On 2014 Sep 07, Ivan Oransky commented:

This paper has been retracted, and one of the authors is being sought in an alleged fraud scheme: http://retractionwatch.com/2014/09/04/retraction-appears-for-psychiatrist-sought-for-arrest-in-alleged-fraud-scheme/

On 2013 Jun 19, Markus Meissner commented:

In this study Gaji et al. present a new methodology to indentify host cell factors that are involved in Toxoplasma gondii invasion. They performed a high throughput screen and identified several candidates, where the knockdown results in less efficient host cell invasion by this parasite. The authors speculate that six identified candidates affect parasite invasion by modifying actin dynamics. Although at this point no novel mechanistic concept can be presented, the results of this elegant screen will provide the field with novel ideas for future investigations of host cell factors that are involved during invasion by apicomplexan parasites. Currently our view of host cell invasion and the mechanisms involved during this process are challenged by intriguing results from several groups that do not fit the current models. Therefore this study is very timely and provides the field with a new resource for hypothesis driven follow up studies on some of the identified candidates.

On 2016 Aug 23, Ben Goldacre commented:

This trial has the wrong trial registry ID associated with it on PubMed: both in the XML on PubMed, and in the originating journal article. The ID given is NCT016648060. We believe the correct ID, which we have found by hand searching, is NCT01664806.

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

Many thanks,

Jessica Fleminger, Ben Goldacre*

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

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

On 2015 Jun 09, Bill Cayley commented:

A great example of "less-is-more": https://lessismoreebm.wordpress.com/2015/05/11/oronasopharyngeal-suction-versus-wiping-of-the-mouth-and-nose-at-birth-a-randomised-equivalency-trial/

On 2014 Mar 23, Hilda Bastian commented:

Readers of this Cochrane review (Gøtzsche PC, 2013) may also be interested in other key reviews that assess much the same body of evidence. One of these is the systematic review undertaken for the US Preventive Services Taskforce (USPSTF) (Nelson HD, 2009). Another is the review by the Independent UK Panel on Breast Cancer Screening (Independent UK Panel on Breast Cancer Screening., 2012; Marmot MG, 2013; full report). In addition, the Canadian Task Force on Preventive Care used the USPSTF review as the basis for its findings and recommendations (Canadian Task Force on Preventive Health Care., 2011).

Update on 1 May 2014: Another review was published in JAMA in April 2014 (Pace LE, 2014). Its data on breast cancer death use the USPSTF review. The Swiss Medical Board published a review in April 2014 too: its findings and recommendations are based on interpreting the Cochrane, USPSTF and Independent UK Panel data (Takiura K, 1973). And I posted a guide to understanding mammography evidence on my blog at Scientific American.

Update on 30 October 2014: The WHO published a review of systematic reviews of trials and observational studies, with a search date up to December 2012 (WHO, 2014). Their data interpretation is similar to that of the UK Independent Panel, and they recommend 2-yearly screening from 50 to 69 years of age, where there's a good screening program and informed decisions. Their estimates of harm are lower than those of some others, taking into account more recent practice.

Differences in the estimates and conclusions about the effect of breast screening with mammography on breast cancer mortality between these reviews are not due to different trials being assessed. The differences principally arise from differing judgments on the strengths and limitations of individual trials, and a focus on local screening practices (which vary in terms of women's ages and whether screening is every one, two or three years).

There were also some differences in methodologies for analyzing the data. The meta-analyses done by both the review for the USPSTF and the Independent UK Panel used random effects models, there being differences between the trials. The review for the USPSTF used a Bayesian analytic framework. The Cochrane review used a fixed effects model. A fixed effect model assumes that the effect would be consistent across trials.

The Independent UK Panel by Marmot et al re-analyzed the trial data included in the 2011 version of the Cochrane review (with the same trials and estimates as this version). The Panel derived a comparison of the estimates of various authors, including the reviews included here (Independent UK Panel on Breast Cancer Screening., 2012). In order to prevent one woman's death from breast cancer, the number of women who would need to be invited for screening was estimated as:

• Cochrane review: 2,000
• USPSTF, for women aged 50 to 59: 1,339 and for women aged 60 to 69: 377

• Independent UK Panel, for women aged 55 to 79: 235

  In order to prevent one woman's death from breast cancer, the number of women who would need to be screened was estimated as:

• Canadian Task Force, for women aged 50 to 69: 720

• Independent UK Panel, for women aged 55 to 79: 180

The Independent UK Panel estimated that about 20% of breast cancers detected by mammography screening may be over-diagnosis. They recommended screening only every 3 years to reduce the risk. The Cochrane review suggested this may be 30% or more.

Longer term follow-up on one of the trials included in these reviews has subsequently been published (Canadian National Breast Screening Study, Miller AB, 2014). That trial is one of the trials judged by reviewers to be of high quality, and has consistently found no significant reduction in deaths attributed to breast cancer. It is the trial with results least favorable to mammography included in these meta-analyses.

A further systematic review has looked at the question of non-breast cancer mortality in breast cancer screening trials (Erpeldinger S, 2013). Breast cancer trials were not designed to answer this question. These authors conclude that the trials show neither a decrease nor increase in non-breast cancer mortality associated with screening.

The review for the USPSTF identified two systematic reviews relevant to the question of psychological harm from breast screening with mammography (Brewer NT, 2007, Brett J, 2005). The reviewers concluded false-positives are associated with distress, but no consistent effect on anxiety and depression has been shown for screening with mammography. A more recent systematic review has also looked at the impact of false-positive mammogram results, coming to similar conclusions (Bond M, 2013).

Marmot pointed out that the members of the UK Independent Panel were chosen both for expertise and not having previously published on the subject, to minimize the risk of a biased approach to analyzing and interpreting evidence (Marmot MG, 2013). The USPSTF commissioned the independent Agency for Health Care Research and Quality (AHRQ) to conduct the review used for its decision-making (Nelson HD, 2009).

On 2013 Aug 16, Martin Fenner commented:

I've written a blog post about this paper, and a plugin for the Jekyll blogging platform that automatically detects database links in blog posts, currently supporting ENA/GenBank/DDBJ, Uniprot, PDB and MGI.

It is common practice in the life sciences to add tags right into the text. I don't think we necessarily need identifiers for databases, as proposed by William. Writing the tags as links would already be a major step forward, and that is why I wrote the jekyll plugin.

Even better would be to include database tags in the references of a paper. They would not only be easier to find, but we could also add metadata to the document. But we are probably a few years away from this as we have a strong community practice to have database tags right in the text.

On 2013 Aug 15, William Gunn commented:

I think what's really needed here is identifiers for databases, so we don't end up with the same problem that we have for authors and institutions, where there is so much ambiguity. Another job for ORCID?

On 2013 Jul 04, John Overington commented:

A standard for database tag structures would be really useful in general - 1ABC is a PDB code, but it's also many other things, so PDB1ABC would be more general and useful. However, as a database provider this paper highlighted several features that I didn't know and will now explore - e.g. the NLM JATS DTD.

On 2016 Jun 08, David C. Norris commented:

The abstract above must be appreciated in context of the Jun 2014 Erratum, which reports findings of a post-publication review by 3 independent reviewers assigned by Health Affairs. Those findings nullify the abstract’s key statistical claim:

Reviewers found that the authors’ use of a cluster-robust variance estimator was inappropriate in light of the small number of clusters (two) used in this analysis, because variances estimated by this method are biased downward toward zero as the number of clusters diminishes—a problem that had not been detected in the initial reviews of the paper. As a consequence, the standard errors reported in the article are understated, and the reported finding of a significant difference in mortality between the experimental and control groups is not supported by evidence presented in the article.

On 2014 Feb 02, Jan Tunér commented:

This conclusion of this study must be questioned. Not only that a 10 W laser poses a much higher risk of burning and eye injury and is more expensive than a class 3B laser - a Class 3B laser is quicker! The high output forces a sweeping motion or irradiation from a distance, thereby causing a lot of energy loss at the deep target. The time spent was 5 minutes, which is more than required by a conventional Class 3B session for this condition. With a 3B laser in firm contact over tender points and a sweeping motion over the actual condyle, more energy at target can be applied in 2-3 minutes. The authors of the paper above swept over an area of 45 cm2. By spreading the light over a large area, using a wide beam area and irradiating from a distance, the dose became 6.6 J/cm2 and the power density only 22 mW/cm2, which is very low. Irradiating in contact with 10 W is not possible, but with a 3B laser in firm contact, an optimal penetration is achieved and less time is required.

On 2014 May 01, G L Francis commented:

Given the role of IGF-II in embryonic development,including muscle, pancreas etc., as well as postnatally in tissue and wound repair (such as liver regeneration after partial hepatectomy),was the local expression level of this growth factor considered rather than IGF-I?

On 2016 Feb 10, Anders von Heijne commented:

In a recent case with a very large testicular epidermoid cyst we found an ADC-value of 0.544. IT seems that testicular epidermoid cysts have distinctly lower ADC-values than their intracranial counterparts.

On 2016 Aug 23, Ben Goldacre commented:

This trial has the wrong trial registry ID associated with it on PubMed: both in the XML on PubMed, and in the originating journal article. The ID given is NCT01576461. We believe the correct ID, which we have found by hand searching, is NCT01576471.

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

Many thanks,

Jessica Fleminger, Ben Goldacre*

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

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

On 2015 Oct 12, Bill Cayley commented:

One example of when a less medical approach may actually be better for possible malaria: https://lessismoreebm.wordpress.com/?s=malaria

On 2015 Sep 24, Bill Cayley commented:

A good example of when "less" is "more" in Obstetric care: https://lessismoreebm.wordpress.com/tag/obstetric-gynegologic/

On 2014 Feb 14, David Keller commented:

Were the benefits due to lower glucose levels, pleiotropic effects of exenatide, or lack of a placebo control?

The possible beneficial effect of exenatide on the progression of Parkinson disease might have been due to the mild sustained decrease in blood glucose levels which is the usual intended effect of this medication in diabetics, or to the pleiotropic neuroprotective effects hypothesized by the investigators, or to a combination of effects, including the placebo effect. Self-injection is a powerful placebo procedure, especially in a condition like Parkinson's disease, in which the magnitude of the patient's symptoms are affected by their psychological state and mood. Because the comparison group did not self-inject daily, the placebo effect was not controlled for in this study. Some of these questions could be addressed by comparing exenatide to self-injected basal insulin in future studies, dosed to produce an equivalent degree of glucose-lowering but without frank hypoglycemia. A slight lowering of blood glucose (within the normal range) might be neuroprotective by means of decreasing metabolism, and thereby decreasing the oxidative stress and the free radicals generated by metabolic reactions. Any benefit due to reduced metabolism caused by lowered blood glucose should be equivalent for equipotent doses of exenatide and basal insulin. Any additional benefit of exenatide over equipotent basal insulin could be ascribed to pleiotropic neuroprotective effects of the former.

A recent meta-analysis found that Parkinson patients treated with active drug had significantly less objectively measured motor response to the same intervention if they knew there was a chance that they were receiving placebo, even with effective double blinding (1). This decreased response, dubbed "the lessebo effect", could account for up to 4.1 UPDRS units of motor improvement for patients in studies lacking double-blinded placebo controls.

Reference

1) Mestre TA, Shah P, Marras C, Tomlinson G, Lang AE. Another face of placebo: The lessebo effect in Parkinson disease: Meta-analyses. Neurology. 2014 Apr 22;82(16):1402-9. doi: 10.1212/WNL.0000000000000340. Epub 2014 Mar 21. PubMed PMID: 24658930; PubMed Central PMCID: PMC4001195.

On 2014 Feb 23, David Keller commented:

A new approach or a step backward?

The "new approach" to disease-modifying drug trials seems to me to be a step backwards. Due to the inability to obtain placebo Byetta pen-injectors, the study was conducted without a true placebo control. Instead, the intervention group self-injected with actual Byetta pen-injectors daily, while the comparison group did nothing special and was followed passively over time. Thus, there was no control for the powerful placebo effect caused by daily self-injection by the intervention group, which could account for much of the beneficial effect observed. The symptoms of Parkinson disease are known to be somewhat dependent on the psychological state and mood of the patient, which tends to magnify the placebo effect.

A recent meta-analysis found that Parkinson patients treated with active drug had significantly less objectively measured motor response to the same intervention if they knew there was a chance that they were receiving placebo, even with effective double blinding (1). This decreased response, dubbed "the lessebo effect", could account for up to 4.1 UPDRS units of motor improvement for patients in studies lacking double-blinded placebo controls.

The manufacturer of Byetta should be encouraged to donate Byetta pen-injectors filled with normal saline to future clinical trials of exenatide, allowing them to be conducted as proper placebo-controlled and double-blinded studies. If such future trials demonstrate benefits, their results can be interpreted without caveats, and Byetta's manufacturer can expect to be repaid for their support of medical science by the subsequent increased sales to non-diabetic Parkinson patients.

Reference

1) Mestre TA, Shah P, Marras C, Tomlinson G, Lang AE. Another face of placebo: The lessebo effect in Parkinson disease: Meta-analyses. Neurology. 2014 Apr 22;82(16):1402-9. doi: 10.1212/WNL.0000000000000340. Epub 2014 Mar 21. PubMed PMID: 24658930; PubMed Central PMCID: PMC4001195.

On 2013 Jun 27, Markus Meissner commented:

Reply to Gary Ward:

Hi Gary. Thank you for your comments. We are glad you find the review helpful. For now, I prefer to focus on the first two comments and just mention a few information on the collar. 1) Regarding Non-essential and non-important. I agree with you. In fact all the discussed genes are probably essential in vivo. Although we only have preliminary data for the ama1KO that shows that this parasite is highly attenuated, similar data were obtained for a knockdown of MyoA and MIC2 (Meissner et al., Science 2002; Huynh et al., 2006). I have no doubt that other mutants behave similar. Furthermore, we know that MLC1, GAP45 and act1 are essential and depletion leads to parasite death. However, depletion does NOT lead to a block in host cell invasion. Therefore, none of the discussed genes can be defined as "essential for the process of host cell invasion". I agree that they are important for invasion. Invasion is however a multistep process (attachment, reorientation, junction formation, penetration) and we need to know which step is influenced by removal of the respective gene in order to obtain a clear picture of the (real) invasion mechanism. 2) Regarding interpretation of KO data you propose a third possibility, which relies on the accumulation of compensatory mutations or changes in gene expression. This explanation is certainly appealing and valid for some of the effects seen. For example it could be argued that deletion of an attachment factor can be compensated by upregulation of another, as seen in Plasmodium. Especially in case of non-essential genes (in vitro), long term adaptations are a strong possibility and like you we do observe this effect for some of the KOs. However, in case of conditional KOs for essential genes (i.e. actin) we observe that the whole culture dies within 10 days due to the loss of the apicoplast (Andenmatten et al., 2013). During this whole period the parasites remain able to invade. How would you imagine a scenario, where a gene remains essential for two processes (apicoplast division and egress) but not for invasion? I would strongly argue against a scenario, where an actin-like protein can form a filament (which has been never demonstrated in apicomplexans) that can be used by MyoA only during invasion but not during egress.

Regarding the Collar, we are not sure at this point what exactly it reflects. In the provided images wild type parasites were analysed and it will be certainly interesting to investigate if KO parasite show an increase in collar formation. Clearly, we need to analyse the collar in detail in the future.

On 2013 Jun 24, Gary Ward commented:

Thanks to the authors for this timely reanalysis of the current model of apicomplexan invasion. Recent work from the Meissner group has shown that several of the parasite proteins previously thought to be essential for invasion can be knocked out, casting some doubt on the model. I agree with much of what they write, but have three comments:

1) Non-essential does not mean non-important. In several of these knockouts, invasion and motility are dramatically impaired (e.g., ~80-85% inhibition of invasion) and defects of this magnitude can translate into greatly reduced virulence in vivo (e.g., Meissner et al, Science [2002] 298, 837). While the new data show clearly that MyoA and AMA1 are not essential for invasion, they at the same time show them to be important for invasion. Whether they are important for the reasons predicted by the current model is a separate question.

2) In the authors' view, the data either show that the "parasites use a single entry mechanism and hence the current invasion model is wrong and needs to be replaced by a new model, [or] the current model is overall valid but an additional, motor independent invasion mechanism is at work that facilitates host cell invasion in KO mutants of the glideosome". Redundant mechanisms are a common feature of parasite biology (e.g., erythrocyte-binding proteins of malaria parasites, Trends in Parasitology [2012] 28, 23), so I agree with these two possibilities. However, I would add a third: by knocking out a parasite protein that plays an important role in a process that is so critical to the parasite lytic cycle, enormous selective pressure is put on the parasites to come up with a way around the problem. Compensatory mutations or changes in the expression of other proteins that can "fill in" for the missing protein may occur. In fact, we have seen an improvement over time in the ability of some of these mutants to invade, which likely represents some advantageous mutation or change in gene expression that is being selected for in culture. Such changes will be hard to track down and even harder to rule out, but the phenotype observed in these knockouts will be due to some combination of the knockout itself and whatever the parasite does to overcome it.

3) The collar seen around the invading tachyzoite in Fig. 2 is intriguing, and unlike what we typically see by EM during invasion of human foreskin fibroblasts. How rare are these events, and are they specific to this cell type? This profile could reflect an alternative invasion mechanism, as proposed. On the other hand, these cells might have an unusually impenetrable cortical cytoskeleton and the parasites push but can't get in. In this case the moving junction would in fact really be a moving junction and would be pulled along the body of the stationary parasite, much like occurs during Cryptosporidium invasion and consistent with the standard model of invasion.

On 2013 Jun 24, Gary Ward commented:

None

On 2014 Dec 29, David Keller commented:

Might the addition of sargramostim to combination checkpoint inhibition reduce adverse events?

Recently, Hodi et al demonstrated that addition of sargramostim (GM-CSF) to high-dose ipilimumab monotherapy (10 mg/kg) resulted in significantly improved median overall survival, and also significant reduction in the rate of adverse effects compared with high-dose ipilimumab alone (1). It seems imperative to test the proposition that sargramostim might provide similar increase in benefit and decrease in risk when administered with combination checkpoint inhibition.

Reference

1: Hodi FS, Lee S, McDermott DF, Rao UN, Butterfield LH, Tarhini AA, Leming P, Puzanov I, Shin D, Kirkwood JM. Ipilimumab plus sargramostim vs ipilimumab alone for treatment of metastatic melanoma: a randomized clinical trial. JAMA. 2014 Nov 5;312(17):1744-53. doi: 10.1001/jama.2014.13943. PubMed PMID: 25369488.

On 2013 Jun 20, Martin Fenner commented:

The systemic therapy for metastatic melanoma changed dramatically in 2010 when ipilimumab, an antibody against cytotoxic T-lymphocyte–associated antigen 4 [CTLA-4], was shown PMCID: PMC3549297 to improve survival in patients previously treated with chemotherapy. In 2011 ipilimumab was shown Robert C, 2011 to also improve survival when given in combination with dacarbazine compared to dacarbazine alone in previously untreated metastatic melanoma patients.

The present study is a dose-finding phase Ib study looking at the combination of ipilimumab and nivolumab, an antibody against the programmed death 1 [PD-1] receptor. Fifty-five patients received concurrent therapy of the two drugs, whereas 33 patients previously treated with ipilimumab were given nivolumab (sequential therapy). The objective response rate in the 55 patients treated with combination therapy was 40% with 53% of patients experiencing grade 3 or 4 adverse events. In the 33 patients treated with sequential therapy, 20% showed an objective response and 18% had adverse events related to therapy.

The study results demonstrate clinical activity of the combination therapy with manageable adverse events (although the rate of adverse events was increased in the concurrent therapy group). What the publication unfortunately fails to do is to clearly describe the study design. According to the information at ClinicalTrials.gov the primary endpoint of the trial was safety (as expected for a phase I trial), and this primary endpoint is mentioned neither in the abstract nor the methods section. What the publication also fails to mention is that according to the Clinicaltrials.gov information this is an ongoing trial with an estimated enrollment of 136 patients and an estimated study completion in August 2014. With all the excitement about new treatment options for metastatic melanoma patients we shouldn't forget best practices of reporting clinical trial results.

On 2013 Jul 05, Brian Caffo commented:

None

On 2013 Jul 05, Brian Caffo commented:

This is a nice manuscript with a fundamentally sound message. However, node selection in brain network analysis using fMRI or DTI remains a fundamental problem. Moreover, as the author has pointed out here and elsewhere, integrating network estimation across modalities and resolutions is the key for success of the BRAIN project.

On 2013 Oct 23, Stephen Turner commented:

This paper warrants a closer look for both the strategy and implementation for pulling out microbial next-generation sequencing (NGS) reads from a highly contaminated host background. IMSA (integrated metagenomic sequence analysis) is a computational pipeline that does this and is flexible enough to allow the user to select and update which databases they're using and the stringency for removing host sequence. It also has some decent post-processing and output functionalities.

The algorithm has a series of steps to remove host sequences, each more computationally intensive than the previous step (e.g. Bowtie... BLAT... BLAST). After that, it BLASTs everything against NCBI/nt. It scores reads in a simple but intuitive manner (a read that maps perfectly and uniquely to a sequence in the reference database gets a score of 1; a read that maps perfectly to two conserved regions scores 0.5; a read that maps to three scores 0.333; etc.). It then outputs a list of taxonomic IDs and annotated FASTQ files of filtered reads aligning to those IDs that can then be used downstream (assembly, etc.).

They ran this pipeline on a combined set of viral reads from two different human papillomaviruses (HPVs) in two different cell lines and were able to distinguish the two strains and pull out reads from those strains at the expected proportions. Interestingly, they filter against both the genome and the transcriptome. They found that when they filtered against RefSeq RNAs alone, their read coverage for certain regions in HPV dropped to zero. This is because RefSeq still contains annotation errors, where some genes annotated as human actually contain HPV sequence.

In addition to outputting a breakdown of what's in the sample and an annotated FASTA file of sequences that aligned to taxa, the pipeline also has tools to output data in a format for phylogenetic tree analysis with Treeview, Cluster, etc. With respect to performance, they claim 50bp single-end reads can be processed at 4.5 hours per million reads per node used.

On 2016 Mar 18, ZHONGMING ZHAO commented:

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

On 2014 Oct 06, Raha Pazoki commented:

None

On 2014 Oct 06, Raha Pazoki commented:

Addendum to previous comment "Tissue-specific online eQTL databases"

In the previous analysis, I compared heart-specific eQTLs from the GTEx consortium with eQTLs from the study by Koopman and co-workers. In that analysis, I considered SNP-gene pairs that appear with exactly the same names in the 2 databases. However, SNPs in high linkage disequilibrium (LD) and genes with various annotations may exist between these databases. It would be interesting to put a little more effort and search for such SNPs and genes to come-up with additional SNPs that consistently change cardiac expression of specific genes.

Raha Pazoki (twitter:@rahap)

On 2014 Sep 20, Raha Pazoki commented:

Tissue-specific online eQTL databases

Online eQTL databases provide exciting opportunities for the researchers in the field of genomics. Tissue-specific eQTL databases are especially important to provide information about functional mechanisms related to diseases that have tissue specific characteristics. Examples are heart-specific eQTL databases presented in the GTEx online eQTL database (GTEx Consortium., 2013) or the human heart eQTL database from a study by Koopman and co-workers (Koopmann TT, 2014). For researchers in the field of cardiovascular genetics, such databases provide exciting candidate genes for further follow-up in human disease populations to predict disease or further investigation in experimental studies to identify novel mechanisms. Such databases also provide an opportunity for comparison across eQTL studies to highlight the most promising eQTLs with consistent effects in tissue-specific manner. In the example above, comparison of the eQTLs identified in the human heart, left ventricle tissue from the GTEx eQTL database and the human heart eQTLs identified in the study by Koopman and co-workers reveals that 18 SNP-gene pairs have been reported in both eQTL studies by passing stringent statistical significance thresholds. These pairs include (rs1006771 -DDTL), (rs1030421 -ADHFE1), (rs11603384 -TRPT1), (rs11880207 -ZNF266), (rs12609437 -MARCH2), (rs1319763 -NT5C3L), (rs17518363 -SUSD4), (rs2054365 -QRSL1), (rs241443 -TAP2), (rs371671 -MRI1), (rs3814231 -CASP7), (rs4970777 -GSTM3), (rs4985407 -EXOSC6), (rs6488713 -C12orf60), (rs651601 -RPS16), (rs8066107 -RPH3AL), (rs863214 -DHFR), and (rs8850 -MRPS10). However, only the effect of rs241443 on the expression level of TAP2 gene shows the same direction in both studies. The magnitude of the effect of rs241443 on TAP2 is greater in the GTEx database (Beta= -0.64, P value= 1.1 ×10^-9 ) than in the study of Koopman and co-workers (Beta=-0.34, P value= 4.11 ×10^-9 ). Obviously, more research work is necessary to identify more tissue-specific eQTLs and consequently consistent and promising functional loci.

On 2013 Jun 24, Dita Gratzinger commented:

Very helpful review of an entity that is poorly described in the spleen, and may easily be mistaken for a low grade lymphoma such as CLL/SLL or marginal zone lymphoma if the peripheral blood smear and/or clinical history are not readily available.

On 2016 May 10, Ramune Jacobsen commented:

On behalf of: Jacobsen R, Abrahamsen B, Bauerek M, Holst C, Jensen CB, Knop J, Raymond K, Rasmussen LB, Stougaard M, Sørensen TI, Vaag AA, Heitmann BL and the D-tect group (The Research Unit for Dietary Studies at the Parker Institute and the Institute of Preventive Medicine, Frederiksberg and Bispebjerg Hospital, The Capital Region, Denmark). In the published paper we describe the design of a Danish societal experiment, the “D-tect study”. Among others, the D-tect study takes advantage of the mandatory vitamin D fortification policy implemented in Denmark, in which we used onset and termination of the vitamin D fortification of margarine to examine the possible effect of food fortification on the risk of adverse health outcomes among individuals from birth through adulthood (Jacobsen R, 2013). Based on official documentation from the Nordic Council of Ministers (1), the commencement of vitamin D fortification was 1961. However, we have recently uncovered new evidence that makes this onset date less secure, and suggests that mandatory fortification may have started even before World War II, for both vitamin A and D (2-4). While this new research weakens our confidence in the onset date of the vitamin D margarine fortification, all data sources we have come across confirms that the date of termination of the mandatory margarine fortification with 50 IU D-vitamin per 100 g margarine was June 1985 (5). Furthermore, the new evidence suggests a change in fortification policies related to mandatory vitamin A fortification around 1961 (an additional 25% vitamin A was added to margarine raising amounts from 20 iu to 25 iu per g margarine) (6). It is feasible that the addition of vitamin A may have programming effects related to both neurodevelopment, immune function and growth (Zhang X, 2009,van de Pavert SA, 2014,Wang YZ, 2009) like those from vitamin D, and that effects seen around initiation, for instance as those we saw in relation to birth weight (Jensen CB, 2015, Jensen CB, 2014), may potentially be explained by the extra vitamin A from fortification (Yassai MB, 1989, Ghebremeskel K, 1994, Tolba AM, 1998). We regret that we had not identified this information prior to study commencement. However, we now have access to analytic epidemiology in order to directly explore links between neonatal vitamin D status and risk of adverse health outcomes, as we have been able to directly measure 25 hydroxyvitamin D concentrations in neonatal dried blood spots over the years of interest. In light of the potential that food supplementation with vitamin D can differentially impact on neonatal and adult health outcomes, we will continue to use the best available evidence to explore this area of research. References: 1.Haraldsdóttir J & Thaarup S: Tilsætning af vitaminer & mineraler til levnedsmidler. Nordisk Ministerråd. 1989; 2.Lov om tilvirkning og forhandling af margarine m.m (Bek. af lov om tilvirkning og forhandling af margarine m.m ). Nr. 229 af 28. juni 1937; 3.Bekendtgørelse angaaende Vitaminvirkning i Margarine. Nr. 247 af 28. juli 1937; 4.Bekendtgørelse om vitaminvirkning i margarine. Nr. 258 af 27. juni 1952; 5.Bekendtgørelse om margarine m.v. Nr. 197 af 20. maj 1985; 6.Bekendtgørelse om vitaminvirkning i margarine. Nr. 344 af 5.december 1961.

On 2017 Nov 15, David Keller commented:

Does tunneling through brain parenchyma to implant DBS leads cause subtle verbal impairment?

In 2013, the following letter to the editor of the NEJM questioned the lack of significant loss of verbal fluency reported in EARLYSTIM, in contrast to that seen in prior trials.[1]

The investigators in the Controlled Trial of Deep Brain Stimulation in Early Patients with Parkinson's Disease (EARLYSTIM) found that “no significant between-group differences were observed for cognitive assessments” when they compared patients who received subthalamic neurostimulation for Parkinson's disease with those who received medical therapy alone. In a recent review, [2] Okun described a meta-analysis finding that “the most common cognitive side effect of deep-brain stimulation was a decrement in verbal fluency.[3] Impaired verbal fluency is characterized by communication difficulties and by problems in generating word lists.” Okun and colleagues also conducted a study that showed that a “decrease in verbal fluency is an effect of surgical electrode implantation, not an effect of stimulation.”[4]

Did the EARLYSTIM investigators use a technique of lead placement that avoided impairing verbal fluency, or were the tests they used for assessing cognitive outcomes not sensitive instruments for measuring verbal fluency?

References 1) Keller DL. Neurostimulation for Parkinson's disease with early motor complications. N Engl J Med. 2013 May 23;368(21):2037-8. doi:10.1056/NEJMc1303485#SA2. PubMed PMID: 23697522. 2) Okun MS. Deep-brain stimulation for Parkinson's disease. N Engl J Med 2012;367:1529-1538 3) Parsons TD, Rogers SA, Braaten AJ, Woods SP, Troster AI. Cognitive sequelae of subthalamic nucleus deep brain stimulation in Parkinson's disease: a meta-analysis. Lancet Neurol 2006;5:578-588 4) Okun MS, Gallo BV, et al. Subthalamic deep brain stimulation with a constant-current device in Parkinson's disease: an open-label randomised controlled trial. Lancet Neurol 2012;11:140-149

The EARLYSTIM investigators replied as follows:

Keller raises questions regarding the effect of neurostimulation on verbal fluency shown in all controlled studies. We assume that verbal fluency is also significantly worse in patients in the neurostimulation group than in those in the control group in EARLYSTIM. Therefore, we have added a second protocol, EARLYSTIM-speech, to compare standardized speech recordings at baseline and at 24 months. This study will provide more information not only on the frequency and severity of changes of word fluency but also on the effect of these changes on communication in real life.

The EARLYSTIM-speech add-on study has not reported results yet, but a recent private communication from Günther Deuschl, M.D.-Ph.D., promised that results will be reported soon.

On 2013 Oct 28, DAVID SANDERS commented:

From "Covalent modifications of the ebola virus glycoprotein" Jeffers SA, 2002 "The conservation of a mucin-like region and its variability between isolates indicate that it is likely to play a critical role in the ecology and pathogenesis of the virus, factors which cannot be assessed in the pseudotype system. The probable surface exposure of the charged sugar moieties in this region may make it a dominant target for the humoral immune system. Indeed, protective monoclonal antibodies recognizing epitopes that lie between sequences that are likely to be modified by O-linked glycosylation have been identified. The toleration of the mucin-like domain for variations could allow the virus to readily escape immune recognition through mutations. Indeed, the protective monoclonal antibodies recognizing the Ebola virus Zaire GP O-linked glycosylation region have been shown to be specific for particular isolates Wilson JA, 2000.

On 2014 Nov 17, Pavel Baranov commented:

Due to a software error in an earlier version of the browser, the data in Figure 4 are not represented correctly. Apologies.

On 2014 May 07, T Eugene Day commented:

This paper addresses a critical aspect of modeling complex systems in healthcare. Dynamic human decision makers exhibit important complexities within systems, and there are demands on their time and attention that should be included in rigorous models. This is especially true in academic environments where attending physicians are required to oversee and instruct residents and fellows. Crucial systemic outcomes depend on these interactions, as well as medical outcomes.

The validation of this model could be more informative if the authors had compared the simulated data to real-world data from their modeled ED. This would allow us to examine how well the inclusion of physician-delegate interactions allowed them to mimic the performance of a real-world ED. This would provide stronger evidence that this model can be used to inform practice.

Ever more lifelike models of human behavior will be required to make useful predictions of systems performance, and this is an important step on that road. The use of pseudo-agents, rather than a strict resource/entity model, allows greater flexibility and autonomy on the part of the simulated human resources.

On 2014 Dec 10, Kath Wright commented:

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

On 2017 May 30, Doug Berger commented:

Methodologic problems in this meta-analysis:

(1) This meta-analysis noted whether blinding was incorporated into the trial but did not (and probably cannot) evaluate if blinding was maintained properly.Trials with subjective endpoints (like major depression) that are also unable to maintain double-blinding throughout the trial should be invalidated. These trials cannot say anything about effectiveness of the drug being tested and an unblinded non-inferiority trial of poor quality comparing placebo to unblinded active drug is the result. An exit-analysis of the proportion of subjects and treaters who correctly guessed the arm they were assigned to is needed.

(2) Indications with objective as well as subjective endpoints in differing indications and therapeutic areas were included in this analysis which make interpretation impossible. Any indication with subjective endpoints and inadequate blinding should be excluded from a meta-analysis, however the quality of blinding would be difficult to confirm by this meta-analysis that did not specifically require proof with exit-analysis data.

(3) Clinical drug trials are carried out to confirm if drugs work, the drugs are not yet confirmed to be effective. Comparing placebo to a drug that does not work becomes a [placebo vs drug as placebo] comparison and says little about efficacy of placebo vs approved drug. Most drugs on the market with subjective endpoints (psychiatry) have previously been tested vs blind placebo, however, this meta-analysis did not limit itself only to drugs that went on to approval.

Conclusion: Placebo may function in a clinical setting as a useful tool for certain patients with certain conditions in assuaging some symptoms: pain, worry, hopelessness, etc, however, this meta-analysis had a number of methodologic problems as noted above that limit the conclusions that can be made on the actual effect of placebo vs drugs that have market approval.

On 2015 Feb 25, James Tsung commented:

Link to ultrasound videos: https://youtu.be/A23lPwFcOAs?list=PLHg2xyua_KjsYkxwaVuSpsXcyeLHAYM51

On 2013 Jun 14, Dita Gratzinger commented:

This single institution retrospective study provides needed information on the landscape of acute myeloid leukemia in children. Of note are significant numbers of children with favorable outcomes associated with recurrent translocations such as t(8;21)(q22;q22);RUNX1-RUNX1T1, or t(15;17)(q22;q12);PML-RARA, as well as myeloid leukemia associated with Down syndrome. Unfortunately similarly large groups of children have poor to very poor outcomes in the categories of acute myeloid leukemia with myelodysplasia-related changes and therapy-related acute myeloid leukemia. This study both confirms the relevance of categories in the WHO 2008 classification to childhood acute myeloid leukemias, and points to areas of need for improved therapy.

On 2013 Jun 14, Dita Gratzinger commented:

The authors present a comprehensive and up to date review of an entity that must not be missed due to potentially severe clinical consequences, but is at present diagnosed using a constellation of individually fairly nonspecific criteria. Of note from the perspective of the surgical pathologist or hematopathologist is the fact that while hemophagocytosis itself is one of the 8 criteria that can be used in combination with at least 4 others to diagnose HLH, it is neither required nor very specific for the diagnosis.

On 2013 Nov 19, Allison Stelling commented:

One minor quibble with the authors of this quite thorough review: you keep referring to genetic alterations one can test for in brain tumor patients as "molecular diagnostics". Technically this is correct- genes are, indeed, molecules. (Well, macromolecules.) However, perhaps it may be better to simply refer to sequencing of patient DNA as "genetic diagnostics"- just to avoid confusion between this and true molecular phenotype information. (When I read "molecular analysis", I assume someone has done a crystal structure, FTIR, NMR, and mass spec- usually not the case in tissue research!)

Your call for interdisciplinary cooperation- which is nicely illustrated in Figure 1- necessitates cross border communication as well as orchestration between communities of experts. More nuanced definitions of diagnostic tests may be helpful for facilitating this conversation.

On 2014 Jan 15, Satoko Hattori commented:

"ImageLD" and "ImageEP", image analysis application softwares used in this article, are now freely available from http://www.mouse-phenotype.org/software.html.

On 2016 Aug 23, Ben Goldacre commented:

This trial has the wrong trial registry ID associated with it on PubMed: both in the XML on PubMed, and in the originating journal article. The ID given is NCT0066305. We believe the correct ID, which we have found by hand searching, is NCT00663052.

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

Many thanks,

Jessica Fleminger, Ben Goldacre*

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

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

On 2014 Mar 01, Ellen M Goudsmit commented:

Dr. Melvin Ramsay began writing about the illness now known as ME after the outbreak in north London in 1955. I looked in his book (1988) for a paper written by him in 1959 and found none. The best known article from 1959 was written by the late Dr. Acheson, who gave ME its name in a leader in the Lancet (1956). Dr Ramsay offered a diagnostic protocol but not until the 1980s. I agree with Morris and Maes that the core symptom of ME is an exacerbation of symptoms following minimal exertion (supported by Paul et al who referred to CFS but actually selected patients with ME, pers. comm.). It should also be noted that none of the existing criteria for ME and CFS have been found to have the required specificity and sensitivity. And that includes the 2011 version.

The abstract indicates a lack of attention to detail. This undermines the understanding of the issues and shows a lack of respect, not only for the researchers but also for the patients, 99% of whom would know how to spell the name of arguably one of the most knowledgeable experts in this field. This failure to check for accuracy is a major cause for confusion in the literature on ME and CFS. And what happened to peer review? Any peer would have noticed the problem with the first sentence.

People really interested in ME and CFS may like to purchase an excellent publication by Shepherd and Chaudhuri summarising the knowledge to date. It's available from the ME Association in the UK. An authoritative and accurate review (2013).

Leading article. A new clinical entity? Lancet, 1956, 1, 789-790.

Paul, L et al. Demonstration of delayed recovery from fatiguing exercise in chronic fatigue syndrome. European Journal of Neurology, 1999, 6, 63-69.

Ramsay, AM. Myalgic encephalomyelitis and postviral fatigue states. Second Ed. Gower Medical Publ. 1988. now available from the MEA Association, UK.

On 2013 Jul 16, Matthew Child commented:

A fascinating story, complemented by elegant proof-of-principal experiments presented by Regev-Rudzki, N (PMID:23683579). Like rats from a sinking ship, the parasite seeks to escape the hostile environment induced by the drug. It neatly addresses phenomenological observations noted during P. falciparum culture and transfection; the process of electroporation and subsequent drug selection for a transgenic population can often result in the production of large numbers of gametocytes.

One question and point of epidemiological relevance that arises in light of these data is as follows; is the rate of parasite transmission greater in areas where drug-treatment regimes are instigated? Could it be that we have in fact been inadvertently increasing the likelihood of parasite transmission through drug treatment programs that induce gametocytogensis of the parasite population in an infected individual? The data may already be available to answer this, and I’d be fascinated to hear if anyone out there knows of any published studies that have sought to address this point.

On 2013 Jun 25, Dave Richard commented:

In this paper, Mantel et al provide an in-depth characterization of P. falciparum infected red blood cell derived microvesicles (RMVs) and provide evidence for their role in stimulating the human immune system and interestingly, as a means of cell-to-cell communication leading to increase parasite gametocytogenesis, a phenomenon also described in a recent paper published in Cell by Regev-Rudzki and Wilson et al.

Intriguingly, the authors demonstrate that RMVs are exempt of knob components such as KAHRP and PfEMP1. The latter's role in modulating host responses is well documented so it will be of great interest to identify what components of the RMVs interact with the host immune system. Moreover, to gain insight into the mechanisms behind RMV secretion, it would be interesting to look whether RMVs produced by knobless parasite strains like D10, where PfEMP1 is distributed more uniformly on the erythrocyte surface, would still be devoid of PfEMP1.

On 2014 Aug 30, Michelle Lin commented:

A week-long discussion was held at the ALiEM-Annals of EM Journal Club:

http://www.aliem.com/inaugural-global-em-journal-club-hosted-by-aliem-and-annals-of-em/

On 2014 Apr 10, Patrick Hiepe commented:

congratulations, nice work Philipp !

On 2014 May 08, Ivan Oransky commented:

This paper has been retracted: http://retractionwatch.com/2014/05/05/dubai-ous-journal-yanks-surgery-paper-for-consent-data-issues/

On 2013 Jun 18, Dan Arking commented:

This paper presents data that 88% (range 77% to 94%) of eQTLs are shared across tissues, which is marked contrast to the original analysis of this data (69% to 80% were called cell specific!). A nice feature of this approach is the incorporation of a hierarchical model which does not assume that all tissues contribute equally to an eQTL.

On 2013 Oct 29, Maurice Elphick commented:

This is a really important contribution to our understanding of the evolution of neuropeptide and peptide hormone signalling systems. It provides the most comprehensive framework to date for comparative analysis of the physiological and behavioural roles of peptide signalling systems in different animal phyla. I strongly recommend it to anyone who has an interest in any aspect of neuropeptide/peptide hormone biology.

On 2016 Dec 29, Francisco Xavier Castellanos commented:

Mazza et al. report rates of sudden death or strokes per 100,000 person-years as percents. These must be errors. Please clarify.

On 2014 Dec 17, Sean Ekins commented:

some slides on this work http://www.slideshare.net/ekinssean/enhancing-high-throughput-screeing-for-mycobacterium-tuberculosis-drug-discovery-using-bayesian-models-18617786

On 2014 Dec 17, Sean Ekins commented:

A post on what it took to get this paper published in PLOS ONE http://www.collabchem.com/2013/05/09/my-experiences-with-publishing-at-plos/

On 2014 Feb 16, Lorene M Nelson commented:

This article provides a nice overview of the rationale for proposing a high-fat or ketogenic diet in ALS. A correction is needed, however, in one the authors' statements. ". . . a US case-control retrospective study reported a nonsignificant trend toward increased risk of amyotrophic lateral sclerosis in subjects who reported a diet high in fat calories, however this study was not adjusted for tobacco use [22]." As the author of that study, I would like to point out that the study results were adjusted for pack-years of smoking (see Methods section and Table 3 in Nelson LM, Matkin C, Longstreth WT Jr, McGuire V. Population-based case-control study of amyotrophic lateral sclerosis in western Washington State. II. Diet. Am J Epidemiol. 2000;151(2):164-173.)

On 2015 Jul 12, Egon Willighagen commented:

Dear authors, I just searched for your ontology on BioPortal (we do not seem to have a Chemistry equivalent), but could not find your ontology. Have you considered making it available via BioPortal?

On 2013 Dec 19, Raphael Stricker commented:

Our Letter to the Editor of Lancet Infectious Diseases (2014;14:12) expressed concern about the safety of the new Lyme OspA vaccine from Baxter Bioscience. This concern is based on safety issues related to the previous Lyme OspA vaccine, Lymerix®, which was taken off the market after these safety issues surfaced, as outlined in our letter.

In their response to our letter, the employees of Baxter Bioscience who studied the new vaccine made the following comment: “There are no data in Stricker and Johnson’s cited publications that support the statement that ‘joint-reactive and nerve-reactive antibodies’ are induced in human beings vaccinated with OspA antigen.” This comment is misleading because OspA vaccine-related antibodies against nerve and joint tissue have been detected in animals and humans described in the references below. Furthermore, the fact that antibodies with unknown reactivity were induced by Lymerix® vaccination presents an unresolved safety issue for the new OspA vaccine, and this issue was not addressed by the Baxter Bioscience employees who studied the vaccine.

Once again, the willingness of Baxter Bioscience to ignore legitimate safety concerns bodes ill for the new Lyme vaccine.

Raphael B. Stricker, MD, Lorraine Johnson, JD, MBA

References

1. Stricker RB. Lymerix® risks revisited. Microbe 2008;3:1-2.

2. Smith P, Gaito A, Marks DH. Transcript of FDA Lymerix Meeting, Bethesda, MD, January 22, 2002. Available at: http://www.lymediseaseassociation.org/index.php?option=com_content&view=article&id=532:lymerix-meeting&catid=129:hhsfood-a-drug-administration-fda&Itemid=531

3. Croke CL, Munson EL, Lovrich SD, et al. Occurrence of severe destructive Lyme arthritis in hamsters vaccinated with outer surface protein A and challenged with Borrelia burgdorferi. Infect Immun. 2000;68:658–63.

4. Rose CD, Fawcett PT, Gibney KM. Arthritis following recombinant outer surface protein A vaccination for Lyme disease. J Rheumatol. 2001;28:2555–7.

5. Latov N, Wu AT, Chin RL, Sander HW, Alaedini A, Brannagan TH. Neuropathy and cognitive impairment following vaccination with the OspA protein of Borrelia burgdorferi. Periph Nerv Syst. 2004;9:165–7.

6. Alaedini A, Latov N. Antibodies against OspA epitopes of Borrelia burgdorferi cross-react with neural tissue. J Neuroimmunol. 2005;159:192–5.

7. Souayah N, Ajroud-Driss S, Sander HW, Brannagan TH, Hays AP, Chin RL. Small fiber neuropathy following vaccination for rabies, varicella or Lyme disease. Vaccine 2009;27:7322-5.

8. Marks DH. Neurological complications of vaccination with outer surface protein A (OspA). Int J Risk Saf Med. 2011;23:89-96.

9. Molloy PJ, Berardi VP, Persing DH, Sigal LH. Detection of multiple reactive protein species by immunoblotting after recombinant outer surface protein A Lyme disease vaccination. Clin Infect Dis. 2000;31:42-7.

10. Fawcett PT, Rose CD, Budd SM, Gibney KM. Effect of immunization with recombinant OspA on serologic tests for Lyme borreliosis. Clin Diagn Lab Immunol. 2001;8:79-84.

11. Hanson MS, Edelman R. Progress and controversy surrounding vaccines against Lyme disease. Expert Rev Vaccines 2003;2:683–703.

12. Nigrovic LE, Thompson KM. The Lyme vaccine: a cautionary tale. Epidemiol Infect. 2007;135:1–8.

13. Nardelli DT, Munson EL, Callister SM, Schell RF. Human Lyme disease vaccines: past and future concerns. Future Microbiol. 2009;4:457-69.

14. Smith P. Remarks to Vaccines and Related Biological Products Advisory Committee, Bethesda, MD, January 31, 2001. Available at: http://www.lymediseaseassociation.org/index.php?option=com_content&view=article&id=262:vaccine-remarks&catid=80:controversy&Itemid=76

Disclosure: RBS and LJ are members of the International Lyme and Associated Diseases Society (ILADS) and directors of LymeDisease.org. They have no financial or other conflicts to declare.

On 2014 Jan 31, George W Hinkal commented:

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

https://cananolab.nci.nih.gov/caNanoLab/characterization.do?dispatch=summaryView&sampleId=39124992&page=0&tab=ALL

https://cananolab.nci.nih.gov/caNanoLab/characterization.do?dispatch=summaryView&sampleId=39124993&page=0&tab=ALL

https://cananolab.nci.nih.gov/caNanoLab/characterization.do?dispatch=summaryView&sampleId=39124994&page=0&tab=ALL

https://cananolab.nci.nih.gov/caNanoLab/characterization.do?dispatch=summaryView&sampleId=39124995&page=0&tab=ALL

https://cananolab.nci.nih.gov/caNanoLab/characterization.do?dispatch=summaryView&sampleId=39124996&page=0&tab=ALL

https://cananolab.nci.nih.gov/caNanoLab/characterization.do?dispatch=summaryView&sampleId=39124997&page=0&tab=ALL

https://cananolab.nci.nih.gov/caNanoLab/characterization.do?dispatch=summaryView&sampleId=39124998&page=0&tab=ALL

https://cananolab.nci.nih.gov/caNanoLab/characterization.do?dispatch=summaryView&sampleId=39124999&page=0&tab=ALL

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

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

On 2014 Jan 08, Brett Snodgrass commented:

Dear Authors,

Thank you for the excellent article. Please provide your kind attention to the distinction between the Thebesian veins and the vessels of Wearn. http://bit.ly/JTWearn

http://bit.ly/vasaThebesii

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

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

For additional commentary, please see the following link:

https://twitter.com/BrettSnodgrass1/status/417433946196942848

Comments and suggestions are welcome.

Thank you very much.

On 2016 Aug 30, Ben Goldacre commented:

This trial has the wrong trial registry ID associated with it on PubMed: both in the XML on PubMed, and in the originating journal article. The ID given is NCT0053089. We believe the correct ID is NCT00530894.

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

Many thanks,

Jessica Fleminger, Ben Goldacre*

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

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

On 2015 Aug 23, David Keller commented:

Information theory contradicts Guideline Statement 4: more frequent PSA testing should benefit patients, not harm them

Information theory describes the reconstruction of continuous signals from discrete samples, and the extraction of signals from noise. Screening for prostate cancer involves scrutiny of a man's serial PSA measurements, with the goal of determining the likelihood that his prostate has developed a malignancy which could affect his longevity or quality of life (ie: his mortality or morbidity). Statement 4 from the 2013 Early Detection of Prostate Cancer: AUA Guideline [1] is as follows:

"Guideline Statement 4: To reduce the harms of screening, a routine screening interval of two years or more may be preferred over annual screening in those men who have participated in shared decision-making and decided on screening. As compared to annual screening, it is expected that screening intervals of two years preserve the majority of the benefits and reduce over diagnosis and false positives. (Option; Evidence Strength Grade C)"

Guideline Statement 4 can be proved false using the principles of information theory as follows. Individual PSA blood test results constitute discrete samples of the continuous signal which would result from continuous monitoring of the patient's PSA. The Nyquist-Shannon Sampling theorem states that the minimum sampling rate for perfect reconstruction of a signal is equal to twice the bandwidth of the signal [1]. Expressed another way, the maximum bandwidth of a signal to be perfectly reconstructed from samples taken at a sampling frequency f is f/2.

The crucial signal we wish to detect is a rising PSA consistent with a dangerous prostate cancer. Empirically, the faster a prostate cancer grows, the more rapid the rise in PSA and therefore the higher the bandwidth of the PSA signal. We would like to detect PSA signals which rise rapidly (have high bandwidth) in order to treat the patient while his cancer is confined to his prostate. The more frequently we sample the PSA, the higher the bandwidth of the PSA signal we can detect, meaning the more rapid rises in PSA will not escape detection. So, increasing the PSA sampling rate from once every 2 years to once every year can only improve the detection of the high-bandwidth signal caused by a rapidly growing prostate cancer. In fact, increasing the PSA sampling rate to twice per year, 4 times per year or even higher will only increase the maximum detectable bandwidth of the PSA signal.

Harms associated with PSA screening are generally associated with the prostate biopsy procedure and downstream diagnostic and therapeutic intervetions. The purpose of PSA sampling is to inform us when a prostate biopsy is likely to be more beneficial than harmful. The cumulative harm of multiple biopsies is proportional to the number of biopsies done, so we want to minimize the number of biopsies without missing a dangerous cancer. However, if the PSA signal includes useful information about the presence of cancer, the best way to reduce the number of biopsies is to improve the quality (bandwidth) of the detected PSA signal, which requires increasing the PSA sampling rate.

Reducing the PSA sampling rate in an attempt to reduce the harms caused by prostate biopsy is akin to hiding one's head in the sand. Continuous monitoring of the PSA signal would be ideal, but the maximum practical PSA sampling frequency should be employed to maximize the quality of the reconstructed PSA signal, and thereby increase the likelihood of detecting a fast-growing tumor while it is confined to the prostate. Application of a low-pass filter to the PSA signal should reduce the number of biopsies triggered by noise.

Lastly, the prostate biopsy rate need not be correlated with the PSA sampling rate, and indeed should be inversely correlated with it if the PSA signal has useful information about the presence of dangerous cancer in the prostate.

Reference

1: Shannon CE, Communication in the presence of noise, Proc. Institute of Radio Engineers, vol. 37, no. 1, pp. 10–21, Jan. 1949

On 2013 Jun 28, Julia Gilden commented:

Interesting paper. I would have enjoyed a greater focus on the functional differences between LPS-dependent and Leishmania-dependent exosomes. To me, the most interesting question is whether Leishmania might be have evolved a mechanism for highjacking exosomes for the delivery of GP63. I wish the authors had commented on the quantity of GP63 observed and whether it was enough to potentially effect neighboring cells. I'm also curious as to whether the LPS-dependent exosome preps contain any LPS, since if so, that might contribute to the strongly immunostimulatory effect of those exosomes compared to the other groups.

On 2014 Dec 17, Sean Ekins commented:

some slides on this work http://www.slideshare.net/ekinssean/acs-dispensing-processes-profoundly-impact-biological-assays-computational-and-statistical-analyses

On 2014 Dec 17, Sean Ekins commented:

A post on what it took to get this paper published http://www.collabchem.com/2013/05/03/what-it-took-to-get-the-paper-out/

On 2016 Nov 22, MICHAEL BALLARD commented:

This manuscript has been republished as Li, W., et al. (2014). “Elevation of brain magnesium prevents synaptic loss and reverses cognitive deficits in Alzheimer's disease mouse model.” Mol Brain 7(1): 65. See PubMed: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4172865/ and journal site: https://molecularbrain.biomedcentral.com/articles/10.1186/s13041-014-0065-y

Figures 4 and 5D from the original article have been removed from the republished version.

According to the authors' retraction notice: “This article described the effects of elevating brain magnesium on preventing and reversing cognitive deficits in an Alzheimer's disease mouse model. During recent efforts to extend this work, we discovered errors in the quantification of the expression and/or phosphorylation of a subset of signaling pathways, particularly related to Figures 4 and 5D. Despite these errors, the major conclusions of the paper remain substantiated."

On 2014 Apr 20, Sergio Stagnaro commented:

None

On 2014 Apr 18, Ivan Oransky commented:

This paper has been retracted: http://retractionwatch.com/2014/04/18/authors-retract-study-suggesting-magnesium-prevents-alzheimers-in-mice/

On 2013 Oct 28, Egon Willighagen commented:

The data presented in this paper can be downloaded as CC-BY-SA from the Dutch Dataverse Network with this handle http://hdl.handle.net/10411/10279.

On 2013 Dec 06, John Cannell commented:

I congratulate the authors on their intresting paper. I found my self wondering however, how can they explain the dramatic increase in incidence in this centruy? Didn't Tylenol use remain fairly constant from the year 2000 to the present time?

The question is why do some children exposed to Tylenol may develop autism and some do not? The answer must lie in their immune system. Some mothers and fetuses have enough antioxidant reserve to protect themselves from the oxidative damage induced by paracetamol exposure and some do not.

Certainly, a controlling factor in such reserve is the amount of the key antioxidants superoxide dismutase and thioredoxin reductase expressed by the mother or fetus. It has been known for some time that both of these antioxidants have been shown to be upregulated rather dramatically by the neurosteroid calcitriol or activated vitamin D. Although it is not clear from the papers below, it is probable that a vitamin D response element is involved in directly or indirectly controlling the genetic expression of both antioxidants.

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

Swami S, Raghavachari N, Muller UR, Bao YP, Feldman D. Vitamin D growth inhibition of breast cancer cells: gene expression patterns assessed by cDNA microarray. Breast Cancer Res Treat. 2003;80:49–62.

Palmer HG, Sanchez-Carbayo M, Ordonez-Moran P, Larriba MJ, Cordon-Cardo C, Munoz A. Genetic signatures of differentiation induced by 1α,25-dihydroxyvitamin D3 in human colon cancer cells. Cancer Res. 2003;63:7799–7806.

I propose that much of the autism epidemic is caused by the meeting of a dysfunctional antioxidant reserve with paracetamol. That is, gestational or early childhood vitamin D deficiency causes down-regulation of key antioxidants, which leave the fetus vulnerable to the oxidative damage induced by paracetamol. Thus a combination of vitamin D deficiency and paracetamol exposure is both a necessary and sufficient condition to trigger an unkown percentage of autism and explains the rapid rise in the prevalence of the disorder, at least in the 1980s and 90s.

As far as vitamin D deficiency is concerned, three recent studies, using community controls, have found 25(OH)D levels are significantly lower in children with autism. Two of the studies below (Mostafa et al and Gong et al) also found autism severity, as rated on standard autism rating scales, is inversely correlated with 25(OH)D levels. Mostafa et al found an R value of -.86 for the association of serum 25(OH)D with autism severity.

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

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

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

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

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

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

Eyles DW, Burne TH, McGrath JJ. Vitamin D, effects on brain development, adult brain function and the links between low levels of vitamin D and neuropsychiatric disease. Front Neuroendocrinol. 2013 Jan;34(1):47-64.

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

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

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

It is likely that much of the autism epidemic is caused by the perfect storm of paracetamol meeting a vitamin D deficient immune system.

John Cannell, MD

Vitamin D Council

http://www.vitamindcouncil.org/

On 2014 Apr 04, GREGORY CROWTHER commented:

I understand and agree with the central point of this article, i.e., that biology textbooks should emphasize scientific thinking and scientific investigation, but often don't. What is the solution to this problem? Duncan et al. imply that the textbook authors should simply prepare their books differently: "Textbook authors might better serve students by focusing more on how the information in their chapters was discovered, rather than devoting most illustrations to describing biology by representing what is known." This reasonable-sounding advice sidesteps the fact that authors do not have sole control of their books; the publishers exert much influence based on market considerations, and professional illustrators (who are actually responsible for preparing the figures) have input as well. Thus, making textbooks more research-based is not as simple as telling the textbook authors to "Make it so." An author of one of the texts reviewed by this article told me that he made his book "as data-intensive as reviewers would stand." In other words, he himself was not the bottleneck in getting more research data into the book. One hopes that publishers and editorial teams are now starting to expect more of a research flavor in their texts.

On 2014 Feb 23, Vinay Gopalani commented:

@ conclusion: Human mesenchymal stem cells have a potential to adhere to plastic surface. I think its incorrectly mentioned as Human dermal fibroblasts.

On 2017 Jan 24, Tom Weishaar commented:

This article was apparently published twice by mistake. For the non-retracted version, see https://www.ncbi.nlm.nih.gov/pubmed/23507683

On 2013 Oct 24, Tom Kindlon commented:

In 2011, I was accused by Professors Lloyd & van der Meer of an unscientific and personal attack in a published letter of mine.^1,2 The accusation was made without any explanation, and they never replied when I e-mailed them about this issue. I believe the accusation was clearly false on both counts. Now I find that Prof. Lloyd (while apologising to Stouten et al. for having wrongly claimed that their letter was an unscientific and personal attack, no less) has re-iterated the claim that this was an apt characterization for my letter, as well as letters written by others.³ I would like to take this opportunity to correct the record.

In the letter in question, I challenged the PACE Trial authors’ claims about the safety of cognitive behaviour therapy (CBT) and graded exercise therapy (GET) for chronic fatigue syndrome (CFS), distilling my points into 250 words, the maximum allowed by the journal.² At no point do I attack individuals. As is common in letters to the editor, I challenge points made in the original paper—it has been recognised that such correspondence can be an important part of the scientific process. I subsequently expanded on the points about that particular trial, and the reporting of harms for these interventions in general, in a peer-reviewed paper.⁴ I have had several letters published, before and since, on the subject of CBT and GET interventions in reply to different research groups in a variety of journals.⁵

Incidentally, I do not believe the description is suitable or appropriate for the other letters that the Lancet published either.

References:

1 van der Meer JW, Lloyd AR. A controversial consensus--comment on article by Broderick et al. J Intern Med. 2012;271:29-31. Epub 2011 Nov 11.

2 Kindlon T. The PACE trial in chronic fatigue syndrome. Lancet 2011;377:1833; author reply 4–5.

3 Lloyd AR. Apology. J Intern Med. 2013;273:628.

4 Kindlon T. Reporting of Harms Associated with Graded Exercise Therapy and Cognitive Behavioural Therapy in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Bulletin of the IACFS/ME. 2011;19:59-111.

5 https://www.researchgate.net/profile/Tom_Kindlon2/publications/

On 2013 Oct 31, John Cannell commented:

The authors reported that immune system dysregulation is common in autism spectrum disorder (ASD”. Vitamin D deficiency produces very similar immune dysregulation.

Prietl B, 2013

Kamen DL, 2010

Yang CY, 2013

Baeke F, 2010

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

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

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

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

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

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

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

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

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

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

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

70% of American toddlers do not take the American Pediatric Association's recommended vitamin D supplement of 400 IU/day and few toddlers or pregnant women get any sunshine due to the sun scare. As vitamin D fortified milk consumption and sun exposure has declined, so have toddlers and pregnant women’s vitamin D levels. The dramatic increase in the incidence of ASD occurred during the same time vitamin D levels were falling in toddlers and pregnant women.

Cannell JJ. Autism, will vitamin D treat core symptoms? Medical Hypotheses. 2013 Aug;81(2):195-8. Cannell JJ, 2013

Some autism researchers seem cognizant of the entire body of autism research. For example, a group of well-known European ASD researchers, including Professor Christopher Gillberg of the Gillberg Neuropsychiatric Institute, have recently called for the need for “urgent research” into the vitamin D deficiency theory of ASD.

Kočovská E, Fernell E, Billstedt E, Minnis H, Gillberg C. Vitamin D and autism: clinical review. Res Dev Disabil. 2012 Sep-Oct;33(5):1541-50. doi: 10.1016/j.ridd.2012.02.015. Epub 2012 Apr 21.Kočovská E, 2012

Until all autism researchers become cognizant of the wider body of scientific research, we will continue to wonder how to prevent - and perhaps even treat - this modern day plague.

John J Cannell, MD

Vitamin D Council

http://www.vitamindcouncil.org

On 2014 Jun 20, Alexander (Lex) Nederbragt commented:

I was a reviewer of this paper. My review reports can be found on publons: https://publons.com/review/3891/

On 2016 Sep 26, Lydia Maniatis commented:

Pelli and Bex (2013) make the following assertion:

"Neurally, Campbell and Robson (1968) revealed the presence of multiple channels in vision, each selective to a different band of spatial frequencies. This greatly increased interest in measuring the CSF. Today, the set of thresholds as a function of spatial frequency is usually fit with a contrast sensitivity function (Watson, 2000)."

The claim regarding Campbell and Robson (1968) is false.

It has been made previously by Pelli and coauthors, (and others), e.g. by Solomon and Pelli (1994). In a comment on that article (https://pubpeer.com/publications/6EA25EFC758D6B5C990CFDFD5899BD) I quote Robson and Campbell (1968), as follows:

"Thus, it seems that we cannot satisfactorily model the over-all visual system by a simple peak detector following a spatial filter...As a modification of this theory, we may assume...Thus, we may suppose that the visual system behaves not as a single detector mechanism preceded by a single broadband spatial filter but as a number of independent detector mechanisms each preceded by a relatively narrowband filter 'tuned' to a different frequency...Such a model could account for our findings...

In other words, Robson and Cambell's (1968) results did not bear out their original predictions, and they discuss purely speculative alternatives to account for their data. Between 1968 and 2013, no firmer references apparently became available.

Nevertheless, as is evident from the second part of Pelli and Bex (2013) statement, measurements based on Robson and Campbell's (1968) uncorroborated assumptions have become very popular. These measurements involve "fitting" a "constrast sensitivity function." As Pelli and Bex (2013) note, this fitting involves a minimum of four free parameters. What does this mean?

According to Wikipedia, a free parameter "is a variable in a mathematical model which cannot be predicted precisely or constrained by the model..." The mathematician and physicist Jon von Neumann is quoted as saying that "With four parameters I can fit an elephant, and with five I can make him wiggle his trunk." Investigators at the Max Planck institute have, in fact, fit an elephant with four free parameters (https://publications.mpi-cbg.de/Mayer_2010_4314.pdf).

What four free parameters means, in short, is that the model doesn't have to predict anything. The model assumptions (e.g., "the presence of multiple channels in vision, each selective to a different band of spatial frequencies") can be false, but still be fit to the (qualitatively generic) shape of the data.

The authors are advocating a method to be used to generate a certain score for individuals. But given the situation described above, we really can't say what that score means, in any theoretical sense.

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 NCT017354435. We believe the correct ID, which we have found by hand searching, is NCT01735435.

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

Many thanks,

Jessica Fleminger, Ben Goldacre*

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

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

On 2015 Jul 12, Egon Willighagen commented:

The paper uses the CDK, which you can read about in these two papers:

Steinbeck, C., Han, Y., Kuhn, S., Horlacher, O., Luttmann, E., Willighagen, E., Mar. 2003. The chemistry development kit (CDK):  an Open-Source java library for chemo- and bioinformatics. J. Chem. Inf. Comput. Sci. 43 (2), 493-500. URL http://dx.doi.org/10.1021/ci025584y

Steinbeck, C., Hoppe, C., Kuhn, S., Floris, M., Guha, R., Willighagen, E. L., 2006. Recent developments of the chemistry development kit (CDK) - an open-source java library for chemo- and bioinformatics. Current pharmaceutical design 12 (17), 2111-2120. URL http://dx.doi.org/10.2174/138161206777585274

On 2016 Aug 23, Ben Goldacre commented:

This trial has the wrong trial registry ID associated with it on PubMed: both in the XML on PubMed, and in the originating journal article. The ID given is NCT0029779. We believe the correct ID, which we have found by hand searching, is NCT00297791.

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

Many thanks,

Jessica Fleminger, Ben Goldacre*

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

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

On 2017 Apr 04, Atanas G. Atanasov commented:

Thanks a lot for this very interesting review, I have featured the manuscript at: http://healthandscienceportal.blogspot.com/2017/04/avocado-scientific-review-of-possible.html

On 2013 Jun 30, Jonathan Eisen commented:

Data and higher resolution figures are available at Figshare at http://figshare.com/articles/Phylogeny_of_Bacterial_and_Archaeal_Genomes_Using_Conserved_Genes_Supertrees_and_Supermatrices/692979

On 2013 Nov 13, Daniel Mietchen commented:

Fig. 3 and Animation S1 use materials from Google Earth, which are properly attributed but licensed under terms not compatible with the Creative Commons Attribution License that the entire article has been released under.

On 2016 May 31, Marc Robinson-Rechavi commented:

Link to extra supplementary data: Gene ages, processed expression data, etc http://bioinfo.unil.ch/supdata/Piasecka/datasets/

On 2014 Apr 10, Adam VanWert commented:

This article should be recognized as one of the best in its category. It is written very well with a very logical sequence. The information is presented in a highly understandable manner. Invaluable resource! I'm a pharmacology professor with GI pharmacotherapy/pharmacology as one of my course responsibilities. Thank you for this!

On 2013 Oct 29, Maurice Elphick commented:

This is a really important contribution to our understanding of the evolution of neuropeptide and peptide hormone signalling systems. By analysing genomic/transcriptomic sequence data throughout the animal kingdom, it provides new insights on the origins and evolution of peptide signalling systems. I strongly recommend it to anyone who has an interest in any aspect of neuropeptide/peptide hormone biology.

On 2014 May 05, Neil Saunders commented:

Be aware that there is no available software implementation associated with this publication.

On 2016 Dec 02, Aurélie Névéol commented:

Follow-up work relying on the Scielo database led to the release of a large corpus of parallel scientific publications for biomedicine in three language pairs (EN/ES, EN/FR and EN/PT). The corpus is freely available and it was used in the 2016 conference on Machine Translation (WMT16).

On 2016 Aug 23, Ben Goldacre commented:

This trial has the wrong trial registry ID associated with it on PubMed: both in the XML on PubMed, and in the originating journal article. The ID given is NCT0071879. We believe the correct ID, which we have found by hand searching, is NCT00718796.

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

Many thanks,

Jessica Fleminger, Ben Goldacre*

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

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

On 2015 Oct 30, Christopher Southan commented:

The evolution of the beta secretase is described in http://www.ncbi.nlm.nih.gov/pubmed/24381583 which complements this useful analysis. Howerver, given the major differences in evolutionary trajectories co-evolution seems unlikely

On 2013 Jun 29, Rahul Bakshi commented:

Fascinating. However, I am still puzzled by the emphatic use of the term 'artemisinin-resistant' to describe these parasites. The drug clearly still works. True resistance would have been reproduced using isolates and isolate-derived strains in vitro. More importantly,true resistance would lead to treatment failures all over the place. Is there a demonstrable increase in drug failure directly associated with these parasites?

On 2014 Feb 24, Olaf Hauk commented:

The Matlab tools used for the simulations in this paper are provided here: http://imaging.mrc-cbu.cam.ac.uk/meg/AnalyzingData/DeFleCT_SpatialFiltering_Tools.

On 2016 Nov 01, Michael Axtell commented:

I should also add that the miscellaneous scripts mentioned in this 2013 paper have also been relocated, to https://psu.app.box.com/v/axtelldata in directory 'old_scripts'

On 2016 Nov 01, Michael Axtell commented:

The URLs in this paper for software availability and data availability are out of date; here are the updated URLs:

The ShortStack program is now at github .. the latest release is at https://github.com/MikeAxtell/ShortStack/releases

The datasets used in this 2013 paper are now at https://psu.app.box.com/v/axtelldata in directory 'ShortStackPaperData'

A tutorial and test data for ShortStack are at https://psu.app.box.com/v/axtelldata in directory 'ShortStack_TestData'

Finally, I would like to point out that the current version of ShortStack is much enhanced relative to what was described in this 2013 paper. Many of the advancements are described by my group in Johnson et al. (2016) : https://www.ncbi.nlm.nih.gov/pubmed/27175019

Thanks, Mike Axtell

On 2015 Apr 27, Chloe Wong commented:

Thank you for your interest and comments on our manuscript. As we hope is clear from the Discussion section of our paper, we are very conservative in our conclusions and are the first to recognize the many limitations of doing this type of work. Please also see our articles highlighting the many important issues to consider when undertaking and interpreting epigenetic epidemiological analyses (Mill & Heijmans, 2013; Heijmans & Mill, 2012).

There are many reasons why the standard research approaches developed for genetic epidemiology are not necessarily appropriate for epigenetic studies of common disease. To date, no real precedents have been set about the optimal sample-sizes needed to detect epigenetic changes associated with disease. The number of ASD-discordant twin-pairs available for this study was small - these are extremely rare samples, and we were only able to recruit and characterize six discordant monozygotic (MZ) pairs. Furthermore, it is recognized that standard multiple testing parameters (as used in GWAS analyses) are not necessarily appropriate for genome-wide DNA methylation data ­ first, most of the sites on the commonly-used Illumina EWAS array are actually non-variable, and second there is considerable non-independence between DNA methylation at proximal CpG sites. With the aim of identifying real, biologically relevant within-twin and between-group DNA methylation differences, we therefore decided to use an analytic approach that incorporated both the significance (that is, t-test statistic) and magnitude (that is, absolute DNA methylation difference) of any observed differences to produce a ranked list of DMRs. Of note, we confirmed the variation at selected loci using an independent technology (bisulfite-pyrosequencing) to rule out technical artifacts in the data.

Because individual studies such as this are, by necessity, small, it is absolutely clear that findings should be treated with caution until they are replicated and/or validated using complimentary approaches. In this regard, it is noteworthy that one of the top-ranked differentially methylated regions identified in our twin study ­ located in the vicinity of the OR2L13 gene - is also a top-ranked differentially methylated locus in a more recent epigenetic study of ASD by Berko and colleagues (2014). Furthermore, OR2L13 was found to be significantly differentially expressed in post-mortem brain tissue from ASD cases compared to unaffected controls in the most systematic transcriptomic analysis of autism brain yet undertaken (Voineagu et al, 2011). Finally, this gene has also been implicated in autism by genetic studies that have identified recurrent CNVs spanning the locus in cases.

The main concern raised by Professor Bishop is that methylomic differences are also identified within concordant affected and concordant unaffected twins. We would argue this is not necessarily surprising; given that it is not feasible to directly study brain tissue from our twins, and ASD is a subtle developmental brain problem, it's plausible (perhaps likely) that these individuals are discordant for other traits/exposures that are also associated with epigenetic variation detected in blood. That doesn¹t mean that differences specific to ASD discordant twin-pairs are not interesting. What is clear from our analyses is that i) the sites identified as differentially methylated in the six ASD-discordant twin-pairs are not differentially methylated in concordant-unaffected twin-pairs, and ii) the overall distribution of average within-pair DNA methylation differences is significantly skewed in ASD-discordant twins, with a higher number of CpG sites demonstrating a larger average difference in DNA methylation.

We acknowledge that our data represent only the first step in identifying molecular variation associated with autism. For example, we cannot begin to tackle issues regarding causality in this study, and it is possible (perhaps likely) that many of the changes we identified represent consequences of the disease. As discussed, we were also limited to using DNA derived from blood, and moving forward it will be important to understand the utility of peripheral tissues as a proxy for inaccessible organs such as the brain. We are currently undertaking more systematic analyses in larger samples of twins and post-mortem brain to address many of the limitations of this study.

Berko ER, Suzuki M, Beren F, Lemetre C, Alaimo CM, Calder RB, Ballaban-Gil K, Gounder B, Kampf K, Kirschen J, Maqbool SB, Momin Z, Reynolds DM, Russo N, Shulman L, Stasiek E, Tozour J, Valicenti-McDermott M, Wang S, Abrahams BS, Hargitai J, Inbar D, Zhang Z, Buxbaum JD, Molholm S, Foxe JJ, Marion RW, Auton A, Greally JM. Mosaic epigenetic dysregulation of ectodermal cells in autism spectrum disorder. PLoS Genet. 2014 May 29;10(5):e1004402.

Heijmans BT, Mill J. Commentary: The seven plagues of epigenetic epidemiology. Int J Epidemiol. 2012 Feb;41(1):74-8.

Mill J, Heijmans BT. From promises to practical strategies in epigenetic epidemiology. Nat Rev Genet. 2013 Aug;14(8):585-94.

Voineagu I, Wang X, Johnston P, Lowe JK, Tian Y, et al. (2011) Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Nature 474: 380­384.

On 2015 Apr 25, Dorothy V M Bishop commented:

This is a pioneering study using a clever design with a unique dataset. I am grateful to the authors for making their raw data available. A colleague had suggested that I might be able to use the methods described in this paper with some of my own data, and it was good to have the opportunity to work through the analyses and gain more understanding of what was done.

Unfortunately, having done so, I became dubious as to whether the results show differentially methylated regions associated with ASD, as claimed. Over 23,000 sites were examined for methylation differences, and the numbers where discordant twins differed was not high. Most tellingly, when I used the authors' data to analyse concordant groups in similar fashion, the number of methylation differences was similar. This was true both for twins concordant for ASD (where there were 341 between-twin differences with p < .01, compared with 203 such differences in the discordant twins), and for twins who were concordant for low symptom scores on CAST (where there were 188 between-twin differences with p < .01 – here I selected the first 6 twins from this group to give an equivalent sample size to the discordant twins).

In addition, the findings of correlations between CAST scales and levels of methylation at given site is not impressive, given that the number of correlations computed was over 90,000 (4 per site), so some would be expected to achieve low p-values by chance.

I appreciate this is a new area, and exploratory work needs to be done, but given that the field of molecular genetics has learned the importance for controlling for chance findings when looking for associations with SNPs, I am wondering perhaps the same lesson will prove necessary when examining methylation data. With a twin data set such as this one, I would argue it is very useful to have concordant twins as a comparison group, as they can be used to give an indication of the amount of discordance between twins in methylation that is to be expected regardless of phenotype.

I have uploaded the analysis file I used to compare methylation patterns in different groups here: osf.io/z6w92 so that others can check my working.

On 2013 Oct 31, John Cannell commented:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

70% of American toddlers do not take

On 2015 Jul 18, Jan Tunér commented:

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

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

On 2013 Oct 31, John Cannell commented:

The authors reported that immune system dysregulation is common in autism spectrum disorder (ASD”. Vitamin D deficiency produces very similar immune dysregulation.

Prietl B, 2013

Kamen DL, 2010

Yang CY, 2013

Baeke F, 2010

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

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

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

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

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

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

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

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

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

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

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

70% of American toddlers do not take the American Pediatric Association's recommended vitamin D supplement of 400 IU/day and few toddlers or pregnant women get any sunshine due to the sun scare. As vitamin D fortified milk consumption and sun exposure has declined, so have toddlers and pregnant women’s vitamin D levels. The dramatic increase in the incidence of ASD occurred during the same time vitamin D levels were falling in toddlers and pregnant women.

Cannell JJ. Autism, will vitamin D treat core symptoms? Medical Hypotheses. 2013 Aug;81(2):195-8. Cannell JJ, 2013

Some autism researchers seem cognizant of the entire body of autism research. For example, a group of well-known European ASD researchers, including Professor Christopher Gillberg of the Gillberg Neuropsychiatric Institute, have recently called for the need for “urgent research” into the vitamin D deficiency theory of ASD.

Kočovská E, Fernell E, Billstedt E, Minnis H, Gillberg C. Vitamin D and autism: clinical review. Res Dev Disabil. 2012 Sep-Oct;33(5):1541-50. doi: 10.1016/j.ridd.2012.02.015. Epub 2012 Apr 21.Kočovská E, 2012

Until all autism researchers become cognizant of the wider body of scientific research, we will continue to wonder how to prevent - and perhaps even treat - this modern day plague.

John J Cannell, MD

Vitamin D Council

http://www.vitamindcouncil.org

On 2015 Oct 08, thomas samaras commented:

There's a large body of research that indicates smaller humans live longer. Examples include studies of Okinawans, Spaniards,Sardinian,Japanese in Hawaii, US veterans, basketball players, Harvard male graduates, and US government reports on the age-adjusted mortality of five different ethnic groups.In addition, US males average 9% taller than females and have a 9% shorter life expectancy. Various areas of study supporting the thesis that smaller humans live longer is given in: Evidence from eight different types of studies showing that smaller body size is related to greater longevity: JSRR 2(16): 2150-2160, 2014; article no. JSRR.2014.16.003

On 2017 Dec 18, Shaun Khoo commented:

Open Data: The underlying dataset for this paper is available on Figshare.

On 2014 Feb 19, Valeria Fadda commented:

Co-authors of this Note: Roberta Gatto, Dario Maratea, Sabrina Trippoli, and Andrea Messori (all from the HTA Unit of Estav in Firenze, Italy).

The studies by Surder et al.[1] and by Traverse et al. [2] are a further improvement to the overall knowledge about the effectiveness of stem cell treatment in ischemic heart disease. Very few experiences are in fact available in the scientific literature about this relatively new therapeutic strategy. Since the systematic review of Clifford et al. [3] represents the most accurate previous attempt to shed light on this intervention for the acute treatment of myocardial infarction, adding the two trials (Surder et al.; Traverse et al.) to Clifford’s meta-analysis can be worthwhile. With reference to the end-point of left ventricular ejection fraction, we incorporated the results of the two trials (Surder et al.; Traverse et al.)into the meta-analysis of Clifford et al. The results of our analysis (Figure 1) show the superiority of treatment with intracoronary bone marrow-derived cells over placebo, thus confirming the results reported by Clifford et al. The main difference is that confidence intervals have become slightly wider after the addition of the two above mentioned trials.

References

1. Surder D, Manka R, Lo Cicero V et al. Intracoronary injection of bone marrow-derived mononuclear cells early or late after acute myocardial infarction: effects on global left ventricular function. Circulation. 2013 May 14;127(19):1968-79. doi: 10.1161/CIRCULATIONAHA.112.001035

2. Traverse JH, Henry TD, Pepine CJ et al. Cardiovascular Cell Therapy Research Network (CCTRN). Effect of the use and timing of bone marrow mononuclear cell delivery on left ventricular function after acute myocardial infarction: the TIME randomized trial. JAMA. 2012 Dec 12;308(22):2380-9. Erratum in: JAMA. 2013 Jan 23;309(4):343. PubMed PMID: 23129008; PubMed Central PMCID: PMC3652242.

3. Clifford DM, Fisher SA, Brunskill SJ et al. Stem cell treatment for acute myocardial infarction. Cochrane Database Syst Rev. 2012 Feb 15;2:CD006536. doi: 10.1002/14651858.CD006536.pub3

Figure 1. Comparison of intracoronary stem cell treatment with no stem cells in patients with acute myocardial infarction: pooled difference in mean change in LVEF from baseline to end of study. This figure is available at: http://www.osservatorioinnovazione.net/papers/Figure_1.jpg

Valeria Fadda HTA Unit Estav Regional Health System 50100 Firenze Italy

On 2014 Apr 29, Amanda Capes-Davis commented:

Please be aware that HEp-2 is not a human laryngeal carcinoma cell line. It was shown to be cross-contaminated by Walter Nelson-Rees and is actually HeLa. For a list of known cross-contaminated or otherwise misidentified cell lines, see http://iclac.org/databases/cross-contaminations/.

On 2014 Mar 13, Jonathan Eisen commented:

Richard Grant wrote an article for the Guardian discussing (in part) this article. See Say 'Ome': scientists get silly

On 2014 Mar 13, Jonathan Eisen commented:

Robert Lee Hotz wrote an article in the Wall Street Journal discussing (in part) this article. See Here's an Omical Tale: Scientists Discover Spreading Suffix

On 2014 Jun 20, Alexander (Lex) Nederbragt commented:

Together with three colleagues from my group, I was a reviewer of this paper. All review reports can be found on the journals website (including all versions of the manuscript) or on publons: https://publons.com/publon/4891/

On 2017 Dec 14, Denise N Slenter commented:

The pathway model outlined in Figure 1 is available as free machine readable data in WP4190 in WikiPathways: https://www.wikipathways.org/index.php/Pathway:WP4190

On 2017 Nov 27, Steven Watterson commented:

In our recent paper (https://www.ncbi.nlm.nih.gov/pubmed/28910500) we merge this pathway model with pharmacological data and explore how to create multi-drug therapies that optimally suppress cholesterol synthesis and eliminate off-target effects.