFP is boring. When I came up with the "Tattletales" (TALE-FPn ... I came up with the idea before sgRNA:Cas9 became popular), I immediately realized that multimerizing FP biosensors. The current paper is the same as my what I refer to as "Binary Tattletales", as in: 1. TALE-(linker-epitope tag)n 2. "binder"-(linker-FP)m with Tattletales being T-cells -- TALE FPs/Biosensors. Since I moved to MD Anderson Cancer Center, the first T now refers to "T-cells and Tumor cells". Likewise T-bow refers to rainbow T-cells and Tumor cells for promoter bashing and otherwise multicolor dots labeling cells (rainbow in homage of course to Brainbow mice etc, and especially to real rainbows). For more on Tattletales, Binary Tattletales, and T-Bow, see http://works.bepress.com/gmcnamara/63 http://works.bepress.com/gmcnamara/42

      Giving credit where credit is due: The authors really should have cited the first mammalian cell paper localizing a lot of FPs in one spot (they came 'close' with a Gordon 1997 Cell paper on GFP:LacO in E.coli, but the Tanenbaum paper is all mammalian cells): Robinett et al 1996 JCB http://www.ncbi.nlm.nih.gov/pubmed/8991083 http://jcb.rupress.org/content/135/6/1685.long See their figure 4A. Straight, Robinett et al also published a yeast paper in 1996, http://www.ncbi.nlm.nih.gov/pubmed/8994824 and it would have been useful to cite that.

      The PDF download at http://works.bepress.com/gmcnamara/63 has a table of 130 FP biosensors (if you are Laconic about ATeam and Fire, too bad) and an extensive reference list with ZF-FP, TALE-FP, Cas9-FP (the latter from the Weissman group), and more (PUF's and PPR's are RNA binding protein families with structural similarities to TALEs). My favorite name -- besides Tattletales and T-Bow, of course -- is "TALE-Lights" from Yuan, Shermoen, O'Farrell 2014, http://www.ncbi.nlm.nih.gov/pubmed/24556431


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    1. On 2015 Aug 17, Alem Matthees commented:

      In response to post-publication feedback, I wish to clarify some aspects of the abstract, so there are no further misunderstandings about the scope and content in the full text of this article:

      a) Classification and naming issues aside, ME/CFS occurs at all ages, including young children and adolescents. [1] I never intended to suggest otherwise. The statement about patients being almost exclusively of working age was in context of research cohorts, particularly intervention trials which typically exclude patients under 18 years of age and rarely recruit those over 65 years. It is argued that studies consisting of such cohorts should not use normative data from general populations which include the elderly.

      b) The physical function subscale of the Short Form 36 health survey (PF SF-36) is discussed because it is a commonly used measure in research and was used in the PACE trial. This article is not a defence of the PACE trial, but uses it to exemplify how the issues described earlier in the article can cause normative data to be misinterpreted or misapplied. Selected details on this issue can be found in an BMJ Rapid Response (open-access) which does not require subscription to view. [2]

      c) This article is not meant to be a comprehensive analysis of recovery or case definitions, it is simply a commentary which focuses on using normative data from other comparison groups, one of the issues raised in the review by Adamowicz et al. [3] It explores the appropriate control groups or comparison populations, highlights a problem with using the mean ±1 SD as a threshold if the data does not follow a normal distribution, includes some summary statistics, mentions statistical testing at the group level, and encourages researchers to publish enough information so that others can accurately estimate the functional status of participants. Subjective self-reported measures are important but have potential biases (particularly in nonblinded trials lacking placebo control). Objective measures are also important, particularly when assertions that the intervention is effective at increasing function and activity are contradicted by a range of objective measures. See commentaries by Twisk [4] and others. [5-7]

      References

      1: Bakken IJ, Tveito K, Gunnes N, Ghaderi S, Stoltenberg C, Trogstad L, Håberg SE, Magnus P. Two age peaks in the incidence of chronic fatigue syndrome/myalgic encephalomyelitis: a population-based registry study from Norway 2008-2012. BMC Med. 2014 Oct 1;12:167. doi: 10.1186/s12916-014-0167-5. PMID 25274261. http://www.ncbi.nlm.nih.gov/pmc/articles/pmid/25274261

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

      3: Adamowicz JL, Caikauskaite I, Friedberg F. Defining recovery in chronic fatigue syndrome: a critical review. Qual Life Res. 2014 Nov;23(9):2407-16. doi: 10.1007/s11136-014-0705-9. Epub 2014 May 3. PMID: 24791749. http://link.springer.com/article/10.1007/s11136-014-0705-9

      4: Twisk FN. A definition of recovery in myalgic encephalomyelitis and chronic fatigue syndrome should be based upon objective measures. Qual Life Res. 2014 Nov;23(9):2417-8. doi: 10.1007/s11136-014-0737-1. Epub 2014 Jun 17. PMID: 24935018. http://link.springer.com/article/10.1007/s11136-014-0737-1

      5: Kindlon TP. Objective measures found a lack of improvement for CBT & GET in the PACE Trial: subjective improvements may simply represent response biases or placebo effects in this non-blinded trial. BMJ Rapid Response, 18 January 2015. http://www.bmj.com/content/350/bmj.h227/rr-10

      6: Wilshire CE. Re: Tackling fears about exercise is important for ME treatment, analysis indicates. BMJ Rapid Response, 19 January 2015. http://www.bmj.com/content/350/bmj.h227/rr-7

      7: Faulkner G. In non-blinded trials, self-report measures could mislead. Lancet Psychiatry. Volume 2, No. 4, e7, April 2015. doi: 10.1016/S2215-0366(15)00089-9 http://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(15)00089-9/fulltext


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    1. On 2015 Apr 04, Arnaud Chiolero MD PhD commented:

      A high quality review showing the association between out-of-office BP and target organ damage in children. Much remains to be done


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    1. On 2014 Oct 11, Jonathan Eisen commented:

      Lots and lots and lots of press for this paper. While thie work seems very important, some of the press is seriously overhyped. Paul Knopfler has a nice overview on his blog: http://www.ipscell.com/2014/10/top-10-takeaways-from-harvard-stem-cell-diabetes-paper/.


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    2. On 2014 Oct 11, Jonathan Eisen commented:

      The senior author, Doug Melton has posted the authors version of this paper. See http://hsci.harvard.edu/files/hsci/files/pagliuca_et_al_cell_2014.pdf. Thank you Dr. Melton.


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