On 2016 Jun 17, Jafar Kolahi commented:
Full list of Altmetric to 50 Dental Articles-2014 is available via:
http://www.nature.com/bdj/journal/v220/n11/extref/sj.bdj.2016.411-s1.pdf
On 2016 Jun 13, Christopher Tench commented:
The version of GingerALE employed had a bug that results in no control of the false positive results. This was fixed in version 2.3.6
On 2016 Aug 31, Clive Bates commented:
May I suggest that readers first read Professor Polosa's review below, and then turn to Benowitz NL, 2016 for a more credible and complete account of the cardiovascular effects of nicotine as they relate to e-cigarettes. Benowitz and Burbank review the relevant evidence and summarise the current state of knowledge as follows:
The cardiovascular safety of nicotine is an important question in the current debate on the benefits vs. risks of electronic cigarettes and related public health policy. Nicotine exerts pharmacologic effects that could contribute to acute cardiovascular events and accelerated atherogenesis experienced by cigarette smokers. Studies of nicotine medications and smokeless tobacco indicate that the risks of nicotine without tobacco combustion products (cigarette smoke) are low compared to cigarette smoking, but are still of concern in people with cardiovascular disease. Electronic cigarettes deliver nicotine without combustion of tobacco and appear to pose low-cardiovascular risk, at least with short-term use, in healthy users.
This should be a basis for reassuring and encouraging smokers considering switching to vaping.
As happens too often in this field, an author makes claims that go well beyond the scope of their scientific study or their field of expertise. Remarks made to media by the lead author at a cardiology conference in Rome caused a news storm in Britain, and will have increased interest in this paper. My examination of the basis for the claims made and reported is available on my blog > here.
On 2016 Aug 31, Riccardo Polosa commented:
The scientific letter lacks of many important details about participants' previous smoking history, type of device and e-liquid used in the study sessions.
Nonetheless, this is essentially an acute study showing what it is already know about the acute effect of nicotine on arterial stiffness. Besides, comparable acute changes in stiffness would also occur after drinking coffee (caffeine is not a risk factor for cardiovascular disease), exercising (exercise is beneficial for cardiovascular health), being exposed to emotional stress, and after taking nicotine replacement therapies.
Most of the observed changes in arterial stiffness after e-cigarette use were induced by asking participants to vape continuously for 30 min (!!!) (and only then the effect was similar to puffing a single conventional cigarette). Obviously, vaping continuously for 30 min is NOT a realistic conditions of use.
Besides, there are already two large clinical studies (one acute and the other chronic) that contradict the negative take of this research letter in relation to cardiovascular health:
http://www.ncbi.nlm.nih.gov/pubmed/24958250
http://www.ncbi.nlm.nih.gov/pubmed/26749533
Last but not least, measurement of arterial stiffness after acute exposure to active stimuli has no prognostic value whatsoever. That is why current guidelines on arterial stiffness measurements clearly state that before the measurements subjects should abstain from the use of any stimulants (like nicotine, caffeine and alcohol) for at least 4-6 hours.
On 2016 Jun 18, Zvi Herzig commented:
Drinking coffee also acutely increases aortic stiffness and blood pressure Vlachopoulos C, 2003. It is thus surprising that these transient effects are suggested as possible predictors of harm.
On 2017 Jun 16, David Keller commented:
To the Editor: The study by Eguale and colleagues [1] demonstrates that off-label use of prescription drugs is associated with increased ADEs (adverse drug events) only when such use lacks strong scientific evidence. Specifically, off-label uses of drugs with strong scientific evidence had the same risk of ADEs as on-label use. This finding implies that the extreme expense and delay caused by the process of U.S. Food and Drug Administration (FDA) approval of an already-approved drug for a new indication may not be necessary if strong scientific evidence supports such use. The take-home message of this study is not that we need to crack down on off-label prescribing, but that we need to crack down on unscientific prescribing.[2] Electronic health records should be programmed to discourage unscientific prescribing, not off-label prescribing. Because off-label prescriptions backed by strong evidence are just as safe as prescriptions for FDA-approved indications, the FDA ban on promotion of the former denies patients the benefits of safe and scientifically proven medications. The focus should shift to suppression of off-label prescribing only when it is not backed by strong evidence.
Conflict of Interest Disclosures: None reported.
References
1: Eguale T, Buckeridge DL, Verma A, et al. Association of off-label drug use and adverse drug events in an adult population. JAMA Intern Med. 2016;176(1):55-63.PubMedArticle
2: Good CB, Gellad WF. Off-label drug use and adverse drug events: turning up the heat on off-label prescribing. JAMA Intern Med. 2016;176(1):63-64.PubMedArticle
On 2017 Feb 28, Zvi Herzig commented:
To conclude that dual use does not increase cessation, plausible alternative explanations of the data must be excluded, including the very plausible possibility that treatment failures are more resistant to cessation compared to ordinary smokers.
On 2016 Jun 13, Lamberto Manzoli commented:
Well, the distinction between quitting failures and treatment failures, overall and especially in our study, is based upon no data and, as such, it is just a hypothesis. In any case, even if such a distinction would have been "significant", it would not invalidate the main point: in real life, dual users did not quit tobacco more frequently than tobacco only smokers.
On 2016 Jun 10, Zvi Herzig commented:
The authors note that "dual use did not improve the likelihood of quitting tobacco or e-cigarette use". However, dual use indicates a history of resistance to treatment (ie, e-cigarette use without cessation). This severe bias restrains meaningful comparison of cessation-rates between dual users and other smokers.
Indeed, the authors note: "It has been suggested that dual users are frequently ‘quitting failures’ and thus biased against cessation. However, in our sample, the proportion of those who tried quitting before was quite similar between tobacco smokers (33.7%) and dual users (35.9%)."
However, the source quoted for this suggestion (McRobbie H, 2014) mentions 'treatment failures' rather than 'quitting failures'. This is significant: Regardless of whether dual users have failed cessation or not, they have shown resistance to EC-induced cessation. Furthermore, if indeed dual use is not associated with attempted cessation, then dual users have demonstrated a special interest in nicotine and disregard for health, which likely biases against cessation.
On 2017 Oct 13, Gerhard Nebe-von-Caron commented:
looks like the paper slipped through the review process somehow. Whilst the journal published an erratum to clarify some volumes used, they did not check for coherence of the methodology.
Ultra Rainbow beads were supplied in a dropper bottle, which was inconvenient for volume control. The dropper lid was part of the bottle design and could not be removed. The volume of a drop (50ul) was specified by the datasheet.
Considering that it would be well known to anyone skilled in the art that the accuracy of counting is dependent on the accuracy of the volume of the materials used as clearly described in the spherotech method datasheet http://www.spherotech.com/Updated STN 8-21-07/STN-15 Rev B.pdf "Procedure To obtain accurate absolute cell counts, the SPHEROTM AccuCount Particles are used in conjunction with flow cytometry. The SPHEROTM AccuCount Particles have a concentration of approximately 1x106 particles/mL. The actual concentration is listed on the Technical Data Sheet for the product. The first step during sample preparation is to add the monoclonal antibody to 100μL of the test sample. The sample is then incubated, lysed, washed, and resuspended in 1 to 2 mL of phosphate buffer saline, 0.1M, pH 7.4. If staining and lysing are not necessary, add a known volume of test sample to the 1 to 2 mL of phosphate buffer saline. Washing the AccuCount Particles with the sample prior to analysis is discommended because a reduction in the number of reference particles will occur. Next, add exactly 50μL of the AccuCount Particle to the suspension. The precision during pipetting of the AccuCount Particles is absolutely critical. The sample is then analyzed by flow cytometry. The bead and cell population are gated on the fluorescence and/or side scatter channel. Record the number of events for the AccuCount Particles and the test sample. The absolute cell count is then determined with the following equation. ..."
Considering that the authors claim that they dispensed the particles by reverse pipetting but then claimed the poor reproducibility of the spherotech beads because they used the drops for direct dispensing is ironic. If I remember right the AccuCount beads are screwtop and the normal Ultra Rainbow beads are usually used for detector linearity check for which the dropper dispensation is perfectly adequate, for absolute counting this is inadequate and the authors should have been aware of that. If they wanted to use the beads they had in the fridge they should have just pre dispensed the approximate volume and then pipetted accurately.
and if Fig 1 confuses you - it's probably because they got the axis labels the wrong way round
On 2016 Jun 24, Ole Jakob Storebø commented:
We think that the clinicians prescribing methylphenidate for ADHD and others have been insufficiently critical of the literature for decades, trusting that the quality of methylphenidate research was reasonable. In accordance, Shaw in an editorial accompanying our JAMA article Storebø OJ, 2016 stated that the Epstein et al. review on methylphenidate for adults with ADHD was an example of good assessments of quality Shaw P, 2016. It seems Shaw erred, as the Epstein et al. review has now been withdrawn from The Cochrane Library due methodological flaws Epstein T, 2016.
Banaschewski et al. suggest that we included five trials in our analyses that should have been excluded. We think they are wrong. They highlight four trials which they cite as having used “active controls” whereas these are actually co-interventions, used in both the methylphenidate and the control group. Such trials are includable in accordance with our protocol Storebø OJ, 2015. Moreover, excluding these trials from our review would only have produced negligible changes in our results. Furthermore, the trial including children aged 3 to 6 years ought also to have be included in accordance with our protocol. Excluding all five trials would not have changed our conclusions at all. We concluded that methylphenidate might improve teacher reported symptoms of ADHD. However, the very low quality of the evidence, the magnitude of that effect size is uncertain. A change in the effect size of 0.12 points on the standardised mean difference of this outcome would not change anything.
In a subgroup analysis comparing parallel trials and crossover trials, we did not find a significant difference either. However, we noted considerable heterogeneity between the two groups of trials. It is not recommended to pool cross-over trials which only have “end-of-trial data” with parallel group trials (http://handbook.cochrane.org/) and had we done so we would have would risked introducing a “unit-of-analysis error” as we only had “end-of-trial data” from these cross-over trials.
We agree that the variability of the minimal relevant difference is important which is why we reported the 95% confidence interval of the transformed mean value in our review Storebø OJ, 2015. Banaschewski et al. also suggest that we have overlooked information in the Coghill 2007 trial and thereby wrongly assessed this as a trial with “high risk of bias”. We stated in our protocol that we would consider trials with one or more unclear or high risk of bias domain as trials with high risk of bias Storebø OJ, 2015.
We did not overlook information from the Coghill 2007 trial but twice emailed the authors for additional information. They did not respond. The information required is not available in the published study. We presented the risk of bias assessments for the various domains of all 185 included trials. It is correct that we assessed seven cross-over trials as low risk of bias and not six as reported. Thank you for spotting this error. The seventh trial is reported, however, in our table in which the risk of bias assessments for all the domains is shown. All trials, irrespective of vested interest bias, were regarded as having a high risk of bias due to broken outcome assessor blinding given the easily recognisable, well-known adverse effects of methylphenidate. When adding this seventh cross-over trial to the subgroup analysis on the outcome “teacher-rated ADHD symptoms – cross-over trials”, we now find significant differences between the trials with “high” compared to “low” risk of bias (standardised mean difference (SMD) -0.96 [95% confidence interval -1.09 to -0.82] compared to -0.64 [-0.91 to -0.38]. Test for subgroup difference: Chi² = 4.27, df = 1 (P = 0.04), I² = 76.6%).
Banaschewski et al. focus only on our assessment of risk of bias and do not mention the core instrument for assessing quality of meta-analyses namely the Grades of Recommendation Assessment Development and Evaluation (GRADE) approach Andrews J, 2013. Our assessment of the evidence as “very low quality” is not only based on the assessment of risk of bias, but also on other factors such as heterogeneity, imprecision, and indirectness of the evidence. This is clearly reported in our review.
We downgraded the quality of the included trials in the meta-analysis for imprecision and for moderate heterogeneity. The durations of included trials were short, with an average of 75 days. Most patients receive methylphenidate treatment for substantially longer periods and the beneficial effects may diminish over time Jensen PS, 2007 Molina BS, 2009. The short trial duration could suggest the need for further downgrading for “indirectness” according to GRADE Andrews J, 2013. We did not downgrade for this, but we could have. This further underlines that the evidence for the benefits and harms for the use of methylphenidate for children and adolescents with ADHD is of very low quality.
We have assessed 71 trials as having high risk of bias in the “vested interest” domain as they were funded by the industry and/or the authors were affiliated with the industry.
It is not incorrect for us to state that none of the trials funded by the pharmaceutical industry showed a low risk of bias in all other areas as we considered all the trials as high risk of bias on the domain of blinding. This is clearly reported in our review.
We have now conducted the requested subgroup analysis comparing those trials with high compared to low risk of vested interest bias on the teacher-rated ADHD symptoms outcome. The effect of methylphenidate in the 14 trials with high risk of vested interest bias was SMD -0.86 [-0.99 to -0.72] compared to SMD -0.50 [-0.69 to -0.31] in the 5 trials with low risk of vested interest bias. Test for subgroup differences is Chi² = 8.67, df = 1, P = 0.003. So even in this small sample we find a significant difference.
We recommend Banaschewski et al. to read the essay by John P Ioannidis about vested interests Ioannidis JP, 2016.
It is important to stress that the results of our review would have been the same had we disregarded the issue of vested interest.
Had there been inconsistencies regarding one domain of bias in a few trials they would not change the fact that these trials are to be considered as trials at high risk of bias. For example, in two trials, Konrad 2004 and Konrad 2005, there is inconsistency in how our author teams assessed the randomisation process. However, both trials have several other domains at “unclear risk of bias” or “high risk of bias”. In the Ullman 2006 trial, three domains are assessed as “unclear risk of bias”. In Wallace 1994, five domains are assessed as being of “unclear risk of bias” and one as “high risk of bias”. In Wallander 1987, five domains are assessed as “unclear risk of bias”. Even if there was inconsistency between one or two items, these trials are high risk of bias trials. There may well be small differences in our judgements, but that does not change the fact that the trials included are, in general, trials at high risks of bias Storebø OJ, 2015. It is important to understand that we followed the Cochrane guidelines in every aspect of our review.
Conclusions
We have demonstrated that the trial selection in our review was not flawed and was undertaken with sufficient scientific justification The effect sizes are not too small. We have followed a sound methodology for assessing risk of bias and our conclusion is not misleading. We are concerned about the state of the academic literature and at the financial and academic waste that has occurred, given that more than 250 reviews and 3000 single works have been published on psychostimulants for ADHD treatment. Despite this, there is still no sound evidence regarding the benefits and harms of methylphenidate.
Ole Jakob Storebø, Morris Zwi, and Christian Gluud.
On 2017 Aug 02, Han-Xiang Deng commented:
We recently reported mutations in TMEM230 in familial Parkinson’s disease (PD). Farrer et al raised the concern that mutations in TMEM230 may not be pathogenic to PD. We seriously evaluated Dr. Farrer’s assertions. We obtained updated clinical information and performed several new experiments, including MegaEx chip screening of the family DNA samples with ~2 million SNPs for whole-genome linkage study and re-analysis of whole-exome sequencing data. We did not find any other locus more robust than the chromosome 20p (TMEM230), nor any other variants with better segregation than TMEM230-R141L to explain the inheritance of PD in the large Mennonite family. Based on the new genetic data from the Mennonite PD family, and the robust genetic data showing additional TMEM230 mutations in multiple PD families, we are confident to conclude that TMEM230 is a new PD-causing gene. Further studies of TMEM230 should provide important mechanistic insights into understanding the vesicle/endosome trafficking/recycling defects in the pathogenesis of PD. A detailed response is available in bioRxiv (http://www.biorxiv.org/content/early/2017/07/31/170852).
On 2016 Dec 31, MATTHEW FARRER commented:
We argue that TMEM230 mutations are neither disease-linked nor impair synaptic vesicle trafficking. Analysis of chromosome 20 STR genotyping, and of nucleotide mutations, in the largest Mennonite kindred shows the work by Deng and colleagues is erroneous. A detailed critique is available in bioRxiv (http://biorxiv.org/content/early/2017/01/01/097030). We recommend further assessment of genotype analysis/original samples (available on request) prior to embarking on TMEM230 biology. We caution that TMEM230 results are unlikely to contribute to a molecular understanding of parkinsonism.
On 2016 Jun 24, Erick H Turner commented:
I am the author of the NEJM article cited as reference #17, in which we showed stark differences in antidepressant efficacy according to two data sources–published journal articles and FDA reviews. The authors of this BMJ Open protocol list a number of sources they plan to search. What is not clear is how what they plan to do when faced with results of the same clinical trial from two (or more) sources. In our NEJM article, we found 11 trials which were positive according to journal articles but negative according to the FDA. When one considers that those journal articles were authored by those with a conflict of interest, and that the discrepancies were due to post hoc outcome switching, it seems clear that FDA reviews should be prioritized as the more credible data source.
On 2016 Jul 30, Chandan Kumar commented:
Kumar-Sinha et al, Transcriptome analysis of HER2 reveals a molecular connection to fatty acid synthesis. Cancer Res. 2003 Jan 1;63(1):132-9. PMID:12517789
On 2016 Jun 17, Timothy M Krahn commented:
It is important to emphasize that our study is about documented disclosure of information that should be provided to patients in accordance with minimum ethics standards for consent to IVF. Most of the critical points made by Hilde Bastian are openly avowed in the limitations section of the paper. We explicitly acknowledged the declining participation rate over time and the fact that fewer of the participating Canadian IVF clinics provided us with information sheets. To be clear, the documents we very specifically requested and the documents we reviewed (as stated in the article) were ‘consent documents’ comprised of both consent forms and accompanying information sheets.
As regards our content analysis, disclosure elements were deemed present if mentioned anywhere in the consent documents reviewed. Mere mention of a keyword (or keywords) for an information element was sufficient for that element to be deemed present as part of documented disclosure. We used this strategy to remove any subjectivity as regards the quality of disclosure, and to be as generous as possible (from a clinic perspective) as regards any conclusions that might be drawn. In practice, this meant that if a consent form indicated that information about a disclosure element was in an accompanying information sheet, that element would have been judged as present just on the basis of the keyword and/or a rudimentary description alone.
Thus, while Bastian is correct that information elements might have been present in the information sheets known to exist but not provided to us, reasonable efforts were made to minimize this possibility. We could do no better given that we could only work with the consent documents that the clinics provided. For the 2014 data set, all clinics were sent an initial request by email followed by a posted letter. If there was no response, those remaining were contacted at least once by telephone. In our estimation, there is nothing more we could have done to generate better and more comprehensive information without increased collaboration by Canadian IVF clinics.
We stand behind our conclusion that “the disclosure of information relevant to the interests of those undergoing IVF and those who are born as a result of IVF appears to be decreasing. Furthermore, the information that increasingly is being disclosed in consent documents appears to be directing the orientation and content of these documents away from the primary interests of the relevant women, couples, and children.” [emphasis added] This general and avowedly tentative conclusion is consistent with the limited representativeness of the data and this we openly acknowledged.
On 2016 Jun 11, Hilda Bastian commented:
This is a vitally important issue to address, but the data presented in this study do not support the authors' conclusion that disclosure of information is decreasing.
The study is characterized by a steeply declining availability of data for comparison - in both the response rate and amount of data provided by those clinics responding. From the first to the last year studied:
This suggests that a principal finding, based on a minority of clinics in 2014, is a shift towards providing supplementary information to consent forms, rather than consent forms as the sole formal vehicle of disclosure. If those information sheets were available - and 82% were not in 2014 - the conclusion of this study could be very different.
It would be useful to know if the consent forms indicated that the person signing had been provided with the supplementary information, as part of the formal disclosure. Clarification from the authors would also be useful on whether data from information sheets was included in the results Table, or whether only consent forms themselves were the source.
If both types of consent documents are included, then for 2014, complete consent documents were available for only 2 of 35 clinics (6%), compared with 9 of 17 clinics in 1991 (53%). And the increased coverage of items in the earlier years could be attributable to the enlarged scope of materials assessed.
On 2016 Jun 07, Lily Chu commented:
There is one online self-management resource already available to patients internationally. The website is cfidsselfhelp.org and was founded by Dr. Bruce Campbell, an expert on self-management of chronic diseases, with contributions from Dr. Charles Lapp, a physician specializing in ME/CFS. They also collaborated on another website treatcfsfm.org. Both of these sites contain a plethora of free information/ worksheets patients can use; patients may also join a low-cost online class if that suits their learning better.
As a physician, I am very familiar with the time pressures of clinic and have referred multiple people to these websites with good effect. (I have no financial interest in or relationship to either site.)
On 2016 Jun 22, Christopher Tench commented:
Thanks for the update Xin. The false positives I refer to are in relation to that expected from the stated method. For any method there needs to be a decision made, before the experiment, about what risk of false positive is acceptable. This may be arbitrary, as you say. Nevertheless, the results only meet the accepted risk when the method is implemented correctly. The problem with the implementation prior to 2.3.6 is that it did not control the FWE. As such there was no way to know whether there were any significant results at all until, as you have done, the appropriate checks and updates were performed.
Chris
On 2016 Jun 21, Xin Di commented:
Hi, Chris,
Thank you for your interest in our paper.
The bug you referred to was announced on April 26, 2016 (2.3.6 http://brainmap.org/ale/readme.html). Our data analysis was performed, and our manuscript was submitted before this date. I could not see any possibility that we could use the 2.3.6 version in our paper.
As described in the Brainmap forum, this bug makes cluster-level threshold more lenient. We re-analyzed our data using GingerALE version 2.3.6, and confirmed that some small clusters reported in our analysis were no longer significant at the same threshold of cluster-level p < 0.05. But large clusters for each of the analyses are still significant. The idea of our paper is that there are consistent task modulated connectivity with the amygdala, and different tasks may modulate amygdala connectivity with different brain regions. Our conclusion will not be affected if we used version 2.3.6, because it is not based on any single clusters.
Lastly, your comment that older versions of GingerALE have "a bug that produces false positive results" is only partially correct. Indeed, all statistical methods produce false positive results, not to mention the so-called type II error. The bugged version is more likely to produce false positive results. It doesn't mean that all the results are false positive. The statistical threshold is arbitrary, anyway. Why do we use p < 0.05, but not p < 0.03 or p < 0.080808? My point is, when drawing conclusions from data, we need to consider the pattern of results, but not a specific result from arbitrarily picked threshold.
Best, Xin
On 2016 Jun 13, Christopher Tench commented:
The version of GingerALE used in this paper has a bug that produces false positive results. The bug has recently been fixed in version 2.3.6.
On 2017 Jun 30, Seán Turner commented:
Traore et al. (2015) [PMID 27257486] and Vicino et al. (2016) [PMID 27660714] both claim DSM 29078 to be the type strain of Bacillus andreraoultii and Murdochiella massiliensis, respectively. DSM 29078 is not listed in the DSMZ online catalog of strains as of 30 June 2017.
On 2017 Apr 26, L. Norton commented:
The conclusion is justified. Other studies have shown convincingly that anesthesia acutely raises glucose levels in BL/6J mice in the absence of a glucose load (PMID: 16332272). For some forms of anesthesia, the effect can last for at least 60 minutes. Of course this may differ somewhat between BL/6 strains, but I would expect to see similar results to be honest.
On 2017 Jan 31, Alexander Kraev commented:
The conclusion of this study is not justified, as the authors used only one mouse strain. Also it would be useful to know the correct name for their strain, whether it was C57BL/6J or C57BL/6NCrl. C57BL/6J, which was likely used in this work, is known to have glucose intolerance in the absence of anesthesia due to deletion of the Nnt gene. Hence, the correct conclusion would be that C57BL/6J should not be used in metabolic studies.
On 2017 Jun 12, Daniel Weeks commented:
As Neuron appears to have deleted our original comment, here is a copy for the record.
NR1H3 and multiple sclerosis: questionable assumptions and miscalculated p-values
Wang et al (2016) investigated the role of the nuclear receptor NR1H3 in familial multiple sclerosis (MS), and described two of the highlights of their research as (1) “An arginine to glutamine mutation in NR1H3 causes multiple sclerosis in families” and (2) “Common variants in NR1H3 are associated with primary progressive multiple sclerosis”. Regarding the first claim, in a comment on PubMed Commons (http://www.ncbi.nlm.nih.gov/pubmed/27253448#cm27253448_16159), Eric Vallabh Minikel and Daniel MacArthur raised concerns on the basis of the frequencies of the implicated NR1H3 variant, rs61731956, encoding p.Arg415Gln, in the Exome Aggregation Consortium (ExAC). Minikel and MacArthur point out that “the variant is not significantly enriched in cases over ExAC population controls (P = .56) - indeed, its allele frequency is lower in MS cases (0.02%) than in ExAC European population controls (0.03%)”.
As evidence of co-segregation of rs61731956 with disease, Wang et al (2016) report a maximum LOD score of 2.20 at θ=0. However, this LOD score was computed under a fully penetrant model where “unaffected mutation carriers were treated as having an unknown disease status”. This overstates the evidence for co-segregation because in linkage analysis disease status should be assigned blind to mutation status, and so a reduced penetrance model should have instead been used where unaffected individuals were properly coded as having an unaffected disease status. Indeed, later in their manuscript, Wang et al (2016) cite the presence of “three obligate carriers and an unaffected biological family member” as evidence of incomplete penetrance.
The evidence for the second claim, that “common variants in NR1H3 are associated with primary progressive multiple sclerosis”, is also overstated in Wang et al (2016) because the p-values in their Table 1 were incorrectly computed. The p-values presented were derived by computing a 2 degree of freedom chi-squared statistic based on the 3 x 2 genotype table and then looking up the p-value of that statistic using a 1 degree of freedom distribution. In our Table 1, we present the correct p-values for the 2 degree of freedom chi-squared statistic. But as some of the cell counts are small, it would be more appropriate to use a Fisher’s Exact Test. Using the p-values of a Fisher’s Exact Test, and applying a Bonferroni’s correction for the 15 tests carried out (instead of correcting for only 5 as Wang et al did), none of the findings are significant at the 0.05 level after correction for multiple testing.
Based on the concerns raised by Minikel and MacArthur as well as here, it seems that the original claims were over-stated, and it is likely, based on the data presented, that this variant and gene may play no significant roles in MS. Of course, the collection of additional independent data followed by careful and correct statistical analyses will ultimately clarify whether or not NR1H3 plays a role in MS risk. Indeed the International MS Genetics Consortium has already examined this variant in their data (http://biorxiv.org/content/early/2016/07/01/061366), and found “no evidence that this variant is associated either with MS or disease subtype.”
Simon C. Heath<sup>1,2</sup> and Daniel E. Weeks<sup>3</sup>
<sup>1</sup> CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Baldiri i Reixac 4, 08028 Barcelona, Spain
<sup>2</sup> Universitat Pompeu Fabra (UPF), Barcelona, Spain
<sup>3</sup> Departments of Human Genetics and Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15217 USA. weeks@pitt.edu
References
Z. Wang, A.D. Sadovnick, A.L. Traboulsee, J.P. Ross, C.Q. Bernales, M. Encarnacion, I.M. Yee, M. de Lemos, T. Greenwood, J.D. Lee, et al. Neuron, 90 (2016), pp. 948–954
On 2016 Aug 08, Daniel Weeks commented:
We raise additional concerns in a comment posted in the 'Comments' section of Neuron's web page for this paper, accessible via this link: http://www.cell.com/neuron/comments/S0896-6273(16)30126-X. These additional concerns center on questionable assumptions in Wang et al's LOD score computations as well as miscalculated p-values in their Table 1.
Simon Heath<sup>1,2</sup> and Daniel E. Weeks<sup>3</sup>
<sup>1</sup> CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Baldiri i Reixac 4, 08028 Barcelona, Spain
<sup>2</sup> Universitat Pompeu Fabra (UPF), Barcelona, Spain
<sup>3</sup> Departments of Human Genetics and Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15217 USA
On 2016 Oct 21, Carles Vilarino-Guell commented:
Case-Control Studies Are Not Familial Studies (2016) Neuron; Volume 92, Issue 2, p339–341.
http://www.cell.com/neuron/fulltext/S0896-6273(16)30695-X
On 2016 Jun 29, Chris Cotsapas commented:
We sought to validate the association of rs61731956 with MS susceptibility in our ongoing study of low-frequency missense variation in MS. After stringent quality control, we used linear mixed models to meta-analyze 32,852 cases and 36,538 controls of European ancestry in 14 country-level strata, genotyped for 250,000 low-frequency non-synonymous variants across all exons using Illumina's HumanCore Exome array. We detected the minor allele rs61731956-A in nine of our strata, but find no evidence of association with overall MS risk (meta-analysis beta = 0.06, p = 0.32). As Wang et al report this association specifically with PPMS, we compared 1,399 PPMS cases to 13,537 RRMS cases directly in five strata with available clinical course information, and also find no evidence of association with disease subtype (meta-analysis beta = 2.35, p = 0.39). Our previous linkage analysis of >700 multiplex families [Sawcer S, 2005] further supports this conclusion (multipoint LOD = 0.0), as does earlier work from the Canadian Collaborative Project on the Genetic Susceptibility to Multiple Sclerosis (CCPGSMS) with no evidence of linkage in 40 Canadian families with four or more affected individuals, authored by members of the Wang et al study team [Willer CJ, 2007].
Based on their interpretation of segregation patterns for rs61731956, Wang et al go on to genotype common variants in the NR1H3 locus in 2,053 MS patients and 799 healthy controls, but fail to detect any association with overall MS risk. They then report that four of their familial cases have a clinical course consistent with that of primary progressive MS (PPMS), and perform a secondary, stratified analysis of clinical course with the five tagging SNPs. They reduce their sample size to 420 PPMS and 1,287 RRMS patients for whom clinical course information was available, and describe an association between rs2279238 (OR = 1.35, p = 0.001) and PPMS, but not RRMS, risk. The IMSGC has already reported a disease risk association in this region [International Multiple Sclerosis Genetics Consortium (IMSGC)., 2013] based on 14,498 MS cases and 24,091 controls to rs7120737, which is 420kb away and in moderate LD with rs2279238 (r<sup>2</sup> = 0.62, D'= 0.82 in the 1000 Genomes CEU panel). We also genotyped rs3824866, a perfect proxy for rs2279238 (r<sup>2</sup> = 1, D' = 1 in the 1000 Genomes CEU panel), which shows modest association to MS risk (p = 2.1 x 10<sup>-5).</sup> Conditioning on rs7120737 fully explains this association, indicating that the result reported by Wang et al is a modest proxy for the strong signal we have previously reported.
Our 13-fold larger dataset therefore supports a more conventional interpretation of the data presented by Wang et al: there is no association between the low frequency NR1H3 p.Arg415Gln variant rs61731956 and MS risk, but a common haplotype spanning the NR1H3 locus is associated with overall MS susceptibility, despite the failure of Wang et al to detect it in their modestly sized cohort. Our data does not support an association specific to clinical course or PPMS. The false positive likely arose because Wang et al base their conclusions on a total of four affected carriers of the variant, and contravene standard practice by analyzing only five polymorphisms in the NR1H3 locus, not controlling for population stratification, and failing to meet rigorous thresholds of significance for common variation (p < 5 x 10<sup>-8)</sup> or for family-based linkage (LOD > 3) [Kruglyak L, 1995; Altshuler D, 2008].
Beyond these technical issues, Wang et al appear to have succumbed to an error in logic in their analysis. Although individually rare, coding variants are exceedingly common in the population: of 7,404,909 variants identified by the Exome Aggregation Consortium in 60,706 individuals, 99% have a minor allele frequency of <1% and 54% are seen exactly once in those data. Therefore, there is complete certainty of observing at least one such variant in two closely related individuals, as Wang et al have done. This is reinforced by their observation of rs61731956-A in multiple unaffected individuals and the presence of this variant in 21/60,706 unselected ExAC individuals. This is not a unique false positive finding, as previous studies of equivalently small sample size have reported MS risk associations to low-frequency coding variants in CYP27B1 [Ramagopalan SV, 2011] and SAIE [Surolia I, 2010], with both results failing to replicate in much larger studies with adequate statistical power [Hunt KA, 2011; Ban M, 2013; Barizzone N, 2013].
We note that the experimental demonstration that p.Arg415Gln alters the heterodimerization efficiency between the NR1H3 product liver X receptor alpha and the retinoid X receptor alpha has no bearing on the association to MS pathogenesis. Many non-synonymous variants have dramatic effects on protein function, but in the absence of robust association to disease this alone cannot support a pathogenic argument [MacArthur DG, 2014].
The combination of our negative results from a 13-fold larger dataset and the methodological and logical flaws in the work presented by Wang et al categorically refute the bold claim that NR1H3 variation defines a Mendelian subtype of MS, which would be the first monogenic form of the disease ever described. Such a discovery would have enormous implications for diagnosis of a subset of cases, prognosis and genetic counseling of extended family members, and eventually for clinical management of the disease in carriers. Unfortunately, the evidence provided by Wang et al does not support this conclusion.
A more complete version of this response, including data tables, is available on biorxiv.
Chris Cotsapas, Yale School of Medicine and Broad Institute of Harvard and MIT, on behalf of the IMSGC.
On date unavailable, commented:
None
On 2016 Jun 27, Daniel MacArthur commented:
We thank the authors for their reply, and for their comparison of their results with those for the G2019S variant in LRRK2 and its association with Parkinson's disease. As a well-established and well-studied pathogenic variant, LRRK2 G2019S is indeed an excellent example to illustrate two points:
Genuinely pathogenic variants are enriched in cases over controls. In 23andMe's cohort, the largest dataset for which we were able to find published allele counts, LRRK2 G2019S has an allele frequency of 0.09% in controls and 1.1% in cases, with an odds ratio of 9.6 (Do CB, 2011, see Table S1) for allele frequency breakdown by case/control status]. Another study of Europeans found an allele frequency of 0.8% in idiopathic PD cases (Gilks WP, 2005). The allele frequency in ExAC is accordingly 10-fold lower, 0.04% overall and 0.06% among non-Finnish Europeans. Among PD cases with a positive family history, the variant exhibits even stronger enrichment, with allele frequencies on the order of a few percent (Kachergus J, 2005, Nichols WC, 2005, Di Fonzo A, 2005). Results from other populations are in agreement: among North African Arabs and Ashkenazi Jews, the variant has an allele frequency of 0.6 - 1.4% in the general population, but a frequency of 9 - 19% in Parkinson's disease cases (Lesage S, 2006, Ozelius LJ, 2006).
Pathogenic variants may be found in ExAC, but at a frequency consistent with disease prevalence, penetrance, and allelic heterogeneity. Published estimates of lifetime risk of Parkinson's disease range from 3.7% (Elbaz A, 2002) to 6.7% (Driver JA, 2009). LRRK2 G2019S accounts for ~1% of all cases (as noted above), and is estimated to confer lifetime risk of ~32% (Ozelius LJ, 2006, Goldwurm S, 2007). From these figures, one can infer that allele frequencies even as high as 6.7% * 1% / 32% = 0.2% (a few times higher than what we see in ExAC) would not be surprising for this variant.
On both accounts, LRRK2 G2019S stands in contrast to NR1H3 R415Q. NR1H3 R415Q has no evidence of any enrichment in MS cases compared to population controls, and its allele frequency in ExAC is inconsistent with any but the lowest (<2%) penetrance when one considers that multiple sclerosis is less common than Parkinson's disease, and that this variant is found in only a small minority of cases. This contrast thus simply highlights the inadequacy of the genetic evidence supporting any role of NR1H3 R415Q in the etiology of MS.
Eric Minikel and Daniel MacArthur, Broad Institute of MIT and Harvard
On 2016 Jun 17, Carles Vilarino-Guell commented:
We read Mr. Minikel and Dr. MacArthur’s commentary with interest; although we respect their opinion, we are disappointed to see that it is solely based on two pieces of information. We would encourage anyone interested in the subject to read the whole article, assess all the scientific evidence with an open mind, and reach their own informed conclusion.
Regarding the two points of controversy, we would just like to highlight that in common complex neurological disorders it is not unusual for pathogenic mutations to have reduced penetrance, and to be present in the ExAC database. For example, in Parkinson’s disease (once considered to have no genetic component) widely variable penetrance estimates have been described (Trinh et al. 2014); and the LRRK2 G2019S mutation, which is irrefutably pathogenic, can be found in 47 individuals from the ExAC collection (rs34637584).
On 2016 Jun 13, Daniel MacArthur commented:
This paper reports that an NR1H3 variant, rs61731956, encoding p.Arg415Gln, causes familial multiple sclerosis (MS) (Wang Z, 2016). We have some major concerns about the evidence for the effect of the R415Q variant on risk for MS, which rests on two pedigrees with imperfect segregation with disease.
The reported data allows us to provide an estimate of penetrance for the R415Q variant. This variant was found in 1 out of 2053 individuals in a multiple sclerosis case series, but is also seen (as the authors note in passing) in 21 individuals among the 60,706 present in the Exome Aggregation Consortium (ExAC) collection (11-47290147-G-A). Enrichment in cases over controls is one important criterion for establishing pathogenicity of sequence variants (MacArthur DG, 2014, Richards S, 2015).
The ancestry distribution of the case series reported in Wang Z, 2016 is not stated, but the series was collected in Canada and appears to be of predominantly European ancestry (Sadovnick AD, 1998, Traboulsee AL, 2014). The 21 individuals with this variant in ExAC are all of non-Finnish European ancestry, with 66,738 non-Finnish European chromosomes having genotype calls for this variant. Thus, the variant is not significantly enriched in cases over ExAC population controls (P = .56) - indeed, its allele frequency is lower in MS cases (0.02%) than in ExAC European population controls (0.03%).
A review of lifetime risk estimates for MS found the best estimates of lifetime risk of MS to be 0.25% for women and 0.14% for men (Alonso A, 2008, see Table 1). Using the allele frequencies observed in ExAC and in the case series, along with these estimates of lifetime risk, we can apply formulae for calculating the penetrance or lifetime risk, and confidence intervals thereof, for reportedly Mendelian variants as described in (Kirov G, 2014, Minikel EV, 2016). The upper bound of the 95% confidence interval is 1.7% for women and 0.9% for men, indicating that this variant contributes extremely weakly, if at all, to MS risk.
The functional characterization of the effects of the p.Arg415Gln variant on gene function, while potentially interesting, does not provide independent support for a role of this gene in MS risk.
We urge the community to consider rigorous statistical approaches and independent replication before making strong claims of pathogenicity. In this case, publicly available data (and indeed data that are actually noted in the paper) are sufficient to strongly suggest that this variant has little or no effect on MS risk. Independent analyses of this variant in large case-control studies of MS are needed, and we look forward to seeing the results of such analyses from the MS community in the near future.
Eric Vallabh Minikel and Daniel MacArthur, Broad Institute of MIT and Harvard
On 2017 Sep 10, Misha Koksharov commented:
For rapidly changing metabolites (ATP, other nucleotides, etc), capturing their in vivo levels in brain tissues is particularly challenging (Heller HC, 2011, Wilson DF, 2011, Overmyer KA, 2015). They can change in a matter of seconds after the blood flow is interrupted. This unfortunately hampers investigation of many interesting questions (as well as leads to incorrect nucleotide measurements in quite a few papers). :( Hopefully, new techniques will become available and more widespread to overcome this.
On 2016 Dec 07, Joanne Kamens commented:
Thank you for this helpful set of definitions and clarifications. Common language will make the discussion more productive. I was prompted by an excellent blog by Hilda Bastian (http://blogs.plos.org/absolutely-maybe/2016/12/05/reproducibility-crisis-timeline-milestones-in-tackling-research-reliability/) and the subsequent twitter conversation to mention that these definitions don't address or even seem to mention the potential, influence or use of reagent/materials reproducibility. Experimental results and interpretation can be dramatically enhanced by the use of the correct standards, materials and/or reagents to reproduce a study. Protocol and methods sections alone are not sufficient to account for this as some reagents are not easily remade and are not always validated as being the same (unless subjected to quality control via repository storage or standard validation).
On 2016 Jun 15, thomas samaras commented:
This finding is consistent with other research that has found a positive correlation between height and coronary heart disease (Samaras, Mendall, Allebeck, Shapiro, Elsayed, Mori, Hameed and Gupta). Davenport studied about 1 million military recruits for WW I and found that taller recruits had more heart problems than shorter ones. WHO also reported that before 1900, coronary heart disease was rare in Europe and the US. Adults in 1900 were substantially shorter than they are today. Other studies have found taller people have higher atrial fibrillation, thromboembolism and pulmonary infarction. The Indian Heart Journal provides additional information on height and heart disease: Shorter height is related to lower cardiovascular disease risk--a narrative review.
On 2016 Aug 10, Joaquim Radua commented:
Re: the previous comments, please note that under the null hypothesis of no differences between groups, only 1 out of 20 studies should show differences between groups, which is absolutely not the case when randomizing coordinates or blocks of voxels. Random coordinates and similar approaches, which randomize the location of the findings rather than the individuals between groups, are not a valid way to exactly test this hypothesis. Rather, they are only used to yield approximated p-values that, appropriately thresholded, return a map similar but slightly more conservative than that of FWE-corrected p-values in mega-analyses. Voxel-based meta-analytic methods are young and there is room for improvement, but they are based on evidence.
On 2016 Aug 09, Christopher Tench commented:
This is not a result of confusion, but of the definition of statistical inference. Uncorrected p-values do not control the type 1 error rate. A meta-analysis is performed to improve estimates, and is a statistical problem demanding statistical methods. To threshold at an arbitrary p-value controls neither the FDR nor the FWE, so no quantitative evidence that the results are critical of the null hypothesis is available. You cant know if the results are true positives without doing the full experiment, but meta-analysis is used for the case where the full experiment (mega analysis) has not been done. The one, and only, thing that can be done is to make sure that the null hypothesis is appropriately rejected; arguably the whole point of statistical inference. That requires either FWE or FDR control. Using just random coordinates and an uncorrected p-value will produce results that are apparently publishable, but obviously incorrect. Without any estimate of error rate, there is no quantifiable evidence that the results are meaningful.
On 2016 Aug 01, Joaquim Radua commented:
Re: the previous comment, I think there may be some unfortunate confusion. Raw p-values of current voxelwise meta-analyses have not the same meaning as usual p-values because they are not derived from the usual null hypothesis (“there are no differences between groups”), but from another null hypothesis (“all voxels show the same difference between groups”). Thus, up to the moment one of the only ways to "approximately" know if the results of a voxelwise meta-analysis are neither too liberal nor too conservative is to compare them with the results of a mega-analysis of the same data, and that's what it was done.
On 2016 Jun 13, Christopher Tench commented:
The methods employed in this study are not corrected for multiple statistical tests; uncorrected p-value. This can therefore not be considered a meta-analysis as there is no evidence of statistical significance. The results can not be considered valid.
On 2016 Jun 13, Christopher Tench commented:
The version of GingerALE used (2.3.4) had a bug that produced false positive results. This was fixed at version 2.3.6
On 2016 Oct 29, David Keller commented:
Why MACRA seems unlikely to reduce costs or improve the quality of medical care
The Centers for Medicare and Medicaid Services (CMS) recently released nearly 2400 pages of new regulations, comprising the "Medicare Access and CHIP Reauthorization Act" (MACRA). The acronym "MACRA" actually contains another acronym within it (an homage to Kafka?), "CHIP", for Children's Health Insurance Program. New regulations introduced by MACRA mandate fundamental changes in the way doctors are paid and how they provide medical services. The following is but a partial description:
1) The main purpose of MACRA is to reduce the cost of Medicare, after the failure of the Sustainable Growth Rate (SGR) law to do so. However, the demand for real medical services, such as hernia repairs, cataract extractions, colonoscopies, skin biopsies, chemotherapy, etc., will continue to grow, while MACRA will funnel out money to clinicians for endless reports on quality metrics, and to entrepreneurs, for participating in risk-sharing ventures. Diversion of scarce CMS funds away from direct clinical care services can only worsen the looming Medicare financial collapse, and the entrepreneurs are likely to get the best of the risk-sharing ventures.
2) CMS states that physician quality-of-care bonuses will be financed with fines obtained from other doctors, however this "zero sum" financial balance is only achieved in a static model. The losers in this system, who will sustain fines that substantially reduce their Medicare reimbursements, will have their already-thin operating margins cut further, and many may decide to stop accepting Medicare. As they drop out, physicians farther up the "quality of service" food chain will see their quality score percentile ranks diminish in turn, creating a vicious cycle of [increasing fines] >>> [reduced net payments] >>> [physician dropouts] >>> [increasing fines]. Thus, in the dynamic model, fines cannot finance bonuses because doctors who pay fines will be more likely to drop out of the system, eliminating themselves as a source of funds to pay for bonuses.
3) MACRA seems designed to nurture a cohort of doctors who excel at tasks like reporting patient satisfaction surveys, and reducing costs by not performing clinical services. The demand for clinical services will not go away, however, and if paying for required medical services is causing Medicare losses, these losses can only worsen when the cost of running the MACRA bureaucracy is piled-on.
4) The original fee-for-service Medicare system is preferred by both doctors and patients, partly due to the choices and autonomy it allows for both patients and doctors. Fee-for-service also aligns the interests of the patient, who wants to receive the best medical care appropriate for his condition, with those of the physician, who wants to earn a living by providing medical care. The problem, of course, is costly overtreatment, but this is well-policed by CMS, and by the natural reluctance of patients to undergo procedures. When working for capitated fees, physicians are incentivized to provide less care, which can result in undertreatment, a far more dangerous and insidious situation, and harder to police. How will CMS guard against physicians becoming too parsimonious with their capitation money, and doing too little for their patients?
5) MACRA was implemented nationwide too quickly, rather than studied, debated and rolled out slowly. Physicians were given 2 months to study the final MACRA document during the public comment period, requiring them to read 40 pages of dense regulatory language per day, every day, during that period. Such massive changes require sufficient time to fully educate doctors about their effects. We await evidence that these measures actually reduce costs or increase quality of care.
In summary, MACRA will increase spending on non-clinical activities, worsening the financial status of Medicare. MACRA is overly intrusive in dictating how doctors should practice medicine, basing physician incentives on their performance of incentivized services, which may not be relevant or beneficial in some individuals or subpopulations. MACRA introduces capitation to original Medicare, a payment system which disincentivizes clinical services by making them an expense to the physician, rather than a source of income. Based on the above considerations, MACRA seems unlikely to improve either the financial prospects or the clinical quality of Medicare.
On 2016 Jul 24, James Yeh commented:
Editor's Comment
E-Cigarettes and Smoking Cessation — Polling Results
James S. Yeh, M.D., M.P.H., and Edward W. Campion, M.D.
The goal of smoking cessation is to reduce the effect of smoking on mortality and morbidity. Despite the dramatic reduction in the prevalence of smoking over the past 50 years, the use of tobacco still contributes significantly to morbidity and mortality.[1] About 1 in 5 deaths in the United States each year can be attributed directly or indirectly to cigarette smoking, and life expectancy among smokers is 10 years shorter than that among nonsmokers.[2] Quitting before 40 years of age reduces the risk of dying from smoking-related illness by 90%.[3]
The use of e-cigarettes has become more prevalent; 16% of U.S. high-school students use e-cigarettes,[4] and about 4% of U.S. adults use e-cigarettes on a regular basis.[5] There is no doubt that e-cigarettes engender tremendous interest from the public, the medical community, and the Food and Drug Administration (FDA) with respect to their potential as lifesaving nicotine-delivery devices for persons with tobacco dependence. Recent modeling research has projected a 21% reduction in death attributed to tobacco-smoking if e-cigarettes are used.[6] However, despite the potential benefit, there remain concerns about the safety of e-cigarettes and their efficacy for smoking cessation; for this reason, the FDA has recently extended its regulatory authority to cover e-cigarettes.[7]
In June, we presented the case of Mr. O’Malley, a 29-year-old man who had been smoking since he was 15 years of age and more recently was smoking up to 1.5 packs per day.[8] Readers were invited to vote on whether to recommend that Mr. O’Malley try using e-cigarettes for smoking cessation. Mr. O’Malley had a history of obesity, hypertension, and childhood seizures. In the past, he had quit smoking “cold turkey” and had used various nicotine-replacement therapies, but he had never been able to sustain smoking abstinence for an extended period of time.
More than 35,000 readers viewed the Clinical Decision case, and 666 readers in 62 countries responded to the poll. The largest group of respondents, representing more than 45% of the votes, was from the United States and Canada (306 voters), followed by respondents from Europe (235). Two thirds of the respondents (66%) voted to recommend the use of e-cigarettes for smoking cessation, and the remaining respondents voted against recommending e-cigarettes. This result suggests that a majority of the poll respondents believe that e-cigarettes are a reasonable strategy for smoking cessation, at least for a patient such as the one described in the case vignette.
A substantial proportion of the 41 voters who submitted comments emphasized the health benefits derived from reducing or quitting tobacco use. These benefits, which include a lowering of the risks of cardiovascular-related death, lung cancer, and pulmonary symptoms, are especially important in this case of an asymptomatic young tobacco-dependent smoker who already has some risk factors for cardiovascular disease.
Commenters raised several related recurring themes. They emphasized the difficulty of current smoking-cessation regimens, such as nicotine-replacement therapy, varenicline, or bupropion, in sustaining smoking abstinence. A number of commenters considered e-cigarettes to be a reasonable complementary smoking-cessation aid to kick-start the process of reducing and quitting tobacco smoking, along with the more traditional smoking-cessation aids, with the eventual goal of weaning smokers off e-cigarette use altogether.
Many readers also commented that the quality and the safety of the e-cigarettes could not be relied on, since e-cigarettes were an unregulated nicotine-delivery device at the time. Some readers indicated their belief that e-cigarettes should be regulated by the FDA and that e-cigarettes should not be recommended until there is reliable evidence that they are less hazardous than tobacco smoking and that they are efficacious in reducing tobacco smoking. Others expressed concern about the availability of e-cigarettes to adolescents. Thus, for some, uncertainty about the performance and safety of e-cigarettes deterred them from recommending their use as a smoking-cessation aid.
REFERENCES
[1] Fiore MC, Baker TB. Treating smokers in the health care setting. N Engl J Med 2011;365:1222-31. [2] 2014 Surgeon General’s report: the health consequences of smoking—50 years of progress. Atlanta: Centers for Disease Control and Prevention (http://www.cdc.gov/tobacco/data_statistics/sgr/50th-anniversary/index.htm). [3] Jha P, Ramasundarahettige C, Landsman V, et al. 21st-Century hazards of smoking and benefits of cessation in the United States. N Engl J Med 2013;368:341-50 [4] Singh T, Arrazola RA, Corey CG, et al. Tobacco use among middle and high school students — United States, 2011 ̶ 2015. MMWR Morb Mortal Wkly Rep 2016;65:361-7. [5] Schoenborn CA, Gindi RM. Electronic cigarette use among adults: United States, 2014. NCHS data brief no. 217. Hyattsville, MD: National Center for Health Statistics, 2015. [6] Levy DT, Borland R, Villanti AC, et al. The application of a decision-theoretic model to estimate the public health impact of vaporized nicotine product initiation in the United States. Nicotine Tob Res 2016 July 14 (Epub ahead of print). [7] FDA takes significant steps to protect Americans from dangers of tobacco through new regulation. Silver Spring, MD: Food and Drug Administration, May 5, 2016 (http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm499234.htm). [8] Yeh JS, Bullen C, Glantz SA. E-cigarettes and smoking cessation. N Engl J Med 2016;374:2172-4.
On 2016 Jun 30, Riccardo Polosa commented:
In this case study of a 29-yr old man (Mr. O'Malley) interested in giving up smoking using e-cigarettes, two experts are providing their personal recommendations.
Expert no.1, Dr Christopher Bullen, is recommending e-cigarettes for smoking cessation because he thinks that Mr. O’Malley has limited pharmacologic treatment options (contraindications for bupropion and varenecline prescription due to his history of seizures; inability to abstain from smoking on several occasions despite being on NRT).
Expert no.2, Dr Stanton Glantz, is not recommending e-cigarettes because the results of his - flawed (1) - metaanalysis shows that these products are not proven to assist smoking cessation (2).
The case study presented here is more challenging than actually appears and that for several reasons.
Mr. O'Malley is relatively young and quit rates in young adults are know to be very low as proven by the Mr. O’Malley’s history of frequent relapses. As there is no evidence demonstrating efficacy of FDA-approved smoking cessation drugs for young adults, these cannot be recommended in this specific age group.
Mr. O’Malley’s is at high risk of relapse and very little can be done to manage smokers with a history of frequent relapses (3).
Mr. O’Malley is overweight and has hypertension. Stopping smoking is known to lead to weight gain (4). Hence, it is important to consider that Mr. O’Malley - if successful - will have to deal with the burden of post-cessation weight gain with its important negative health consequences, particularly in consideration of the fact that obesity and hypertension are well known risk factors for cardiovascular disease.
Mr. O’Malley would benefit from switching to a much cleaner source of nicotine. His personal preference for the e-cigarettes should be respected and the health care provider should offer a balanced overview of their risk/benefit ratio (5,6).
More specifically, relevant to Mr. O’Malley’s case, it worth noticing that: 1) e-cigarettes have helped abstaining from conventional cigarette young adults as well (7); 2) e-cigarettes have been shown to reduce post-cessation weight gain in quitters (8); 3) smokers with elevated blood pressure who quit by switching to e-cigarettes may lower their BP in the long-term (9).
Ref.
On 2016 Jun 16, David Keller commented:
Rarely-laundered lab coats and neckties risk transmission of harmful bacteria
It is all well and good that patients prefer their doctors to wear white lab coats, but the safety and well-being of patients demands they not be exposed to the highly unsanitary white coat which is laundered only once a week or even once a fortnight. And when, if ever, was the last time you autoclaved your neckties? Never, like me. And think of all the bacteria the distal tip of your tie has picked up over the years. No, my colleagues, our attire must only consist of freshly-laundered garb each day: if you wore it before, then wear it no more. The necktie must be forever banished from clinical areas. Bow-ties are creepy and clearly a form of nerd micro-aggression; therefore, we must wear our clean shirts open at the neck, regardless of how casual and relaxed this may cause us to feel, or to be perceived.
On 2016 Jun 04, H Horvath commented:
Many questions arise.
Did you obtain human subjects research approval for this study (and its interview questions and questionnaires) from your institutions? Did the school district's Board give approval? How did you come up with your interview questions and questionnaire? How did you validate them? It would also have been useful to see the consent form these parents signed -- I wonder whether they really understood that you would be introducing such disorienting, disturbing concepts to young children. Two year study -- Over how many cumulative hours, days, weeks were the interviews and "guided group questionnaire" sessions conducted?
You present only year 2 results, simply saying that "outcome measures were not included in the 1st year." Do you mean to say that the first year was a complete waste of everyone's time and that you have no data to report? Or do you mean that you are planning to report year one results for different outcomes in a separate paper? As formulated, your explanation for the absence of year one outcome data in the current paper suggests selective outcome reporting.
What possible good could come from making small children endure these confusing interviews and "group questionnaire" sessions with "trained researchers"? Who were these "trained researchers"? What proportion of parents didn't consent for their children to participate? What were characteristics of consenting vs. non-consenting parents? What proportion of consenting parents did not further respond? What were parents told of their children's specific responses? What happened with kids whose parents didn't consent? Were they included in the study anyway, filling out questionnaires in groups and being interviewed? You do not describe other activities given to non-consented children, and there is no indication that these activities took place outside ordinary school hours -- which suggests that non-consented children were brought along for the ride. What were children's thoughts and concerns about the interviews and questionnaire sessions? What clarifying questions did they ask of the "trained researchers"? What measures did you take to protect child privacy? Did children benefit from this study, and if so, how? Did you follow up to learn of any harmful effects on children? What were these effects?
What does any of this have to do with reading, writing, arithmetic, geography, history etc.? Never mind biology, in which kids still might learn that in humans, there is a male sex and a female sex, with very few exceptions (i.e. in the case of disorders of sexual development). "Gender" is merely sex role stereotyping. It is not good to instill in young children the false notion that performing stereotypes of appearance, behavior and mannerisms normally used by the opposite sex will somehow enable them to change sex. This wasn't the "goal" of your study, I know, but the children no doubt are now a lot more confused about themselves. You can't conduct "gender" programming like this in small children and expect that the world will applaud it, despite ethical sloppiness or actual lapses. Children are not mere guinea pigs for social programming research. To be fair to your paper, most other "gender" studies in children are ethically-challenged, to say the least.
On 2016 Jun 03, Ewen Gallagher commented:
An Extra View article related to our published analysis investigating the role of Mekk1 (encoded by Map3k1) in T cells using Map3k1<sup>ΔKD</sup> and Lck<sup>Cre/+</sup> Map3k1<sup>f/f</sup> mice (1). Examines the role of Mekk1 in Th17 differentiation, and includes a comparison between the roles of Mekk1 and Tak1 (encoded by Map3k7) in the liver T cells using Map3k1<sup>ΔKD</sup>, Lck<sup>Cre/+</sup> Map3k1<sup>f/f</sup> and Lck<sup>Cre/+</sup> Map3k7<sup>f/f</sup> mice.
Related research. (1). Suddason T, Anwar S, Charlaftis N, Gallagher E. T-Cell-Specific Deletion of Map3k1 Reveals the Critical Role for Mekk1 and Jnks in Cdkn1b-Dependent Proliferative Expansion. Cell Rep 2016; 14:449-57.
On 2016 Jun 03, Clive Bates commented:
There are several weaknesses in the reasoning in this paper.
Singh et al assert: “exposure to e-cigarette advertisements might contribute to increased use of e-cigarettes among youths.” The study is cross-sectional and does not (and cannot) establish that advertising causes e-cigarette use. Even if the authors acknowledge that their study does not establish a causal relationship, that has not stopped them drawing conclusions as if it does.
The finding that higher advertising exposure would be associated with greater e-cigarette use is quite likely, but there are many possible explanations. It could be that e-cigarette users see more advertising because of the way they live and their interests direct them to where such advertising is visible. Alternatively, teenagers already using the products may just be more interested and have better recall of advertising they have seen, even if exposure is no different.
Marijuana is not advertised but its prevalence among high school students is higher (23.4%) than tobacco (22.4%) on the basis generally used by CDC (used at least once in the last 30 days) - see CDC Youth Risk Behavior Surveillance — United States, 2013. It may be that better explanatory variables than advertising exposure are needed to interrogate prevalence of youth risk behaviours.
Even if we allow that e-cigarette advertising may be increasing youth e-cigarette uptake, something that is far from established, the authors need to consider the likelihood that this is displacing cigarette smoking. Given that independent risk factors for teenage vaping and smoking are likely to be similar, it would be surprising if vaping was not adopted as an alternative to smoking, at least in some cases. In this event, the health effect of e-cigarette use is positive, and, therefore, so is any role that advertising plays in it.
The observed sharp decline in teenage cigarette smoking that has coincided with the sharp rise in teenage e-cigarette use does not establish a causal relationship between these trends, but it does suggest that it is a plausible hypothesis that vaping is reducing smoking and therefore that great care should be taken when designing policies that may attenuate this effect. See data: CDC Tobacco Use Among Middle and High School Students — United States, 2011–2014.
The authors jump to a policy conclusion that goes far beyond the limitations of their study: "Multiple approaches are warranted to reduce youth e-cigarette use and exposure to e-cigarette advertisements”.
Before making such policy proposals, the authors should consider several issues and potential unintended consequences beyond the scope of this paper: that young people might smoke instead of using e-cigarettes; that e-cigarette advertising might be an effective form of anti-smoking advertising; that such restrictions may reduce adult switching from smoking to vaping and thus create damage to adult health; that excessive restrictions on advertising protect incumbent industries (cigarettes) and reduce the returns to innovation in the disruptive entrants (e-cigarettes).
The assertive and unqualified nature of the policy proposal raises concerns of an unacknowledged investigator bias. This would not be that surprising. The authors are from CDC, and the media release that accompanied this survey abandoned all caution about causality or unintended consequences. It reflected the CDC’s adversarial prior policy stance on these issues, none of which are supported by the survey itself:
“The same advertising tactics the tobacco industry used years ago to get kids addicted to nicotine are now being used to entice a new generation of young people to use e-cigarettes,” said CDC Director Tom Frieden, M.D., M.P.H. “I hope all can agree that kids should not use e-cigarettes.”
Conclusions: CDC should adopt a more dispassionate and careful approach to both reporting and communicating survey findings. In publishing for peer-reviewed journals, CDC staff should disclose relevant CDC policy and advocacy positions as non-financial competing interests.
On 2017 Mar 06, Misha Koksharov commented:
A really nice FP tool and screening/engineering work.
I have a few questions:
1) "Bioluminescence characterization in vitro. Each protein was diluted to 2 nM in 30mM MOPS 100mM KCl pH 7.5 with 0.1% BSA, and a final concentration of 20 μM substrate was used."
a) Do you mean you have used 20 μM for both LH2 and ATP in case of firefly luciferase (Ppy luc2)?
b) Was Mg<sup>2+</sup> added to the reaction buffer in case of Fluc?
2) "Hexahistidine-tagged proteins were expressed in E. coli at 30°C for 30 h"
How active was Fluc after growing E.coli at 30°C? I'd expect that this should noticeably decrease its specific activity compared with growing at 18-22°C. (Although, this is usually not important in mammalian cells where chaperones compensate for thermolability of Ppy luc2).
3) Comparison of Nanoluc, Antares vs Fluc in live cells, tissues and animals.
What would be the difference when corrected for protein and mRNA half-life - essentially, for actual protein levels in cells during recording/imaging? For example, Fluc luc2 has a protein half-life of 5-8 hours while NanoLuc is much more stable.
4) Do you know what are the actual concentrations of Nanoluc, Fluc, etc in live mammalian cells in relevant experiments (in μM, for example)? So far it seems like no one knows, even Keith Wood himself. :(
On 2016 Jul 25, Yonwoo Jung commented:
Thanks very much for your comment. We just found there is wrong description about sample size. Actual sample size is that 11 offsprings from 3 saccharin receive dams and 14 offsprings from 3 nicotine received dams. We will contact to publisher and try to correct this one. I really appreciate your comment. I also checked your paper about psedoreplication. It is excellent point of view. I will keep that in mind for future experiment. We are very welcome for any comment. Thanks again for your comment.
On 2016 Jul 02, Stanley Lazic commented:
The results in this paper are hard to interpret for two reasons. First, the sample size has been incorrectly determined in most experiments, and thus the p-values are artificially too small. This is the problem of pseudoreplication (Lazic SE, 2010, Vaux DL, 2012). For example, the experiment in Fig 1b uses 25 slices from 10 brains (animals), and the appropriate sample size is 10, not 25.
Second, in some experiments (e.g. Fig 1b again) nicotine was applied to pregnant dams and the effects were measured in the offspring. Here, the sample size is the number of dams and not the number of offspring (Lazic SE, 2013, Lazic SE, 2013, and references therein). The number of dams was not mentioned, and so the worst case scenario is that the 5 control mice are from one litter and the 5 nicotine mice are from another, making the sample size 2.
Nature Neuroscience should be commended for their detailed reporting requirements, which allow readers to better evaluate the evidence.
On 2017 May 24, Jordan Anaya commented:
This paper has been retracted: http://retractionwatch.com/2017/05/24/authors-retract-much-debated-blockchain-paper-f1000/
On 2017 Mar 09, Daniel Himmelstein commented:
Please see my blog post describing why Irving & Holden's timestamping implementation is broken. According to Carlisle's method, there is no record in the Bitcoin blockchain proving the existence of the clinical trial protocol from this study.
WARNING: Users should not rely on Irving & Holden's method for producing blockchain-verifiable timestamps. Doing so could expose them to invalid timestamps, accusations of fraud or misconduct, financial loss, and sabotage. As discussed in my blog post, there are several established solutions for Blockchain timestamping that have been reviewed by expert cryptographers. I strongly encourage users to rely on one of these methods and to disregard this study from Irving & Holden.
Feel free to reference my blog post:
Daniel S. Himmelstein (2017) "The most interesting case of scientific irreproducibility?" Satoshi Village. http://blog.dhimmel.com/irreproducible-timestamps/
Or the GitHub analysis behind it:
Daniel Himmelstein (2017) "dhimmel/irreproducible-timestamps v1.0: Initial replication analysis for the Satoshi Village blog post" Zenodo. DOI: 10.5281/zenodo.375952 https://doi.org/b2tz
I will update this comment if Irving & Holden provide cryptographic proof of their timestamp and the validity of their method. Until then, I strongly urge readers to avoid advertising or building on this study.
On 2016 Jul 20, Jordan Anaya commented:
Readers of this article may be interested in this post at Retraction Watch or this post by Neuroskeptic.
On 2016 Jun 15, thomas samaras commented:
Many studies indicate that short, lean people have much lower risk of coronary heart disease compared to taller people. Scores of studies find either no relation between height and CHD or a positive relation between height and CHD. Studies finding taller height is related to increased CHD include the works of Shapiro, Mendall, Mori, Elsayed, Allebeck, Hameed and Gupta. Other studies have found taller people have higher rates of abdominal aortic aneurysm, arial fibrillation, thromboembolism and pulmonary infarction. The only populations that have been found to be free of CHD or stroke are Solomon islanders, Papua New Guinea, Kalahari bushmen, Congo pygmies, and Kitavans. These populations range from less than 5 feet to about 5 feet 6 inches. (These findings are based on 20th C studies.) A report by the World Cancer Research Fund found that the process of industrialization has increased our height, weight and chronic diseases (including CHD). This report also stated that the Western diet has promoted chronic diseases. Trowell and Burkitt also reported that pre-western populations following their traditional diets were free of major chronic diseases common in the West. The studies finding shorter people have more CHD are confounded by a number of factors, including overweight, smoking, diet,lack of exercise, socioeconomic status, and catch up growth when in early childhood due to low birthweight. Rapid growth in childhood has been found to be related to chronic diseases at older ages. The Japanese experience shows the weakness of studies showing shorter people have higher CHD; for example, Mainland Japanese are shorter than Hawaiian Japanese and have substantially higher CHD. In addition, Hawaiian Japanese are shorter than Californian Japanese and have lower CHD.
On 2016 May 31, David Keller commented:
None
On 2016 May 30, David Keller commented:
My ColoGuard cancer screening was reported as "negative" in April, 2016. I immediately requested the results of two tests done as part of the ColoGuard screening algorithm, specifically my fecal hemoglobin concentration, and my ColoGuard Composite Score [of colon cancer risk]. These are important tests with easily interpreted results, which every patient's physician should review.
Exact Sciences, the manufacturer and retail seller of Cologuard screening tests, stated that the test results I requested cannot be reported due to FDA regulations, which require stand-alone approval of all tests, even those used as part of an approved screening kit. The test results I requested, although conveying unique, accurate and medically important information, thus cannot be reported to the patient or his doctor, even if severely abnormal results are found.
Patients have an ethical right to demand all of their test results, even for tests which are performed without specific FDA approval, but as part of an FDA-approved algorithm of tests.
The regulations being enforced at this time will lead to avoidable patient harms, and must be revised to mandate patient access to the results of all medical tests performed on them.
On 2016 May 29, David Keller commented:
Please see the final version of my article, which is published online above. I posted it here temporarily during a dispute with an affected commercial entity.
On 2016 May 29, David Keller commented:
Additional comments and suggestions related to MultiTarget fecal testing"
The MultiTarget composite score can be negative for colon neoplasia despite an elevated fecal hemoglobin concentration consistent with another disorder.[1] In such cases, FDA regulations prohibit release of any MultiTarget test data except whether the overall screening test was positive or negative for colon neoplasia.[2]
I screened myself with the MultiTarget screening method because it is more sensitive and has a smaller false negative rate than FIT screening, leading to fewer missed cancers. I intend to screen myself again with MultiTarget the next time I am eligible for full Medicare reimbursement in 3 years. The down side is that MultiTarget has a lower specificity and a higher false positive rate than FIT, resulting in more unnecessary colonoscopies with MultiTarget; this is a trade-off I chose to accept. Because Medicare (with a standard Medigap policy) pays for MultiTarget screening in full, its higher cost than FIT was not an issue for me.
Additionally, I will screen annually with a FIT test, to detect occult fecal hemoglobin elevations not reported by MultiTarget. Performing FIT testing in parallel with MultiTarget testing in this way will result in even higher sensitivity and lower specificity, but less so than predicted by the "parallel testing" formula, since these two tests are not completely independent.
I have written to the FDA requesting them to allow the makers of MultiTarget to release all the intermediary data generated by their test, including the patient's composite score, fecal hemoglobin and all DNA test results. It is not ethical or in the public interest for the FDA to refuse to allow patients or their physicians to have access to this data, in my opinion.
References
1: Keller DL, Patients Should Not Be Denied Access to Their Test Results, online publication, temporarily removed, American Journal of Medicine, May 2016
2: Telephone discussion with MultiTarget laboratory director, May 2016
On 2017 Apr 13, Randi Pechacek commented:
Holly Ganz wrote a blog post about this paper and the significance of its findings on MicroBEnet. Read about it here
On 2016 Jul 04, Stephen Tucker commented:
This version of the article contains a production error: labels and annotations are missing in Figure 1A-B and Figure 5A. This has been pointed out to the publishers and will be corrected soon.
On 2016 May 30, Simon McGrath commented:
Authors’ abstract
(An abstract wasn’t required for this editorial, but the authors felt it would be helpful to add this one for PubMed. I am one of the authors.)
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is as prevalent and disabling as multiple sclerosis, diabetes and rheumatoid arthritis but biomedical research into the condition has been grossly underfunded. However, the NIH is committed to ramping up funding for this illness and there are now promising research leads. We indicate clues to the biological mechanisms that may perpetuate the condition and suggest the key elements of a concerted research programme. In the absence of effective treatments, study of mechanism remains a key priority including the possible role of stochastic factors.
We identify the three most interesting major categories of causal model: (1) the brain is responding normally and symptoms are due to persistent signal input from peripheral tissues, such as cytokines or metabolites; (2) there is a persistent abnormality of ‘housekeeping’ processes in the brain, such as an increase in activation of microglia; and (3) there is a persistent abnormality in neural signalling in sensory pathways.
We recommend seven important, practical steps to make progress towards effective treatments: (1) build research infrastructure, including population-based cohorts with close attention to diagnostic criteria; (2) use new, developing techniques for brain imaging; (3) pursue promising immunological leads, such as natural killer cell abnormalities, cytokine shifts, auto-antibodies, and immune responses to viruses such as Epstein-Barr virus; (4) further explore autonomic/endocrine regulation; (5) extend the research on post-exertional changes in physiology; (6) attempt to replicate key findings to determine which are robust; and (7) present data in a way that allows subgroup analysis, and always provide raw data.
We conclude that the problem of ME/CFS now looks solvable and we call on the wider biomedical research community to target the condition.
On 2016 May 29, Claudiu Bandea commented:
Remarkable results, questionable report
“Our findings raise the intriguing possibility that β-amyloid may play a protective role in innate immunity and infectious or sterile inflammatory stimuli may drive amyloidosis” (1). Indeed, fascinating findings. What Kumar et al. did not articulate, though, is that their result is one of many findings, observations, and arguments supporting the theory (2,3) that:
(i) β-amyloid, tau, α-synuclein, huntingtin, TDP-43, prion protein and other primary proteins implicated in neurodegenerative diseases are members of the innate immune system;
(ii) The isomeric conformational changes of these proteins and their assembly into various oligomers, plaques, and tangles are not protein misfolding events as defined for decades, nor are they prion-replication activities, but part of their normal, evolutionarily selected innate immune repertoire;
(iii) The immune reactions and activities associated with the function of these proteins in innate immunity lead to Alzheimer’s, Parkinson’s, Huntington’s, ALS and Creutzfeldt-Jakob Disease, which are innate immunity disorders.
Generating data and observations, although essential, represents only half of the scientific process; the other is their interpretation and integration into the existing knowledge and paradigms. That’s where the article by Kumar et al. falls short.
Perhaps the authors were not fully familiar with the literature and paradigms in the field of neurodegenerative diseases. Or, perhaps, Kumar et al. did not consider it relevant to discuss their results in the context of previous findings, ideas and hypotheses. For example, the authors did not address or explain their results in context of the ‘prion’ paradigm, which has dominated the thinking in the field of Alzheimer’s and other neurodegenerative diseases in the last few years (e.g. 4-7). Nor did they refer to a related study entitled “Alpha-synuclein expression restricts RNA viral infections in the brain” (8), which is highly relevant considering the fact that alpha-synuclein, a putative member of the innate immune system and the primary protein implicated in Parkinson’s, is a significant player in Alzheimer’s disease. Also, some might consider highly questionable leaving out the study by Kobayashi et al. entitled “Binding sites on tau proteins as components for antimicrobial peptides” (9).
Given these omissions, it's no wonder in her The New York Times article on Kumar et al. study, Gina Kolata wrote: “The Harvard researchers report a scenario seemingly out of science fiction”.
References:
(1) Kumar et al. 2016. Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer's disease. Sci Transl Med. 25;8(340); Kumar DK, 2016
(2) Bandea CI. 2013. Aβ, tau, α-synuclein, huntingtin, TDP-43, PrP and AA are members of the innate immune system: a unifying hypothesis on the etiology of AD, PD, HD, ALS, CJD and RSA as innate immunity disorders. bioRxiv. doi: 10.1101/000604; http://biorxiv.org/content/biorxiv/early/2013/11/18/000604.full.pdf
(3) Bandea CI. 2009. Endogenous viral etiology of prion diseases. Nature Precedings; http://precedings.nature.com/documents/3887/version/1/files/npre20093887-1.pdf
(4) Frost B, Diamond MI. 2010. Prion-like mechanisms in neurodegenerative diseases. Prion. 1(3):155-9; Frost B, 2010
(5) Nussbaum JM, Seward ME, Bloom GS. 2013. Alzheimer disease: a tale of two prions. Prion. 7(1):14-9; Nussbaum JM, 2013
(6) Watts JC et al. 2014. Serial propagation of distinct strains of Aβ prions from Alzheimer's disease patients. Proc Natl Acad Sci U S A. 11(28):10323-8; Watts JC, 2014
(7) Jaunmuktane et al. 2015. Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy. Nature. 525:247-50; Jaunmuktane Z, 2015
(8) Beatman et al. 2015. Alpha-Synuclein Expression Restricts RNA Viral Infections in the Brain. J Virol. 90(6):2767-82; Beatman EL, 2015
(9) Kobayashi et al. 2008. Binding sites on tau proteins as components for antimicrobial peptides. Biocontrol Sci. 13(2):49-56. Kobayashi N, 2008
(10) Kolata G. 2016. Could Alzheimer’s Stem From Infections? It Makes Sense, Experts Say. The New York Times; May 25, 2016.http://www.nytimes.com/2016/05/26/health/alzheimers-disease-infection.html?_r=0
On 2016 Oct 18, Konstantinos Farsalinos commented:
I am surprised that a completely irrelevant to the study (or to my post) comment is published here. I am satisfied to see that Hong Yin had no comment whatsoever on the content of my analysis on the problems of the paper by Ji et al. (1). I invite Hong Yin to comment on anything inappropriate or inaccurate, and of course i will respond accordingly and even correct any inaccuracies in my analysis. Instead of doing that, Hong Yin characterized the critical approach to studies with major methodological problems, which is a fundamental purpose of science and the duty of a scientist, as an "attack". There is no need to further comment on that, especially since i am in the process of finalizing the comprehensive and detailed replication of the New England Journal of Medicine research letter, which will provide further justification for the well constructed analysis on the need for retraction (2).
The disclosure of any COI was not only transparent from my side but also included declaration of funding of the institute which took place more than 3 years ago. According to ICMJE guidelines, it was not necessary to declare this, but i did it for the shake of full transparency. Thus, the initial sentence in the comment by Hong Yin is unjustifiable.
Additionally, Hong Yin omitted to mention that a very detailed response to the alleged "problems" of my paper has been published in response to the Shihadeh et al. commentary, both by the authors of the original study (3) and by the editor of Addiction journal (4). In my response, i clearly presented the case that our study (5) evaluated the widely-known organoleptic parameter of dry puff detection in e-cigarettes. This phenomenon can easily result (and unfortunately is frequently resulting) in abuse of e-cigarettes in the laboratory and misleading reports on e-cigarette emissions which are irrelevant to human exposure. The authors of the letter characterized dry puffs as a term with "tenuous ontological status", despite the fact that this phenomenon has been described in the literature since 2013 (6) and is well-known and explained by e-cigarette users long before that.
The act of writing a comment is irrelevant when the content of the criticism is not examined. I will be happy to accept and respond to any criticism about the content of my research or my comments.
References:
Ji EH, Sun B, Zhao T, Shu S, Chang CH, Messadi D, Xia T, Zhu Y, Hu S. Characterization of Electronic Cigarette Aerosol and Its Induction of Oxidative Stress Response in Oral Keratinocytes. PLoS One. 2016 May 25;11(5):e0154447.
Bates CD, Farsalinos KE. Research letter on e-cigarette cancer risk was so misleading it should be retracted. Addiction. 2015 Oct;110(10):1686-7. doi: 10.1111/add.13018.
Farsalinos K, Voudris V, Poulas K. Response to Shihadeh et al. (2015): E-cigarettes generate high levels of aldehydes only in 'dry puff' conditions. Addiction. 2015 Nov;110(11):1862-4. doi: 10.1111/add.13078.
West R. Conflicts of conscience in Addiction. Addiction. 2015 Nov;110(11):1864. doi: 10.1111/add.13069.
Farsalinos KE, Voudris V, Poulas K. E-cigarettes generate high levels of aldehydes only in 'dry puff' conditions. Addiction. 2015 Aug;110(8):1352-6.
Farsalinos KE, Romagna G, Tsiapras D, Kyrzopoulos S, Voudris V. Evaluation of electronic cigarette use (vaping) topography and estimation of liquid consumption: implications for research protocol standards definition and for public health authorities' regulation. Int J Environ Res Public Health. 2013 Jun 18;10(6):2500-14. doi: 10.3390/ijerph10062500.
On 2016 Oct 18, Clive Bates commented:
Dr. Farsalinos has provided a full disclosure statement. It would be better if the authors or their supporters responded to substantive criticisms of their work than complaining about who is making them.
This comment suggests that criticising other papers is somehow an 'attack'. Normally we refer to evidence-based criticism as 'science'.
With all due respect, the criticism of Jensen RP, 2015 by Farsalinos and I in a letter published in Addiction is well-founded. No adequate response to these criticisms has been made or will be. The reason is that the letter points to fundamental flaws in the study design: operating the device at excessively high temperature, and thereby running in 'dry puff' conditions that no human user ever experiences for more than an instant. Though completely unrealistic for humans, laboratory machines will reliably, but misleadingly, measure emissions under these conditions for hours.
The tendency among researchers and journals unfamiliar with actual vaping and vapers, but keen to publish laboratory results, is to overlook these real-world phenomena. That is why responsible researchers in the field need to know what methodology was used so they can decide whether the results are possibly interesting or whether they should be discarded as another failure of scientific comprehension, unchecked by peer review.
On 2016 Sep 14, Hong Yin commented:
Since Konstantinos Farsalinos had unrestricted funds from electronic cigarette companies, a full disclosure of the relationship to electronic cigarette industry is needed before making this kind of judgmental comment.
Similar attack was made on another published paper in The New England Journal of Medicine entitled “Hidden formaldehyde in e-cigarette aerosols” (1, 2).
In his comment, Farsalinos cited his recent publication “E-cigarettes generate high levels of aldehydes only in 'dry puff' conditions” (3). This paper received comments such as “Insufficient Method Description”, “Incomplete Result Reporting”, and “Unjustified Conclusions" (4) (quoted from the commentary).
References:
Jensen RP, Luo W, Pankow JF, Strongin RM, Peyton DH. Hidden formaldehyde in e-cigarette aerosols. N Engl J Med. 2015 Jan 22;372(4):392-4.
Bates CD, Farsalinos KE. Research letter on e-cigarette cancer risk was so misleading it should be retracted. Addiction. 2015 Oct;110(10):1686-7.
Farsalinos KE, Voudris V, Poulas K. E-cigarettes generate high levels of aldehydes only in 'dry puff' conditions. Addiction. 2015 Aug;110(8):1352-6.
Shihadeh A, Talih S, Eissenberg T. Commentary on Farsalinos et al. (2015): E-cigarettes generate high levels of aldehydes only in 'dry puff' conditions. Addiction. 2015 Nov;110(11):1861-2.
Disclosure: I have nothing to disclose with any cigarette industry.
On 2016 Jul 14, Clive Bates commented:
It is disappointing that the only reaction to Farsalinos' comment so far (anonymously via PubPeer) has been in relation to a disclosure statement, which in any event he has now added. There has been no substantive criticism of his work or response to his critique. Perhaps now the discussion should return to addressing the multiple methodological weaknesses he has identified in the Ji et al study.
Farsalinos and colleagues' study at ref #2 above shows clearly how machine measurements of e-cigarettes can become a misleading proxy for human exposure as power increases. Laboratory machines lack a critical control feedback - the reaction to a harsh taste by rapidly stopping vaping - that human subjects have. The acrid taste arises in situations where the liquid is undergoing thermal decomposition and its chemistry changes. If this is the case in the present experiment, the measurements are made under conditions that create exposures no human will experience. If Ji et al did not control to prevent this 'dry puff' condition arising during their experiment, the paper does not offer a basis for making any human risk assessments and is easily open to misinterpretation.
The uncertainty over the magnitude of the implied exposure, the lack of comparative context (the obvious comparator being tobacco smoke) and an uncertain operating regime capable of creating completely unrealistic exposures are major deficiencies. No conclusions about e-cigarette use and human health should be drawn from this study and the authors should discourage any over-interpretation of their findings.
Disclosure: I am a longstanding advocate for evidence-based 'harm reduction' approaches to public health. I was director of Action on Smoking and Health UK from 1997-2003. I have no competing interests with respect to any of the relevant industries.
On 2016 Jul 06, Konstantinos Farsalinos commented:
Paracelsus, the herald of modern toxicology, mentioned in the 16th century that: nothing is a poison and everything is poisonous; solely the dose determines that a thing is not a poison (Sola dosis facit venenum) (1). This principle, which still stands today and forms the basis of the dose-response concept, has been largely ignored by many scientists including the authors of this study. This study represents an unfortunate case of complete failure of the peer-review and editorial process of the journal.
One of the basic prerequisites for accepting a manuscript for publication is to provide a clear and detailed presentation of the methodology used in the experimental setup. In this case, the authors provide no information about:
1. The electronic cigarette device used in the experiment
2. The power settings on the electronic cigarette device that were used in the experiment
3. The puffing patterns (puff duration and interpuff interval). A range of 2 to 5s puff duration was mentioned only for the assessment of particle number concentration but not for cell exposure
4. The number of puffs performed during the aerosol generation procedure
5. The amount of liquid consumed during the aerosol generation procedure
6. The amount of aerosol dilution into the cell medium. There is no mention of the amount of cell medium used in the impingers and the amount of aerosol that was diluted into the cell medium.
7. The authors cite a study which has not been published or even accepted for publication but is marked as "submitted" for further details on the methodology (reference 11 of the manuscript)
Omissions 1-3 are extremely important because it is well-known that electronic cigarettes can be easily abused in a laboratory setting, which may result in the evaluation of unrealistic, dry puff, conditions. Such conditions are irrelevant to human exposure (2).
Omissions 4-6 are extremely important because they violate the basic principle of toxicology which dictates that the dose determines the toxicity. In fact, it is very easy in a cell culture to create an adverse cell response, just by manipulating the dose of exposure. Therefore, it is crucial to present the level (dose) of exposure and ensure that this is relevant to human exposure. Otherwise, the findings cannot be extrapolated to human effects and can only be used for comparing two different exposures. For the latter, it is surprising that the authors did not attempt to perform the same experiment with the same conditions and the same level of exposure with tobacco cigarette smoke. Thus, the study findings cannot even be used for comparative purposes.
Omission 7 is really unprecedented. It is the first time that i see a reference to a non-existing publication (marked as "submitted", so, not reviewed and not accepted) being accepted by the reviewers and the editor.
These omissions raise some important issues about the peer-review process and the editorial assessment of that study. In my opinion, this is a typical example of failure of the peer-review process and the study should be retracted or revised.
Disclosure. No funding or other support was provided for this comment. The author has no financial or other interest on e-cigarette companies. Two studies (unpublished) were performed with unrestricted funds provided to the institution (Onassis Cardiac Surgery Center) by 2 electronic cigarette companies in 2013, for which no researcher (including the author of this comment) received any financial compensation. Funding was provided more than 3 years ago, so the declaration is not necessary based on the ICMJE guidelines. Two published studies were performed using funds provided by the non-profit association AEMSA in 2013 (less than 3 years ago) and one published study was funded by the non-profit association Tennessee Smoke-Free Association in 2015.
References
1. Borzelleca JF. Paracelsus: herald of modern toxicology. Toxicol Sci. 2000 Jan;53(1):2-4.
2. Farsalinos KE, Voudris V, Poulas K. E-cigarettes generate high levels of aldehydes only in 'dry puff' conditions. Addiction. 2015 Aug;110(8):1352-6.
On 2016 Jul 13, Jenna Wong commented:
None
On 2016 Jul 16, David Keller commented:
Doxepin - an antidepressant with strong scientific evidence supporting its off-label use for insomnia
Wong wrote: "Regarding the off-label use of antidepressants for insomnia, we disagree with Keller that it is supported by strong scientific evidence".
To demonstrate that Wong is incorrect, I cite doxepin, an antidepressant with strong evidence supporting its off-label use for insomnia at the 10 mg dose approved only for depression. Both of the references cited by Wong to contradict me were published in 2005, 5 years before the FDA approval of doxepin for insomnia. In 2010, the FDA approved doxepin for insomnia at the doses of 3 mg and 6 mg, which can be given sequentially if needed. Physicians continue to prescribe cheap generic doxepin 10 mg to treat insomnia (off-label at 10 mg), based on the strong scientific evidence supporting its FDA-approved insomnia doses of 3 mg and 6 mg. Doxepin 10 mg is the lowest dose approved for use as a cheap generic antidepressant, and I daresay that the vast majority of prescriptions for that dose are written off-label for insomnia, which has the benefit of saving the patient substantial money on the high cost of the doses branded for insomnia.
On 2016 Jul 13, Jenna Wong commented:
We thank Keller for his comment. We agree that the level of supporting scientific evidence is the most important aspect to consider when determining the appropriateness of off-label drug use. In our article, we state that our findings “highlight the need to evaluate the evidence supporting off-label antidepressant use,” which neither assumes that all off-label antidepressant use is inappropriate, nor assumes that all off-label indications require official regulatory approval. In cases where off-label use lacks scientific evidence, our position is that physicians should exercise caution and carefully consider the potential risk-benefit ratio when prescribing antidepressants for off-label indications. However, to assess risk-benefit, physicians must have easy access to sources of knowledge that evaluate and summarize the existing scientific evidence.
Regarding the off-label use of antidepressants for insomnia, we disagree with Keller that it is supported by strong scientific evidence. In fact, the article [1] that he cites to support this claim states that “[the] NIH State of Science Conference on insomnia treatments reviewed the status of antidepressants reporting minimal scientific evidence supporting their use,” and that “[of] particular concern in using antidepressants for insomnia are a number of unique potential side effects”. Other review articles have also made similar conclusions [2].
References:
[1] Asnis GM, Thomas M, Henderson MA. Pharmacotherapy Treatment Options for Insomnia: A Primer for Clinicians. Int J Mol Sci. 2015;17(1).
[2] WB M. A review of the evidence for the efficacy and safety of trazodone in insomnia. J Clin Psychiatry. 2005;66(4):469-476.
On 2016 Jun 29, David Keller commented:
In Defense of Off-Label Prescribing of Antidepressants
Wong and colleagues report that, in their study, 29.4% of all antidepressant prescriptions were written "for non-depressive indications, including unapproved (off-label) indications that have not been evaluated by regulatory agencies" [1]. The authors imply that patients treated for unapproved indications with antidepressants would benefit if these off-label treatments were evaluated by regulatory agencies. However, the small profit margins of generic medications make the cost of regulatory approval for every beneficial indication prohibitively expensive.
Recently, a study by Eguale and colleagues demonstrated that off-label use of prescription drugs is associated with increased adverse drug events only when such use lacks strong scientific evidence [2]. Wong and colleagues found that the two most common off-label indications for antidepressants were insomnia and pain [1], both of which are supported by strong scientific evidence [3], [4]. Less common off-label indications, such as migraine, also have strong scientific support [5].
The findings of Eguale and colleagues demonstrate that patient safety does not require specific regulatory approval for every off-label indication, and that it is not necessary to spend the large sums of money which would be required to obtain FDA approval for every off-label indication. [6]
References
1: Wong J, Motulsky A, Eguale T, Buckeridge DL, Abrahamowicz M, Tamblyn R. Treatment Indications for Antidepressants Prescribed in Primary Care in Quebec, Canada, 2006-2015. JAMA.2016;315(20):2230-2232. doi:10.1001/jama.2016.3445.
2: Eguale T, Buckeridge DL, Verma A, Winslade NE, Benedetti A, Hanley JA, Tamblyn R . Association of Off-label Drug Use and Adverse Drug Events in an Adult Population. JAMA Intern Med. 2016 Jan 1;176(1):5563. doi:10.1001/jamainternmed.2015.6058. PubMed PMID: 26523731.
3: Asnis GM, Thomas M, Henderson MA. Pharmacotherapy Treatment Options for Insomnia: A Primer for Clinicians. Int J Mol Sci. 2015 Dec 30;17(1). pii: E50. doi: 10.3390/ijms17010050. PubMed PMID: 26729104; PubMed Central PMCID:PMC4730295.
4: Janakiraman R, Hamilton L, Wan A. Unravelling the efficacy of antidepressants as analgesics. Aust Fam Physician. 2016 Mar;45(3):113-7. PubMed PMID: 27052046.
5: Jackson JL, et al. A Comparative Effectiveness Meta-Analysis of Drugs for the Prophylaxis of Migraine Headache. PLoS One. 2015 Jul 14;10(7):e0130733. doi:10.1371/journal.pone.0130733. eCollection 2015. PubMed PMID: 26172390; PubMed Central PMCID: PMC4501738.
6: Keller DL. In Defense of Off-label Prescribing. JAMA Intern Med. 2016 Jun 1;176(6):861. doi: 10.1001/jamainternmed.2016.1403. PubMed PMID: 27273485.
On 2017 Apr 13, Randi Pechacek commented:
Marcus Leung, 1st author of this review, wrote a blog post giving a more personal background to the paper. Read about it here
On 2016 Jun 09, Ali Poormohammadi commented:
None
On 2017 Jan 09, Jennifer L Kuk commented:
I completely agree with your comment regarding the "steeper positive association between BMI and glucose tolerance" and will keep this in mind for future publications. We used the term glucose tolerance because the values are from an oral glucose tolerance test and thus the graph is showing the association between BMI and glucose tolerance. But because higher numbers indicate intolerance, I can see how this rapidly becomes confusing. Hopefully our conclusion "Therefore, consumption of aspartame is associated with greater obesity-related impairments in glucose tolerance." made it clear.
On 2016 Dec 12, C. Alan Titchenal commented:
Thanks for your reply Jennifer and excuse my slow follow-up. My main point may have been missed. In the abstract, the statement that ". . . those reporting aspartame intake had a steeper positive association between BMI and glucose tolerance" seems to be incorrect because your paper (Fig 1) shows a positive association between BMI and glucose INTOLERANCE based on 2-hour glucose levels. The way I read the abstract, it indicates that people with higher BMI values had better glucose tolerance - the opposite of what I think you intended to say based on your data and your reply to my previous comment.
On 2016 Jun 08, Jennifer L Kuk commented:
It is possible that individuals with impaired glucose tolerance could be opting for artificial sweeteners to decrease their carbohydrate intake. However, our results were the same with and without individuals with diabetes. Further, these observations were not seen with fasting glucose. As OGTTs are not commonly done in individuals without elevated fasting glucose, it is unlikely that these individuals would know to change their diet. Finally, given that there are studies that report a possible physiological rationale for our observation, we thought that our interpretation may be more likely.
Our conclusion that individuals who consume aspartame and have obesity, have worse glucose tolerance is entirely consistent with the interpretation that there is a steeper positive slope. From the graph, you will see that the greater slope between BMI and glucose intolerance in aspartame consumers means that there is a higher glucose intolerance for only individuals with a higher BMI.
On 2016 May 27, C. Alan Titchenal commented:
There appears to be a discrepancy in this abstract. It states that ". . . those reporting aspartame intake had a steeper positive association between BMI and glucose tolerance" (i.e. as BMI increases, so does glucose tolerance) and then it concludes that aspartame consumption is associated with "obesity-related impairments in glucose tolerance." It also seems that their conclusion could suggest that overweight/obese people with impaired glucose tolerance are more likely to opt for artificial sweeteners in attempts to decrease their carbohydrate intake.
On 2016 Jun 01, Kenneth Witwer commented:
These data cannot be used to conclude differential expression of miRNAs between soybean strains (only one sample per strain), but the authors are commended for publishing this study, which is interesting and potentially instructive for several reasons. Four RNA samples were prepared: one each from two soybean strains that were genetically modified using modern biotechnology and one each from the two parent strains that were genetically modified by traditional breeding approaches. A sequencing library was prepared from each RNA sample.
The first interesting aspect of the study is that the small RNA profile of soybean was overwhelmingly dominated by fragments of longer RNAs, especially the rRNAs, such that only single digit percentages of miRNAs are mapped. It would be good to compare these results with other soybean studies to determine if sample quality or processing issues contributed to degradation. To this end, it would be helpful to know more about the quality control that was mentioned. rRNA degradation fragments are variable in length and well conserved (in contrast with erroneous suggestions of species-specificity, e.g. Zhou Z, 2015), and they should not be confused with miRNAs. A study of one family, previously called "MIR2911," showed that the family does not associate with RNA regulatory machinery (Yang J, 2015) and is thus unlikely to be involved in RNA regulation, within or across organisms.
A second and more substantive contribution of the study comes from the 14 newly predicted miRNAs. Although at low abundance and not reportedly associated with "GM" strains, these may be worth some follow-up through bioinformatics and perhaps even in the lab.
As a third matter of note, the study reminds us to check data and not rely only on abstracts and conclusions in the text. Unfortunately, no conclusions can be drawn about differential expression of miRNAs between parental and "GM" strains, since there are no biological replicates. More reported differences were found between the two traditionally genetically modified "parent" strains than between parent and biotech, yet curiously this is not emphasized. The very minor reported differences, which are inconsistent between the two parent-daughter strain pairs, could be due to any number of factors that have nothing to do with biotechnology-introduced modifications, from growing, harvesting, storage, shipping, and other handling conditions (all out of the control of the authors...presumably these beans were not grown side-by-side in the same field); to a variety of technical factors introduced during isolation of RNA, library prep, and sequencing; to chance.
Finally, the study prompts reflection on the term "genetically modified," which applies to all strains examined here. The popular media definition is used in this study to refer only to molecular biotechnology-produced strains, not the parents produced by legacy methods of genetic modification.
On 2016 Jun 02, Michael Tatham commented:
Is SUMO5 a pseudogene?
There are known to be many SUMO pseudogenes in humans (http://www.ncbi.nlm.nih.gov/pubmed/12383504). A fair position when confronted with a claim that a new SUMO paralog has been discovered is to assume it is a non-expressed pseudogene until otherwise convincing evidence is provided. This paper lacks one piece of critical evidence supporting the idea that SUMO5 really exists as a protein, and that is the presence of endogenous protein.
When BLAST searched, the nucleotide sequence of SUMO5 (originally termed SUMO13 according to the authors’ GenBank entry: FJ042790.1), returns a top hit of “Homo sapiens SUMO1 pseudogene 1 (SUMO1P1), non-coding RNA Sequence ID: ref|NR_002189.3|”. The only difference is a single nucleotide T23 (in SUMO13/SUMO5), which is C in SUMO1P1. This may be a primer synthesis error or a DNA sequencing error.
To put beyond reasonable doubt that SUMO5 is not a pseudogene at least two pieces of new experimental evidence showing SUMO5 is expressed in cells is required. I can think of three good ways to do this:
(1) Mass-spectrometric evidence of a peptide unique to SUMO5.
(2) Cross-reaction of a SUMO5-specific antibody with an endogenous protein.
(3) Editing of the genome to insert an epitope tag into the endogenous SUMO5 gene, with the intention of detecting the protein using an antibody specific to the tag.
All three of these pieces of evidence will be strengthened by parallel studies comparing cells with and without SUMO5-specific knock-down.
RTPCR experiments intending to detect mRNA are particularly uninformative given that DNA contamination often leads to false-positives. This is especially true for SUMO5 given the fact the gene is intronless, a notable characteristic of pseudogenes.
On 2016 Aug 17, Karyn Schmidt commented:
Please note SLNCR1 and LINC00673 refer to the same non-coding transcript. While this manuscript was being prepared, multiple other manuscripts were published referring to the lncRNA as LINC00673: Childs EJ, 2015, Shi X, 2016, Zheng J, 2016, and Invalid PMID: 27260162.
On 2016 May 29, Sonia Kharay commented:
Effect size, confidence intervals and P value misinterpretations are explained with ample examples. It is an exemplary article on errors in presentation of statistical data.
On 2016 May 28, Arnaud Chiolero MD PhD commented:
This unexpected review is welcomed: it is well written, readable by non-statisticians, and comprehensive. Highly recommended for students in public health and epidemiology and for health researchers.
On 2017 Mar 24, Atanas G. Atanasov commented:
I started regularly drinking kefir recently and really experience positive effects, thanks a lot for putting together this interesting review. I have featured the manuscript at: http://healthandscienceportal.blogspot.com/2017/03/the-health-promoting-and-microbiota.html
On 2017 Jun 01, Lawrence Moon commented:
There is a typo regarding SPSS Syntax in Supplementary Information. prepop should read preop
Thanks to Merrick Strotton for finding it!
On 2016 Nov 05, Lawrence Moon commented:
You may also find this short PDF useful if you have empty cells in your dataset that represent missing data.
On 2016 Nov 05, Lawrence Moon commented:
I will happily help people learn to analyse their own data using this protocol if you get in touch by email. Best wishes, Lawrence
On 2016 May 20, Donald Forsdyke commented:
FACTS BEFORE COUNTERFACTS
Counterfactual explorations can provide intriguing insights (1). But we have to be sure that the facts themselves are correct in the first place. In the context of Weldon, reference to "bad-tempered conflict with Mendel’s followers," really means conflict with William Bateson. While it is correct that the doctrinaire "Mendelian ‘genes for’ approach is increasingly seen as out of step with twenty-first-century biology" (1), for Bateson (1861-1926) the approach was also seen as out of step with twentieth-century biology.
Well aware of developmental and environmental factors, Bateson recognized that the biochemical characterization of genes should be high on the twentieth century research agenda. Thus, near the end of his life he declared that “Our knowledge of the nature of unorganized matter must first be increased. For a long time we may have to halt” in getting to grips with the underlying biological principles (2). However, he argued forcefully for looking beyond the visible characters of an organism (its conventional phenotype) to what we now regard as its genome phenotype (3). It was here that the answer to Darwin's fundamental question - the origin of species - was likely to lie.
Weldon had allied himself with Pearson whose brilliant work (later built on by Fisher), was to create modern biostatistics. But those were early days and they made elementary mistakes that Bateson was quick to point out. For example, Bateson would have bridled at the idea that “first year biologists” could serve as a reliable “control” against which to compare “second year humanities undergraduates” (1). Yes, we should “study Mendel, but let him be part of his time”(1). And as related by Meijer (4), Mendel followed the statistics of his time. Indeed, his results have withstood the test of time.
(1) Radick G (2016) Teach students the biology of their time. Nature 533:293 Radick G, 2016
(2) Cock AG, Forsdyke DR (2008) "Treasure Your Exceptions." The Science and Life of William Bateson. Springer, New York.
(3) Forsdyke, D. R. (2010) George Romanes, William Bateson, and Darwin's "Weak Point." Notes Rec R Soc Lond 64:139-154.
(4) Meijer OG (1982) The essence of Mendel’s discovery. In: Gregor Mendel and the Foundations of Genetics. Orel V (ed). The Mendelianum of the Moravian Museaum, Brno, pp. 173-200.
On 2016 Oct 04, Atanas G. Atanasov commented:
None
On 2016 Jun 06, Thomy Tonia commented:
We would like to thank Melissa Vaught for her interesting and stimulating thoughts on our paper. She states that the title and description of our trial’s objective is misleading. However, it is clearly stated in the abstract and in the introduction that we randomised IJPH papers into two arms one of which involved IJPH social media exposure at 3 time points; moreover, our Methods section describes this intervention in detail.
Melissa Vaught makes a very valid point stating that we did not include any measures of reach/exposure such as re-tweets, shares or other users’ dissemination of our papers in social media etc. We have touched upon this issue when we discussed the limitations of our study.
She also refers to potential confounding factors. Given the randomised design of our study, however, systematic confounding cannot be an issue; our analysis is what one would call “intention to treat” in clinical trials. There are some interfering factors that we could not control, which we tried to outline in our paper. This is why we standardised our intervention as much as possible, randomising only original articles (and not systematic reviews that generally tend to receive more attention) and stratifying for open access status. We have not issued any press releases for any of the randomised papers but we could not control for any press or other exposure coming from other sources such as authors’ institutions.
Although we agree that SM strategies could influence outcomes, the studies by Fox CS, 2016 and Adams CE, 2016 cited by Melissa Vaught did not directly compare different intensities of interventions such as multiple postings per day versus less frequent postings. Additionally, as we mention in our limitations, we could not have the data on paper views which could be different from the download data.
Melissa Vaught mentions that only the study by Sorenson 2014 looked at SM promotion by the journal. However, the studies by Fox CS, 2015 and Fox CS, 2016 which were randomised and bigger in size also assessed the promotion of papers from Circulation journal on their own social media and found no effect on article views.
We fully agree with the last remark of Melissa Vaught. Indeed, having social media presence as a journal can have benefits that lie beyond downloads and citations and this is one of the reasons our Journal is active on social media.
Indeed, social media exposure and its effects on scientific is a complex and multi-layered subject. Our trial looked at only one specific aspect of this, namely the effects of exposure of our own papers on our own social media channels. Nevertheless, we believe that it adds useful information to the existing body of literature. We hope that future RCTs will assess the effect of other measures of reach and exposure in order to give a fuller picture of the effect.
On 2016 May 24, Melissa Vaught commented:
This interesting article presents the impact of a journal's social media activity on article-level metrics - one of very few randomized trials on the topic. Notably it uses a traditional (citation counts) and an alternative metric (article downloads) as outcomes.
However, the title and descriptions of the trial's objective and intervention are a bit misleading. The authors state, "We sought to investigate whether exposing scientific papers to social media (SM) has an effect on article downloads and citations." But the study does not evaluate social media exposure. Rather, it measures the effect of a journal promoting its content via its own social media channels. The study did not include any measures of reach or exposure, such as retweets, shares, or likes of their posts. It also did not examine whether other users disseminated articles in the trial via social media.
Still, this study addresses a pertinent question: Does publisher promotion of publications via social media influence reading or citation? For IJPH, there is no apparent association. Of course, there are potential confounding factors, some beyond the journal's control. Did IJPH or authors' institutions issue press releases for any publications in the trial? Did any articles garner attention in mainstream media or on social media? Would easier access to publications affect outcomes? The authors report no difference in outcomes for social media promotion vs. control, when stratified for open access; however, there were few open access articles in the trial—10% in control, and 5% in intervention group.
Using citations as an outcome is a valuable contribution of this trial. Other randomized trials have evaluated effects of social media promotion by publishers on article views, which may moderately correlate with citations. In two separate trials (Fox CS, 2015, cited by the authors, and Fox CS, 2016), Circulation found that Facebook and Twitter posts did not significantly affect views at 7 or 30 days. By contrast, the Cochrane Schizophrenia Group (Adams CE, 2016) found a significant increase in 7-day page views for systematic reviews shared on Twitter and Weibo (a popular social media site in China).
Social media strategies could influence outcomes. By using Weibo, Adams CE, 2016 extended reach to a distinct audience. Post frequency and schedules likely affect audience reach as well. For instance, tweets posted at the same time weeks apart (as in the IJPH trial) might not be as effective as multiple posting over one or two days (as in Fox CS, 2016 and Adams CE, 2016). Overall social media engagement and post volume could also come into play.
The authors note that many observational studies show positive correlation between social media exposure and article views, downloads, or citations. They suggest the difference may be due to design (randomized vs. observational). Contexts and sizes of the studies could also contribute to differences in results. Only Sorenson M, 2014 looked at social media promotion by the journal; this was only for a small number of publications (3 promoted and 3 non-promoted). Other cited studies looked at third-party or global social media activity, for a handful to thousands of publications.
Ultimately this trial evaluates whether a journal's social media activity affects reading or citation of its own publications. So who follows journals on social media, and why? Social media uptake in scholarly communities is growing. But it's far from replacing other methods for discovering articles (Ware M, 2015, pp. 52-5, 134-5). Researchers are still likely to read articles recommended by colleagues (Tenopir C, 2015), and we might expect this trend to be reflected in social media. In other words, individuals on social media may have a degree of influence that publishers do not. The benefits of journal social media accounts may lie with other outcomes.
On 2016 Jun 29, David D Leedahl commented:
In the accompanying editorial1, Calkins offers some insightful comments regarding the relatively high rate of stroke or TIA observed in the recent investigation by Gillinov et al.2 We would like to offer two important considerations related to these findings.
First, cardiac surgeons and physicians caring for cardiac surgical patients in the immediate postoperative period have a reluctance to initiate anticoagulant strategies for fear of bleeding complications. Accordingly, bridging strategies with parenteral anticoagulants are infrequently used when initiating warfarin therapy for POAF, potentially resulting in a greater length of time until therapeutic anticoagulation is achieved. Delaying anticoagulant initiation for one to two days to avoid bleeding and another two to three days to become therapeutic may leave patients unprotected for a longer period of time than recognized.
Secondly, using direct-acting oral anticoagulants for the treatment of POAF may improve the time to therapeutic anticoagulation and lower the bar for surgeons to decide to anticoagulate their patients. Although our hospital has some published experience with this approach,3 the effect on stroke or TIA incidence in patients with POAF remains uncertain.
Cornelius Dyke, M.D. Sanford Health, Fargo, ND 58122
David Leedahl, Pharm.D. Sanford Health, Fargo, ND 58122
On 2016 May 20, Mayer Brezis commented:
Did the physical activity increase in the intervention group? Did insulin sensitivity improve? Is it possible that this was the reason for the lack of effect?
On 2016 May 20, Clive Bates commented:
The paper raises well-known fire and explosion risks from lithium-ion batteries, which arise in any products that use them. However, the paper goes on to draw an inappropriate and alarmist conclusion that e-cigarettes constitute a "significant public health risk" on the basis two case studies and four inconclusive media reports.
The problem is that they apply this alarming label without defining what constitutes a significant public health risk, a concept that must depend on the magnitude of the risk involved and how this compares to other risks.
Comparison to smoking-related accidents and injuries
The most important feature of e-cigarettes is that they are alternatives to smoking cigarettes. The authors have not made a comparison with smoking-related accidents or injuries (let alone disease) or made an estimate of the net impact that arises from consumers who switch from smoking to e-cigarette use. The accidents and injuries associated with smoking do actually appear like a "significant public health risk". The U.S. National Fire Protection Service provides useful data:
In 2011, U.S. fire departments responded to an estimated 90,000 smoking-material fires in the U.S., largely unchanged from 90,800 in 2010. These fires resulted in an estimated 540 civilian deaths, 1,640 civilian injuries and $621 million in direct property damage; deaths were down substantially from the year before.
Home structure fires dominated all these measures of loss except for fire incidents. In 2011, an estimated 17,600 smoking-material home structure fires caused 490 civilian deaths (19% of all home structure fire deaths), 1,370 civilian injuries and $516 million in direct property damage. The other 72,400 smoking-material fires in 2011 were mostly outdoor fires (60,200 fires in trash, vegetation and other outdoor combustibles).
Comparison to other risks
Some broader context may be useful - each year there is one significant injury episode for every eight Americans. U.S. data from CDC:
Morbidity
Number of medically attended injury and poisoning episodes in the population: 39.5 million
Episodes per 1,000 population: 126.3
Mortality
Number of injury deaths: 192,945
Deaths per 100,000 population: 60.2
Just about every practice in everyday life involves some risk: cooking, eating, walking, showering, using a laptop, walking up stairs, anything that involves electricity, heat or glass etc.
For example, according to the U.S. National Fire Protection Service home grills account for damage and injuries as follows:
In 2009-2013, U.S. fire departments responded to an average of 8,900 home fires involving grills, hibachis, or barbeques per year. These 8,900 fires caused annual averages of 10 civilian deaths, 160 reported civilian injuries, and $118 million in direct property damage. Almost all the losses resulted from structure fires
How does the e-cigarette compare to the ubiquitous and much-loved BBQ?
There are also persistent reports of exploding iPhones. Should iPhones be designated a "significant public health risk"?
Conclusion
Claims that products or behaviours cause significant public health risks need to be proportionate and reflect both absolute risks (how much harm is caused) and relative risks - i.e. set in appropriate context by reference to risks arising from other common products and activities. Risk is a quantitative concept or it is meaningless.
The authors did not reflect on whether there is a net public health gain in terms of accident risk through the substitution of smoking by e-cigarette use, which is by far the most common pattern of use. It is irresponsible to draw attention to one risk associated with a behaviour, without considering whether it reduces more significant risks. Given the rarity of e-cigarette battery incidents and the preponderance of smoking-related fires, it seems more likely that the net impact on accidents through e-cigarette use will be a significant reduction and therefore a public health win.
This is not a call for complacency but for proportionality. Regulators could have addressed fire risks from e-cigarette batteries some years ago, but have been spending their time on grandiose and excessive regulatory schemes that have yet to achieve anything and may not even solve this problem when they finally apply.
On 2017 Oct 19, Julien Bobe commented:
Thank you for pointing this out. We will add a corrigendum to the original publication.
On 2017 Oct 17, Anne Niknejad commented:
Error in the list of RNA-seq raw sequence data accessions from NCBI SRA:... ', SRP058863 (cave fish), SRP058865 (Atlantic cod), and SRP058863 (surface fish).'
should be read
', SRP058863 (cave fish), SRP058865 (Atlantic cod), and SRP058866 (surface fish).
On 2016 Jul 21, Donald Forsdyke commented:
THEORY-DRIVEN RESEARCH
The results of Enard et al. Enard D, 2016 "draw a broader picture where adaptation against viruses involves not only the specialized antiviral response, but also the entire population of host proteins." Indeed, Petrov has remarked: "Organisms have been living with viruses for billions of years" so on theoretical grounds alone "those interactions have affected every part of the cell."
Given recent disparagement of theoretical work Lander ES, 2016, it is nice to see results that are consistent with theory (e.g. Trends Immunol (2002) 23:575-579; Paper with Endnotes). Enard et al. now "conservatively estimate" that "viruses have driven close to 30% of all adaptive amino acid changes in the part of the human proteome conserved within mammals." Such "virus interacting proteins" vastly exceed the known proteins that regularly engage in immune responses to viruses (e.g. protein kinase R).
This is consistent with the 2002 postulate of the existence of intracellular protein "immune receptors" Forsdyke DR, 2002. Thus, over evolutionary time a protein that primarily evolved for a distinct function, but also happened to cross-react with some virus component, would in addition be selected by virtue of the latter function.
On 2017 Oct 06, Lily Chu commented:
Thank you for the response, Dr. Loy. Many medical resources used by clinicians continue to conflate CFS with SEID and suggest that cognitive behavioral and/or graded exercise therapy are appropriate for patients who fit SEID criteria despite there being no trials of CBT and GET using SEID criteria. I was concerned your group's article might contribute to this confusion.
(In fact, the US Centers for Disease Control and Prevention are working on removing CBT and GET as treatments from their ME/CFS website. See: http://www.npr.org/sections/health-shots/2017/10/02/554369327/for-people-with-chronic-fatigue-syndrome-more-exercise-isnt-better.)
On 2017 Sep 01, Bryan Loy commented:
Thank you for commenting on our paper, and for your contributions to this field. We agree that the ME, CFS, and SEID case definitions are not the same, which is why we provided a citation of each major case-defining paper in the first sentence of our introduction. We then wrote in the “Data searches” section that we were looking for papers using any of the 3 major case definitions, and cited them again. We further acknowledge the differences in the “Diagnostic characteristics” section of the paper, where we coded studies based on the criteria used to diagnose the participants within each study that was included in the meta-analysis. As you point out in table 1, we only found studies that had used the CDC or Fukuda criteria. We wrote ME/CFS/SEID in the title, abstract, and paper to be consistent with the naming used in the IOM report “Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness” and the first sentence in the report brief, “Between 836,000 and 2.5 million Americans suffer from myalgic encephalomyelitis/chronic fatigue syndrome-commonly referred to as ME/CFS” (https://www.nap.edu/resource/19012/MECFS_ReportBrief.pdf). While our conclusions may pertain only to people diagnosed using the CDC or Fukuda criteria, we wanted to still refer to the disease as ME/CFS/SEID since ME and SEID have been recommended as new names for CFS. We hope the results of this initial summary of the existing literature will encourage future research that includes other case definitions, and improves the lives of people living with the disease.
On 2017 Aug 24, Lily Chu commented:
I am one of the co-authors for the SEID (Systemic Exertion Intolerance Disease) case definition. The SEID and ME case definitions are not the same as the CFS case definition. Otherwise we would not have different names for them. The authors of this study seem to think they are equivalent to each other. The title and abstract is misleading: they should be clear that ALL of the studies examined by the authors (in Table 1) used only the 1994 Fukuda CFS case definition. Consequently, any results and conclusions drawn are only about CFS.
On 2017 Aug 30, Hilda Bastian commented:
Although the authors draw conclusions here about cost and effectiveness of simply offering badges if certain criteria are met, the study does not support these claims. There are, for example, no data on costs for the journal, peer reviewers, or authors. Any conclusions about effectiveness are hampered by the study's design, and the lack of consideration and assessment of any potentially negative repercussions.
It was not possible for the authors to study the effects of offering badges alone, as this intervention was part of a complex intervention: a package of 5 co-interventions, announced by the journal in November 2013 to begin taking effect from January 2014 (Eich E, 2014). All were designed to improve research transparency and/or reproducibility, and signaled a major change in editorial policy and practice. Any manuscript accepted for publication after 1 January, while being eligible for these badges, was also subject to additional editorial requirements of authors and reviewers. All authors submitting articles from 2014 faced additional reproducibility-related questions before submission, that included data disclosure assurances. Other authors have shown that although these did not all lead to the changes sought, there was considerable impact on some measures (Giofrè D, 2017).
Data on the impact on submissions, editorial rejections, and length of time until publication of accepted articles is not provided in this paper by Kidwell and colleagues. These would be necessary to gain perspective on the burdens and impact of the intervention package. I had a look at the impact on publications, though. It is clear from the data as collected in this study, and from a more extended timeframe based on analysis of date of e-publication, that the package of interventions appears to have led to a considerable drop in publication of articles (see my blog post, Absolutely Maybe, 2017). The number of articles receiving badges is small. During the year in this study from the awarding of the first badge, it was about 4 articles a month. That first dropped, then rose since, while at the same time the number of publications by Psychological Science has dropped to less than half the rate it was in the year before this package of interventions was introduced, leading to a substantial increase in percentage, while the absolute numbers of compliant articles remains small.
Taken together, it appears that it was likely there was a process of "natural selection", on the side of the journal and authors, leading to more rigorous reporting and sharing among the reduced number of articles reaching publication. The part that badges alone played in this is unknowable. Higher rates of compliance with such standards have been achieved without badges at other journals (see the blog post for examples). There is some data to suggest that disinclination to data disclosure is part of a range of practices adopted together more by some psychology researchers than others, in one of the studies that spurred Psychological Science to introduce these initiatives (<PMID:26173121). The data in Giofrè D, 2017 tend to support the hypothesis that there is a correlation between some of the data disclosure requirements in the co-interventions, and data-sharing (see my follow-up blog post).
In addition to not considering a range of possible effects of the practices, or being able to isolate the impact of one of the set of co-interventions, the study used only one data extractor and coder for each article. This is a particularly critical potential source of bias, as assessors could not be blinded to the journals, and the badging intervention was developed and promoted from within the author group.
It would be useful if the authors could report in more detail what was required for the early screening question of "availability statement, yes or no". Was an explicit data availability statement required here, whether or not there was indeed additional data than was included in the paper and its supplementary materials?
It would be helpful if the authors could confirm the percentage of articles eligible for badges, where the offer of a badge was rejected.
At the heart of this badge approach for closed access journals, is a definition of "open-ness" that enables potentially serious limitation of the methodological information and key explanatory data available outside paywalls. In de-coupling the part of the study included in the paper from the study's data, and allowing it be inaccessible to many who could potentially use it or offer useful critique, the intervention is promoting a limited form of open-ness. The trade-off assumed is that this results in more open-ness than there otherwise would be. However, it may have the reverse effect, for example, by encouraging authors to think fully open access doesn't matter and can be foregone with pride and without concern, and if journals believe this "magic bullet" is an easy way out of more effective intensive intervention.
Disclosures: I have a long relationship with PLOS (which has taken a different approach to increasing openness), including blogging at its Blog Network, and am a user of the Open Science Framework (which is produced by the group promoting the badges). My day job is at NCBI, which maintains literature and data repositories.
This comment was updated with the two references and data on the question of correlation between data disclosure and data sharing on 1 September, after John Sakaluk tweeted the Giofrè paper to me.
On 2016 May 27, Hans Morreau commented:
Massive Chromosomal Loss with Subsequent Whole Genome Doubling is seen in a Wide Variety of Rare Tumor Types:
The authors Zheng et al. performed an impressive molecular characterization of 91 cases of adrenal cortical carcinoma (ACC). The integrated analysis is the way to understand the behaviour of this rare disease far better and hopefully will lead to better treatment options. They conclude that there is a subset of ACCs showing massive chromosomal loss with subsequent whole genome doubling (WGD). The authors state that this chromosomal loss leads to a hypodiploid karyotype. Such a phenomenon “was only matched by chromophobe renal cell carcinoma”. The latter is partly correct. In 2012 we published the occurrence near-haploidisation with or without subsequent endoreduplication (whole-genome doubling) in oncocytic follicular thyroid carcinoma (FTC-OV) and anaplastic thyroid carcinoma (ATC) derived from FTC-OV (Corver et al., 2012). In combined SNP array analysis and DNA content analysis the genomes of these lesions were seen as near-homozygous genomes (NHG) with DNA indices of 0.6-1.4 depending on the absence or presence of endoreduplication. Wagle et al. independently confirmed our observations in the New England Journal of Medicine with the description of one ATC patient who showed a spectacular treatment response upon giving the mTOR inhibitor everolimus. The patient’s ATC derived from FTC-OV and high density SNP analysis clearly identified NHG in the tumor. The phenomenon of NHG with or without endoreduplication is similar to the pattern that is seen by Zheng et al, although the terminology to describe this is slightly different. In 2014 we also showed that in a subset of ACC and parathyroid carcinoma NHG and endoreduplication can be seen, especially in tumors with oncocytic metaplasia (Corver et al., 2014). As seen by Zheng et al the “allelic states” (Corver et al., 2008) in ACC indicated the presence of more chromosomal breakpoints than seen in FTC. In fact similar observations of NHG or widespread chromosomal loss with endoreduplication of the complete genome has been described in peripheral chondrosarcomas (Bovee et al., 2000) and a subset of childhood acute lymphoblastic leukemia (Holmfeldt et al., 2013) and other uncommon cancers (Mandahl et al., 2012). It is intriguing what is eventually responsible for the widespread chromosomal loss with or without endoreduplication. In our model we proposed a stepwise process that might be related to metabolic processes, something that still needs to be proven. It might now be a step forward in understanding the underlying biology of endoreduplication/WGD with the observation of Zheng et al. that TERT expression is higher in the WGD group of ACCs. In conclusion the combined analysis of different tumor types with massive chromosomal loss with subsequent WGD might lead to further insights underlying this remarkable process.
References:
Zheng S, Cherniack AD, Dewal N, Moffitt RA, Danilova L, Murray BA, Lerario AM, Else T, Knijnenburg TA, Ciriello G, et al. (2016). Comprehensive Pan-Genomic Characterization of Adrenocortical Carcinoma. Cancer Cell. 29(5):723-36.
Corver, W. E., Ruano, D., Weijers, K., den Hartog, W. C., van Nieuwenhuizen, M. P., de Miranda, N., van Eijk, R., Middeldorp, A., Jordanova, E. S., Oosting, J., et al. (2012). Genome haploidisation with chromosome 7 retention in oncocytic follicular thyroid carcinoma. PLoS ONE 7, e38287.
Wagle N, Grabiner BC, Van Allen EM, Amin-Mansour A, Taylor-Weiner A, Rosenberg M, Gray N, Barletta JA, Guo Y, Swanson SJ, et al.(2014) Response and acquired resistance to everolimus in anaplastic thyroid cancer. N Engl J Med. 371(15):1426-33.
Corver, W. E., van, W. T., Molenaar, K., Schrumpf, M., van den Akker, B., van, E. R., Ruano, N. D., Oosting, J., and Morreau, H. (2014). Near-haploidization significantly associates with oncocytic adrenocortical, thyroid, and parathyroid tumors but not with mitochondrial DNA mutations. Genes Chromosomes Cancer 53, 833-844.
Corver, W. E., Middeldorp, A., Ter Haar, N. T., Jordanova, E. S., van Puijenbroek, M., van Eijk, R., Cornelisse, C. J., Fleuren, G. J., Morreau, H., Oosting, J., and van Wezel, T. (2008). Genome-wide allelic state analysis on flow-sorted tumor fractions provides an accurate measure of chromosomal aberrations. Cancer Res 68, 10333-10340.
Bovee, J. V., van Royen, M., Bardoel, A. F., Rosenberg, C., Cornelisse, C. J., Cleton-Jansen, A. M., and Hogendoorn, P. C. (2000). Near-haploidy and subsequent polyploidization characterize the progression of peripheral chondrosarcoma. Am J Pathol 157, 1587-1595.
Holmfeldt, L., Wei, L., Diaz-Flores, E., Walsh, M., Zhang, J., Ding, L., Payne-Turner, D., Churchman, M., Andersson, A., Chen, S. C., et al. (2013). The genomic landscape of hypodiploid acute lymphoblastic leukemia. Nat Genet 45, 242-252.
Mandahl, N., Johansson, B., Mertens, F., and Mitelman, F. (2012). Disease-associated patterns of disomic chromosomes in hyperhaploid neoplasms. Genes Chromosomes Cancer 51, 536-544.
Hans Morreau, also on behalf of Willem Corver and Tom van Wezel, Dept of Pathology, Leiden University Medical Center The Netherlands Email: j.morreau@lumc.nl.
Note: This comment was also posted on the website of Cancer Cell attached to the manuscript of Zheng et al 2016. This will however not be visible in the PubMed domain. I do not have conflicts of interest to declare.
On 2016 Jun 21, Dinesh Barupal commented:
Some links to DBs for getting pesticides lists in the supplement file are broken/not working - below are the updated links -
On 2016 Jun 16, thomas samaras commented:
The increase in BMI is certainly puzzling in view of a recent study by Aune et al.(2016) that found a BMI of 20-22 was best for non-smokers over the long term. The study involved a meta-analysis of 230 studies involving 30 million subjects and almost 4 million deaths. When BMI increases, most biological factors get worse, starting for a BMI of less than 21(Lamon-Fava). This includes increases in blood pressure, total cholesterol, LDL, TG and lower HDL. Other studies have found that insulin and IGF-1 increase with BMI. Higher levels of insulin and IGF-1 have been found to be inversely related to longevity. Also, APO-B increases with BMI and is related to a higher risk of heart disease. In addition, APO-A decreases with increasing BMI and this trend is associated with increasing heart disease.
On 2017 Mar 20, Andrew Ibrahim commented:
Here is the visual abstract: https://twitter.com/AnnalsofSurgery/status/768877921406681088
On 2017 Jun 30, Pertti Hakkinen commented:
The authors and readers might be interested in the following publications (these focused on research conducted in the United States):
1) Neil, N., Slovic, P., and Hakkinen, P.J. 1993. Mapping consumer perceptions of risks. Chemical Manufacturers Association, Washington, D.C.
2) Hakkinen, P.J. and Leep, C.J. 1996. Industry’s use of risk, values, perceptions, and ethics in decision making. In: Handbook for environmental risk decision making. Values, perceptions, & ethics. C.R Cothern, ed. CRC Lewis Publishers, Boca Raton, FL.
This is an excerpt from the 1996 publication: “How can risk perceptions of chemical and consumer products be assessed? In 1993, the Chemical Manufacturers Association published a document based on research sponsored by P&G. This document demonstrates how consumer perceptions of risk can be quantified and examined, presents examples of consumer risk perception data for a wide range of consumer products, and discusses the importance of assessing and considering perceptions of risk as part of the development of a product. The 47 household chemical products covered in this document are shown in Table 2. Each of these products was evaluated for the 15 topic areas shown in Table 3.”
On 2016 Jul 05, Tom Kindlon commented:
A (science) blogger has written about why he feels these results might be relevant to people with ME/Chronic Fatigue Syndrome* in this: "The Exercise Intolerance in POTS, ME/CFS and Fibromyalgia Explained?" http://www.healthrising.org/blog/2016/07/04/exercise-intolerance-fibromyalgia-chronic-fatigue-pots-explained/
*The National Academy of Medicine (previously called Institute of Medicine) after reviewing the evidence suggested that Chronic Fatigue Syndrome be renamed Systemic exertion intolerance disease (SEID) last year.
On 2016 Aug 01, Gary Goldman commented:
The study by Kawail et al demonstrates that HZ incidence has increased over a 60 year period from “0.76 per 1000 person-years (PY) (95% confidence interval [CI], .63–.89) in 1945–1949 to 3.15 per 1000 PY (95% CI, 3.04–3.26) in 2000–2007” with a 2.5% per year rate over the time period after adjusting for age and sex (adjusted incidence rate ratio, 1.025 [95% CI, 1.023–1.026]; P < .001). [1] The authors do not provide an explanation for this increase, yet state, “This increase is unlikely to be due to the introduction of varicella vaccination….”
Unfortunately, Kawail et al do not report details of how widespread the uptake of varicella vaccine was in Olmstead County during 2000-2007. In fact, there were still substantial outbreaks of varicella during 2000 and 2001 (with a period of 9 months that the vaccine was unavailable). Minnesota did not require varicella vaccination for students entering kindergarten and 7th grade who lacked proof of having had chickenpox until 2004. In 1999, based on a CDC National Immunization Survey, varicella vaccine coverage was 61.6% among children aged 19-35 in Minnesota. [2] Approximately 50% of children aged less than 10 years must be vaccinated to effectively reduce exogenous boosting to initiate a noticeable increase in HZ incidence. Likely, only during 2003 through 2007 was varicella vaccination sufficiently widespread in Olmstead County to begin influencing (increasing) HZ incidence rates.
It was first hypothesized by Hope-Simpson [3] that “The peculiar age distribution of zoster may in part reflect the frequency with which the different age groups encounter cases of varicella and because of the ensuing boost to their antibody protection have their attacks of zoster postponed” [3]. However, prior to 1999, only limited studies existed that supported this hypothesis. For example, in 1983, Arvin et al. noted a boost in cell-mediated immunity (CMI) in 71% of adults who were exposed to varicella patients in the family [4]. In 1995, Terada et al. reported that Japanese pediatricians aged 50–69 who received multiple VZV exposures, demonstrated HZ incidence rates one-half to one-eighth that of the general population [5]. Gershon et al. in 1996 showed an immunologic boost that reduced the risk of HZ among leukemic children by reexposure to VZV, either by vaccination or by close exposure to varicella [6]. A 1998 study by Solomon found that pediatricians who had a greater incidence of exposure to VZV had lower rates of HZ than psychiatrists who had the lowest VZV exposure rates [7]. More recent studies by Thomas et al. [8] and Salleras et al. [9] have also demonstrated that re-exposure to VZV via contacts with children was associated with reduction in the risk of HZ in adults. In more recent times, during the varicella vaccination era, additional studies, including those derived from the Antelope Valley Varicella Active Surveillance Project (VASP) in a community with widespread varicella vaccination, have emerged that have provided data that validates Hope-Simpson’s hypothesis. [10-12]. In support of the VASP trends [10-11] between 2000 and 2006, a more recent 2013 study by Guzzetta et al suggests that each episode of exposure to VZV increases protection against HZ and that ‘‘this mechanism may be critical in shaping HZ patterns’’. [12]
Thus, while Kawail et al is unable to provide an explanation for the mean 2.5% annual increase in HZ incidence over six decades, one logical hypothesis for the increase is related to societal changes. Living conditions have gradually changed during the past six decades from multiple generations of families residing in a single household, to more independent living as children aged 18 years and over have increasingly moved out of their parent's home and elderly and sedentary individuals are placed in care facilities. Interesting, a Census Bureau reports, “In 2010, there were 40.3 million people aged 65 and above, comprising 13% of the overall population. (This total is 12 times the number it was in 1900, when this group constituted only 4.1% of the population.)” [13] Thus, due to changing trends in society structure and increases in the elderly population, parents and grandparents generally have fewer opportunities for exogenous boosting of their cell-mediated immunity due to reduced contact to children infected with varicella—giving rise to the steady increase in HZ incidence—especially in decades prior to the varicella vaccination era.
In the Antelope Valley VASP, varicella vaccination was widespread in the community with approximately 50% of children aged <10 years vaccinated by 2000. By 2000, exogenous exposures to natural varicella (producing immunologic boosts) were dramatically reduced, especially after a marked decline in varicella seasonality in 1999. After 2 years of active HZ surveillance (2000 and 2001), the number of HZ case reports had maintained or increased in every adult age category except elderly adults aged 70 years and older. Using the paired t-test, there was a statistically significant (p < 0.042; t = 2.95, dF = 4) 28.5% increase in HZ case reports from 158 to 203 from 2000 to 2001 for the population aged 20–69 years. [10] Moreover, the 2007 VASP annual summary to the CDC presents data (not ascertainment corrected) demonstrating a statistically significant increase in HZ incidence rates, from 3.90 to 4.70 per 1,000 p-y in from 2006 to 2007 among adults aged 50 years and older. [11]
Finally, there is a further worrying reason to suspect future increases in HZ incidence. When a child is administered the varicella (or Oka-) strain and then later is exposed to either a child with natural chickenpox or an adult with herpes zoster (almost always due to the reactivation of the natural or wild-type strain), the child harbors two similar but possibly sufficiently heterologous strains--that now are both subject to reactivation. This could potentially double the chances for the reactivation of herpes zoster, or at a minimum, at least increase the chances for reactivation of shingles relative to the pre-varicella vaccination era. [14]
[1] Kawai K, 2016 [2] http://www.cdc.gov/vaccines/imz-managers/coverage/nis/child/index.html [3] HOPE-SIMPSON RE, 1965 [4] Arvin AM, 1983 [5] Terada K, 1995 [6] Gershon AA, 1996 [7] Solomon BA, 1998 [8] Thomas SL, 2002 [9] Salleras M, 2011 [10] Goldman GS, 2013 [11] Goldman GS, 2014 [12] Guzzetta G, 2013 [13] Raphel A. Trends and statistics relating to U.S. seniors, elderly: Census Bureau 2014 report. August 5, 2014. http://journalistsresource.org/studies/society/public-health/trends-statistics-relating-us-seniors-elderly-census-bureau-2014-report [last accessed 07/26/2016] [14] Weinmann S, 2013
On 2017 May 25, Cicely Saunders Institute Journal Club commented:
This paper was discussed on 2.5.17, by students on the KCL Cicely Saunders Institute MSc in Palliative Care
The paper explores the experiences of cleaning staff in a hospital setting on various wards. We thought it was a very interesting and thought-provoking topic which had not been examined in depth before. The study uses a mixed methods approach with qualitative interviewing and focus groups, followed by a questionnaire study for quantitative data.
The study gives an interesting perspective of staff who have regular and prolonged contact with patients, but are little studied in this regard. It prompted discussion regarding the input that non clinical staff can give.
Recruitment for the qualitative part was difficult leading to low numbers and saturation not being reached. The recruited participants were all female and many were non-native speaking.
According to the COREQ criteria, we would have liked more information about who the researchers were, their relationship with the participants, the settings of the interviews and whether this could influence their responses.
It would also have been beneficial to understand how the questionnaire was developed from the themes identified in the qualitative part of the study and of any attempt at validation etc. We were unclear if they meant to use this questionnaire for future research or service implementation, like for instance psychological support to "non-clinical" staff.
We noticed the long time interval between the study taking place (questionnaires were distributed in 2008) and publication, and it would be useful to know the reasons behind this and if there was any follow up research in the intervening years.
Future research would be interesting in other settings: for example in a hospice where patients die more frequently than various hospital areas or among other components of "non clinical" staff, as for instance secretaries or volunteers.
Anna Oriani, Sarah Hanrott and Konstantina Chatziargyriou
On 2016 Nov 22, Alex Vasquez commented:
Correspondence on this article has been published but as of 22 Nov 2016 (more than a month after publication on 19 Oct 2016) has not been appropriately linked; the citation is as follows: Vasquez A. Correspondence regarding Cutshall, Bergstrom, Kalish's "Evaluation of a functional medicine approach to treating fatigue, stress, and digestive issues in women.” Complement Ther Clin Pract. 2016 Oct 19 doi: 10.1016/j.ctcp.2016.10.001 http://www.ctcpjournal.com/article/S1744-3881(16)30107-4/abstract
Critiques of this article are described in the following paragraphs.
Description of treatments: The authors state that treatments were “personalized” but provide little data on how or why the treatment was allocated other than to divide patients into two groups for the “adrenal protocols” which are faintly outlined in the footnotes; no dosages are provided as all of the product formulations appear to be proprietary. Table 1 which outlines the “adrenal protocols” shows the treatments to be remarkably similar between the high and low salivary cortisol groups. The authors administered “DHEA drops” and “pregnenolone drops” but the varying dosages of the hormones, administered three times each per day, are not provided. Authors need to provide the actual dosages of all treatments, including hormones.
Use of hormonal therapy: The authors need to have described the laboratory methodology. Salivary DHEA levels were found to increase, decrease, and change unreliably, thus rendering these results worthless. Table 5 of the results shows that Cortisol/DHEA ratio started at 5.2 and resulted at 12 at the end of the study. Consistently throughout the medical literature, respectively higher levels of cortisol and lower levels of DHEA are causatively associated with insulin resistance, intra-abdominal obesity, hippocampal atrophy, and bone loss[1,2]; to the contrary of the bulk of the peer-reviewed literature, these authors present these results as beneficial changes. The “DHEA drops” and “pregnenolone drops” are not described either in dosage or formulation. Pregnenolone and DHEA are mood-elevating neurosteroids[3-5]. DHEA administration raises androgens and estrogens[6] which promote cancers[7,8]. The authors should have described appropriate serologic and clinical follow-up, risk considerations, and limits to duration of treatment. By failing to describe the dose of the steroid hormones used, the authors present that these hormones can be used without regard to dosage or duration; this presents a potential hazard by modeling unsafe use.
Accurate description of functional medicine: The authors define functional medicine as “The functional medicine model is focused on restoring optimal functioning of 3 body systems: hormonal, digestive, and detoxification.” The authors’ sweeping statement “Restoring these 3 body systems has positive effects on stress, energy, fatigue, digestive issues, and quality of life” has no citations. The definition of functional medicine provided by these authors is discordant with more authoritative descriptions published by the Institute for Functional Medicine[9] and International College of Human Nutrition and Functional Medicine.[10] The authors use the terminology “adrenal and digestive cleanse protocols” without definition, justification, or citation. In scientific publications, unique statements require substantiation and citation.
Controlling for external influences: The authors describe the dates of the study as “September 2014 through April 2015” but did not control for vitamin D levels and sunlight exposure which are known to affect mood and cognition[11,12]. The severity of depression, pain, and “functional disorders” has been reported to vary seasonally with exacerbations in fall and winter and alleviation in spring and summer.[13,14] The “lifestyle and nutritional counseling” included a 1-hour in-person coaching session at the start of the study, followed by various telephone contacts and “online group sessions” including “nutrition coaching and follow-up with diet compliance.” Patients may have felt better simply as a result of season change or social contact.
Disclosure of commercial interests: The authors deny conflict of interest and that “The study sponsors had no involvement in the study design; in the collection, analysis, and interpretation of data; in the writing of the manuscript; or in the decision to submit the manuscript for publication.” However, the authors do not disclose the identity of the sponsors. One of the authors (Kalish) is a consultant/speaker for a large distributor of nutritional supplements[15] and also a consultant/speaker/endorser of the laboratory used in this study[16]; these relationships are not disclosed in the article. According to the authors' interview[17] and press release[18] regarding their publication, they provide "training in functional medicine" and seminars related to the treatments used in this study. The authors fail to provide the identity of the study sponsors and the nature of the conflict(s) of interest.
Fecal microbiologic testing; antimicrobial treatments: The authors fail to detail the laboratory methodology for the microbiologic testing. Per the footnote describing the mastic product, the authors do not clearly describe the identity nor the ingredients of this treatment.
This clinical trial was not registered: The authors make no mention of having registered this clinical trial, and no record of the trial is available at https://clinicaltrials.gov/.
While the functional medicine approach to healthcare is science-based, eclectic, and effective[19], the field is not benefited by poorly conducted research, especially that which does not accurately reflect the practice, which employs poor methodology, and/or which uses steroid hormones without appropriate risk/benefit considerations. This publication is not an accurate representation of the clinical practice of functional medicine. The study design and description present several errors, the methods are not reproducible, the treatments were not sufficiency described, and the study cannot be either validated or refuted scientifically due to design flaws and/or inadequate description of treatments.
[1] Brown et al. Biol Psychiatry. 2004 Jan 1;55:1-9 [2] Ferrari et al. Eur J Endocrinol. 2001 Apr;144:319-29 [3] Brown et al. Neuropsychopharmacology. 2014 Nov;39:2867-73 [4] Fung et al. J Autism Dev Disord. 2014 Nov;44:2971-7 [5] Gaby AR. Alt Med Rev 1996;1:60-69 [6] Arlt et al. J Clin Endocrinol Metab. 1999 Jun;84:2170-6 [7] Folkerd E, Dowsett M. Breast. 2013 Aug;22 Suppl 2:S38-43 [8] Stoll BA. Eur J Clin Nutr. 1999 Oct;53:771-5 [9] Vasquez A. Reprint from Textbook of Functional Medicine: Web-like interconnections of physiological factors. Integrative Medicine 2006 April;5:32-37 [10] Vasquez A. Textbook of Clinical Nutrition and Functional Medicine. ICHNFM.ORG; 2016:134-146 [11] Kent et al. Environ Health. 2009 Jul 28;8:34 [12] Vieth et al. Nutr J. 2004 Jul 19;3:8 [13] Schlager et al. Compr Psychiatry. 1995 Jan-Feb;36:18-24 [14] Schlager et al. Br J Psychiatry. 1993 Sep;163:322-6 [15] emersonecologics.com/drkalish and emersonecologics.com/Webinars-DrKalish. June 10, 2016 [16] "BioHealth Adrenal Testing – Dan Kalish", "Premenopause Hormone Profiles: In Brief – Dan Kalish", and "Functional Lab Testing – Dan Kalish". biohealthlab.com/multimedia-archive/. June 17, 2016. [17] Functional Medicine Plan Treats Fatigue, Stress and Digestive Issues in Women. medicalresearch.com/author-interviews/functional-medicine-plan-treats-fatigue-stress-and-digestive-issues-in-women/25012. June 23, 2016. [18] Research Conducted with Mayo Clinic Practitioners and Kalish Institute Confirms Efficacy of Functional Medicine. businesswire.com/news/home/20160524005553/en/ June 23, 2016. [19] Vasquez A. Inflammation Mastery, 4th Edition. http://www.ICHNFM.ORG 2016 Dr Vasquez, Director ICHNFM and Consultant to Biotics Research
On 2016 Sep 27, James Tsung commented:
Link to Case Videos: https://youtu.be/BnCqMV_ETtM?list=PLHg2xyua_Kjtk47mTO0qK-t0q-8oRLZzs
On 2016 Jun 17, Lydia Maniatis commented:
(This is a response to the abstract only). The authors conclude that perception of distance ratios is relatively accurate, but this result is purely contingent on the stimuli. Perception of relative distances can be more or less accurate. The outcome depends strictly on the structure of the retinal stimulus and the rules of organisation built into the visual system. By choosing a particular physical stimulus to project to the retina, the authors produced relatively accurate outcomes; by choosing a different one, they could have produced very different outcomes. Pictorial images, for example, can obviously produce very inaccurate perception of relative distances. Unless the authors explicitly discuss the relationship between the structure of the environment and the structure of the retinal projection, they haven't added anything to the conversation.
On 2016 Jul 27, Duke RNA Biology Journal Club commented:
This is a summary of a journal club discussion:
This is one of four articles using similar imaging techniques to study translation in living cells published at the same time. These publications add to the growing number of techniques used to image translation such as mature fluorescent proteins Yu J, 2006, TRICK Halstead JM, 2015, and RNA-binding protein/mRNA co-fluorescence Wu B, 2015. The technique presented in this article is similar to the last except that it uses Suntag to image the nascent chain and PP7 aptamers on the mRNA. The colocalization of the two represents active translation in polysomes.
The technique is novel because co-localization is detected as the protein is translated. This brings fluorescent V4-peptide antibodies into concentrated foci at a single point, and can thus be used to follow multiple rounds of translation. Because of this, only detection of the translated protein is needed and indeed, past the first figure, the mRNA fluorescence is not shown. Fast changes in translation can be detected as shown using the ATF4 ORF construct translational response to stress shown in Figure 4 with the possibility of extending the time of tracking to hours by anchoring the mRNA Yan X, 2016 or using fast 3D imaging techniques. One unusual observation the authors made was the vast heterogeneity of transcript translation within a single cell; at any given time only a subset of the transcripts undergo translation and translation rates may vary depending on as yet unknown factors. A related observation is the diffusion of polysomes within the cell: polysomes translating cytosolic transcripts have slower diffusion rates in the perinuclear region of the cell compared to the cytoplasm. This could be due to the restrictive architecture of a membranous area but the exact mechanism remains unknown. A second surprising observation indicates mRNAs that have begun translation and are associated with polysomes can be transported in dendrites, contrary to earlier reports Besse F, 2008. However, the authors cannot detect if translation is temporarily stalled during transport.
While this technique makes substantial findings in the area of single transcript translation behavior, there are limitations. All in all, these images are dots that respond to translation inhibitors, meaning the resolution is not good enough to detect codon resolution and should be coupled with other techniques to verify observations and determine their mechanism. Additionally, since detection of the nascent chain wouldn’t be detected until the majority of the V4 peptides were translated, initiation would be overlooked; however, TRICK is an existing technique for studying the first round of translation.Our main criticism with this technique is the extensive construct engineering that must be performed which raises concerns over disturbing the mRNA and protein functions from both the PP7 aptamers, the Suntag peptides and an ornithine decarboxylase tag to facilitate rapid degradation of the protein. These engineering steps add over 2 kb to the original gene. Additionally, an antibody against the Suntag and a fluorescent PP7 coat protein must be expressed in the cytosol. While the constructs studied did not cause harm to the cell, each construct of interest must be tested individually. Along this line, while there is the possibility to multiplex by changing the aptamer loop or peptide-antibody combination, it would be difficult to multiplex above two individual transcripts. Thus large-scale studies involving individual translation dynamics of mRNA subsets would remain time consuming and technically challenging.
A quick comparison with the three other papers show agreements among all of them Iwasaki S, 2016 however, there is a great opportunity to learn by reading the papers to compare experimental approaches of three groups. We look forward to see what novel findings this technique uncovers as it becomes adopted in different laboratories.
On 2016 Jun 22, Lydia Maniatis commented:
Reading the title of this article, one might get the idea that we learn the 3D structure of objects from 2D views. Looking at it a little more closely, we might experience some confusion as to the distinction being made between “structure” and “shape.” Isn't it a little tautological to say that grasping structure depends on grasping shape? And what do they mean by “format”?
In fact, the idea that we learn 3D structure from 2D views, which the authors want us to take for granted, is false. But isn't it the case that “a large body of research shows that viewpoint-invariant recognition is learned by viewing 2-D examples of an object (Bulthoff, Edelman, & Tarr, 1995; Hayward & Tarr, 1997; Tarr, Williams, Hayward & Gauthier, 1998)”? In fact, the references cited in no way support this bold claim. One of them is irrelevant, and the other two make claims that are highly qualified, tentative, and in need of corroboration. Given that nothing more definite seems to have developed in the two decades or so since these hopeful publications, the relevant body of research seems neither large nor solid. Another claim is also unsupported by its accompanying citation: “It is thought that during learning people use structural information in the 2-D image to infer the 3-D structure of the object (Nakayama, Shimojo, & Silverman, 1989).” In fact, the cited article addresses issues of figure ground segmentation, and not 3-D shape. Its text doesn't even include the terms 3-D, structure, or shape. So the authors are giving readers a false impression that their project is on empirically solid ground.
In fact, the claim that 3-D structure is learned from 2-D views has long been known to be false on logical and empirical grounds. In a more general sense, the idea that we either can or do learn to perceive in 3-D from 2-D experience is not defensible. No one has to learn to see 3-D objects; it happens automatically. “Newborns can recognize...the same rectangle placed at different slants.” (http://nwkpsych.rutgers.edu/~alan/Gilchrist_NN_2003.pdf). Individual 2D views produce 3D percepts; these percepts may or may not be veridical, but knowledge does not affect the basic process. Each view entails its own necessary 3D perceptual response based on shape rules that assume characteristics such as convexity. View “x” will not produce a different shape percept even if we know the one we see is false, just as a 3D-looking flat image does not look flat even though we know it is. We can't learn to see a Necker cube as flat, from no matter how many angles we inspect it.
The idea that we learn 3-D structure also fails for logical reasons. How does a collection of 2D images, a pack of flat cards, in effect, become a - qualitatively different - 3D percept? On what basis is this conversion made? Is each new sample - of the infinite number of possible samples - a new piece of information? Multiple 2D views don't resolve the fundamental ambiguity of the projection/3D percept relationship. The Ames window is not correctly seen despite a complete set of views around an axis. Shape ambiguity is resolved on the basis of rules of organization, not on the basis of collecting ever new views which are themselves ambiguous. (Even when we know a shape is unchanging, the necessary link between individual views and 3D percepts can produce a changing percept, e.g. https://www.youtube.com/watch?v=jRqYkQz0G-g). Furthermore, how or when does the visual system draw the conclusion that a series of projections, such as are shown to subjects in the task chosen by these authors, are projections of the same single and unchanging 3D shape?
Don't the study's subjects exhibit learning of 3D structure form 2D views? If they did it would be a kind of miracle, but the results don't require us to believe in miracles. Subjects' (rather poor) performance in no way requires that their exposure to a series of views of a very strangely-shaped object produce a consistent, learned, 3D percept. Memory for details can do the trick (a single sharper angle, for example, in one of two objects to be discriminated can allow them to eliminate it without having grasped the whole or even part of the 3D shape). And a lot of the time they are just guessing.
A final thing that should be clear to researchers with some knowledge of perceptual phenomena is that the results of this task are totally contingent on the shapes used. The authors here crudely divide objects into novel and familiar. But whether projections of a single, novel object consistently produce the same 3D percept (which, as we saw, applies to some objects viewed by infants) depends on the shape of the object. There is no absolute expectation of constancy. Different, more rational (as far as the expectations of the visual system) shapes would have produced better outcomes than the random ones used here; others may have produced worse. The numbers here are meaningless because the authors haven't analyzed the role of shape.
As for the finding with regard to “format,” it is well-known that both line drawings and chiaroscuro drawings can both produce good 3D shape percepts, and that silhouettes tend to look flat, lacking any indication of relief. If the results of this study had not borne this out, these facts would have remained intact.
In sum, the results of this study can be interpreted as consistent with a false (on the basis of logic and experiment) premise because the task was not designed to distinguish between this (im)possibility and more plausible (and theoretically uninteresting) alternatives.
It would be nice if people doing research in perception spent a little time actually learning the basics.
p.s. In their discussion, Tian et al: "suggest that stereo provides a behavioral benefit only if it resolves ambiguity in the interpretation of the 3-D structure of objects that cannot be resolved from other sources of information."
This is very similar to the titular claim of an earlier article by Pizlo, Li, Steinman (2008): "Binocular disparity only comes into play when everything else fails; a finding with broader implications than one might suppose."
On 2016 Sep 15, Kelly Drew commented:
Thank you for this comprehensive contribution to our understanding of pre-hibernation remodeling in the Syrian hamster. Our studies in the arctic ground squirrel suggest that pre-hibernation remodeling and torpor onset involves increased sensitivity of A1 adenosine receptors with a subsequent inhibition of thermogenesis. See Olson et al., Circannual rhythm in body temperature, torpor, and sensitivity to A₁ adenosine receptor agonist in arctic ground squirrels. J Biol Rhythms. 2013 Jun;28(3):201-7. doi: 10.1177/0748730413490667. PubMed PMID: 23735499; PubMed Central PMCID: PMC4423736.
and Jinka et al., 2011 Season primes the brain in an arctic hibernator to facilitate entrance into torpor mediated by adenosine A(1) receptors. J Neurosci. 2011 Jul 27;31(30):10752-8. doi: 10.1523/JNEUROSCI.1240-11.2011. PubMed PMID: 21795527; PubMed Central PMCID: PMC3325781.
On 2017 Aug 25, Robert Badgett commented:
The website referred to in this letter for calculating the time in therapeutic range for the population of patents at a clinical site is http://qitools.github.io/
On 2016 May 13, thomas samaras commented:
This study certainly refutes the earlier studies reporting that some overweight was healthy. The World Cancer Research Fund Report (2007)recommended a BMI as low as possible within the normal range of 18.4-24.9. Fontana and Hu (2014) recommended a BMI of 20-21. Also, Hosegood found the optimum BMI for women in S. Asia was about 18.5-19.5. In addition, there are many biological parameters that become worse with increasing BMI from the low end of the BMI range. A few are listed below. Most involve undesirable increases in levels of the following parameters: Homocysteine, C-Reactive Protein, Sex Hormone Binding Globulin (higher is better), left ventricular mass, blood pressure, adiponectin (higher is better), mTOR, total cholesterol, low-density lipoprotein, high-density lipoprotein (higher is better), IGF-1, insulin, glucose, ApoB, and ApoA-1 (higher is better).
All of these have been found to increase mortality due to one or more of these causes: CVD, cancer, type 2 diabetes and all-cause mortality. Therefore, it is hard to see how higher levels of BMI have health benefits with the exception of special cases, such as frail, elderly people who lack adequate nutrition, suffer from digestive problems or have a chronic illness.
On 2016 Jun 26, David Smith commented:
All statistical maps derived from the re-analysis with GingerALE 2.3.6 have been uploaded to the NeuroVault repository: http://neurovault.org/collections/1406/
We emphasize that the re-analysis confirmed that all of our key claims are valid.
On 2016 Jul 22, Christopher Tench commented:
Excellent. This is science!
On 2016 Jun 24, David Smith commented:
Thanks for pointing this out. Our original analyses used a conservative threshold, and we have confirmed that our key results hold with a cluster-level FWE of p = 0.05, as implemented in the latest release of GingerALE (v2.3.6).
Within the main text, two clusters failed to replicate in our new analyses. First, the inferior lateral occipital cortex (iLOC) cluster in Figure 3C (amygdala seed with emotion studies) did not pass cluster-level FWE of p = 0.05 (with a cluster-forming thresholds of p = 0.001 or p = 0.005). Second, the dorsolateral prefrontal cortex (DLPFC) cluster in Figure 3B (DLPFC seed with cognitive control studies) did not pass cluster-level FWE of p = 0.05 (with a cluster-forming thresholds of p = 0.001 or p = 0.005). Additionally, our re-analyses failed to confirm the findings in Supplemental Figure 2.
We will reach out to the journal (HBM) to address these issues and indicate that our key claims were not affected by the bug in GingerALE (which was corrected after our article was accepted).
Thanks again for bringing this to our attention.
On 2016 Jun 14, Christopher Tench commented:
This article uses a version of GingerALE (2.3.3) that has a known bug, which produces false positive results. The bug was fixed at 2.3.6. There is no evidence of statistical significance.
On 2016 Jun 21, Andrew W Swartz commented:
Based upon post hoc questionnaire analysis, Shoag et al. claim that the PLCO was confounded by more prostate cancer (PCa) screening in the control group than in the intervention group. This seems highly unlikely because it is incompatible with other more objective outcomes of this trial.
First, the cumulative incidence plots for PCa [1,2] are consistent with comparison of a screened group to an unscreened (or at least less screened) group. During the first four years of screening the intervention group was diagnosed with PCa at a rate 48% greater than the control group [2]. Then, after the intervention period, the rate of prostate cancer diagnosis in the intervention group drops to that of the control group and the lines go parallel, implying similar screening exposure from that point forward. These are the expected plot shapes for screening with overdiagnosis. The Shoag et al. claim directly implies that the group with the overdiagnosis (the intervention group) was the LEAST screened. This seems implausible, as it would be contrary to all screening theory and experience.
Second, the Shoag et al. claim is also incompatible with the previously reported tumor stage-shifting. The intervention group had more favorable staging than the control group [1,3]. Though the magnitude of this effect is smaller in the PLCO than other PCa screening trials, the direction still favors the intervention group. It is highly unlikely that the intervention group would have better tumor staging if the control group had more screening.
The overdiagnosis and tumor stage-shifting are objectively measured outcomes which indicate that there was more screening in the intervention group than the control group. Therefore Shoag et al. have more likely discovered a bias in the questionnaire answers [4,5] than a flaw in the PLCO. We should also consider the possibility that this is simply the product of the “researcher degrees of freedom” which inherently accompany reanalyses[6].
Andrew W. Swartz MD, Emergency and Family Medicine, Yukon-Kuskokwim Health Corporation, Bethel, Alaska
1] Andriole G, Grubb R, Buys S, Chia D, Church T, Fouad M, et al. Mortality results from a randomized prostate-cancer screening trial. New England Journal of Medicine. 2009;360:1310–9. Andriole GL, 2009 Full Text
2] Andriole GL, Crawford DE, et al. Prostate Cancer Screening in the Randomized Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial: Mortality Results after 13 Years of Follow-up. J Natl Cancer Inst. 2012;104:125–132. Andriole GL, 2012 Full Text
3] Ilic D, Neuberger MM, Djulbegovic M, Dahm P. Screening for prostate cancer. Cochrane Database of Systematic Reviews 2013, Issue 1. Art. No.: CD004720. DOI: 10.1002/14651858.CD004720.pub3. Ilic D, 2013
4] Hebert JR, Clemow L, Pbert L, Ockene IS, Ockene JK. Social desirability bias in dietary self-report may compromise the validity of dietary intake measures. Int J Epidemiol. 1995;24(2):389-98. Hebert JR, 1995
5] Adams SA, Matthews CE, Ebbeling CB, et al. The Effect of Social Desirability and Social Approval on Self-Reports of Physical Activity. Am J Epidemiol. 2005;161(4):389-98. doi:10.1093/aje/kwi054. Adams SA, 2005 Full Text
6] Christakis DA, Zimmerman FJ. Rethinking reanalysis. JAMA. 2013;310(23):2499-500. doi: 10.1001/jama.2013.281337. Christakis DA, 2013
On 2016 Jul 17, Lise Bankir commented:
Thank you Dr Pontzer for these interesting comments.
I apologize for saying that you forgot "cooking" since you had indeed mentioned it, briefly. I may have put too much emphasis on cooking.
Actually, I was very impressed by this brillant TED conference. But I am not a specialist of metabolism and energy needs, and I probably did not appreciate well the relative importance of different factors.
On 2016 Jul 05, Herman Pontzer commented:
Thank you for the comment. We haven't forgotten about the importance of cooking: we include it among the critical human adaptations that make more energy available (reference 25, Carmody et al. 2011). In the penultimate paragraph of the main text, we write:
"...the adoption of cooking<sup>25</sup> ... effectively increase[s] the net energy gained from foraging, and may have had an essential role in the evolutionary expansion of the hominin energy budget."
However, as we discuss in the paper, increased food energy intake is necessary but not sufficient in accounting for the suite of metabolically costly human traits. To take advantage of the extra calories from cooking (or from other dietary changes that increase the mean calories/gram of food) requires evolved physiological changes to increase the metabolic rate. Previously, the prevailing view of metabolic evolution in humans (and other mammals) assumed that metabolic rates were similar across the hominoids, with no difference in calories/day (accounting for size) across humans and other apes. Our paper shows that humans have undergone an evolutionary increase in metabolic rate that accounts for the (estimated) extra caloric expenditure on brains, reproduction, etc. It will be interesting, in future analyses, to begin parsing the contributions from cooking, dietary changes, and other adaptations to the evolution of human metabolic rate.
On 2016 Jun 24, Lise Bankir commented:
In this interesting paper, the authors explore the mechanisms by which the human lineage has experienced an acceleration in metabolic rate, providing energy for larger brains. I think they forgot an important aspect of human evolution, that is the benefit of COOKING our food. This made food nutrients much more efficient and allowed a better energy supply to our body at a lesser cost. This is very well explained in a TED conference entitled "What is special in the human brain?" by Suzana Herculano-Houzel. Here is the link.
On 2016 Oct 24, Sean Ekins commented:
the attached slides bring this article and this effort upto date http://www.slideshare.net/ekinssean/open-zika-presentation
On 2016 Aug 10, Joaquim Radua commented:
Re: the previous comments, please note that under the null hypothesis of no differences between groups, only 1 out of 20 studies should show differences between groups, which is absolutely not the case when randomizing coordinates or blocks of voxels. Random coordinates and similar approaches, which randomize the location of the findings rather than the individuals between groups, are not a valid way to exactly test this hypothesis. Rather, they are only used to yield approximated p-values that, appropriately thresholded, return a map similar but slightly more conservative than that of FWE-corrected p-values in mega-analyses. Voxel-based meta-analytic methods are young and there is room for improvement, but they are based on evidence.
On 2016 Aug 09, Christopher Tench commented:
This is not a result of confusion, but of the definition of statistical inference. Uncorrected p-values do not control the type 1 error rate. A meta-analysis is performed to improve estimates, and is a statistical problem demanding statistical methods. To threshold at an arbitrary p-value controls neither the FDR nor the FWE, so no quantitative evidence that the results are critical of the null hypothesis is available. You cant know if the results are true positives without doing the full experiment, but meta-analysis is used for the case where the full experiment (mega analysis) has not been done. The one, and only, thing that can be done is to make sure that the null hypothesis is appropriately rejected; arguably the whole point of statistical inference. That requires either FWE or FDR control. Using just random coordinates and an uncorrected p-value will produce results that are apparently publishable, but obviously incorrect. Without any estimate of error rate, there is no quantifiable evidence that the results are meaningful.
On 2016 Aug 01, Joaquim Radua commented:
Re: the previous comment, I think there may be some unfortunate confusion. Raw p-values of current voxelwise meta-analyses have not the same meaning as usual p-values because they are not derived from the usual null hypothesis (“there are no differences between groups”), but from another null hypothesis (“all voxels show the same difference between groups”). Thus, up to the moment one of the only ways to "approximately" know if the results of a voxelwise meta-analysis are neither too liberal nor too conservative is to compare them with the results of a mega-analysis of the same data, and that's what it was done.
On 2016 Jun 13, Christopher Tench commented:
The methods employed provide no control over the type 1 error rate. There is no evidence that the results are statistically significant.
On 2017 Jun 12, Xue-hai Liang commented:
The sequence data related to this paper has been deposited to GEO, with the accession number: GSE99658.
On 2016 May 24, Atanas G. Atanasov commented:
Consumer Health Digest Scientific Abstract based on this article is available at: https://www.consumerhealthdigest.com/general-health/obesity-metabolic-inflammation-and-insulin-resistance.html
On 2017 Feb 01, Martine Crasnier-Mednansky commented:
It is astounding that the authors totally ignore the specific effects of cAMP on the lag phase of the glucose-lactose diauxie. Not only does addition of cAMP eliminate the diauxic lag, it also clearly impairs growth on glucose (see figure 1 in Ullmann A, 1968). An increased level of cAMP triggers a 'leaky' expression of CRP-cAMP-dependent genes and operons (including the lactose operon) thereby affecting growth on glucose. Leaky expression of genes reduces fitness in glucose, with a trade-off for a shorter diauxic lag (or, as in figure 1 mentioned above, a complete elimination of the lag phase resulting in biphasic growth). In the Escherichi coli glucose-lactose diauxie, there is a correlation between the cAMP level and the cost-benefit trade-off.
On 2017 Jun 27, Seán Turner commented:
According to the JCM web site, the type strain of Lutibacter profundi is JCM 30586. Strain JCM 30585 is the type strain of "Mariprofundus micogutta" Makita et al. 2017 [PubMed Id 27766355].
On 2016 May 01, Daniel Tsin commented:
We performed appendectomies using a suprapubic port when the vaginal port access was not feasible in : Tsin DA, Colombero LT, Mahmood D, Padouvas J, Manolas P. Operative culdolaparoscopy: a new approach combining operative culdoscopy and minilaparoscopy.J Am Assoc Gynecol Laparosc. 2001 Aug;8(3):438-41. PMID 11509789
We later did a small series of 4 appendectomies and 7 cholecystectomies. http://www.slideshare.net/tsin/minilaparoscopy-as-an-alternative-to-natural-orifice-surgery-7832507
On 2016 Apr 28, Donald Forsdyke commented:
RNAS ENCODING HBZ AND EBNA1 PROTEINS ARE BOTH PURINE-LOADED
The sensitive quantification of HBZ protein levels in various clinical conditions (1) is a major advance. Unlike other HTLV1 proteins, the latency-controlling HBZ protein is encoded by the antisense strand. Thus, whereas the main-gene-encoding ‘top’ strand of the latent virus is pyrimidine-rich, the complementary, ‘bottom,’ strand that encodes HBZ is purine-rich. Likewise, most genes in Epstein-Barr virus are encoded by pyrimidine-rich strands, but the latency-controlling EBNA1 protein is encoded by a purine-rich strand.
The speculation that this purine-loading militates against the formation of double-stranded RNA and hence dampens the host immune response (2) is in keeping with:
(a) the “extremely low expression and immunogenicity of HBZ in natural HTLV-1 infection,”
(b) the possibility that “the most important actions of HBZ, which are critical to HTLV-1 persistence, are exerted at the RNA level, and not the protein level,” and
(c) the view that “minimized HBZ protein translation is a sophisticated viral strategy for evasion from the host T cell response.”
(1) Shiohama et al. (2016) Retrovirology 13:29 Shiohama Y, 2016
(2) Forsdyke DR (2014) Microbes and Infection 16, 96-103 Forsdyke DR, 2014
On 2017 Jul 03, P Jesper Sjöström commented:
Thanks for your interest in our work. I would like to make the following points:
We did not actually say 'no connections in mature cortex' -- that quote is certainly not lifted from Mizusaki et al Nat Neurosci 2016. We said "In fact, it was recently reported that, surprisingly, pyramidal cells in visual cortex of mature animals do not seem to interconnect at all, neither bidirectionally nor unidirectionally12," where 12 refers to Jiang et al. We thus say that Jiang et al report that PCs do not seem to interconnect, we do not say that there are no PC-PC connections in mature cortex. What Jiang et al state and what our opinion about that statement is, those are different things.
The intention of that passage in Mizusaki et al is to point out that Brunel is using my data from Song et al as a gold standard, but this may or may not be appropriate, since my connectivity data was acquired from a developmental snapshot in time (just after eye opening, typically postnatal day 14-16), whereas Brunel is in fact focussing on the functioning of the mature brain, when circuits are wired up. Our intention was thus to acknowledge that my own data need not be the ground truth, and this has important implications for the validity of the Brunel study. The Tolias study provides an alternative view: "the most compelling and consistent difference across experiments is the age of the animals tested, suggesting that mature cortical circuits are not identical to developing circuits." Such a developmental difference would important in the context of the Brunel study. Again, this is not necessarily my opinion, but as scientists, we have to acknowledge this possibility.
In the Tolias study, they report in Fig S14 that they found precisely zero L5 PC-PC connections even after 150 attempts, which is in stark contrast to my connectivity data presented in Song et al. Indeed, if you do a Chi-squared test for 931/8050 versus 0/150, you will find that this is a highly significant difference. We can debate the accuracy of the Tolias measurement (like they do in Barth et al Science 2016 353:1108, as you point out), but if we do so, we should also debate the accuracy of my measurements in juveniles, as presented in Song et al. While it is true that my data in Song et al is more in line with e.g. Thomson et al Cereb Cortex 2002 than with Jiang et al, the key point in the context of Brunel's theoretical study is that the ground truth is not necessarily well established.
In summary, I certainly believe in my own connectivity data set, and I think Brunel's study provides a very compelling theoretical framework for explaining such connectivity patterns, but I feel obliged to point out a few possible caveats associated with my connectivity data set. Jiang et al provide one such key caveat. I hope this clarifies somewhat.
On 2017 Jun 27, Gabriele Scheler commented:
There is a technical comment from Barthetal2016 in Science which sums this up, and gives more detail as to why the connectivity in Xiangetal2015 is underestimated.
On 2017 Jun 27, Gabriele Scheler commented:
Very surprisingly, Mizusaki etal report: " In fact, it was recently reported that, surprisingly, pyramidal cells in visual cortex of mature animals do not seem to interconnect at all, neither bidirectionally nor unidirectionally (12)." The reference (12) is to Xiangetal2015, where they state: "Finally, the connectivity among mature pyramidal neurons, particularly among L5 pyramidal neurons, was much lower than the connectivity among pyramidal neurons within the same range of intersoma distance in juvenile slices [figs. S13B (average, 91 ± 4μm) and S14 and supplementary text]". The percentages noted in the table S14 range from 4,8% to 0% for ~150 connections tested. Quite clearly, the percentages are low, but to summarize this as 'no connections in mature cortex' does not seem to be adequate. Note that the number of connections tested is not very high and that "evoking unitary excitatory or inhibitory postsynaptic potentials [uE(I)PSPs] on postsynaptic neurons with brief depolarizing current pulses applied in presynaptic neurons" may not be sufficient to map all synaptic connections.
On 2017 Sep 08, Youhe Gao commented:
A strategy named 4F-acts was proposed a few years ago trying to minimize false positives and false negatives. Fast Fixation is necessary to study real-time protein-protein interactions under physiological conditions. Fast formaldehyde crosslinking can fix transient and weak protein interactions. With brief exposure to a high concentration of formaldehyde during the crosslinking, the complex is crosslinked only partially, so that the complex is small enough to be resolved by SDS-PAGE, and the uncrosslinked parts of the proteins can be used for identification by shotgun proteomics. Immunoaffinity purification can Fish out complexes that include the proteins of interest. Because the complex is covalently bound, it can be washed as harshly as the antibody-antigen reaction can stand; the weak interactions will remain. Even if the nonspecific binding can persist on the beads or antibody, it will be eliminated at the next step. To Filter out these complexes, SDS-PAGE is used to disrupt non-covalent bonds, thereby eliminating uncrosslinked complexes and simultaneously providing molecular weight information for identification of the complex. The SDS-polyacrylamide gel can then be sliced on the basis of the molecular weight without staining. All the protein complexes can be identified with the sensitivity of mass spectrometry rather than sensitivity of the staining method. The advantages are the following: (i) The method does not involve tagging. (ii) It does not include overexpression. (iii) A weak interaction can be detected because the complexes can be washed as hard as the antigen-antibody reaction can stand as the complexes are crosslinked covalently. No new covalent bond can form as a false positive result. (iv) The formaldehyde crosslinking can be performed at the cellular, tissue, or organ level fast enough so that the protein complexes are fixed in situ in real time. Proteome Science 2014, 12:6 doi:10.1186/1477-5956-12-6
On 2016 Jun 19, Lukas Marti commented:
We thank Dr. Stanley Goldberg for pointing out, that we do not include in our PSP operation a levatorplasty. We therefore do not as he calls it "tackle the perineal hernia". It might be that adding a levatorplasty to perineal procedures as Rehn-Delorms, Altemeier's sigmoidectomy and the described PSP, lowers recurrence rate. But there is no randomized controlled trial to prove that. On the other hand adding a levatorplasty would make the procedure more complex and therefore it would become probably more prone to complications, something we want to avoid in the very frail patients to which we offer a PSP operation.
On 2016 Jun 01, Dr, Stanley Goldberg commented:
This operation does nothing for the perineal hernia which should be attacked in a perineal operation.
On 2016 Aug 10, Joaquim Radua commented:
Re: the previous comments, please note that under the null hypothesis of no differences between groups, only 1 out of 20 studies should show differences between groups, which is absolutely not the case when randomizing coordinates or blocks of voxels. Random coordinates and similar approaches, which randomize the location of the findings rather than the individuals between groups, are not a valid way to exactly test this hypothesis. Rather, they are only used to yield approximated p-values that, appropriately thresholded, return a map similar but slightly more conservative than that of FWE-corrected p-values in mega-analyses. Voxel-based meta-analytic methods are young and there is room for improvement, but they are based on evidence.
On 2016 Aug 09, Christopher Tench commented:
This is not a result of confusion, but of the definition of statistical inference. Uncorrected p-values do not control the type 1 error rate. A meta-analysis is performed to improve estimates, and is a statistical problem demanding statistical methods. To threshold at an arbitrary p-value controls neither the FDR nor the FWE, so no quantitative evidence that the results are critical of the null hypothesis is available. You cant know if the results are true positives without doing the full experiment, but meta-analysis is used for the case where the full experiment (mega analysis) has not been done. The one, and only, thing that can be done is to make sure that the null hypothesis is appropriately rejected; arguably the whole point of statistical inference. That requires either FWE or FDR control. Using just random coordinates and an uncorrected p-value will produce results that are apparently publishable, but obviously incorrect. Without any estimate of error rate, there is no quantifiable evidence that the results are meaningful.
On 2016 Aug 01, Joaquim Radua commented:
Re: the previous comment, I think there may be some unfortunate confusion. Raw p-values of current voxelwise meta-analyses have not the same meaning as usual p-values because they are not derived from the usual null hypothesis (“there are no differences between groups”), but from another null hypothesis (“all voxels show the same difference between groups”). Thus, up to the moment one of the only ways to "approximately" know if the results of a voxelwise meta-analysis are neither too liberal nor too conservative is to compare them with the results of a mega-analysis of the same data, and that's what it was done.
On 2016 Jun 14, Christopher Tench commented:
The method employed here offers no protection against type 1 error rate. It cant be considered a meta-analysis. Uncorrected p-values provide no evidence of statistical significance when large numbers of voxel-wise tests are performed.
On 2017 Jul 19, David Mage commented:
The authors have done a thorough survey of the sudden unexpected infant death (SUID) investigations in several U.S. states. They report on the autopsy and death scene investigations (DSI) of the case infants performed to determine which if any of the three conditions considered to form SUID may be involved: [ICD-10 sudden infant death syndrome (SIDS R95); unknown causes (UNK R99); accidental suffocation and strangulation in bed (ASSB W75)]. However, it is well known that the DSI have an inherent problem if the infant under review has been moved upon discovery by the parents or other caregiver: “cases of sudden death are associated with so much shock to the family that an accurate history is impossible to obtain” (Farber S. NEJM 211 (4):157;1934); “The suddenness of death so stuns the family that attempts to obtain a reliable history on the first visit to the scene are frequently unsuccessful” (Werne J, Garrow I. AJPH 37(June):678;1947); When a possible SIDS infant is immediately picked up on discovery the final resting position is reconstructed from subjective recall, which complicates the DSI (Willinger M, James LS, Catz C., Pediatric Pathology 11: 677-684, 1991). The writer notes that to calculate accurately the reduction of oxygen and the increase in carbon dioxide from possible rebreathing exhalations at the infant’s nares, the distance between the nares and the possible obstruction must be known to the millimeter, that is lost when the infant is picked up on discovery (Mage DT. Forensic Sci Med Pathol 9:2013; 283.) The reader should note that when a SUID infant is picked up on discovery and the DSI is compromised, the ICD-10 code chosen (R95 or R99 or W75) may be incorrect but the totals for SUID remain unchanged.
On 2016 Sep 22, Natalie Clairoux commented:
Free version of this article available after July 1, 2017 at http://hdl.handle.net/1866/13955
On 2016 May 04, Martine Crasnier-Mednansky commented:
There are several discrepancies in this paper which cannot be reconciled. For example, figure 1a and table S1 indicate a growth rate of 0.76 hr<sup>-1</sup> for maltotriose with ammonia as nitrogen source. The glucose-maltotriose diauxie with ammonia (Figure 2a, upper and middle panel) indicates a growth rate for maltotriose of 0.37 hr<sup>-1.</sup> In diauxie, the growth rate on each sugar is characteristic of that sugar (Monod, 1942). Therefore, the glucose-maltotriose diauxie should exhibit a growth rate of 0.76 hr<sup>-1</sup> for maltotriose. It is likely that the presence of the reporter gene in the diauxie experiment (figure 2) is affecting the growth rate on maltotriose.
On 2016 Jun 02, Clive Bates commented:
The measured markers are not a reliable proxy for disease risk
The authors are careful not to attribute serious disease risk to these measured changes in vascular function. That caution is well-founded. It is worth pointing out that similar effects are observed in coffee drinkers. See for example:
Papamichael CM, 2005 Effect of coffee on endothelial function in healthy subjects: the role of caffeine
The study examined similar effects as they arise from coffee consumption and concluded:
In conclusion, coffee exerts an acute unfavourable effect on the endothelial function in healthy adults, lasting for at least 1 h after intake. This effect might be attributed to caffeine, given that decaffeinated coffee was not associated with any change in the endothelial performance.
A comparison with coffee would have made a worthwhile additional arm to this study and may have helped with interpreting whether there is a material risk of harm. If the effects are similar to those experienced by coffee drinkers, that might have provided valuable reassurance for smokers making an informed choice about quitting smoking by switching to e-cigarettes.
The role of nicotine
The authors suggest several possible mechanisms for the observed changes in vascular function, including changes induced by nicotine. This is a promising explanatory hypothesis because achieving a satisfactory nicotine dose is common to both smoking and e-cigarette use. One might expect, therefore, similar physiological changes to arise from both ways of taking nicotine if nicotine is the primary cause of these observations.
However, that would also be reassuring to e-cigarette users. Nicotine has well-documented effects on the body but these effects have not been found to be a significant cause of the diseases attributed to smoking, including cardiovascular disease. The effect of nicotine separated from tobacco smoke exposure has been studied through assessments of medical nicotine replacement therapy (discussed on TreatTobacco.net) and snus, a form of smokeless tobacco that delivers high doses of nicotine - see Lee PN, 2013.
The danger of over-interpreting these findings
No one should underplay any potential risks from e-cigarettes. But neither should activists jump to exaggerations about disease risk based on these findings. Overstating the risks of e-cigarettes is logically and ethically equivalent to understating the risks of tobacco smoking. The latter was the practice of tobacco companies 30 years ago and it is essential to challenge the former in today's public health discourse.
As an example, one campaigner has already declared that this study means "e-cigarettes could be half as dangerous as conventional cigarettes" here.
I hope the authors will distance themselves from such extreme over-interpretation of their work. The authors could have pre-empted the need for that by explaining in the discussion that disease is not an inevitable consequence of these changed markers of vascular function.
To be fair, the authors do point to the need for further studies, "to clarify the chronic vascular effects of E-cigarette smoking". To which they might have added "if any" for completeness.
On 2016 Jul 07, GianCarlo Panzica commented:
Further comments on this topic are on Bourguignon JP, 2016 and Kortenkamp A, 2016
On 2016 Aug 22, Anthony Jorm commented:
The Royal Australian and New Zealand College of Psychiatrists (RANZCP) has recently published clinical practice guidelines on schizophrenia Galletly C, 2016, eating disorders Hay P, 2014 and mood disorders Malhi GS, 2015. 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.
On 2016 Sep 25, Lydia Maniatis commented:
I would respectfully ask the authors to justify their fundamental assumption, as this is straightforwardly asserted in their opening sentence:
“Visual sensitivity is limited by both the strength of the neural signals, and the noise in the visual nervous system1 (Levi DM, Klein SA, Chen I. 2005).”
I am interested in the reference to “the noise in the visual nervous system.” What is the basis of the claim that “noise in the visual nervous system" affects the percepts generated under the conditions of this study? What is the nature of this noise, where does it occur, and what is the evidence for it?
The single reference provided for the claim doesn’t provide answers as it, too, takes the it for granted. It does provide two other supporting references; but on inspection, these are equally inadequate.
According to Levi et al (2005) :
“It has been recognized for well over a century that visual perception is limited by both the strength of the neural signals, and by the noise in the visual nervous system…The notion that internal noise in the visual system acts like light, even in the absence of a stimulus, i.e., dark light, led Barlow (1957) to formulate a very influential model of visual detection which posits that visual sensitivity is limited “by the difficulty of distinguishing a weak signal from the background of spurious signals, or ‘noise’, which occurs without any light signal at all”. Barlow (1957) quantified the dark noise by determining the amount of actual light that produced the same amount of noise in the eye that is present in the dark, using the now widely used prescription for quantifying the noise, known as the equivalent input noise technique (Pelli, 1990).”
To clarify, Barlow (1957) is suggesting that there are “low levels of intrinsic retinal noise even in complete darkness.” He is interested in absolute thresholds. He states that his results “fit the theoretical predictions for the case of stimuli of short duration and small area (against a background of large area) for a range of background intensities up to about 10 scotopic trohinds [i.e. very, very low intensities].”
Levi, Klein and Chen (2005) however, are not referring to absolute thresholds or to retinal noise. They tell us that Pelli (1990); Pelli (1981) provided a new description of the equivalent input noise as a contrast function.
The theoretical rationale provided by Pelli (1990) is as follows:
Thus [in the case of electronic amplifiers] we can measure [“specify” would be more accurate] the intrinsic noise by finding an equivalent input noise. This is sometimes called 'referring the amplifier's noise to its input'. Essentially the same approach can be applied to vision. Indeed, this is analogous to Barlow's (1957) dark light measurements. By a similar analogy we can apply this idea to the contrast domain.”
More casual assumptions follow as Pelli (1990) elaborates the application of this analogy to the human visual system.
I submit that vague analogies should not be admitted the status of theoretical arguments.
It should be noted that Zomet et al (2016) in no way test the casually adopted and elaborated assumption that I am challenging. They simply interpret data as though it were true; their procedure can’t tell if it’s false. (The claim is, in fact, so vague that it’s not clear how one would go about testing it).
Postscript: The criteria for publication in Scientific Reports are that: "In this journal a paper is not assessed based on its perceived importance, significance or impact, but it is enough to be just scientifically valid." Testable hypotheses, and testing of assumptions prior to applying them as though they were true, is a fundamental criterion of scientific validity, which I believe is absent in the present case.
On 2016 Sep 08, Andrea Messori commented:
Active rheumatoid arthritis with inadequate response to methotrexate monotherapy: incremental benefit for infliximab plus methotrexate versus methotrexate alone
Andrea Messori, Sabrina Trippoli HTA Unit, ESTAR, Regional Health Service, Firenze, 50100 Italy
One strength of the meta-analysis by Hazlewood and co-workers [1] is that all pharmacological interventions aimed at rheumatoid arthritis have been evaluated in terms of efficacy. Since infliximab biosimilar has recently become available and its cost is lower than that of infliximab originator, evaluating the magnitude of the incremental benefit for infliximab plus methotrexate versus methotrexate alone is of interest.
In patients with active rheumatoid arthritis with inadequate response to methotrexate monotherapy, Hazlewood and co-workers [1] report a total of 5 randomised studies.
According to the end-point of ACR50 response at 30 weeks, the results found in these trials are shown in Table 1. The heterogeneity assessment (carried out according to Higgins and Thompson [2]) showed an I squared of 0% (with p=0.71).
If one analyses these data based on traditional pairwise meta-analysis (OMA software, Open Meta-Analyst, version 4.16.12, Tufts University, url http://tuftscaes.org/open_meta/), the pooled risk difference in favour of infliximab plus methotrexate vs methotrexate alone is +19.7% (95% confidence interval: +15.4% to +24.1%; fixed-effect model).
References
Hazlewood GS, Barnabe C, Tomlinson G, Marshall D, Devoe D, Bombardier C. Methotrexate monotherapy and methotrexate combination therapy with traditional and biologic disease modifying antirheumatic drugs for rheumatoid arthritis: abridged Cochrane systematic review and network meta-analysis. BMJ. 2016 Apr 21;353:i1777.
Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002 Jun 15;21(11):1539-58.
Table 1. Data of ACR50 response reported in 5 randomized trials: comparison between Remicade plus methotrexate (R+MTX) vs methotrexate alone (MTX). Detailed references for the 5 trials are given in the Appendix.
ACR50 response
Abe 2006: R+MTX=15/49 (30.6%) vs MTX=4/47 (8.5%)
Lipsky et al 2000 (ATTRACT): R+MTX=18/86 (20.9%) vs MTX=7/88 (8.0%)
Mac Isaac 2014: R+MTX=6/30 (20.0%) vs MTX=0/31 (0.0%)
Westovens et al 2006 (START): R+MTX=110/360(30.6%) vs MTX=33/361 (9.1%)
Zhang 2006: R+MTX=38/87 (43.7%) vs MTX=22/86 (25.6%)
Overall crude rate R+MTX=187/612 (30.5%) vs MTX=66/613 (10.8%)
Appendix
-Abe T, Takeuchi T, Miyasaka N, et al. A multicenter, double-blind, randomized, placebo controlled trial of infliximab combined with low dose methotrexate in Japanese patients with rheumatoid arthritis. J Rheumatol 2006;33:37-44
-Lipsky PE, Van Der Heijde DMFM, St. Clair EW, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. New Engl J Med 2000;343:1594-602
-Mac Isaac KD, Baumgartner R, Kang J, et al. Pre-treatment whole blood gene expression is associated with 14-week response assessed by dynamic contrast enhanced magnetic resonance imaging in infliximab-treated rheumatoid arthritis patients. PLoS ONE 2014;9 (12) (no pagination)
-Westhovens R, Yocum D, Han J, et al. The safety of infliximab, combined with background treatments, among patients with rheumatoid arthritis and various comorbidities: a large, randomized, placebo-controlled trial.[Erratum appears in Arthritis Rheum. 2007 May;56(5):1675 Note: Dosage error in article text]. Arthritis Rheum 2006;54:1075-86
-Zhang FC, Hou Y, Huang F, et al. Infliximab versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: A preliminary study from China. APLAR Journal of Rheumatology 2006;9:127-30
On 2016 Apr 27, Ana Herrmann commented:
The authors state that 1) "animals were used for only one experiment and in a single behavioral test, to reduce interference from apparatus exposure", and later they state that 2) "Animals were allowed to freely explore the novel tank for 6 min, after which they were removed from it and exposed to the scototaxis tank". Which one was it?
On 2016 May 24, Stefan Hofmann commented:
See: http://www.ncbi.nlm.nih.gov/pubmed/27009055
On 2016 May 06, Margaret Sampson commented:
The initial posting for this article contained an error in the order of the authors, as did the article posted on the JCE website on 18 April 2016. The correct author order for "The Single-Case Reporting guideline In BEhavioural Interventions (SCRIBE) 2016 Statement" is as follows: Tate, Perdices, Rosenkoetter, Shadish, Vohra, Barlow, Horner, Kazdin, Kratochwill, McDonald, Sampson, Shamseer, Togher, Albin, Backman, Douglas, Evans, Gast, Manolov, Mitchell, Nickels, Nikles, Ownsworth, Rose, Schmid, and Wilson. As a check, please ensure that Vohra is the 5th author (Posted May 6, 2016, revised May 19, 2016)
On 2017 Mar 02, Melissa Rethlefsen commented:
I thank the authors for including the full version of their search strategies in the appendix. This is a valuable tool for readers to more comprehensively analyze the systematic review's methodology and outcomes.
In the appendix containing the full search strategies, the MEDLINE search and the Embase search appear identical. It is unclear if these databases were searched simultaneously using Ovid's multifile searching capability, or whether the search listed for MEDLINE is in fact not the search used for the MEDLINE search. It is of course also possible that the same search was used for each database, though searched individually.
The primary complication with the MEDLINE search as reported is that many of the search terms used are Embase-specific Emtree terms that are not searchable in MEDLINE. This includes: "crossover procedure"; "double blind procedure"; "single blind procedure"; "triple blind procedure"; "animal"; "nonhuman"; "human"; "human cell"; and "ulcerative colitis." Because these are not the correct MeSH terms for these concepts, searches for these terms as indicated would produce no results. This unfortunately impacts two major components of the search, from the recommended Cochrane Embase sensitive search for randomized control trials (lines 1-18) and the disease state section (lines 21-24). Multifile Ovid searching does try to map thesaurus terms to corresponding thesaurus terms across databases, which may resolve some of these issues. However, a best practice would be to include both Emtree and MeSH terms in a search instead of relying on multifile term mapping. If the authors did rely on multifile searching, it would be appropriate to note this in the methods section to alert readers.
In addition, lines 26 and 27 both search for the MeSH heading "Mesalamine," and lines 28 and 29 both search for the MeSH heading "Sulfasalazine." This was perhaps adapted from the previous version of this review (Feagan BG, 2012), which also utilizes this duplication. It is not clear why these terms were duplicated in either case, though this version of the review did update the rest of the search strategy to be more comprehensive and also more specific.
On 2016 Aug 18, Andrew Kewley commented:
Expression of concern over un-interpretable statistics of multiple candidate gene association studies.
The lack of replication of candidate gene association studies has led to much discussion and debate. It is generally considered that each candidate cannot be considered to be an independent hypothesis, hence the alpha level needs to be corrected for multiple comparisons. There is no discussion of this in the paper.
This research group have published multiple candidate gene manuscripts in addition to this study [1,2,3,4] (Most of which are not listed on pub-med), and may have other unpublished data. Hence it is difficult to know what alpha should be used for significance, after correcting for multiple comparisons. If correcting for 678 comparisons, then none of the results reach significance and the overall conclusion should be quite different.
In general, future genetic studies should utilise genome-wide association methodology to avoid such biases.
[1] Examination of Single Nucleotide Polymorphisms (SNPs) in Transient Receptor Potential (TRP) Ion Channels in Chronic Fatigue Syndrome Patients. Sonya M. Marshall-Gradisnik, Peter Smith, Ekua W. Brenu, Bernd Nilius, Sandra B. Ramos and Donald R. Staines Immunology and Immunogenetics Insights 2015:7 1-6
[2] Genotype Frequencies of Transient Receptor Potential Melastatin M3 Ion Channels and Acetylcholine Muscarinic M3 Receptor Gene Polymorphisms in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis Patients. Marshall-Gradisnik, SM; Chacko, A; Johnston, S; Smith, P; Nilius, B; et al. Immunology and Immunogenetics Insights 8 (2016): 1-2.
[3] Examination of Single Nucleotide Polymorphisms in Acetylcholine Receptors in Chronic Fatigue Syndrome Patients. Marshall-Gradisnik, Sonya; Smith, Peter; Nilius, Bernd; Staines, Donald R. Immunology and Immunogenetics Insights 7 (2015): 7-20.
[4] Killer Cell Immunoglobulin-like Receptor Genotype and Haplotype Investigation of Natural Killer Cells from an Australian Population of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis Patients. T. K. Huth, E. W. Brenu, D. R. Staines, and S. M. Marshall-Gradisnik. Gene Regulation and Systems Biology 2016:10 43-49
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 NCT0255810. We believe the correct ID, which we have found by hand searching, is NCT02558101.
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
On 2017 Mar 29, Zvi Herzig commented:
Despite the fact that this study relates to e-cigarette (EC) vapor dissolved in a liquid medium, the authors surprisingly attribute outcomes to fine particulate matter:
… our findings suggest it is not nicotine or toxic combustion product that activates the hemostatic system, but instead the hemostatic system is most responsive to fine particulate matter
This conclusion is puzzling because particulate matter of EC aerosol are in fact liquid droplets. When these are merged with the liquid medium, their former particle sizes become irrelevant. (Solid particles emitted from EC hardware are at quantities below safety limits Farsalinos KE, 2015 and thus unlikely to be of significance).
It is also unclear what the causes or the relevance of these in vitro platelet effects are. For example, propylene glycol and glycerol are not rapidly metabolized here as they are in vivo. Indeed, Hom et al write:
There are some important limitations to the work presented here, including the use of an ex vivo static system, without negative hemostatic regulators (such as endothelial cells), to evaluate the effects of e-vapor on platelet functions.
In contrast, a recent clinical study of smokers switching to Tobacco Heating System 2.2 (whose emissions also include the limited cigarette smoke toxicants present in EC vapor Schaller JP, 2016) shows a level of reduction in platelet activation among switchers approaching those of quitters Lüdicke F, 2018:
Reductions in 8-epi-prostaglandin F2α (biomarker of oxidative stress), 11-dehydro-thromboxane B2 (biomarker of platelet activation)… occurred in the menthol tobacco heating (mTHS) system group compared with the menthol conventional cigarette group. The changes in the mTHS group approached those in the smoking abstinence group.
This would indicate that the outcomes of Hom et al are not manifested in real use. While it can be countered that perhaps EC flavorants not emitted by heated tobacco have induced the platelet effects, this is unlikely considering that outcomes were similar for two disparate EC products tested.
It would also be interesting to consider the effects of air bubbles present from bubbling the aerosol through the extraction buffer. It's well-known that air bubbles induce platelet activation Sandgren P, 2011 and this might help explain the strange outcome.
On 2016 May 23, Jonathan Heald commented:
Posted on behalf of the American Academy of Sleep Medicine:
These recommendations for the use of adaptive servo-ventilation for the treatment of congestive heart failure related central sleep apnea are updates to the 2012 recommendations found in the guideline "The treatment of central sleep apnea syndromes in adults: practice parameters with an evidence-based literature review and meta-analyses." These recommendations serve as an essential supplement to the 2012 practice parameter document:
On 2016 Jun 06, Christopher Southan commented:
Since the molecular structure of HM71224 is not disclosed the journal has allowed the publication of work that cannot be reproduced. This consequently obfuscates the clinical trial entry from Eli Lilly
https://clinicaltrials.gov/ct2/show/NCT02628028
On 2017 Sep 13, Seán Turner commented:
According to the CCM catalog of strains, the type of Paenibacillus cucumis Kampfer et al. 2016 is CCM 8655, not CCM 8653. The authors have later assigned CCM 8653 as the type of Isoptericola cucumis Kampfer et al. 2016 (PMID 27045419) which is consistent with the assignment in the CCM catalog of strains.
On 2017 Sep 13, Seán Turner commented:
None
On 2016 Jul 14, Marcus Munafò commented:
This study provides deeper theoretical insights than might be imagined from a cursory reading. Evolutionary life history theory addresses how organisms, including humans, vary in the allocation of resources to growth, survival and reproduction across the life course. Life history strategies are defined by key decisions that trade off finite resources against competing demands to achieve reproductive goals [1, 2]. Both across and within species, the trade-off between the allocation of resources to growth and to reproductive efforts results in organisms employing varying strategies that can be characterised, loosely, as ‘slow’ or ‘fast’. A ‘slow’ life history strategy is characterized by later maturity and proportionally greater investment of resources in a smaller number of offspring, while a ‘fast’ life history strategy involves more effort directed towards reproduction, such as earlier puberty and sexual activity [2, 3]. Typically, animals pursue a fast life history strategy (‘live fast, die young’) under adverse environmental conditions of high extrinsic mortality. In such conditions, as Day and colleagues suggest, earlier sexual maturation may increase reproductive fitness. However, Day and colleagues also suggest that associations between earlier puberty and a greater propensity for risk-taking behaviours, lower educational attainment, and adverse health outcomes, contradicts this evolutionary perspective. On the contrary, directing effort into risky and aggressive behaviour is best considered as an important part of a fast life history strategy, in which competition for mates is crucial [1]. Viewed in this light, adolescent behaviours of unprotected sex and earlier pregnancy, as well as violence, law breaking, and substance abuse, can be seen as central components or consequences of a fast strategy in which the future is discounted relative to the present [1, 4]. Variation in these physiological and behavioural traits in response to changing environments may reflect a suite of adaptations – psychological and somatic – that increase fitness on average despite poor social and health consequences [5], as resources are diverted from longevity towards short-term reproductive goals under conditions of adversity.
The human life history literature suggests strategies are contingent on variation in the environment rather than variations in genotype. Day and colleagues illustrate the central role genetics can play in testing key hypotheses arising out of life history theory, where reliance on observational data has previously limited causal inference. The key point is that variants identified in GWAS studies may reflect environmental (and hence modifiable) risk factors, as well as direct genetic effects [6]. An ever-increasing range of social and psychological traits relevant to life history theory are proving tractable to GWAS, including, for example, social deprivation [7] and endocrine biomarkers including cortisol [8] and sex steroids [9]. Genetic instruments associated with social outcomes could be used as a proxy for environmental harshness, while instruments for endocrine status may provide causal evidence for status seeking and reproductive behaviours known to occur in other species, but that are not amenable to experimental analysis in humans. The results of emerging GWAS therefore provide us with unprecedented opportunities for testing the predictions of life history theory, with implications for our understanding of the determinants of health and social behaviour. The elegant demonstration by Day and colleagues of causal links between earlier puberty and both key reproductive traits and adverse outcomes provides compelling evidence that evolutionary life history theory can shed light on human reproductive behaviour, health and disease, even in a modern Western environment. Combining causal analysis from genetic epidemiology and theoretical insights from evolutionary models may help to launch a science of evolutionary social epidemiology, combining knowledge of ‘how’ exposures lead to certain outcomes with an understanding of ‘why’ these relationships may exist. Reframing our understanding of the development of significant social and health outcomes in this way may lead to novel insights to inform future interventions.
Rebecca Lawn, Abigail Fraser, Marcus Munafò and Ian Penton-Voak
On 2016 May 15, Arnaud Chiolero MD PhD commented:
In a life course epidemiology perspective, this is a great review to understand strengths and limitations of intergenerational approach of prevention of obesity and related conditions. In this domain, the words are elegant and the concepts are appealing; the evidence is however weak, letting us short of knowing how to act. We need trials to go further.
On 2017 Mar 02, Simina Boca commented:
Code for analyzing the processed data available at https://github.com/SiminaB/DMD-metabolomics
On 2016 Jul 26, Fernando Castro-Chavez commented:
Dear Reader, This is my most recent article and in it I present the match between the Vigesimal Numerical System of the Maya Culture from the Yucatan Peninsula, in Mexico, and the twenty amino acids with suggested systems of anatomical mnemonics in the Education of Molecular Biology, i.e., using the twenty appendages of our extremities (fingers and toes), and another to remember the purines and pyrimidines with hands and feet. Furthermore, by the suggestion of my chemistry tutoring student Ana Baleva, I have also explored the Icosahedron as an alternate way to represent the twenty amino acids for the Graphics Design in Bioinformatics, containing in one of its triangular cells, an on/off switch. To see the rest of a suggested set of correspondences, please go to my Facebook page and (if you wish) befriend me: https://www.facebook.com/fernando.castrochavez.90. I deeply appreciate feedback, and/or constructive comments, for this and for The Rest of my: Publications in PubMed, by Fernando Castro-Chavez:. And my LinkedIn: https://www.linkedin.com/in/fernando-castro-chavez-6744a322. Sincerely, Fernando Castro-Chavez. P.D. An updated image inspired by this research:
The First Ten plus Zero Numerals of the Vigesimal Mayan System
On 2016 Jun 29, Fernando Castro-Chavez commented:
None
On 2017 Nov 30, Joe G. Gitchell commented:
Readers may find the follow-up letter to this article (http://ajph.aphapublications.org/doi/full/10.2105/AJPH.2016.303456) and the authors' reply to the letter (http://ajph.aphapublications.org/doi/full/10.2105/AJPH.2016.303476) of interest.
On 2016 Apr 25, Dita Gratzinger commented:
Dr. Itkin and colleagues provide a tour de force overview of hematopoeitic stem and progenitor cell maintenance and trafficking within the context of distinctive capillary/arteriolar and sinusoidal vascular beds in the mouse. In parallel to their findings in mouse, we have previously described the analogous vascular beds in intact human marrow, particularly the nestin+ capillary/arteriolar bed, which is tightly wrapped in SMA/CD146+ pericytes/vascular smooth muscle which in turn is wrapped in CD271+ mesenchymal stromal cells (MSCs), as distinct from the nestin-negative sinusoidal endothelium in direct contact with MSCs; the MSCs are then in direct contact with CD34+ hematopoietic progenitor or stem cells Flores-Figueroa E, 2012. CD105 is a specific sinusoidal vascular marker and nestin as a specific capillary/arteriolar marker in intact human bone marrow, allowing for quantification of the distinct vascular beds in the setting of myelodysplastic syndromes Ewalt MD, 2016.
On 2016 Apr 14, Fernando Suarez-Obando commented:
Great paper
On 2016 Dec 15, Victoria MacBean commented:
Plain English Summary:
Parasternal intercostal electromyography (EMGpara) is a new way to measure breathing difficulty. Research needs to be carried out because body parts used in breathing, like the lungs, need to be properly checked over for breathing problems to be managed, but the testing methods aren’t always suitable for children who are very young or ill. The parasternal intercostal muscles are muscles that move at the same time as the diaphragm (a thin sheet of muscle under the lungs) when you breathe in and out. EMGpara measures signals from the brain which are sent to these muscles without putting any instruments into the body, so it is ideal for children. EMGpara was measured using stickers on the front of the chest while the participants (92 healthy, 20 wheezy and 25 with a machine (ventilator) to help them breathe) were breathing in and out in a resting state. For the wheezy children, measurements were taken before and after a substance to widen air passages (reliever inhaler, or bronchodilator) was used; for the critically ill children, these were taken during ventilator-assisted breathing, then with just mild air pressure to keep the airways open (continuous positive airways pressure). It was found that as age, weight and height increased, EMGpara decreased. This is because when children are growing up, big changes take place in the respiratory system, decreasing the effort needed for breathing. EMGpara in the healthy children was the lowest; in the wheezy children it was higher before the bronchodilator was used, dropping to similar levels to the healthy children afterwards. In the critically ill children, EMGpara was higher than in the wheezy children when the ventilator was used, and even higher with continuous positive airways pressure when they were having to breathe without support. This study has shown that measuring EMGpara is possible in children of a range of ages and levels of health. The results from the healthy children have shown important age-related changes in EMGpara, and those from the wheezy and critically ill children have shown that EMGpara is affected by changes in how hard the breathing muscles have to work because of different diseases and treatments. EMGpara could be a really helpful method in testing the breathing ability of patients who are usually difficult to assess.
This summary was produced by Lottricia Millett, Year 12 student from Burntwood School, London, as part of the investigators' educational outreach programme.
On 2016 Aug 31, Joanna Hudson commented:
We thank Ben Goldacre and the opentrials.net project for bringing this to our attention. We have informed the journal of this anomaly and will ensure all future publications are cited with the correct trial registry ID.
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 NCT023528702. We believe the correct ID, which we have found by hand searching, is NCT02352870.
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
On 2016 May 12, Heidi Schulz commented:
Note that according to HGVS guidelines, the novel variant described as c.717delG in the paper should be referred to as c.718del p.Val240*.
On 2016 Apr 20, Anderson Santos commented:
Dear users of the MED pipeline, The MED web server address has been migrated to this new one: http://med.compbio.sdu.dk/ in the Denmark. The MED web server administrator is negotiating a web address forward but no responses from Saarland till now. An important clue about MED: keep the proteins names small and simple, avoid punctuation characters or your processing can fail. I hope to correct such weakness in a further version. Best regards, Anderson Santos - Author
On 2016 Apr 30, Clive Bates commented:
Missing the Point
The priorities elaborated in Matthew Myers' editorial are misplaced will have only trivial impact on the cigarette market. I have proposed five more fundamental tobacco-related regulatory issues for FDA or Congress to address. Please see this e-letter response to the journal Tobacco Control: e-letter Missing the point
An expanded version of this is available with links in this posting The tobacco control high command has lost its way - what we learn from its views on FDA priorities
On 2016 May 27, Carmine Pariante commented:
We are grateful to Dr. Carroll for his comment, which has allowed us to clarify this point. Dr. Carroll is right that we use 'specific' as indicating the outcome of statistical analyses. However, we refer to pathways and genes 'specifically' regulated in depressed patients (or, indeed, in the group that does not develop depression) because these genes/pathways are only regulated in the depressed (or in the non-depressed) group. In this sense, we are using 'specific' to differentiate these genes/pathways from the many genes/pathways that are regulated equally in both groups. We also agree that there are limitations in using IFN-alpha as a model of ordinary major depressive disorder, although we are confident that our findings are relevant to at least the subgroup of depressed patients with high levels of peripheral inflammation. We hope that this reply is helpful.
On 2016 May 08, Bernard Carroll commented:
Several issues arise with this report. 1. Authors claimed that "specific signatures" of gene expression changes distinguished depressed versus non-depressed patients. After reading the full paper plus the Supplemental material it is clear that specificity was not established. No data were presented on conditional probabilities or on diagnostic confidence or prognostic confidence. 2. Multiple, misleading, references to specificity in the article actually just denote statistically significant differences in gene expression between the 2 groups of patients. 3.No group-wise differences in cytokine concentrations were found. 4. Validity of IFN-alpha induced depression as a model of ordinary major depressive disorder has not been established.
On 2016 Jul 20, Rohan Maddamsetti commented:
While gene flow is certainly important in the evolution of gut microbiota, given current evidence I do not believe that gene flow is a good explanation for synonymous variation in E. coli. I've written a short post on my blog explaining my thinking: http://rohanmaddamsetti.weebly.com/blog/a-retraction-of-sorts
On 2017 Apr 27, Randi Pechacek commented:
Katherine Dahlhausen wrote an engaging blog post on microBEnet about this review. She explains how this review emphasizes our "knowledge gaps in the understanding of the fate of antibiotics in our environments."
On 2016 Apr 13, Anders von Heijne commented:
Recommended reading - Note the important aspect of including the scale/lexicon as a footnote in all radiology reports!!
On 2016 Apr 16, Aiguo Ren commented:
The lowest and highest point estimates of NTD prevalence were obtained from two studies in China. However, these two studies are not comparable in terms of geographical area, time period, and, most importantly, method of calculation. The estimate from Beijing was obtained from a maternity hospital and the numerator was the number of NTD cases in pregnancies of 28 weeks of gestation or greater. In Beijing, every pregnant woman receives ultrasound scanning for fetal structural defects around 20 weeks of gestation, and virtually all fetuses with NTDs will be detected by 28 gestational weeks, and terminated based on informed choice of the mother. This explains, in a larger part, the low NTD prevalence in Beijing. Other national or hospital-bases data from China suffer from the same problem. Please see our most recent report PMID: 26879384.
On 2016 Jun 22, Vatsalya Vatsalya commented:
Research highlight at NIAAA June 2016 Council Meeting: http://www.niaaa.nih.gov/about-niaaa/our-work/advisory-council/directors-reports-council/niaaa-directors-report-institute-12
On 2016 Aug 01, Joaquim Radua commented:
Re: the previous comment, I think there may be some unfortunate confusion. Raw p-values of current voxelwise meta-analyses have not the same meaning as usual p-values because they are not derived from the usual null hypothesis (“there are no differences between groups”), but from another null hypothesis (“all voxels show the same difference between groups”). Thus, up to the moment one of the only ways to "approximately" know if the results of a voxelwise meta-analysis are neither too liberal nor too conservative is to compare them with the results of a mega-analysis of the same data, and that's what it was done.
On 2016 Jul 22, Christopher Tench commented:
Control in statistics is not achieved by fixed p-value threshold when there are many tests. There are very fundamental reasons for using FWE and FDR, and as a minimum these must be estimated to quantify the risk of false positives. Applying a fixed p-value and fixed cluster extent is a bit like having a fixed steering wheel in a car: it will work really well when the road is straight, but fail terribly when there is a bend! Controlled methods necessarily adapt themselves to the data. Without them, there is no quantifiable evidence that an effect is truly critical of the null.
I appreciate the validation study. Unfortunately it only tested known positive data. In statistics this cant be considered validation as it promotes confirmation bias. I am aware of the claim that the threshold is equivalent to corrected 0.05, but unfortunately this is not correct. Correction implies adaptation to the data and its null, but fixed thresholds are not able to do this.
On 2016 Jun 21, Fabio Richlan commented:
1) Whether or not a study can be considered a meta-analysis does not depend on the use of a correction for multiple comparisons. 2) As usual for coordinate-based meta-analyses, statistical significance was assessed by a permutation test (thresholded at a voxel-level (height) of p < 0.005 and a cluster-level (extent) of 10 voxels). Note that the use of a cluster extent threshold is a way of controlling false positives. In addition, only voxels with z > 1.0 were considered statistically significant. Based on an empirical validation, it was shown that, at least for seed-based d Mapping (SDM), this combination of voxel-level and cluster-level thresholds optimally balances sensitivity and specificity and corresponds to a corrected p-value of 0.05 (http://www.ncbi.nlm.nih.gov/pubmed/21658917). More details on the SDM method can be found at http://www.sdmproject.com/
On 2016 Jun 15, Christopher Tench commented:
The method employed in this study offers no control over the 10<sup>5</sup> statistical tests performed. The results are can not be considered statistically significant or a meta-analysis.
On 2017 Apr 09, Harri Hemila commented:
A manuscript version is available at HDL.
On 2016 Apr 30, Morten Oksvold commented:
Please note that this publication is actually a retraction of the Leukemia article. There is no indication in this PubMed notice that this is a retraction.
I will strongly suggest that all retractions in the future are written clearly in the beginning of the article title.
On 2017 Jul 24, Joseph J Drabick commented:
Thank you for the comment for our article. We will clarify the literature searching strategy we used in the meta-analysis here. We used Pubmed, Cochrane Library, Ovid Medline and Ovid Healthstar databases, which are accessible from our medical center library. Other details for the search strategy, such as keywords, inclusion and exclusion criteria, are shown in our manuscript.
On 2017 Jul 20, Irma Klerings commented:
Remarks concerning the literature search
The authors state that they conducted the review in accordance with Cochrane guidance, which is commendable. However, both the Cochrane Handbook for Systematic Reviews of Interventions and the Methodological Expectations of Cochrane Intervention Reviews state that the full search strategies for each database need to be included in an appendix of the review.
Unfortunately, this is not the case here. As far as I can see, this article does not include a replicable search strategy in the text or in an appendix.
The description of the databases used is also puzzling: “PubMed database, Cochrane database, and Ovid database”
Ovid is not a database, but a platform that hosts many different databases. Which one(s) were used is not discernible. Similarly, it is not quite clear what is meant by “Cochrane database”. This might refer to the Cochrane Library which contains a number of databases or it might refer to only one of the databases produced by Cochrane (CDSR, CENTRAL).
In short, the authors may have adhered to Cochrane guidance when they conducted this review. But when it comes to the literature searches there is no way to tell because the reporting is insufficient. This means the reader has no way of judging the comprehensiveness and the quality of the literature search process.
On 2016 May 08, Amitav Banerjee commented:
The study by Deshmukh et al,[1] entitled, “Taken to Health Care Provider or Not, Under-Five Children Die of Preventable Causes: Findings from Cross-Sectional Survey and Social Autopsy in Rural India,” published in the current issue of Indian Journal of Community Medicine, raises some serious debatable issues which need to be revisited.
On the whole this cross sectional study, covering rural areas from 16 districts in 8 states of India to identify the causes of death among under-five children and health seeking behavior of caregivers by verbal autopsy, does not yield any novel information. No one with a basic understanding of public health in India would find surprising that mortality was mostly due to neonatal etiologies and preventable causes such as acute respiratory infections, diarrhea, and so on. The fact that most caregivers preferred private health care facilities over government health centers is also to be expected given the poor quality and availability of public health facilities in rural areas. Many studies have brought out these factors ad-nauseam.
This study would have passed as a benign redundant study but for the fact that it has raised a serious debatable issue by some very casual inferences which can misguide the reader, the policy makers and the lay public.
The issue concerns the authors’ claim that this study is the first study on Sudden Unexplained Deaths (SUDS). They found 1.4% (21 out of 1488) of deaths among under-five children otherwise healthy before death which they labeled as SUDS. Well, so far, so good. However, while discussing the implications of this finding vis-à-vis Adverse Effects Following Immunization (AEFI), one wonders why they drag in AEFI in their discussion since it was not one of the study objectives. Further, they also claim, naively, that no vaccination histories were available for these cases. So one would like to know by what stretch of imagination one can conclude, in either direction, the relationship between immunization and these cases of SUDS from the data they provide. Authors have resorted to speculation in absence of scientific reasoning.
They claim that the findings regarding SUDS in their study could serve as a baseline for future assessment of SUDS in Indian children and could be used for analysis and in contextualizing SUDS and AEFI deaths in India. Well, again, so far, so good. Now follows the gaffe.
The authors have made the following statement, “…SUDS and AEFI deaths in India …have been wrongly attributed to new vaccine in the lay press (here they have cited two references, 25 and 26).” This statement and the references labeled as “lay press” are very misleading. Reference number 25 (cited as “lay press”) is a very balanced editorial, published in the Indian Journal of Medical Ethics, a reputed journal indexed in PubMed and Scopus among others. Reference number 26 is “Weekly Epidemiological Record from WHO Geneva!!” One wonders whether the authors have read these references before citing them, otherwise they would not have made this blunder of labeling them as “lay press.”
One would strongly recommend all readers who read Deshmukh et al’s paper[1] to also read these references cited as “lay press” by the authors. Puliyel in his editorial in the Indian Journal of Medical Ethics,[2] has very elegantly with simple calculation (he resorted to all causes mortality since SUDS specific mortality was not available) demonstrated that unexplained deaths after introduction of pentavalent vaccine increased much beyond the base rate for all causes infant mortality rate in Kerala. If Deshmukh et al[1] suggest that data from their present study regarding SUDS be used to contextualize AEFI and SUDS then Puliyel’s caution about adverse effect of pentavalent vaccine becomes stronger as only 2.3% of all cause infant mortality would be expected as SUDS (and co-incidental to administration of pentavalent vaccine). While their data on SUDS supports Puliyel’s concerns about AEFI deaths after pentavalent vaccine (in fact more than Puliyel’s own editorial, since based on this data SUDS would be only a fraction of all causes infant mortality), they casually dismiss his editorial as “lay press.”
Similarly the other reference cited by the authors as “lay press”, i.e. The Weekly Epidemiological Record from WHO[3] cautions that in the context of evaluating a safety signal, it is important that countries understand their own infant mortality rates and underlying causes. If a particular serious AEFI is identified as a concern, additional epidemiological studies should be conducted to ascertain factors that can be used to evaluate the evidence for risk hypothesis. SUDS, among other causes of infant mortality, would benefit from detailed epidemiological studies. The report by WHO in this issue of the WER, concedes that there have been deaths following pentavalent vaccine in Sri Lanka, Bhutan, India and Vietnam leading to temporary suspension of vaccination in some countries. Albeit in the end the report concludes that pentavalent vaccine is to be considered safe. This perhaps may be due to lack of proper baseline data on SUDS and inadequate epidemiological investigations of AEFI.
Based on Deshmukh et al[1] findings on SUDS, the WHO may be persuaded to reconsider its position on safety of pentavalent vaccine. Lastly, we hope Deshmukh et al appreciate their contribution to understanding AEFI – they have raised the bar of vaccine safety – not realizing they have done so!!
References
Deshmukh V, Lahariya C, Krishnamurthy S, Das MK, Pandey RM, Arora NK. Taken to health care provider or not, under-five children die of preventable causes: Findings from cross-sectional survey and social autopsy in Rural India. Indian J Community Med 2016;41:108-19
Puliyel J. AEFI and the pentavalent vaccine: Looking for a composite picture. Indian J Med Ethics 2013;10:142-6.
Weekly epidemiological record. Geneva: World Health Organization 2013; 88: 301 – 12. .
Dr Amitav Banerjee, Professor Community Medicine, Dr DY Patil Medical College, Hospital and Research Centre, Pune, India
On 2016 Apr 08, Dr. Kam Cheong Wong commented:
Dear readers,
The full article can be freely accessed via the following open access link: http://jmedicalcasereports.biomedcentral.com/articles/10.1186/s13256-016-0850-6
In a spirit of continual improvement, I have updated Figure 3 in this article. The haematological and endocrinological causes of pain in the right upper quadrant of the abdomen have been grouped in “other systems” in the Figure 3, which can be freely downloaded via the following link:
This article has referred to the use of Ishikawa diagram. Readers who would like to revisit “how to apply Ishikawa diagram in a clinical setting” can freely access the article via the following link:
http://jmedicalcasereports.biomedcentral.com/articles/10.1186/1752-1947-5-120
I look forward to receiving your feedback.
Thank you.
Yours sincerely, Dr. Kam Cheong WONG; MBBS(UQ),MSc(NUS),BE(NUS),FRACGP.
On 2017 Apr 21, Randi Pechacek commented:
Katherine Dahlhausen, or as I know her, Katie, is the first author on this paper. She wrote an entertaining and honest post on microBEnet about the whole process of using crowdfunding for research. As someone who personally works on her "Koala Project," I highly recommend reading her blog post here.
On 2016 Dec 18, Laura Williams commented:
Our online journal club discussed this paper on April 25, 2016. https://www.youtube.com/watch?v=aj8mqOw83Bo
On 2016 Aug 24, Jim Woodgett commented:
A relatively minor point, but the inhibitors used here, lithium and SB216763 (and also BIO, which is mentioned in the Discussion) are not selective for GSK-3beta as they are equipotent towards the GSK-3alpha isoform. This could be simply remedied by deleting the "beta" from each mention of GSK-3beta. Of note, there are currently no isoform-selective small molecule antagonists of GSK-3. Both isoforms are largely redundant (though there are some differences), similarly regulated and widely expressed.
On 2016 Apr 06, Donald Forsdyke commented:
PROTEIN SIZE AND CONCENTRATION DETERMINE DOSAGE-SENSITIVITY?
With the goal of understanding “the evolution of incomplete sex chromosome dosage compensation mechanisms in general,” the authors confirm that, among dosage-sensitive genes, those whose products specifically engage in stoichiometric complexes with other gene products, have a high degree of dosage-compensation. However, most genes are not dosage-limited by stoichiometry and “perplexing questions” remain. It is suggested that “certain loci … simply lack dosage effects” (my italics). In other words, certain loci “simply” contribute more to dosage effects than others.
While far from simple, this proposal is consistent with dosage compensation being more concerned with collective protein functions than with the specific functions of individual proteins (1). In the crowded cytosol the protein collective should exert an entropy-driven aggregation pressure on individual proteins, as part of a process of intracellular self/not-self discrimination (2). It is predicted that small, low concentration, proteins, will hardly influence aggregation pressure, so here there is no necessity for dosage compensation between the sexes. However, large, high concentration, proteins will greatly influence aggregation pressure, so here regulation of dose, on a gene-by-gene basis or otherwise, should be critical. Failure to regulate such dosage in human females would explain their susceptibility to autoimmune diseases (3-5).
1.Forsdyke DR (1994) Relationship of X chromosome dosage compensation to intracellular self/not-self discrimination: a resolution of Muller's paradox? J Theor Biol 167:7-12. Forsdyke DR, 1994
2.Forsdyke DR (2009) X chromosome reactivation perturbs intracellular self/not-self discrimination. Imm Cell Biol (2009) 87:525-528.Forsdyke DR, 2009
3.Dillon SP et al. (2012) Sex chromosome aneuploidies among men with systemic lupus erythematosus. J Autoimmun 38:J129-J134. Dillon SP, 2012
4.Forsdyke DR (2012) Ohno's hypothesis and Muller's paradox: sex chromosome dosage compensation may serve collective gene functions. BioEssays 34:930-933. Forsdyke DR, 2012
5.Wang J et al. (2016) Unusual maintenance of X chromosome inactivation predisposes female lymphocytes for increased expression from the inactive X. Proc Natl Acad Sci USA doi/10.1073/pnas.1520113113 Wang J, 2016
On 2016 Sep 30, Jackie Marchington commented:
The Global Alliance of Publication Professionals (GAPP) submitted a timely response to this article to BMC Medical Ethics in May 2016. In September 2016 we received the author’s response to our correspondence. In the light of current (as of September 2016) correspondence on a subsequent, similar article by the same author in the British Medical Journal (http://www.bmj.com/content/354/bmj.i4578/rapid-responses), we consider our original response to this article to be redundant, but would encourage readers to visit the BMJ correspondence.
Disclosure: All members of GAPP declare that we have provided or do provide ethical medical writing services to academic, biotechnology, or pharmaceutical clients, and are active in national and international not-for-profit associations that encourage ethical medical writing practices. Details of GAPP members can be found at http://gappteam.org