On 2014 Nov 17, Raphael Levy commented:

None

On 2014 Sep 17, Klaas Vandepoele commented:

A supplementary website containing all genes/modules/functions described in this paper is available at http://bioinformatics.psb.ugent.be/cig_data/plant_modules/

On 2014 Mar 24, Dinesh Barupal commented:

None

On 2016 Jun 02, Dinesh Barupal commented:

R code and a new web version of MetaMapp software is available here - https://github.com/barupal/metamapp

On 2016 Oct 16, Jaime A. Teixeira da Silva commented:

This paper has been retracted: "The Scientific World Journal has retracted this article. The article was found to contain images with signs of duplication and manipulation in Figures 2 and 3."

On 2015 Jul 14, Bill Cayley commented:

A good example of when Less is More: https://lessismoreebm.wordpress.com/2015/07/15/a-new-improved-accelerated-diagnostic-protocol-safely-identifies-low-risk-patients-with-chest-pain-in-the-emergency-department/

On 2013 Oct 01, Markus Meissner commented:

Dr Elena Jimenez-Ruis (Meissner lab):

The apicomplexan parasite Toxoplasma gondii employs secretory organelles; the micronemes, rhoptries and dense granules that are sequentially secreted during the invasion process. The knowledge on the evolution biogenesis, maintenance and regulation of these unique organelles is insufficient. The present paper describes the function of the sortilin-like receptor (TgSORTLR) in the vesicular trafficking within this parasite. This protein was previously described by the authors as a transmembrane protein with a luminal cargo-binding domain (Fauquenoy et al., 2008). In this study, the transmembrane protein was colocalised with Golgi and endolysosomal system. Although, sometimes difficult to judge based on the provided images, the authors demonstrate a co-localisation of TgSORTLR with known markers of the Golgi and endosomal like compartments. The authors suggest that this protein is involved in the endocytic/exocytic system in T. gondii.However, to date endocytosis in T. gondii remains unclear. Importantly, TgSORTLR coprecipitates with micronemeal and rhoptry proteins, suggesting that TgSORTLR is a cargo receptor for ROP and MIC proteins between Golgi and endolysosomal system. Strikingly, in a conditional knockdown mutant micronemal and rhoptry proteins are mislocalised and appear to enter the constitutive secretory pathway. In electron microscopy a lack of micronemes and rhoptries has been confirmed in this mutant. Overall, this very nice study significantly contributes to broaden our understanding of the secretory pathway in T. gondii parasites. TgSORTLR is important for the correct delivery of the microneme and rhoptry proteins to their respective organelles . However, the question why the parasite stops their replication and seems to die after the ablation of TgSORTLR should be addressed in the future. The authors focus a lot on micronemal and rhoptry proteins, which they identify as interactants in co-IPs. However, this does not exclude other cargo that travels through the endosomes in TgSORTLR dependent manner. A more thorough analysis of the inner membrane complex, apicoplast and nuclear division would be helpful in the future. For example dominant negative expression of TgSORTLR appears to have a clear effect on parasite replication (see Fig. 2, where several parasitophorous vacuoles with only 3 nuclei are shown). However, this effect cannot be due to ablation of micronemes and or rhoptry biogenesis, since in this case no major replication defect is obvious (see Breinich et al., 2009; Beck et al., 2013 or Mueller et al., 2013).

On 2014 Apr 02, GREGORY CROWTHER commented:

“The discovery and biochemical characterization of Plasmodium thioredoxin reductase inhibitors from an antimalarial set” is a very nice paper showing progress in the important but challenging task of following up on hits from a high-throughput screen against Plasmodium cells. Expression and purification of full-length, untagged TrxR from multiple species was achieved, a huge accomplishment for Plasmodium proteins, which are notoriously hard to express in E. coli. A clever assay is reported, in which the substrate concentrations may be maintained at their Km’s (or some other desired level) for screening purposes. And inhibition of TrxR by the hit compounds was characterized in some detail.

In my view, the main limitation of this paper is the odd way in which it dances around the issue of the mechanism of action (MoA) of the hit compounds. The Abstract, Introduction, and beginning of the Discussion all emphasize the value of knowing the MoA by which a given compound or series kills a pathogen, and this study was apparently done to investigate whether any compounds in the TCAMS set act through inhibition of TrxR. Yet in the end, no direct opinion is offered as to whether the seven compounds are likely to kill Plasmodium cells via their inhibition of TrxR! Moreover, the challenges of inferring MoA from biochemical inhibition are not discussed. For example, if a particular protein target does indeed represent a compound’s MoA, it is generally expected that the compound’s IC50 against the protein will be less than its IC50 against whole cells, but that was not true for the newly discovered TrxR inhibitors. Is this IC50 reasoning appropriate here? If not, why not? In light of these issues, the following sentence from the Discussion seems awfully vague: “only experimental verification by testing the compounds in an appropriate biochemical screen of an essential target can provide a definitive link between the observed whole cell inhibition and a specific antimalarial mode of action." By "definitive link," I don't know if the authors mean something like a correlation, or whether they see their evidence as stronger than that. In the end, I can't really tell whether they believe that inhibition of TrxR is a primary MoA of their compounds.

On 2014 Feb 27, George W Hinkal commented:

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

https://cananolab.nci.nih.gov/caNanoLab/characterization.do?dispatch=summaryView&sampleId=33685504&page=0&tab=ALL

https://cananolab.nci.nih.gov/caNanoLab/characterization.do?dispatch=summaryView&sampleId=33685505&page=0&tab=ALL

https://cananolab.nci.nih.gov/caNanoLab/characterization.do?dispatch=summaryView&sampleId=33685506&page=0&tab=ALL

https://cananolab.nci.nih.gov/caNanoLab/characterization.do?dispatch=summaryView&sampleId=33685507&page=0&tab=ALL

https://cananolab.nci.nih.gov/caNanoLab/characterization.do?dispatch=summaryView&sampleId=33685508&page=0&tab=ALL

https://cananolab.nci.nih.gov/caNanoLab/characterization.do?dispatch=summaryView&sampleId=33685509&page=0&tab=ALL

https://cananolab.nci.nih.gov/caNanoLab/characterization.do?dispatch=summaryView&sampleId=33685510&page=0&tab=ALL

https://cananolab.nci.nih.gov/caNanoLab/characterization.do?dispatch=summaryView&sampleId=33685511&page=0&tab=ALL

https://cananolab.nci.nih.gov/caNanoLab/characterization.do?dispatch=summaryView&sampleId=33685512&page=0&tab=ALL

https://cananolab.nci.nih.gov/caNanoLab/characterization.do?dispatch=summaryView&sampleId=33685513&page=0&tab=ALL

https://cananolab.nci.nih.gov/caNanoLab/characterization.do?dispatch=summaryView&sampleId=33685514&page=0&tab=ALL

https://cananolab.nci.nih.gov/caNanoLab/characterization.do?dispatch=summaryView&sampleId=33685515&page=0&tab=ALL

https://cananolab.nci.nih.gov/caNanoLab/characterization.do?dispatch=summaryView&sampleId=33685516&page=0&tab=ALL

https://cananolab.nci.nih.gov/caNanoLab/characterization.do?dispatch=summaryView&sampleId=33685517&page=0&tab=ALL

https://cananolab.nci.nih.gov/caNanoLab/characterization.do?dispatch=summaryView&sampleId=33685518&page=0&tab=ALL

https://cananolab.nci.nih.gov/caNanoLab/characterization.do?dispatch=summaryView&sampleId=33685519&page=0&tab=ALL

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

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

On 2014 Mar 12, George W Hinkal commented:

None

On 2014 Feb 16, S Sundar commented:

Pattern of benign and premalignant lesions detected by screening flexible Sigmoidoscopy

The reduction in cancer incidence and cancer-specific mortality in PLCO trial is almost certainly due to detection and treatment of ‘selected’ premalignant lesions that would have progressed to cancer. (1, 2) It would be helpful if the PLCO team can provide information (type, size, anatomical site and mode of treatment) on these precursor lesions, which in turn, if validated, would could serve as surrogate markers for chemoprevention studies.(3).

References

1. Croswell JM, Ransohoff DF, Kramer BS. Principles of cancer screening: lessons from history and study design issues. Semin Oncol 2010;37:202–15.
2. Schoen RE, Pinsky PF, Weissfeld JL, et al. Colorectal-Cancer Incidence and Mortality with Screening Flexible Sigmoidoscopy. N Engl J Med [Internet] 2012;Available from: http://dx.doi.org/10.1056/NEJMoa1114635
3. Cooper K, Squires H, Carroll C, et al. Chemoprevention of colorectal cancer: systematic review and economic evaluation. Health Technol Assess 2010;14:1–206.

On 2014 Mar 24, Andrew Sharp commented:

Readers of this article should be aware of a Viewpoints piece we published that raises major concerns about the validity of the conclusions that there is a link between CNV and hypomethylation, see: http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003332

A counter-point piece was then published by the original authors here: http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003333

Interested readers should also look at a thorough discussion that details the problems in the original analysis methods that is shown in the ensuing comments thread here: http://www.plosgenetics.org/annotation/listThread.action?root=62329

On 2015 Dec 07, Aleksandar Milosavljevic commented:

This recently published paper provides independent validation of the association of hypomentylation and genomic instability: http://www-ncbi-nlm-nih-g...

Quoting from the discussion section of the paper: "In addition, we found two lines of evidence associating NAHR breakpoints with hypomethylation: lower frequency of C to T SNPs in CpG motifs and an enrichment with demethylated regions in sperm. NAHR breakpoints have been previously suggested to be associated with hypomethylation [ref. 41]; however, the findings were debated with the notion that technical variability may explain the association [ref. 42]. In our SNP aggregation analysis, we used roughly 70% of the human genome sequence where SNPs could be confidently determined. Demethylated regions in sperm used in our study were determined from comparative analysis of methylation profiles that are directly inferred from whole-genome bisulfide sequencing in sperm and embryonic cell. Such comparative analysis is not likely to be influenced by technical artefacts. We, thus, state that the observed association of NAHR breakpoints with hypomethylation is not artefactual, although not as strong as suggested in ref. 41. It also corroborates association of NAHR breakpoints with open chromatin."

On 2017 Jan 20, Andy Collings commented:

A subset of experimental results from this study were the focus of a replication attempt as part of the Reproducibility Project: Cancer Biology (https://osf.io/e81xl/wiki/home/). The experimental designs and protocols were reviewed and approved in a Registered Report (http://dx.doi.org/10.7554/eLife.04180) and the results of the experiments were published in a Replication Study (http://dx.doi.org/10.7554/eLife.21634).

On 2014 Jan 08, Brett Snodgrass commented:

Dear Authors,

Thank you for the excellent article. Cognizance of the vessels of Wearn as distinct anatomic connections provides a cogent explanation that links pulmonic stenosis, hypertensive right ventricle, coronary arteriopathy, and myocardial infarction.

Please consider the following hypothesis, the patient had pulmonary stenosis, increasing pressure in the right ventricle, increased flow/pressure through the vessels of Wearn, altered endothelial sheer stress, secondary fibromuscular dysplasia, limitations of coronary blood flow, and subsequent myocardial infarction.

http://bit.ly/JTWearn.

For additional commentary, please see the following link.

https://twitter.com/BrettSnodgrass1/status/417465214804570112

Comments and suggestions are welcome.

Thank you very much.

On 2015 Jan 21, Henry T Robertson commented:

A reader pointed out a copy-paste error to me in Table 1. I am available to send the corrected version; my updated e-mail is htrobertson@seton.org.

On 2015 May 29, Saidulu Mattapally commented:

Saidulu Mattapally

On 2017 Jun 04, Boris Barbour commented:

Readers and users of this article may be interested in the following preprint:

https://arxiv.org/abs/1705.09509

I reproduce the abstract here:

Recent work using plasmonic nanosensors in a clinically relevant detection assay reports extreme sensitivity based upon a mechanism termed inverse sensitivity, whereby reduction of substrate concentration increases reaction rate, even at the single-molecule limit. This near-homœopathic mechanism contradicts the law of mass action. The assay involves deposition of silver atoms upon gold nanostars, changing their absorption spectrum. Multiple additional aspects of the assay appear to be incompatible with settled chemical knowledge, in particular the detection of tiny numbers of silver atoms on a background of the classic ‘silver mirror reaction’. Finally, it is estimated here that the reported spectral changes require some 2.5 × 10E11 times more silver atoms than are likely to be produced. It is suggested that alternative explanations must be sought for the original observations.

The analysis summarises comments I made on the relevant PubPeer thread (as Peer 2)

https://pubpeer.com/publications/3E8208F0654769A44C22D4E78DA2B8

Attempting to correct the literature has in this case been an exercise in complete frustration. Despite Nature (group) proclaiming their desire to embrace criticism and help disseminate corrections of the literature:

http://blog.pubpeer.com/?p=214

three of their journals in relevant subject matters, including Nature Materials, certainly did not "gladly help disseminate" the manuscript. Three other journals also rejected it, including PLoS One (because the MS contained no new data). At only one journal were scientific reviews obtained and then only one referee read the MS in any detail; (s)he agreed with the majority of my arguments.

The editors at Nature Materials have been aware of the issues for 3.5 years at least. The authors were probably made aware of the issues at the time of the discussion on PubPeer and were informed directly about 18 months ago. Nobody has provided any scientific response to the points raised in the preprint.

Post-publication peer review and the ArXiv would appear to be the ONLY ways to warn readers that the result of this paper are apparently impossible.

On 2016 Nov 18, Morten Oksvold commented:

An investigation committee at Wayne State University (WSU) recommends that 42 articles from Fazlul Sarkar to be retracted (report finished August 31, 2015). This article represents one of them.

This information was published by Retraction Watch (November 17, 2016) and you can find a link to the full report here:

http://retractionwatch.com/2016/11/17/details-of-investigative-report-into-sarkar-released-by-aclu/

This article should therefore no longer be cited.

On 2015 Oct 05, Jan Egger commented:

Videos demonstrating the template-based segmentation can be found here: https://www.youtube.com/c/JanEgger/videos

Best wishes, Jan

On 2014 Jan 07, Brett Snodgrass commented:

Dear Authors,

Thank you for the excellent article. Please provide your kind attention to the vessels of Wearn which are highlighted in the following image.

https://twitter.com/BrettSnodgrass1/status/419161554668380160

Comments and suggestions are welcome.

Thank you kindly.

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 NCT004768053. We believe the correct ID, which we have found by hand searching, is NCT00768053.

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 Dec 10, Kath Wright commented:

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

On 2013 Oct 28, Ahmet Erdemir commented:

A download package incorporating the macro- and micro-scale mesh definitions and scripts for model generation, solution, and post-processing of results, is freely accessible in the ‘Downloads’ section of the project web site https://simtk.org/home/j2c.

On 2013 Dec 19, Fulvio Celsi commented:

The pararagraph describing the murine and rat cells is somewhat confusing. It states:"Two commonly used cell lines of this type are the BV2 and N9 microgliacell lines which are derived from rat and mouse, respectively." So, it seems that BV2 cells are derived from rat. But the original article (cited in the paper) is clear: "Immortalization of murine microglial cells by a v-raf/v-myc carrying retrovirus" (PMID:2110186). So a small correction may be necessary? Also, it could be interesting if the Authors could explain how they got HMO6 cells, because the original owner is not willing to share with anyone (proposed collaboration and/or money exchange)

On 2013 Nov 05, Pedro Mendes commented:

This yeast metabolic reconstruction improves on the work described in Herrgård MJ, 2008 and Dobson PD, 2010, and has since been further improved by Heavner BD, 2013. The up to date data set is available from http://yeast.sf.net/.

On 2014 Jan 16, Tom Kindlon commented:

Knudsen and colleagues raise an interesting issue. However, I believe they could have helped ensure better matching by using other groups of patients with chronic illnesses such as multiple sclerosis which, as the authors highlighted, had previously been found to have higher online activity than Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Perhaps in time the field will develop and statistical tools like regression could help isolate which independent variables predict online activity, and hence help isolate communities with unusual patterns.

It would have been interesting if the authors had gathered qualitative information on the topics discussed, to see if there were differences not just in the quantity of activity but also in terms of the range of topics discussed, and how they were discussed in different groups. ME/CFS is often said to be a heterogeneous condition (1); similarly in my experience, users of ME/CFS online forums are not all the same in terms of their interests (what they like to discuss or read about). This can be seen in the different types of groups that show up in a search of www.yahoogroups.com, for example: there are chat groups; groups interested in experimental therapies; groups interested in activism of one sort or another; groups interested in discussing research findings, etc.

The authors suggest that the high level of activity in ME/CFS could be explained by action proneness (2). However that study was retrospective and thus could be affected by recall bias. Research that utilised an "action proneness" questionnaire, when individuals were actually ill with ME/CFS, found lower levels compared to the general population (1).

The paper also mentions the "boom-bust" theory with regard to activity levels in ME/CFS. However, there is evidence that activity levels in ME/CFS patients don't fluctuate any more than control groups (3,4).

We are told that "research on support group participation for CFS/ME sufferers indicates that active members report greater symptom severity and less improvement of the disorder than inactive members (5)". However the study, which also involved fibromyalgia, found that employment rates, an important measure of overall functioning was not statistically different between the two groups.

If there are particular issues in ME/CFS that are driving patients to internet forums, perhaps in time they will improve e.g. the stigmatisation mentioned. Also, more effective therapies for ME/CFS may become available - currently there are no FDA approved drugs for the condition, which can lead patients to be interested in numerous speculative therapies.

References:

(1) Kindlon T. Reporting of Harms Associated with Graded Exercise Therapy and Cognitive Behavioural Therapy in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Bulletin of the IACFS/ME. 2011;19(2):59-111 http://iacfsme.org/BULLETINFALL2011/Fall2011KindlonHarmsPaperABSTRACT/tabid/501/Default.aspx (last accessed: January 4, 2013)

(2) Van Houdenhove B, Onghena P, Neerinckx E, Hellin J. Does high 'action-proneness' make people more vulnerable to chronic fatigue syndrome? A controlled psychometric study. J Psychosom Res. 1995 Jul;39(5):633-40.

(3) Meeus M, van Eupen I, van Baarle E, et al. Symptom fluctuations and daily physical activity in patients with chronic fatigue syndrome: a case-control study. Arch Phys Med Rehabil. 2011 Nov;92(11):1820-6.

(4) van der Werf SP, Prins JB, Vercoulen JH, van der Meer JW, Bleijenberg G. Identifying physical activity patterns in chronic fatigue syndrome using actigraphic assessment. J Psychosom Res. 2000 Nov;49(5):373 -9.

(5) Friedberg F, Leung DW, Quick J. Do support groups help people with chronic fatigue syndrome and fibromyalgia? A comparison of active and inactive members. J Rheumatol 2005;32:2416-20

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

On 2013 Nov 01, Stephen Turner commented:

This paper presents a methodology and software implementation that allows users to discover a set of transcription factors or epigenetic modifications that regulate a set of genes of interest. A wealth of data about transcription factor binding exists in the public domain, and this is a good example of a group utilizing those resources to develop tools that are of use to the broader computational biology community.

High-throughput gene expression experiments like microarrays and RNA sequencing (RNA-seq) experiments often result in a list of differentially regulated or co-expressed genes. A common follow-up question asks which transcription factors may regulate those genes of interest. The ENCODE project has completed chromatin immunoprecipitation-sequencing (ChIP-seq) experiments for many transcription factors and epigenetic modifications for a number of different cell lines in both human and model organisms. These researchers crossed this publicly available data on enriched regions from ChIP-seq experiments with genomic coordinates of gene annotations to create a table of gene annotations (rows) by ChIP-peak signals, with a presence/absence peak in each cell. Given a set of genes of interest (e.g. differentially regulated genes from an RNA-seq experiment), the method evaluates the over-/under-representation of target sites for the DNA-binding protein in each ChIP experiment using a Fisher's exact test. Other methods based on motif enrichment (using position weight matrices derived from databases like TRANSFAC or JASPAR) would miss DNA-binding factors like the retinoblastoma protein (RB), which lacks a DNA-binding domain and is recruited to promoters by other transcription factors. In addition to overcoming this limitation, the method presented here also has the advantage of considering tissue-specificity and chromatin accessibility.

On 2015 Mar 04, Jakob Suckale commented:

Main question: Can the harm of fatty food on heart blood vessels be prevented by exercise?

Study system: Mice on a high fat diet and given an exercise wheel coupled with biochemical analysis.

Main result: Running works against the negative effects of a fatty diet in the mice examined.

On 2015 Jul 21, Eric Johnson commented:

The authors may have left an incorrect impression about the cost of carrying out RAD-Seq library preparation when they write, "we use a double restriction enzyme (RE) digest (i.e., a restriction digest with two enzymes simultaneously) that results in at least five-fold reduction in library production cost–complete ddRADseq libraries cost ~$5 per sample, while the necessary enzymatic steps following the initial restriction digest and ligation in random shearing RAD libraries alone introduce a cost of ~$25 per library (NEB, Ipswich, MA)."

RAD-Seq genotyping when performed on a population involves a pooling step of combining 12-48 individuals before shearing. Thus, the $25 cost for shearing is typically $1 or less for each individual in a pool. A single-sample ddRAD library would usually include a Pippen Prep size-selection step, driving the cost towards $50. ddRAD is a fine method and can stand on its own without needing poorly constructed comparisons.

The article may also leave readers with the impression that RAD-Seq cannot be carried out with less than 100 ng DNA, when the authors write "Furthermore, the elimination of several high-DNA-loss steps permits construction of ddRAD libraries from 100 ng or less of starting DNA." Rad-Seq does just fine with 50 ng, so the elimination of the steps is not what permits libraries to be made with 100 ng or less.

On 2013 Oct 31, John Cannell commented:

I congratulate the authors on a fine study. I wonder if they are aware that 3 recent large steadies have associated SGA and low birth weight with maternal 25(OH)D levels?

Burris HH, 2012

Bodnar LM, 2010

Gernand AD, 2013

While the authors conducted a fine study and an important work but it shows how little communication is occurring among scientists. Each scientist seems to be immersed in his or her own research interest but seemingly oblivious to the larger body of research.

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.

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, 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

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. As milk consumption has fallen, so have toddler’s vitamin D levels.

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 autism 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

However, these scientists appear to be in the minority. Until all autism researchers become cognizant of the wider body of autism 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 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 NCT002226096. We believe the correct ID, which we have found by hand searching, is NCT00226096.

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

Many thanks,

Jessica Fleminger, Ben Goldacre*

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

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

On 2013 Oct 31, John Cannell commented:

I congratulate the authors on a fine review. I wonder if they are aware that Mostafa et al found that an anti neural antibody found in autism had a -.84 correlation coefficient with 25(OH)D levels? If not, it goes to show that scientists become experts in their own niche but apparently do not keep up with relevant science in other fields.

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

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.

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, 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

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. As milk consumption has fallen, so have toddler’s vitamin D levels.

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 autism 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

However, these scientists appear to be in the minority. Until all autism researchers become cognizant of the wider body of autism 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 Dec 02, Walter Vogel commented:

While this study suggested a strong inverse relationship between BCL11B phosphorylation and sumoylation, subsequent results (http://www.ncbi.nlm.nih.gov/pubmed/25423098) now reveal a complex pattern of multisite phosphorylation and dephosphorylation temporally linked to desumoylation and resumoylation. Using MRM (SRM) mass spectrometry we followed the site-specific phosphokinetics (18 sites) and sumoylation kinetics (one site, both SUMO1 and SUMO2/3) following cellular stimulation and found that phosphorylation and dephosphorylation was rapidly and simultaneously occurring on nearby sites. We concluded that Desumoylation and Resumoylation occur in different phospho-BCL11B contexts.

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 NCT0036819. We believe the correct ID, which we have found by hand searching, is NCT00368199.

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

Many thanks,

Jessica Fleminger, Ben Goldacre*

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

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

On 2013 Oct 31, John Cannell commented:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

70% of American toddlers do not take

On 2017 Jul 23, Raphael Stricker commented:

None

On 2017 Aug 22, Raphael Stricker commented:

Another LYMErix Whitewash.

Raphael B. Stricker, MD

Union Square Medical Associates, San Francisco, CA, USA. rstricker@usmamed.com

The Aronowitz article presents an unsatisfactory analysis of the LYMErix vaccine debacle. The spin in the article is a classic example of blaming the victims for their misfortune while ignoring the problems leading to that misfortune.

The spin in the article is that the science underlying the LYMErix vaccine was sound and beyond question, that the vaccine was proven to be safe beyond a shadow of a doubt, and that the antiscience lobbying of misguided Lyme activists brought down the vaccine. Considering that the LYMErix vaccine was the object of a class-action lawsuit brought by patients who claimed to have been harmed by the vaccine (1), and in view of the safety concerns described below, the article spin is impossible to defend.

The premise of the article is that the LYMErix vaccine was proven to be safe. This ignores substantial reports of LYMErix-induced patient harm in the peer-reviewed medical literature (2-6), and studies using animal models and in vitro systems support these safety concerns (7,8). The vaccine-induced rheumatological and neurological complications are what alarmed the Lyme community and ultimately led to rejection of the vaccine as unsafe. An intriguing and disturbing scientific aspect of the LYMErix vaccine is that, although it was made from a subunit protein, the vaccine elicited all manner of immune responses in vaccinees, and these remain unexplained (9,10). Thus there was significant clinical and laboratory evidence underlying doubts about the safety of this ill-fated vaccine.

Another curious spin is that the author blames Lyme activists for spreading fear about the vaccine that ultimately diminished its use and prevented an adequate assessment of its clinical value. In reality, the vaccine was pulled off the market to avoid disclosure of Phase IV data that would have shown limited efficacy and significant safety concerns related to LYMErix (11-13).

Aronowitz divides the Lyme universe into "orthodox" and "heterodox" camps. The "orthodox" camp defines Lyme disease in a narrow fashion that excludes various clinical manifestations and chronic forms of the disease despite growing evidence to the contrary (14). Thus a patient who develops fibromyalgia or fatigue symptoms after receiving the Lyme vaccine would not have complications related to the vaccine because fibromyalgia and fatigue are separate entities unrelated to Lyme disease. This narrow definition serves to enhance the benefit of the vaccine (ie, no Lyme symptoms) while dismissing potential complications of the vaccine (ie, fibromyalgia and fatigue are separate and unrelated problems). It is easy to see why the Lyme community would be reluctant to go along with this selective view of the vaccine.

In contrast, Aronowitz defines the "heterodox" camp as having a broad view of Lyme disease that requires prolonged treatment with antibiotics rather than any attempt to prevent the disease. The implication that this patient group is opposed to a Lyme vaccine because its members are invested in being chronically ill and taking prolonged courses of antibiotics strains credibility. The recognition that numerous patients fail the "orthodox" approach to Lyme disease and remain chronically ill is what drives these patients to seek better treatment, and certainly a vaccine that is safe and effective would be welcome (15). Unfortunately as outlined above, LYMErix was not it.

References 1. LDA website: Vaccine lawsuit. Available at: https://www.lymediseaseassociation.org/about-lyme/controversy/vaccine/1157-vaccine-suit-lda-ltr-a-judgement. Accessed July 22, 2017. 2. Rose et al, J Rheumatol. 2001;28:2555-7. 3. Latov et al, Periph Nerv Syst. 2004;9:165-7. 4. Souayah et al, Vaccine 2009;27:7322-5. 5. Nardelli et al, Future Microbiol. 2009;4:457-69. 6. Marks DH, Int J Risk Saf Med. 2011;23:89-96. 7. Croke et al, Infect Immun. 2000;68:658-63. 8. Alaedini & Latov, J Neuroimmunol. 2005;159:192-5. 9. Molloy et al, Clin Infect Dis. 2000;31:42-7. 10. Fawcett et al, Clin Diagn Lab Immunol. 2001;8:79-84. 11. Hanson & Edelman, Expert Rev Vaccines 2003;2:683-703. 11. Nigrovic & Thompson, Epidemiol Infect. 2007;135:1-8. 13. LDA website: LYMERIX Meeting; LDA Meets with FDA. Available at https://www.lymediseaseassociation.org/about-lyme/controversy/vaccine/261-lymerix-meeting. Accessed July 22, 2017. 14. Stricker RB, Fesler MC. Chronic Dis Int 2017;4:1025. 15. Stricker RB, Johnson L. Lancet Infect Dis 2014;14:12.

Disclosure: RBS is a member of the International Lyme and Associated Diseases Society (ILADS) and a director of LymeDisease.org. He has no financial or other conflicts to declare.

On 2017 Jun 05, Boris Barbour commented:

See discussion about the article that is the subject of this News and Views:

https://www.ncbi.nlm.nih.gov/pubmed/22635043#cm22635043_69529

On 2016 Sep 12, Morten Oksvold commented:

Please note that this article has been retracted and should therefore not be cited.

On 2014 Feb 20, Egon Willighagen commented:

Figure 4 is available as WikiPathway at http://www.wikipathways.org/index.php/Pathway:WP2291

On 2017 Mar 21, Wenwen Shen commented:

As I am curious about the prevalence and natural course of addiction, I read the article with great interest. In the article, in the 2nd paragraph, the author claims 'the National Institute on Alcohol Abuse and Alcoholism demonstrate that addiction, as defined by the DSM-IV criteria for substance dependence, peaks in adolescence and early adulthood, but, in the majority of cases, has resolved permanently, without clinical intervention, by the late twenties or early thirties (Anthony and Heltzer 1991; Compton et al. 2007; Kessler et al. 2005a; 2005b; Stinson et al. 2005; Warner et al. 1995).' I searched the references. I haven't got access to the first ref. But the rest of them are all available. It turns out that the refs are telling a different story (for example,see Compton 2007 http://jamanetwork.com/journals/jamapsychiatry/fullarticle/482282). They are talking about the 12-month prevalence and lifetime prevalence, and the onset age of the disorders. It seems to me that the conclusion Pickard made comes from her misinterpretation of the chart of onset age.There is no evidence in these refs showing '(drug problems) resolved by the late twenties...' Tell me if I were wrong. I just eager to read any statistics about the lifetime course of addiction.

On 2014 Feb 21, Alexis Verger commented:

A direct link to watch the movie can be found here : http://www.youtube.com/watch?v=WlMV_l88Lus A very nice animation that facilitates learning and teaching.

On 2015 Nov 12, University of Kansas School of Nursing Journal Club commented:

Reviewers (Team 2): Jennifer Patton, Jessica Reed, Kendal Miller, Brittany Nedblake, Christena Beer, Melissa Zanski-Loughlin, & Haydee Fewell (Senior Nursing Students - Class of 2016)

Background Introduction:

        Within Section 2 of the Process Elements of Healthy Work Environments, in our Microsystems course, we have examined many factors that produce healthy work environments. With the alarmingly high rate of nurse turnover that influences many new graduate nurses to leave the nursing profession, a need for examination of the various factors that lead to burnout is present. Many of our class discussions have examined different leadership styles as a prominent aspect involved in cultivating various types of work environments that can positively or negatively affect employees. Negative work environments that lack strong, influential leaders can lead to workplace bullying and other undesirable behaviors between coworkers. Laschinger, Wong, & Grau (2012), examine the impact of authentic leadership in reducing workplace bullying that leads to burnout and turnover in new graduate nurses. Our group felt that this article aligned with our recent class discussion while incorporating a unique perspective on the relationship between authentic leadership and healthy work environments.

Methods:

        Our group retrieved the article using Google Scholar as our research database. Within the Google Scholar database we searched for the key words “Authentic Leadership” and “New Graduate Nurses” to obtain an article that aligns with recent class discussion about leadership styles. We felt that this article was relevant to the entire class because we will soon be new graduate nurses entering the nursing profession. This article portrays the importance of selecting a job on a unit that has a healthy work environment supported by an authentic leader.
        According to Laschinger, Wong, & Grau (2012), “The aim of this study was to test a model linking new graduate nurses’ perceptions of their immediate supervisor’s authentic leadership behaviors to their experiences of workplace bullying and burnout in Canadian hospital work settings, and ultimately to job satisfaction and turnover intentions” (p. 1269). It is a cross-sectional study, which involves the analysis of data collected from a target population. The study focused on 342 new graduate nurses in acute care settings in Ontario, Canada, with less than two years of practice experience. A survey that measured detailed components of authentic leadership, workplace bullying, nurse burnout, job satisfaction, and a turnover intention was sent to the home addresses of the nurses selected to participate. The survey contained standardized questionnaires to assess the study variables. Once the surveys were completed and returned, the data was analyzed using the Statistical Package for the Social Sciences, and the Analysis of Moment Structures statistical software programs. The statistics were then analyzed using structural equation modeling techniques, which ultimately led to the use of a path analysis to finalize the findings.

Findings:

Of the 342 new graduated nurses who were surveyed, 92% were female averaging 28 years of age and 1.04 years of nursing. All respondents were baccalaureate prepared nurses working on a critical care unit (23%) or a medical-surgical floor (55%), with either full time (62%) or part time (28%) employment. Laschinger, Wong, & Grau (2012), found that the new graduate nurses’ ratings of their managers authentic leaders behaviors were categorized as ‘sometimes’ and ‘fairly often’ (M= 2.47), and the overall mean frequency of work-related bullying was low (M= 1.57). One interesting finding was nurse burnout. Although the average years of nursing was 1.04, the emotional exhaustion average was 2.90, meaning that they are already approaching severe burnout. Authentic leadership was correlated significantly to increased job satisfaction (r=0.40) and decreased workplace bullying (r= -0.37). Job satisfaction and work-related bullying were strongly related to one another as well. These findings highlight the importance of authentic leadership in creating bullying-free environments as well as preventing burnout, and encouraging retention of new graduate nurses. Although this study takes place in Canada, there is not direct comparison or contrast between different international settings (i.e. Canada vs United Stated). This is a limitation because without a comparison, it is unknown whether these findings correlate internationally or not. Another limitation is that this is a cross-sectional study design. This particular design impedes the ability to make cause and effect statements. Therefore, further longitudinal designed research is necessary in order to track changes over time to better interpret the transition process. Another limitation of this study was the use of surveying, because individuals can chose to participate or not. Within this study, Laschinger, Wong, & Grau (2012), tried to facilitate the process by encouraging feedback and the importance of evaluating authentic leadership and how it correlates to workplace bullying, retention rates, intent to leave, and job satisfaction. A final limitation of this study: factors not measured, such as personal dispositional variables (resilience or coping self-efficacy). It would have been beneficial to explore, because these factors could contribute to retention rates and job satisfaction.

Implications:

The selected literature is important to nursing and nursing practice. As seen from the results, authentic leadership behaviors are associated with new graduates’ experience of bullying, job satisfaction, burnout, and job turnover intentions within the first two years of practice. After reading this article, as a soon-to-be baccalaureate graduates, we have discovered that authentic leadership will personally affect our future job satisfaction, bullying, and the decision to stay in the nursing profession. When interviewing for future positions at a facility, we will use this time to ask some authentic leadership questions to assess how the manager would handle certain situations. Having authentic leadership within the workplace is important on a personal level, because we want to work somewhere free of bullying, where there is less burnout and high levels of job satisfaction. This is also vital to the microsystem because with less burnout, there will be more consistency within the workplace. Staff will bond better in a stable work environment, which will lead to better patient outcomes, better job satisfaction, and a more trusting environment that facilitates teamwork and collaboration. This is fundamental for the nursing profession to achieve because patient care is at the core of the microsystem and in order to encourage patient satisfaction and better outcomes, authentic leadership is essential.

Reference: Laschinger, H. K. S., Wong, C. A., & Grau, A. L. (2012). The influence of authentic leadership on newly graduated nurses’ experiences of workplace bullying, burnout and retention outcomes: A cross-sectional study. International Journal of Nursing Studies, 49(10), 1266-1276.

On 2013 Dec 20, Raphael Stricker commented:

Clinical Evidence for Rapid Transmission of Lyme Disease Following a Tickbite: Response to Sugar.

Raphael B. Stricker, MD,* Eleanor D. Hynote, MD,* and Phyllis C. Mervine, EdM.*

*International Lyme and Associated Diseases Society, P.O. Box 341461, Bethesda, MD 20827-1461. www.ILADS.org

Sugar complains about the lack of seroconvesion from IgM to IgG in our promptly treated patients, but then acknowledges that the IgM response may be persistent, as seen in our patient with acute Lyme disease and Babesia duncani coinfection. Although the IgM response may persist for long periods in some patients with Lyme disease (Craft et al, 1986; Aguero-Rosenfeld et al, 1996; Kalish et al, 2001; Porwancher et al, 2011), reversion to seronegative status has been associated with response to treatment in other patients with acute infection (Engstrom et al, 1995; Trevejo et al, 1999). Contrary to the statement by Sugar, serological testing appears to have adequate sensitivity and specificity to establish a diagnosis of Babesia infection (Abrams, 2008; Prince et al, 2010). Thus the clinical and laboratory features of our cases comply with standards for the diagnosis of tickborne diseases.

Our report confirms studies in both animals and humans that document transmission of Lyme disease within 24 hours of a tickbite (Piesman et al, 1987; Patmas and Remorca, 1994; Strle et al, 1996a, 1996b; Angelov, 1996; Sood et al, 1997). When animal and human studies produce apparently conflicting results, the contradictory findings should be given serious consideration, even if they contravene existing clinical dogma.

References

1. Abrams Y. Complications of coinfection with Babesia and Lyme disease after splenectomy. J Am Board Fam Med. 2008;21:75-7.
2. Aguero-Rosenfeld ME, Nowakowski J, Bittker S, Cooper D, Nadelman RB, Wormser GP. Evolution of the serologic response to Borrelia burgdorferi in treated patients with culture-confirmed erythema migrans. J Clin Microbiol. 1996;34:1-9.
3. Angelov L. Unusual features in the epidemiology of Lyme borreliosis. Eur J Epidemiol. 1996;12:9-11.
4. Craft JE, Fischer DK, Shimamoto GT, Steere AC. Antigens of Borrelia burgdorferi recognized during Lyme disease. Appearance of a new immunoglobulin M response and expansion of the immunoglobulin G response late in the illness. J Clin Invest. 1986;78:934-9.
5. Engstrom SM, Shoop E, Johnson RC. Immunoblot interpretation criteria for serodiagnosis of early Lyme disease. J Clin Microbiol. 1995;33:419-27.
6. Hynote ED, Mervine PC, Stricker RB. Clinical evidence for rapid transmission of Lyme disease following a tickbite. Diagn Microbiol Infect Dis. 2012;72:188-92.
7. Kalish RA, McHugh G, Granquist J, Shea B, Ruthazer R, Steere AC. Persistence of immunoglobulin M or immunoglobulin G antibody responses to Borrelia burgdorferi 10–20 years after active Lyme disease. Clin Infect Dis 2001;33:780–5.
8. Patmas MA, Remorca C. Disseminated Lyme disease after short-duration tick bite. J Spiro Tick Dis. 1994;1:77-78.
9. Piesman J, Mather TN, Sinsky RJ, Spielman A. Duration of tick attachment and Borrelia burgdorferi transmission. J Clin Microbiol. 1987;25:557-8.
10. Porwancher RB, Hagerty CG, Fan J, Landsberg L, Johnson BJ, Kopnitsky M, Steere AC, Kulas K, Wong SJ. Multiplex immunoassay for Lyme disease using VlsE1-IgG and pepC10-IgM antibodies: improving test performance through bioinformatics. Clin Vaccine Immunol. 2011;18:851-9.
11. Prince HE, Lapé-Nixon M, Patel H, Yeh C. Comparison of the Babesia duncani (WA1) IgG detection rates among clinical sera submitted to a reference laboratory for WA1 IgG testing and blood donor specimens from diverse geographic areas of the United States. Clin Vaccine Immunol. 2010;17:1729-33.
12. Sood SK, Salzman MB, Johnson BJ, Happ CM, Feig K, Carmody L, Rubin LG, Hilton E, Piesman J. Duration of tick attachment as a predictor of the risk of Lyme disease in an area in which Lyme disease is endemic. J Infect Dis. 1997;175:996-9.
13. Stricker RB, Hynote ED, Mervine PC. Clinical evidence for rapid transmission of Lyme disease following a tickbite: response to Piesman and Gray. Diagn Microbiol Infect Dis. 2012;73:104-5.
14. Strle F, Nelson JA, Ruzic-Sabljic E, Cimperman J, Maraspin V, Lotric-Furlan S, Cheng Y, Picken MM, Trenholme GM, Picken RN. European Lyme borreliosis: 231 culture-confirmed cases involving patients with erythema migrans. Clin Infect Dis. 1996a;23:61-5.
15. Strle F, Maraspin V, Furlan-Lotric S, Cimperman J. Epidemiological study of a cohort of adult patients with Erythema migrans registered in Slovenia in 1993. Eur J Epidemiol. 1996b ;12:503-7.
16. Trevejo RT, Krause PJ, Sikand VK, Schriefer ME, Ryan R, Lepore T, Porter W, Dennis DT. Evaluation of two-test serodiagnostic method for early Lyme disease in clinical practice. J Infect Dis. 1999;179:931-8.

Disclosure: RBS is a member of the International Lyme and Associated Diseases Society (ILADS) and a director of LymeDisease.org. He has no financial or other conflicts to declare.

On 2014 May 06, Melissa Vaught commented:

When this paper was first published, some media outlets reported that popcorn flavoring was linked to Alzheimer's. Here are two posts I wrote then about the study and the media coverage of it.

Popping up trouble with butter and Alzheimer’s

Science, reporting, & communication

On 2016 Jun 07, Kevin Hall commented:

This interesting randomized controlled trial by Dr. David Ludwig’s group has been widely recognized as demonstrating a substantial metabolic advantage of carbohydrate restriction following a period of weight loss. The reported differences in total energy expenditure (TEE) amounted to as much as 325 kcal/d between isocaloric diets. However, in addition to the confounding differences in protein between the diets, there are several reasons to be skeptical about this conclusion. In particular, the data from this study are internally inconsistent at a fundamental level suggesting that some of the measurements were simply erroneous.

Following a run-in period of weight loss, subjects consumed three “weight-loss maintenance” diets in a randomized crossover fashion with each diet lasting one month. The very low carbohydrate (VLC) diet had ~50% more protein than both the low glycemic index (LGI) diet and the low fat (LF) diet, but energy intake was claimed to be held constant at ~2600 kcal/d. However, the measured TEE was between ~200-500 kcal/d greater than the reported energy intake for all diets. Therefore, the corresponding negative energy balance should have resulted in several kilograms of weight loss over the three month period consuming these diets. However, no such weight loss occurred since the mean body weight at the end of the run-in weight loss phase (105.0 kg minus 14.3 kg of lost weight = 90.7 kg) was slightly lower than the reported body weights during the different diets (91.5 kg for the LF diet; 91.1 kg for the LGI diet; and 91.2 kg for the VLC diet) which were not significantly different from each other.

What could be responsible for these inconsistencies in the data? It is highly likely that the energy intake measurements were inaccurate since diet adherence during outpatient feeding studies is typically poor even when all study foods are provided. If the energy intake measurements were consistently biased (such that energy intake was underestimated equally for all three diets) then the relative constancy of body weight suggests that TEE during the isocaloric VLC diet could not have been ~300 kcal/d greater than the LF diet. Such a difference in energy balance should have led to a cumulative difference in stored energy amounting to ~9000 kilocalories which translates to more than 1 kg of weight difference between the diets over the one month diet period. Since this weight difference was not observed, the inescapable conclusion is that the body weight, energy intake, and TEE data from this study are internally inconsistent and at least one of these measurements is fundamentally in error.

Since the body weight data are likely correct, either the subjects were eating ~300 kcal/d more during the VLC diet as compared to the LF diet (in which case the study was poorly controlled) or the TEE data were simply erroneous. The latter explanation is quite likely since the observed differences in TEE between the diets may have been statistical anomalies. In particular, the reported statistical analyses did not adequately address the multiple comparisons problem for this secondary study outcome which was one of 25 listed in the registration of this clinical trial. Therefore, the chance of obtaining a false positive for any one of these 25 secondary outcomes was quite high. Previous studies investigating the effects of isocaloric diets on energy expenditure have not seen such large effects, thereby adding further support to the conclusion that the TEE differences reported in this study were unlikely to be real.

Interestingly, the primary endpoint of this study was resting energy expenditure (REE) and the high protein VLC diet was the only diet showing a statistically significant difference compared to the LF diet. However, the magnitude of the REE effect was only ~67 kcal/d and was therefore clinically insignificant. The moderate carbohydrate, LGI diet with protein and calories matched to the LF diet failed to show a statistically significant difference in either REE or TEE despite a 34% decrease in carbohydrate compared to the LF diet. In other words, when comparing diets differing in protein, the primary REE outcome of the study showed a small effect that has been largely ignored and the secondary TEE outcome showed a large effect that was likely to be a false positive.

In conclusion, this study suffered from the same pitfalls that are typical of outpatient studies where poor diet adherence is the norm. Furthermore, the measurements were internally inconsistent and the reported beneficial effects of carbohydrate restriction on energy expenditure are likely to be incorrect.

On 2016 Jun 08, DAVID LUDWIG commented:

In the post below (dated June 7, 2016), Kevin Hall claims that the main findings of our JAMA 2012 study are false because of fundamental inconsistencies and measurement problems. On behalf of my coauthors Cara Ebbeling and Henry Feldman, I address each of Hall’s criticisms below.

1. Was total energy expenditure mismeasured? Hall bases his argument on the difference between calculated energy intake (in prepared meals) and total energy expenditure (TEE) of about 300 kcal/d. However, this observed difference, 10% of TEE, is quite small compared to reported discrepancies several fold that magnitude in outpatient behavioral studies in which participants consume self-prepared meals. Because our participants were not kept in a locked ward for the 7-month protocol, it is likely that some non-study foods were consumed – providing a simple explanation for the observed discrepancy. However, Hall offers no reason to believe that this small degree of non-compliance would invalidate results of the stable isotope measurement, let alone produce a systematic error favoring the very-low-carbohydrate. Indeed, multiple biomeasures of macronutrient composition (such as RQ, triglyceride, non-HDL-cholesterol, HDL-cholesterol) changed strongly and in the hypothesized directions – evidence that the feeding protocol produced substantive differences in dietary intakes as intended. Should we also dismiss those objective findings based on the possibility of marginal non-compliance? By this reasoning, no meaningful interventional nutrition research could ever be conducted for more than a month or two, the practical limits of human research under confinement. In fact, feeding protocols such as ours provide an important design alternative to the short-term locked-ward studies such as those of Hall (with poor generalizability) Hall KD, 2015 and dietary behavioral counseling trials (often with lack of attention to differentiation between diets). Furthermore, our estimates of the diet effects on TEE compare well with those of Hall himself, based on his recent metabolic ward study.

2. Does body weight on the test diets indicate internal inconsistency? Hall claims that the very-low-carbohydrate diet should have produced a 1 kg weight loss as a result of the 325 kcal/d greater TEE compared to the low-fat diet, and the lack of a significant difference in this regard leads to the “inescapable conclusion” of internal inconsistency and fundamental error. However, body weight is well recognized to be an imprecise measure of energy balance over the short term. Body weight can vary by 2 kg or more on a daily basis related to hydration status, amount of stool in the colon, and other physiological factors. Moreover, since body fat holds much more energy than lean tissue, energy balance may shift by thousands of calories without translation into weight change, if relatively small changes in body composition have occurred. (Diets that reduce insulin secretion have been shown to alter substrate partitioning favoring lean tissue, as for example Pawlak DB, 2004.) In addition, TEE was measured during the final 2 weeks of each test diet. Hall assumes the TEE differences emerged immediately, but the literature suggests that the process of fat adaptation may take 1 or 2 weeks Hawley JA, 2011 Vazquez JA, 1992 Veum VL, 2017. Finally, Hall assumes that the observed weight at the end of each test diet represents the effects of that diet alone, neglecting the cross-over design. In fact, the weight at any timepoint represents the cumulative effects of prior diet arms. Based on the randomized design, each test diet would come after at least one of the other diets two-thirds of the time. We analyzed change in body weight occurring during each test diet, and consistent with the TEE findings, results were numerically greater on the very-low-carbohydrate versus low-fat diet, by 0.55 kg (VLC: -0.78; LGI: -0.76; LF: -0.23 kg). (NB, this small overall weight loss averaged only 20 g/d -- if there were any minimal confounding as a result, it would have biased against the VLC and toward the null hypothesis.)

3. Is the resting energy expenditure finding meaningless? Resting energy expenditure (REE) was obtained through an independent method (indirect calorimetry by measurement of respiratory gases) and yielded a result consistent with TEE. However, Hall dismisses this finding too, arguing that the observed 67 kcal/day difference was too small to be meaningful. He disregards that this statistically significant difference would represent an entirely novel effect of dietary composition not recognized in the conventional approach to obesity treatment. By his own calculations, an energy gap of 1/10th this magnitude (30 kJ or about 7 kcal per day) “underlies the observed average weight gain” throughout the population Hall KD, 2011. Moreover, REE represents only one component of energy expenditure, which is why we also studied TEE (for which the observed difference was substantially larger). In any event, the aim of our relatively small study wasn’t to establish precise estimates of effect sizes, but rather to explore whether macronutrient composition might attenuate the biological adaptations to weight loss that antagonize successful weight loss maintenance.

4. Does dietary protein fatally confound study findings? The very-low-carbohydrate diet had 30% protein (consistent with the initial phase of the Atkins program, upon which this diet was modeled) compared to 20% for the other 2 diets. A protein difference of this magnitude can’t explain differences in REE in the fasting state, long after the thermic effects of food have dissipated. Nor could this difference explain the 325 kcal/day difference in TEE. Listed below are 10 studies involving differences in protein intake equal to or greater than that in our study, and also within the physiological range for dietary protein. In no case did TEE differ by more than 100kcal/day, and the average effect considering all studies was virtually null. Dulloo AG, 1999 Hochstenbach-Waelen A, 2009 Lejeune MP, 2006 Luscombe ND, 2003 Mikkelsen PB, 2000 Veldhorst MA, 2009 Veldhorst MA, 2010 Westerterp KR, 1999 Westerterp-Plantenga MS, 2009 Whitehead JM, 1996

5. Were the statistical methods faulty? Hall states that because we examined multiple secondary outcomes, the probability is “quite high” that any statistically significant results (and those for TEE in particular) were false positives, but this assertion lacks merit. We reported 22 secondary outcomes, including 20 in the table of study outcomes and 2 in the text, with statistical significance tests for diet trend ranging from p<0.0001 to p=0.78. We specified a threshold of p<0.05 for declaring significance, i.e., a 5% type I error rate. We can calculate the false discovery rate (FDR) according to the method of Benjamini and Hochberg, which takes into account the number of comparisons and their attained significance levels. This calculation reveals an overall 6.7% FDR, comparable in stringency to the 5% type I error rate. For the 22 tests of equality across the 3 diets (unordered, or “overall”), we calculate the FDR as 6.1%. For TEE, the risk of FDR is likely to be even lower, in view of its relatively robust statistical significance (p=0.003).

In summary, our feeding study obtained substantially greater differentiation between dietary treatments than conventional behavioral studies, as demonstrated by multiple biomeasures of compliance, allowing for a rigorous test of pre-specified study hypotheses. The outcomes were assessed with state-of-the-art techniques and analyzed according to accepted statistical methods. The manuscript passed rigorous peer-review at a selective journal. Hall’s claims of fatal problems involving the study findings are based on factual error and misinterpretation.

On 2017 Jan 11, Kevin Hall commented:

Dr. Ludwig and his co- authors claimed in their 2012 JAMA article that “the main strength of our study was use of a controlled feeding protocol to establish weight stability following weight loss”. However, in the edited PubMed Commons comment below, Dr. Ludwig now reveals that the study did not establish weight stability but actually led to weight loss during all three test diets (VLC: -0.78 kg; LGI: -0.76 kg; LF: -0.23 kg). These newly revealed weight losses are qualitatively consistent with an overall state of negative energy balance as indicated by the reported energy intake and TEE measurements, although the mean weight losses remain quantitatively somewhat lower than might be expected based on the reported ~200-500 kcal/d negative energy balance. Furthermore, the 0.55 kg mean difference in weight loss during the VLC versus LF diets amounts to an approximate energy imbalance of ~150 kcal/d which is about half the reported mean difference in TEE. Without body composition measurements, it is impossible to be more definitive regarding the concordance between the mean reported TEE, energy balance, and weight loss.

On 2016 Apr 18, PAMELA RONALD commented:

Following the publication of this Article, we discovered that Xanthomonas oryzae pv. oryzae (Xoo) lacking the peptide Ax21 is still able to trigger XA21-mediated immunity^1. Furthermore, we were unable to consistently reproduce experiments demonstrating that synthetic AxYS22 triggers XA21-mediated immunity^2,3,4.

In light of these results, we repeated the experiments reported in this Article. We found that neither AxYS22 nor Xoo enhance accumulation of the XA21-GFP protein beyond that observed following mock treatment. Shredding of leaf tissue (mock), with or without treatment, induces higher levels of XA21-GFP protein and correspondingly higher levels of the cleavage product as compared with the unshredded control. The presence of higher levels of cleavage product after wounding or Xoo treatment facilitates detection. Based on these results, we can no longer ascribe a role for Xoo or AxYs22 in XA21-GFP cleavage.

These findings do not alter the main conclusion of this Article that XA21-GFP is cleaved and translocates to the nucleus of protoplasts when transiently overexpressed and that the putative nuclear localization sequence (NLS) is required for localization. We are currently investigating the in vivo biological relevance of the putative NLS in the rice immune response. This notice of correction was first submitted to the editors April 7, 2014.

1. Bahar, O. P., Pruitt, R., Luu, D. D., Schwessinger, B., Daudi, A., Liu, F., Ruan, R., Fontaine-Bodin, L., Koebnik, R. & Ronald, P. C. The Xanthomonas Ax21 protein is processed by the general secretory system and is secreted in association with outer membrane vesicles. PeerJ 2, e242 (2014).
2. Lee, S. W., Han, S. W., Sririyanum, M., Park, C. J., Seo, Y. S. & Ronald, P. C. A type I-secreted, sulfated peptide triggers XA21-mediated innate immunity. Science 326, 850–853 (2009).
3. Lee S. W., Han S. W., Sririyanum M., Park C. J., Seo Y. S. & Ronald P. C. Retraction. Science 342, 191 (2013).
4. Ronald P. C. 2013. Lab Life: The Anatomy of a Retraction, Scientific American. October 10, 2013. http://blogs.scientificamerican.com/food-matters/2013/10/10/lab-life-the-anatomy-of-a-retraction/

On 2016 May 28, Simon Young commented:

This is an interesting article, but it contains a number of statements that are problematic.

1. The abstract concludes with the statement that the results support the hypothesis “higher tryptophan and vitamin B6 intake at breakfast could promote the synthesis of serotonin via light stimulation in the morning in children”. The first issue is whether higher dietary intake of tryptophan (Trp) can stimulate serotonin synthesis. Meals containing protein will increase plasma Trp but will not increase brain Trp or serotonin Sainio EL, 1996. This is because Trp is taken up into the brain from the blood by a transport system that is active towards all the large neutral amino acids (LNAA). The different amino acids compete with each other for the transport system, and as a rough approximation brain Trp levels will follow the plasma ratio of Trp to the other LNAA (Trp/LNAA). Because of the low abundance of TRP in most proteins this ratio will decline after a meal. The decline is small enough that there is unlikely to be any important decline in brain TRP and serotonin synthesis. Protein-containing meals certainly do not raise brain serotonin synthesis in humans Teff KL, 1989. In the pineal there is no blood-brain barrier, so meals containing Trp might cause a small increase in serotonin and melatonin. The only function for serotonin in the pineal is to act as a precursor of melatonin. In daytime melatonin levels are very low and any change in levels are unlikely to have any effect. Therefore, even if increased serotonin in the morning could enhance morning typology, and I am not aware of any such evidence, there would still be no valid rationale for the idea that the Trp content of breakfast will influence serotonin in any way that will promote morning typology.

2. The last paragraph of the article starts with the sentence “From these results, it might be suggested that a higher Trp and Vi-B6 intake may promote the synthesis of serotonin via light stimulation in the morning and have a natural sleep-inducing effect when converted to melatonin at night.” When plasma Trp rises due to Trp intake it is metabolized rapidly. For example, even after ingestion of pure Trp equivalent to several times the normal daily intake plasma levels are back to normal within 8 hours Yuwiler A, 1981. Plasma Trp varies throughout the day due to diurnal variation and the intake of meals during the day Fernstrom JD, 1979. Intake of Trp at breakfast will not influence melatonin at bedtime.

3. The last sentence of the first paragraph of the article states “The exposure to sunlight in the morning can be hypothesized to accelerate the synthesis of serotonin from Trp in the pineal gland [8]”. The reference cited, which is an abstract from a meeting, does not state that sunlight increases the synthesis of serotonin from Trp in the pineal. Bright light suppresses serotonin and melatonin synthesis in the pineal, a fact that has been known for more than 50 years, see e.g. WURTMAN RJ, 1964. However, it may increase serotonin synthesis in the brain. Sunlight is associated with an increase in serotonin synthesis in human brain Lambert GW, 2002, possibly due to a direct neural connection between the retina and the cell bodies of serotonin neurons in the raphe nuclei of the brainstem Ren C, 2013.

4. In the second paragraph of the Discussion the authors state “Among essential amino acids, the Trp content in food is quite small, and thus it is necessary to make a special effort to consume a sufficient amount in one’s diet”. Trp deficiency can occur in conjunction with protein deficiency, but otherwise is rare and related to genetic and other diseases Sainio EL, 1996. The requirement of adults for Trp is 4 mg/kg/day Elango R, 2009, and the daily requirement for 10-12-year-old children it at most 120 mg/day NAKAGAWA I, 1963, so the daily requirement for Trp of the 2-6-year-old children in this study will be small. This explains why billions of people in the world are able to obtain sufficient Trp in their diet even though they do not “make a special effort” to obtain enough Trp, due to lack of knowledge of Trp.

5. As stated in the first paragraph of the paper vitamin B6 (Vi B6) is “a coenzyme in the tryptophan-serotonin pathway”. It is the coenzyme of aromatic amino acid decarboxylase (AADC), the second enzyme on the pathway. The first enzyme on the pathway is Trp hydroxylase, which is the rate-limiting enzyme on the pathway. This, and the fact that Trp hydroxylase is not normally saturated with Trp, explains why increases in brain Trp will increase serotonin synthesis. Given that Trp hydroxylase is the rate-limiting enzyme on the pathway from Trp to serotonin, changes in AADC activity, except for very large decreases in activity, would not be expected to alter the rate of serotonin synthesis. I am not aware of any evidence that, in the absence of Vi B6 deficiency, variations in Vi B6 intake can alter the rate of serotonin synthesis in human brain.

6. This paper demonstrates an association between morning typology and intake of Trp plus exposure to light. An association does not necessarily imply causation. The authors do not consider any possible confounders that might explain both phenomena. They also do not consider reverse causation. For example, if the parents have morning typology they may be more likely to give their children a nutritionally balanced breakfast containing sufficient protein. More protein in a meal means that there will be more tryptophan in the meal. Also, if the parents have morning typology they may encourage their child to spend more time outside before arriving at nursery school or kindergarten. The timing of daily circadian behavior in humans is determined by both genetics and the environment Azzi A, 2014, so if the parents demonstrate morning typology the children are also likely to exhibit morning typology. Thus, a morning typology in the parents may cause the child to have a greater intake of Trp at breakfast and be exposed to more light in the morning. Furthermore, a morning typology in the parents could be responsible for a morning typology in the child, due to both genetic and environmental factors. This is one possible explanation for the results.

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 NCT0148309. We believe the correct ID, which we have found by hand searching, is NCT01483092.

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

Many thanks,

Jessica Fleminger, Ben Goldacre*

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

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

On 2014 Jul 20, Torsten Seemann commented:

The URL for the software is not in the abstract. You can find it at https://github.com/slindgreen/AdapterRemoval

On 2017 Jul 04, Parmit Singh commented:

Since spore killers are also dominant suppressors of meiotic silencing, it is very interesting results that this suppressor is not able to suppress meiotic silencing of unpairing at rsk locus due to deletion. This suggests that suppressor of meiotic silencing in spore killer is a weak suppressor like the one identified in the wild isolated strain CMG (https://www.ncbi.nlm.nih.gov/pubmed/21295150). It might be that nature selects only weak suppressor of meiotic silencing. It is also possible that un-pairing at the rsk locus due to deletion of resistant allele causes pairing at the suppressor locus in a heterozygous cross due to the presence of several inversions that surround Sk allele. It could be tested easily by making a cross, which is heterozygous for GFP also, by putting an ectopic copy of GFP in one of the parental strain.

On 2015 Jun 25, Donald Forsdyke commented:

In the light of new reviews (Zhang J, 2015 and Forsdyke DR, 2015), the following email to the senior author (July 2 2012) may be of interest:

'Your fine new paper on dosage compensation in PNAS Early Edition links up nicely with your previous paper on protein misinteraction; that is, if you care to consider the hypothesis I advanced in 1994 (http://post.queensu.ca/~forsdyke/dominanc.htm), which is updated in my textbook (http://post.queensu.ca/~forsdyke/book05.htm). The basic point is that proteins have collective functions (such as the well-known Donnan equilibrium), as well as specific functions. Over evolutionary time protein concentrations have been fine-tuned to serve such collective functions. My 1994 paper postulated a novel collective function – aggregation pressure – through which an individual cell can initiate self/not-self discrimination. Each protein contributes to, and is acted upon by, this aggregation pressure. The more abundant a protein, the more it contributes and is acted upon.

Subsequent work on X chromosome dosage compensation has nicely supported this view ( http://post.queensu.ca/~forsdyke/theorimm7.htm). If a human female fails to compensate to some degree (both Xs expressed so aggregation pressure is high), then autoimmune disease is more likely. From the point of view of evolution, this would be a short-term effect and individuals would be negatively selected. On the other hand, if she were to excessively compensate (say part of a singly expressed X not expressed, so aggregation pressure is lowered), then she would stand an increased risk of getting infections. But since there are many alternatives for combatting infections, this would tend to be a long-term effect from the point of view of evolution. Thus, in your words “chromosome-wide expression halving has been tolerated” because “Y degeneration is stepwise” so that “expression reduction happened gradually to more and more X-linked genes during evolution.”'

On 2015 Mar 07, Prof.Dr.Jogenananda Pramanik commented:

Prof.Dr.Jogenananda Pramanik and Zury Azreen,Research Intellect organization, Penang, Malaysia:<br> Knowledge, attitude and practice (KAP)studies regarding Complimentary Indigenous Malay Therapy( CIMT)are urgently needed. We appreciate the current KAP study conducted by Lua PL using most common CIMT ingredients, such as dried medicinal roots, herbs and sea cucumber products. Numerous health drinks are commercially available which are commonly prepared after processing Golden Sea Cucumber. However, proper scientific evaluation of such products are lacking. There are ever increasing list of highly impressive claims like: 1.Helps to produce blood, 2.strong anti-inflammatory and anti-oxidant properties, 2. Decreases cholesterol level, thrombosis and diminishes the growth of atherosclerosis 3. Aids to improve the regeneration of cells. 4.Improves immunity, prevent cancer, delay aging and relieve arthritis. 5. Speed up wound recovery, maintain the suppleness and elasticity of skin, promotes healthy joints and prevents osteoporosis. We would like to recommend stringent scientific studies to substantiate such claims about CIMT products.

On 2014 Apr 24, Christine Houghton commented:

This paper misquotes the scientific literature in a manner that one might be associated with the declared commercial interest. The issue in summary is this:

1. NuSkin sells a product named ‘AgeLOC’ which contains 3 ingredients as a proprietary blend totalling 450 mg; one of those ingredients is Broccoli Seed Extract.
2. Whole broccoli sprouts contain a precursor compound, glucoraphanin and an enzyme, myrosinase, compartmentalised within the plant cell. When the cell is ruptured, the enzymatic reaction occurs, yielding the bioactive compound, sulforaphane (SFN).
3. The Broccoli Seed 'Extract' is known to be devoid of the myrosinase enzyme necessary for sulforaphane to be generated. Broccoli Seed Extract is a source ONLY of the precursor compound, glucoraphanin.
4. The authors discuss at length the science of SFN including its potential therapeutic effects, even though the NuSKIN product does not yield SFN. 5.In their Citation #36, they refer to a published clinical trial confirming the therapeutic benefits of broccoli seed.
5. Riedl’s cited study DID NOT use broccoli ‘seed’; Riedl used a fresh broccoli sprout homogenate which was shown to yield SFN. Riedl’s findings can not be used to support the ‘extract'.
6. Riedl’s paper has been misquoted, claiming benefits for seed extract that the study did not demonstrate.
7. The authors also refer to the essentiality of the myrosinase enzyme for SFN to be formed; they claim it is present in the seed or produced by the human intestine.
8. Whilst there is some evidence that an uncertain group of colonic microflora do have some myrosinase activity, the effect has been shown to be small and highly-variable across individuals.

Even though the authors declare their commercial interest, a reader may therefore incorrectly assume that the biochemistry discussed at length in the paper supports the products marketed by the company.

On 2015 Aug 09, Hiten Patel commented:

The actual mean or median follow-up within each group is not reported nor can I find an appropriate Kaplan-Meier curve to confirm that information was available on time from implant to time of infection/revision surgery. These are critical pieces of information needed to read the study.

On 2016 Feb 18, Kristina Hanspers commented:

The gene regulatory network in figure 2 is available in the "Open Access Publication" collection at WikiPathways: http://www.wikipathways.org/index.php/Pathway:WP2852. This pathway can be downloaded for use in network analysis tools such as Cytoscape and PathVisio.

On 2013 Jun 15, Hilda Bastian commented:

Assessment of the methodological quality of primary studies plays a central role in interpreting bodies of evidence. This evaluation of an extensively used method is of critical importance for systematic reviewing of clinical effectiveness research.

On 2015 Nov 12, University of Kansas School of Nursing Journal Club commented:

Reviewer (Team 2): Jennifer Patton, Jessica Reed, Kendal Miller, Brittanny Nedblake, Christena Beer, Melissa Zanski-Loughlin, & Haydee Fewell (Senior Nursing Students Class of 2016)

Background and Introduction:

        Healthcare is currently going through a major reform due to multiple factors, including a change in government funding and a decline in the economy. As this is reforming, work environments in the health professions are becoming more stressful. Studies have shown that empowered healthcare providers have more of an effect on improving work environments, and effective leadership helps empower the workplace. The purpose of this article was “to test a model linking authentic leadership of manager with nurses’ perceptions of structural empowerment, self-rated performance, and job satisfaction” (Wong & Laschinger, 2012, p. 948). Leadership styles of nurse managers contribute immensely to a healthy work environment and researchers want to test the effectiveness of the authentic leadership style, since it is relatively new. Our team chose this article because we feel that it proved how well authentic leadership could positively affect the nursing work environment and how it can be applied to a wide range of settings.

Methods:

Our group used Google scholar to find research articles related to what we have been discussing in class. We searched the phrase “authentic leadership” and made sure parameters were set to articles that were published in the last five years and found an article that encompassed many of the topics we have discussed in class this year including: authentic leadership, healthy work environments, structural empowerment, and job satisfaction. The study first started out by gathering data from a random sample of 600 registered nurses (excluding manager, charge, or educator positions). They were sent questionnaires that evaluated their current work environments. The Authentic Leadership Questionnaire measured nurses’ perception of how their manager’s leadership style matched up to be an authentic leader. The Conditions of Work Effectiveness Questionnaire II was used to measure their working environment’s empowerment. The Global Job Satisfaction Survey was used to measure job satisfaction, and overall job performance was measured using the General Performance scale (Wong et al., 2012). Due to a 48% response rate, a final sample of 280 participants was utilized for the study. The data received from these surveys was analyzed using SPSS version 19.0 for Windows and the hypothesized model (authentic leadership’s direct affects on structural empowerment which then indirectly impacts job satisfaction and performance) was examined with the AMOS 19.0 version. The target population in this study was registered nurses, because they were the ones that were being affected the most by the leadership styles and empowerment of the nurse manager. The problem of stressful work environments impacts both nurses and patients. Stressful working environments lead to nurses who don’t give as good of care to the patients as they would if they were more content with their job. Restoring a healthier work environment would improve patient safety and better patient health outcomes.

Findings:

        The average age of nurses in the sample used for the research study was 43.4 years and these nurses had about 19 years of experience in the nursing field, working on medical-surgical units or ICU’s. Another important demographic to note is the education level. The majority of nurses represented were diploma prepared. Nurses’ described moderate job satisfaction and performance, which is indicated with a mean of 3.65 and 3.72, and standard deviation of 1.01 and 0.49, respectively. After analyzing the data collected through the different surveys, the researchers found some inconsistencies between the hypothetical model and covariance data that would suggest a direct, instead of indirect, relationship between authentic leadership and nurses’ job satisfaction (Wong et al., 2012). The final model proved to be statistically significant. According to the evidence, “structural empowerment mediated the relationship between authentic leadership and job satisfaction and performance”  (Wong et al., 2012, p. 953). It was also determined that “authentic leadership had a statistically significant positive direct and indirect effect on job satisfaction through empowerment” (Wong et al., 2012, p. 954).  Because this study is one of the first to observe how authentic leadership affects structural empowerment, which in turn impacts nurses’ job satisfaction and performance, further studies of this kind need to be done in order to provide higher external validity and make it transferable to other populations.  Another limitation of this study was that it used self-report measures; so common method variance could potentially be a factor. The authors also note that other studies should be done in order to explore other possible mediators between authentic leadership and job satisfaction and performance (Wong et al., 2012). This study was done in Ontario, Canada, so its important to be aware of the differences between possible studies performed here in the U.S. The demographics in the U.S. may be slightly different, altering the data results. As compared to Canada, nurses working in the U.S. are mainly ADN or BSN prepared nurses.  This education level can impact the degree of job satisfaction and performance as described in the surveys.

Implications:

        This article is one of many that play a key role in nursing practice, because it offers insight on how certain leadership styles can positively influence nursing work environments. When nurse managers empower their employees, they create an atmosphere where nurses are more satisfied and perform their tasks more efficiently. This ultimately increases patient outcomes and leads to higher, quality nursing care. Components of an authentic leader include “transparency, balanced processing, self-awareness, and high ethical standards” (Wong et al., 2012, p. 955). By understanding the qualities that are needed for effective leadership, nurses can further the movement to creating healthy work environments. As future nurses, we believe that this study provides certain criteria that are critical as we begin to search for jobs. We see the value in leadership styles and how that impacts the overall work environment. In addition, according to Kanter’s theory of structural empowerment by having access to opportunity, resources, support and information, nurses feel more autonomous in their jobs and report more meaningful work environments (Laschinger, Gilbert, Smith & Leslie, 2010). All these components are interrelated and strongly impact the microsystem. Our role as healthcare providers is to offer our patients the highest, quality care that results in better patient outcomes. In order to accomplish this, we must establish relationships with our coworkers that are respectful, open and encouraging so that we then feel empowered to practice to the fullest extent of our nursing education. This will transform the nursing profession and the care provided to our patients. 

References

Wong, C.A. & Laschinger H.K.S (2012). Authentic leadership, performance and job satisfaction: the mediating role of empowerment. Journal of Advanced Nursing 69(4). 947-959.

Laschinger, H.K.S., Gilbert, S., Smith, L.M., & Leslie, K. (2010). Towards a comprehensive theory of nurse/patient empowerment: Applying Kanter’s empowerment theory of patient care. Journal of Nursing Management. DOI: 10.1111/j.1365-2834.2009.01046.x

On 2015 Mar 23, Christopher Southan commented:

Unfortunately this report niether specifies the structure of JNJ-39393406 nor indicates it became an NCATS repurposing candidate. There is a molecular resolution at http://cdsouthan.blogspot.se/2015/03/mystery-of-jnj-code-number-structure.html

On 2014 Apr 22, James C Coyne commented:

This is a badly done meta analysis that seems to jump to a conclusion to which the authors seemed already committed: The authors systematically searched the literature, but found too few studies to justify their sweeping conclusion: that strength of evidence for psychotherapy for depressive symptoms among cancer patients warrants widespread dissemination of existing treatments and implementation routine care.

They claim to have identified only 6 effect sizes from RCTs for psychotherapy. But three are from collaborative care studies in which patients assigned to the intervention group did not necessarily get psychotherapy and many patients got medication with or without therapy. Patients assigned to the control group in two of these studies had to pay for any treatment whereas it was free for patients in the intervention group. Two effect sizes came from ta single study, violating the assumption of independent effect sizes, and a support group was counted as psychotherapy. It is usually considered a control condition. If it had served as such for the CBT treatment, CBT would have had a negative effect size.

You can read more at my 2 blog posts.

http://blogs.plos.org/mindthebrain/2014/04/15/meta-analyses-conducted-professional-organizations-trustworthy/

http://jcoynester.wordpress.com/2014/04/22/does-psychotherapy-work-for-depressive-symptoms-in-cancer-patients/

On 2014 Apr 29, Amanda Capes-Davis commented:

Please be aware that Hep-2 cells are not from laryngeal cancer. The cell line is cross-contaminated with HeLa, a cervical carcinoma cell line. For a list of cross-contaminated or otherwise misidentified cell lines, see http://iclac.org/databases/cross-contaminations/.

On 2013 Dec 13, Sébastien Talbot commented:

Beautiful work by a foremost investigator

On 2013 Nov 03, Dale D O Martin commented:

In Figure 2, amino acids 512, 552 and 586 should be listed as caspase cleavage sites, not phosphorylation sites, and should be aspartate residues, not serines.

Caspase cleavage of HTT is reviewed here: http://www.ncbi.nlm.nih.gov/pubmed/21311053

These sites are well established as caspase cleavage sites and are also listed on the Human protein resource database here: http://www.hprd.org/summary?hprd_id=00883&isoform_id=00883_1&isoform_name=Isoform_1

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 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 2014 Feb 14, David Keller commented:

Sunshine, not vitamin D, combats depression

Depression is associated with vitamin D deficiency. However, vitamin D supplements do not reduce this depression because depression and vitamin D deficiency are both symptoms of the same underlying problem: lack of sun exposure. Exposing the skin to sunshine promotes endogenous synthesis of large amounts of vitamin D, and is the principal natural source of vitamin D for humans. Likewise, retinal exposure to sunshine prevents or treats depression, by stimulating certain endogenous brain neurotransmitters, which is why light-exposure therapy relieves seasonal affective disorder. These facts are all well established. Expecting vitamin D supplements to reduce depression in sunshine-deprived patients is analogous to treating their vitamin D deficiency with anti-depressants.

On 2015 Apr 03, Saleh Abbas commented:

this is promising, and good piece of work,

On 2014 Feb 27, George W Hinkal commented:

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

https://cananolab.nci.nih.gov/caNanoLab/characterization.do?dispatch=summaryView&sampleId=38010880&page=0&tab=ALL

https://cananolab.nci.nih.gov/caNanoLab/characterization.do?dispatch=summaryView&sampleId=38010881&page=0&tab=ALL

https://cananolab.nci.nih.gov/caNanoLab/characterization.do?dispatch=summaryView&sampleId=38010882&page=0&tab=ALL

https://cananolab.nci.nih.gov/caNanoLab/characterization.do?dispatch=summaryView&sampleId=38010883&page=0&tab=ALL

https://cananolab.nci.nih.gov/caNanoLab/characterization.do?dispatch=summaryView&sampleId=38404096&page=0&tab=ALL

https://cananolab.nci.nih.gov/caNanoLab/characterization.do?dispatch=summaryView&sampleId=38404097&page=0&tab=ALL

https://cananolab.nci.nih.gov/caNanoLab/characterization.do?dispatch=summaryView&sampleId=38404098&page=0&tab=ALL

https://cananolab.nci.nih.gov/caNanoLab/characterization.do?dispatch=summaryView&sampleId=38404099&page=0&tab=ALL

https://cananolab.nci.nih.gov/caNanoLab/characterization.do?dispatch=summaryView&sampleId=38404100&page=0&tab=ALL

https://cananolab.nci.nih.gov/caNanoLab/characterization.do?dispatch=summaryView&sampleId=38404101&page=0&tab=ALL

https://cananolab.nci.nih.gov/caNanoLab/characterization.do?dispatch=summaryView&sampleId=38404102&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 Apr 03, Naresh Kasoju commented:

This work has been highlighted by Nature: http://www.nature.com/nindia/2012/120730/full/nindia.2012.114.html

On 2015 Jun 04, Leonid Teytelman commented:

My dissertation work at Berkeley was on accelerated mutations in heterochromatin of yeasts, and it is truly exciting to see this confirmed in mammals. Teytelman L, 2008

On 2014 Mar 01, Christopher Southan commented:

This study has been updated in http://www.ncbi.nlm.nih.gov/pubmed/24533037. This manuscript is now online at http://figshare.com/articles/Mapping_Between_Databases_of_Compounds_and_Protein_Targets/818979

On 2015 May 26, Paul Brookes commented:

Portions of Figure 3 and Figure 8 from this paper appear more similar than would be expected by chance, when compared to portions of Figure 4 and Figure 5, from Zhao Z-Q, 2015 Eur J Pharmacol 746, 22–30, PMID: 25445044.

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

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

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

On 2016 Aug 30, Ben Goldacre commented:

This trial has the wrong trial registry ID associated with it on PubMed. The ID given is NCT0037079 - the correct ID, which we found within the text of the article itself, is NCT00370799.

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 in PubMed.

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 17, Peter Uetz commented:

The name RsfA is pre-occupied by an unrelated protein. We have thus renamed RsfA to RsfS (Ribosomal silencing factor in stationary phase/starvation). The latter name is now also used in Uniprot. Note that RFSs is also used in PubMed for "resource selection functions".

On 2015 Mar 31, Pedro Mendes commented:

The code for this project is now hosted on GitHub as a subproject of COPASI: https://github.com/copasi/condor-copasi/

On 2015 Mar 01, Joe Newton commented:

I'm an engineer experienced in simultaneous dynamic systems and not familiar with ALS. The findings of 'Regulation of Cellular Component Organization and Biogenesis', and in particular 'Actin Cytoskeleton', both suggest structural components of the plasma membrane are similar to psychiatric anomalies. These categories are expected to influence membrane stiffness and thus volume and/or myelination abnormalities in multiple neuropsychiatric diagnoses. The genetic and pathway based analyses of psychiatric anomalies have all been confounded by diagnostic (in the absence of biomarkers) and statistical uncertainty. Best wishes, Joe Ray Newton

On 2015 Dec 11, Harri Hemila commented:

Translation available at http://www.mv.helsinki.fi/home/hemila/T12.pdf

On 2013 Oct 23, Pedro Mendes commented:

I am completely at a loss to understand how they compared their software to the other ones mentioned (at least for Copasi, Gepasi, and Jarnac) because these other packages are not intended for pathway reconstruction. Neither the paper nor the supplementary data show how they obtained the numbers mentioned in their performance comparison.

On 2014 Oct 22, Mark Jones commented:

The mortality effect reported in this study can be explained by time-dependent bias. Out of 1,859 included patients, 416 (25%) of 1,676 treated with NAI died compared to 76 (42%) of 183 of patients untreated. This provides a crude relative risk of 0.60 for NAI (40% reduction in mortality). However this crude analysis fails to take account of the time-dependent nature of NAI exposure. Another naïve way to compare groups is based on rate of events per person day in hospital. The median length of stay for NAI patients was 10 days compared to 6 days for untreated patients. If we assume mean length of stay is similar we have 1,676 x 10 = 16,760 person days in hospital at risk of death for patients treated with NAI, and event rate of 416 / 16,760 = 0.025 deaths per person day. In comparison we have 183 x 6 = 1,098 person days in hospital for untreated patients with event rate 76 / 1,098 = 0.069 thus mortality rate ratio = 0.025 / 0.069 = 0.36, an even larger protective effect of NAI on mortality (64%). However we need to take into account that patients received NAI hours or even days after hospital admission. The delay was a median of 1 day after admission as time from onset of symptoms to admission was a median of 3 days whereas time from onset to treatment was a median of 4 days. If we assume mean delay is also 1 day we need to subtract 16760 days from the person-days estimate of the NAI treatment group and add it to the person-days estimate of the untreated group. This now more accurately reflects the total number of person days at risk of death while untreated as well as total number of person days at risk of death after treatment with NAI. It also makes our estimates of deaths per person day: 416 / 15,084 = 0.028 after NAI treatment compared to 76 / 2,774 = 0.027 while untreated, with rate ratio 1.0, i.e. no difference between groups. Of course this is an approximate analysis and a better analysis would involve including NAI treatment as a time-dependent exposure in a hazards based survival model. It is concerning that the authors did not conduct an appropriate analysis and also that the journal review did not pick up this fatal flaw.

On 2013 Oct 25, Paul Glasziou commented:

These comments are from a journal club at CREBP - www.crebp.net.au/ - where we later had the opportunity to put our questions to the papers first author (F Legare). Chris Del Mar presented this cluster RCT; Elaine Beller presented the Study Protocol (BMC Fam Pract 2011) and pilot Protocol (BMC Fam Pract 2007)

Issues:

1. The paper suggests that randomisation occurred after baseline data were collected (suboptimal). Although loss from each arm was similar, some baseline characteristics were not balanced (eg Table 3 and Table 4). However Légaré tells us in fact the randomisation took place before the baseline data were analysed. An added refinement might be to stratify by prescribing rates (detected in the Baseline phase).
2. The patient recruitment was low: average of 3/physician for the whole season (and some physicians recruited none!). This was apparently because of ‘specialisation’ within practices – (‘Clusters’) -- which are very large (20-40 GPs), and some see only obstetrics or child development, etc (and hence recruited 0 patients). Nevertheless all the GPs in Clusters got the intervention, whether or not they see ‘drop-ins’ (more likely to be ARIs). Lagare comment: Patients were recruited by an RA who was attached full-time in the waiting room of the practice. Thus most eligible patients were recruited in each practice. This means the effect is unlikely to have been greater than reported (by a halo effect).
3. Outcomes: ‘intention to use antibiotics’ is clearly a sub-optimal primary outcome because it is so soft. It was not possible to measure actual ABs dispensed (about 70% are in the private sector, unsubsidised by the Province).
4. What was the intervention? As with all complex interventions, the effective components are sometimes hard to tease out. In this case, was it the ‘epidemiological’ education that did the trick, or the introduction to ‘shared decision-making’?
5. Was the effect sustained? Legare comment: This was not measured in the study, but in the earlier pilot the effect was sustained.
6. Were doctors paid to recruit patients? Legare comment: No – their main incentive was CEM credit.
7. Did the intervention include the option of “delayed prescribing”? Legare comment: No – this was not considered as acceptable practice at the time.
8. More minor things: a. More clusters would be better (and easier in Australia where practices appear to be smaller) b. What’s the financial influence (perverse incentives)? For this trial the practice clusters were not fee-for-service, (although they were in the pilot study. Leblanc A, Legare F, Labrecque M, Godin G, Thivierge R, Laurier C, et al. Feasibility of a randomised trial of a continuing medical education program in shared decision-making on the use of antibiotics for acute respiratory infections in primary care: the DECISION+ pilot trial. Implementation science : IS. 2011;6:5. PubMed PMID: 21241514. Pubmed Central PMCID: 3033351. Epub 2011/01/19. eng. or capitation). c. Was there contamination (despite the controls not having access to the Training, because the GPs were academic doctors who may all have known about the trial, its intent, and its hoped for outcome? We know that the control practices were on a wait-list (they were offered the intervention after the trial, although some the data from this – not published – showed a more modest response than the data from the trial proper. This might have been different (not CIs) offering the intervention to the control clusters.

On 2016 Feb 24, Lily Chu commented:

The free PMC link goes to the wrong article. Can someone please fix this?

On 2016 Jul 06, James Tsung commented:

Video 1 - Small Subpleural Consolidation: https://youtu.be/eYm-IymPKBY?list=PLHg2xyua_KjtXhmD6wo17tyd1Uqc3eTnK Video 2 - Confluent B-lines: https://youtu.be/wdDeg1t5TXk?list=PLHg2xyua_KjtXhmD6wo17tyd1Uqc3eTnK Video 3 - Lung Consolidation with Air Bronchograms: https://youtu.be/APt_uVUyVWI?list=PLHg2xyua_Kjst0PQh3eb-GF6DKKblzmCB Video 4 - B-lines and Lung Consolidation with Air Bronchograms: https://youtu.be/GMmuvaaL4rE?list=PLHg2xyua_Kjst0PQh3eb-GF6DKKblzmCB

On 2014 Feb 02, Huiqi Qu commented:

We want to highlight the stronger association of PNPLA3 polymorphisms and liver aminotransferase levels in younger women.

On 2015 Jun 29, Bill Cayley commented:

A great example of when less is more: https://lessismoreebm.wordpress.com/2015/06/11/198/

On 2013 Oct 29, Hilda Bastian commented:

This systematic review identifies serious publication bias, along with small poor quality trials, as contributing to the over-estimation of benefit of viscosupplementation for osteoarthritis of the knee by some other groups (including Bellamy N, 2006). Rutjes and colleagues found that none of the multiple previous systematic reviews on the subject had included all the trial evidence available at the time.

Relying primarily on larger, better quality studies, the authors conclude that these intra-articular injections have a non-clinically relevant effect on pain, no significant effect on function over time, but are associated with serious unexplained adverse events. It is not clear what effect long-term use of the intervention has on the risk of serious adverse events. Rutjes and colleagues discourage use of the intervention.

An analysis of this systematic review in DARE goes into detail about the methods and data in this review. That assessment suggests that the pooling of baseline and end of treatment effects introduces minor uncertainty around the review's results.

Some other systematic reviews had also failed to identify major clinical benefit from viscosupplementation of the knee (including Lo GH, 2003 and Samson DJ, 2007). Rutjes and colleagues conclude that an individual patient data meta-analysis would be required to clarify questions about serious adverse events.

UPDATE: Bannuru RR, 2015 subsequently published an extensive network meta-analysis, which created a network for comparison that included intra-articular (IA) injection, IA placebo, and oral placebo. While their outcome for IA hyaluronic acid is similar to that in this analysis by Rutjes and colleagues, they identified a clinically relevant difference attributable to IA injection.

(I discussed the implications of the 2015 review in a February 2015 blog post.)

On 2015 Dec 11, James C Coyne commented:

The university considers that there is a lack of value or serious purpose to your request. The university also considers that there is improper motive behind the request. The university considers that this request has caused and could further cause harassment and distress to staff. The university considers that the motive and purpose behind this request is polemical. The university notes the view of the Information Commissioner in decision FS50558352 that the request in that case was ‘more focussed on attacking and attempting to discredit the trial than in obtaining useful information on the topic.’

I believe this response is a blatant rejection of the authors' responsibility to share data when requested. The paper should be provisionally retracted until the data are shared.

On 2015 Dec 12, Alem Matthees commented:

With reference to James C Coyne's comment about KCL rejecting his request for trial data as 'vexatious':

There are crucial facts and context missing from QMUL's (and now KCL's in part) narrative of anti-science harassment against the PACE trial. They appear to conflate all significant criticism with harassment without any regard for the validity of the comments made.

In addition to James Coyne PhD, other senior academics and research scientists have also expressed significant concerns over how the trial was conducted, analysed, or reported. Their assessments are outlined in a series of articles written by David Tuller DrPH (lecturer in journalism and public health at UC Berkeley) see http://www.virology.ws/mecfs/ . Six of them wrote an open letter to the editor of the Lancet, outlined some main problems and called for a fully independent re-analysis of the results. Similarly, over 11,000 individuals signed a petition calling for the retraction of questionable claims (made in relation to the 'normal range' for fatigue and physical function that overlapped with trial entry criteria for severe disabling fatigue), and called for the release of de-identified individual-level trial data so other researchers can re-analyse the results, see http://my.meaction.net/petitions/pace-trial-needs-review-now . As Tuller, Coyne, and others have noted elsewhere, accusations of campaigns of harassment appear to arise whenever legitimate questions are asked about the trial.

As the person who submitted the FOIA request in ICO decision notice FS50558352, I wish to comment. It had absolutely nothing to do with James Coyne. It was my own attempt to clarify confusion about the timing and nature of changes to the PACE trial recovery criteria, which had reached the level of parliamentary debate in the UK House of Lords in 2013, but has not been conclusively resolved. The revised recovery criteria is asserted to be pre-specified but there is good evidence that it is post-hoc and unapproved. I provided QMUL with background about how the confusion arose and then asked specific questions to conclusively resolve the matter.

QMUL presented to the ICO a detailed narrative of harassment and argued that any disclosure under the FOIA is unnecessary as they have procedures for review and dissemination. The ICO accepted QMUL's arguments about feeling harassed, deferred to their authority and judgement, focused on subjective interpretations of tone and circumstances, but did not consider the justifications for the request or the evidence that the procedures for review and dissemination were inadequate in this case. The evidence justifying the request in the first place was deemed outside the scope of the investigation simply because it involved details about the PACE trial. S.14(1) is supposed to account for the justifications for a request in order to judge whether the level of alleged disruption or annoyance caused by the request is justified. With all due respect to the ICO in general (and not to diminish my appreciation for their unequivocal support for my other request), it is difficult to successfully argue that a request or any burden it places on a public authority is justified when the evidence which justifies it is precluded out of the investigation.

Therefore in my opinion, the consideration of evidence was imbalanced, and the ICO staff involved with that particular case were misled by a one-sided presentation of the evidence. QMUL's threshold for examples of harassment apparently includes moderated BMJ Rapid Responses and published letters to the editor etc, without any regard for the validity of the points made in the correspondence. The BMJ encourages patient involvement and does not publish responses it deems inappropriate. It appears that QMUL view all significant criticism of the PACE trial to be a form of harassment simply because they dislike or disagree with it.

It is not harassment to express legitimate concerns about research e.g. major deviations from a published trial protocol, ask sincere questions, disagree with the interpretation of research(ers), highlight factual errors, or be somewhat frank when it is called for. These are all legitimate activities and scrutiny is part of science. It is unclear how disclosing details about methodology could discredit any trial if it was conducted and reported properly. Ben Goldacre's (co-founder of AllTrials) compare-trials.org project expects details about the timing and nature of changes to protocols to be routinely disclosed.

QMUL have misguided assumptions about my beliefs and motives. I maintain that they have no convincing evidence that I intended to harass them instead of seek information to resolve an ongoing confusion and controversy in the patient community. My FOIA request was not perfect, but it is all online so people can judge for themselves whether it was unreasonable given the relevant circumstances of a possible post-hoc analysis being described as pre-specified : https://www.whatdotheyknow.com/request/timing_of_changes_to_pace_trial .

On 2014 Jan 12, Christian Frech commented:

GPHMM authors comment on their project home page (http://bioinformatics.ustc.edu.cn/gphmm/) on the performance of GPHMM in this comparison:

"We would like to point out critical errors found in a recently paper "Comparison of methods to detect copy number alterations in cancer using simulated and real genotyping data" published in BMC Bioinformatics with PMID 22870940, which was trying to compare different computational approaches including the GPHMM method.

As demonstrated in the GPHMM paper, we showed the superior performance of GPHMM on a cell-line dataset (see Figure 1,2,3 and Table 2 in the paper). However in this BMC paper, we found that the authors evaluated our method with the same dataset, but claimed that GPHMM failed to recognize the alteration pattern in the cell-line samples. Astonished by this apparent contradiction, we contacted them and later it became clear that during the test they WRONGLY replaced an important data file (“hhall.hg18_m.pfb”) in the tool package with another file used in their study.

Given the fact that this is a survey paper trying to accurately compare different methods and provide unbiased guidance to readers and the conclusion they made will pose influence on user's final choice of method in their studies, we suggested them to retest GPHMM and update their results. Unfortunately, except an ambiguous statement in the text saying “the baseline shift can be correctly estimated if a PFB with a modified specification is used”, we found the results and conclusion were not changed at all in the final version of this paper. Therefore, we argue that the performance of GPHMM is significantly underestimated in this paper."

On 2014 Jan 08, Brett Snodgrass commented:

Dear Authors,

Thank you for the excellent article.

Might figure 2b exhibit an arteriosinusoidal vessel of Wearn? This particular vessel of Wearn is presumably unusually prominent and may be clinically classified as a fistula.

http://bit.ly/JTWearn

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC555823/

For additional commentary related to the vessels of Wearn, please see https://twitter.com/BrettSnodgrass1/status/418788476016791552

Comments and suggestions are welcome.

Thank you kindly.

On 2014 Jan 08, Brett Snodgrass commented:

Dear Authors,

Thank you for the excellent article. Might the connection to the right ventricle represent a vessel of Wearn?

Might the vessel of Wearn have disrupted vasculogenesis?

http://www.sciencedirect.com/science/article/pii/S1054880712001561

Comments and suggestions are welcome here, through Twitter, or via E-mail brettsnodgrass@hotmail.com

https://twitter.com/BrettSnodgrass1/status/418812162203607040/

Thank you kindly.

On 2013 Dec 23, Wichor Bramer commented:

A comment on this article has appeared in Bramer WM, 2012. However this comment was not linked to the original article because of a mistake by the journal editors.

On 2015 Jan 29, Andrea Messori commented:

Clinical trials evaluating interferon-free treatments for previously untreated genotype 1 hepatitis C infection: state of the art in 2015

Fadda V, Messori A. Hta Unit, Regional Health Service, 50100 Firenze (Italy)

After the publication of the review by Doyle and co-workers (2013), numerous clinical trials have been conducted to evaluate interferon-free treatments for previously untreated hepatitis C infection. To retrieve these trials, we carried out a literature search based on the following criteria: a) enrolment of previously untreated patients with genotype 1 infection; b) administration combination treatments approved by EMA; c) end-point represented by sustained virologic response at the 12th week after completion of treatment (SVR12). Our search was exclusively based on the PubMed version of MEDLINE. The keywords for our initial search were intentionally generic (HCV OR “hepatitis C” combined with the filters of Clinical Trials and period from 2010 to 2014). Among the records extracted through our initial search (N=823), a subgroup of clinical trials (N=24) was selected that evaluated interferon-free treatments. After reading the full text of these 24 articles, we identified the studies that met the inclusion criteria set for our analysis. Our search on PubMed was run on 31 December 2014. The main characteristics of these trials are presented in Table 1.

Table 1. Rates of SVR12 achievement reported in 10 clinical trials (trials are identified based on first author, year of publication, and treatment; rates are reported in parenthesis).

1. Afdal, 2014: SOF/LED-12w (211/214)
2. Feld, 2014 (genotype 1 a): ARIODR-12w (307/322)
3. Feld, 2014 (genotype 1 b): ARIODR-12w (148/151)
4. Ferenci, 2014 (genotype 1 a): ARIOD-12w (185/205) and ARIODR-12w (97/100)
5. Ferenci, 2014 (genotype 1 b): ARIOD-12w (207/209) and ARIODR-12w (209/210)
6. Kowdley, 2014: ARIOD-12w (70/79) and ARIODR-12w (76/79)
7. Kowdley, 2014 (ION-3 trial): SOF/LED-12w (206/216) and SOF/LED-8w (202/215)
8. Lawitz, 2014 (LONESTAR trial): SOF/LED-12w (18/19) and SOF/LED-8w (19/20)
9. Poordad, 2014: ARIODR-12w (191/208)
10. Sulkowsky, 2014: SOF/DAC-12w (41/41)

Abbreviations: w, weeks: ARIODR-12w, ABT-450/ ritonavir/ombitasvir/dasabuvir/ribavirin for 12w; ARIOD-12w, ABT-450/ ritonavir/ombitasvir/dasabuvi for 12w; SOF/DAC-12w, sofosbuvir+daclatasvir for 12w; SOF/LED-8w, sofosbuvir+ledipasvir for 8w; SOF/LED-12w, sofosbuvir+ledipasvir for 12w . Note 1: Trials that reported separate results for patients with genotype 1a and 1b are presented seprately. Note 2: The following combinations treatments, that have been tested in naïve patients with genotype 1 infection, were not included in the above table: daclatasvir+asunaprevir for 24 w; beclabuvir+daclatasvir+asunaprevir for 12w; beclabuvir+daclatasvir+asunaprevir for 24w; sofosbuvir+simeprevir for 24w; sofosbuvir+simeprevir+ribavirin for 12w; sofosbuvir+simeprevir+ribavirin for 24w; sofosbuvir+ledipasvir+ribavirin for 8w; sofosbuvir+daclatasvir for 24w.

References

-Afdhal N, Zeuzem S, Kwo P, et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med. 2014 May 15;370(20):1889-98.

-Doyle JS, Aspinall E, Liew D, Thompson AJ, Hellard ME. Current and emerging antiviral treatments for hepatitis C infection. Br J Clin Pharmacol. 2013 Apr;75(4):931-43. doi: 10.1111/j.1365-2125.2012.04419.x.

-Feld JJ, Kowdley KV, Coakley E et al. Treatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin. N Engl J Med. 2014 Apr 24;370(17):1594-603.

-Ferenci P, Bernstein D, Lalezari J et al. ABT-450/r-ombitasvir and dasabuvir with or without ribavirin for HCV. N Engl J Med. 2014 May 22;370(21):1983-92.

-Kowdley KV, Gordon SC, Reddy KR et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med. 2014 May 15;370(20):1879-88.

-Kowdley KV, Lawitz E, Poordad F et al. Phase 2b trial of interferon-free therapy for hepatitis C virus genotype 1. N Engl J Med. 2014 Jan 16;370(3):222-32.

-Lawitz E, Poordad FF, Pang PS et al. Sofosbuvir and ledipasvir fixed-dose combination with and without ribavirin in treatment-naive and previously treated patients with genotype 1 hepatitis C virus infection (LONESTAR): an open-label, randomised, phase 2 trial. Lancet. 2014 Feb 8;383(9916):515-23.

-Poordad F, Hezode C, Trinh R et al. ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis. N Engl J Med. 2014 May 22;370(21):1973-82.

-Sulkowski MS, Gardiner DF, Rodriguez-Torres M et al. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med. 2014 Jan 16;370(3):211-21. doi: 10.1056/NEJMoa1306218. Erratum in: N Engl J Med. 2014 Apr 10;370(15):1469.

On 2014 Jan 31, Huiqi Qu commented:

Insulin resistance is an important public health issue in Mexican Americans .

On 2016 Apr 05, Marko Premzl commented:

The third party data gene data set of eutherian interferon-γ-inducible GTPase genes FR734011-FR734074 was deposited in European Nucleotide Archive under research project "Comparative genomic analysis of eutherian genes" (https://www.ebi.ac.uk/ena/data/view/FR734011-FR734074). The 64 complete coding sequences were curated using tests of reliability of eutherian public genomic sequences included in eutherian comparative genomic analysis protocol including gene annotations, phylogenetic analysis and protein molecular evolution analysis (RRID:SCR_014401).

Project leader: Marko Premzl PhD, ANU Alumni, 4 Kninski trg Sq., Zagreb, Croatia

E-mail address: Marko.Premzl@alumni.anu.edu.au

Internet: https://www.ncbi.nlm.nih.gov/myncbi/mpremzl/cv/130205/

On 2014 Nov 25, Harri Hemila commented:

The paper has been commented on at the BMJ pages, see: http://heart.bmj.com/content/98/22/1615.responses.

On 2016 Mar 18, ZHONGMING ZHAO commented:

My lab recently moved to the University of Texas Health Science Center at Houston. The web site for this database is now available at https://bioinfo.uth.edu/DTome/.