14,839 Matching Annotations
  1. Jul 2018
    1. On 2014 Jan 11, Sergei Jargin commented:

      Further details are in Jargin SV. Dermatopathology: Practical & Conceptual 2007;13(1):20 continued in 2008;14(2), 2009;15(1), 15(2), 15(4), 2010;16(1), 16(2), 16(3). Unfortunately, the journal Dermatopathology: Practical & Conceptual is currently unavailable on-line.


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    1. On 2015 Oct 28, Peter Gøtzsche commented:

      The authors mention in the abstract of this huge review (55 trials and 5,506 patients) without any reservation that akathisia didn’t occur more often in the chlorpromazine group than in the placebo group. The largest trial that contributed data to this outcome even found significantly less akathisia in the active group than in the placebo group, relative risk 0.57, 95% CI 0.37 to 0.88. Since we know that antipsychotics cause akathisia and that placebo cannot cause akathisia, this result speaks volumes about how flawed trials in schizophrenia generally are. What was seen in the placebo group were cold turkey symptoms caused by withdrawal of the antipsychotics the patients had received before randomisation.

      I believe this fundamental problem renders the review unreliable and I refer readers to another review. The most reliable placebo controlled trials are those of first episode schizophrenia where none of the patients have ever received drugs before. There is a Cochrane review that approaches this ideal, but even this review is biased, as the trials are not limited to first episode patients; the review includes studies “with a majority of first and second episode schizophrenia spectrum disorders” (1).

      The authors of that Cochrane review pointed out that the available evidence doesn’t support a conclusion that antipsychotic treatment in an acute early episode of schizophrenia is effective. They felt this was worrying given the widespread use of antipsychotics in the acute treatment of early episode schizophrenia-type psychoses, and also because the use of antipsychotics for millions of people with an early episode appears based on the trials for those with multiple previous episodes (which we know are highly flawed).

      I suppose this means that we don’t have the evidence to support using antipsychotics at all. In fact, despite the trials being flawed by the cold turkey design, what was seen in recent placebo controlled trials in submissions to the FDA was only a 6 point improvement on the Positive and Negative Syndrome Scale (PANSS) (2,3), far below the minimally relevant clinical effect on this scale, which is about 15 points (4). Benzodiazepines should be preferred, when patients need to be calmed down, as they are far cheaper and less toxic than antipsychotics and also seem to sedate patients better (5).

      1 Bola J, Kao D, Soydan H, et al. Antipsychotic medication for early episode schizophrenia. Cochrane Database Syst Rev 2011;6:CD006374.

      2 Moncrieff J. The bitterest pills. Basingstoke: Palgrave Macmillan; 2013.

      3 Khin NA, Chen YF, Yang Y, et al. Exploratory analyses of efficacy data from schizophrenia trials in support of new drug applications submitted to the US Food and Drug Administration. J Clin Psychiatry 2012;73:856–64.

      4 Leucht S, Kane JM, Etschel E, et al. Linking the PANSS, BPRS, and CGI: clinical implications. Neuropsychopharmacology 2006;31:2318-25.

      5 Dold M, Li C, Tardy M, et al. Benzodiazepines for schizophrenia. Cochrane Database Syst Rev 2012;11:CD006391.


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    1. On 2014 Jul 29, JJ van Middendorp commented:

      With interest I read the retrospective study by Venkatesan et al.<sup>1,</sup> comparing survival outcomes of elderly patients with fractures of the odontoid process of the second vertebral body, the hip and wrist. The authors found that “sustaining an odontoid peg fracture increases the risk of mortality by a factor of seven compared with sustaining a wrist fracture in patients aged >65 years”.<sup>1</sup> I believe, however, that the presented results deserve a more nuanced interpretation.

      In contrast to what has been under-reported in a number of other studies on this topic,<sup>2</sup> the authors presented an informative table on the causes of death of patients with an odontoid process fracture. At the same time this information exposes two critical limitations of presented survival analyses, neither of the two were addressed by the authors. First, the causal description “accidental death” is rather ambiguous, certainly in a group of patients who sustained an isolated odontoid process fracture resulting from a low-velocity fall or accident. Clearly, such injuries do not lead to death directly. Hence the validity of both the retrospectively collected data from the hospital’s bereavement office or coroner’s office and the actual occurrence of ‘isolated’ injuries can be questioned. Second, five of the twelve patients (case 3, 6, 7, 8 and 12) clearly died as a result of medical comorbidities that were pre-existent to, and thus not caused by, the injury of the cervical spine. Considering these two points, it is likely that the unfavourable survival outcome attributed to isolated odontoid process fractures (adjusted hazard ratio of 7.0, 3.6-13.6 95% CI; when compared to wrist fractures) is well overestimated.

      Although Venkatesan et al<sup>1</sup> are one of the first authors comparing survival outcomes of patients with odontoid process fractures with those of patients with other types of musculoskeletal fractures, the comparison itself is methodologically flawed. Comparing 6-year retrospective data on cervical injuries from one hospital with 1-year prospective data from a national registry introduces an unacceptable level of heterogeneity. Only age and gender were considered for the multivariate Cox regression analysis. Previously recommended factors like pre-existing comorbidities, concomitant injuries and cause of death were not adjusted for in the analysis.<sup>2</sup> Moreover, the authors seem to disregard the previously demonstrated adverse effects that bed rest and limited mobility have on mortality rates in elderly patients.<sup>2,3</sup> It may well be that limited physical exercise is the single strongest predictive factor explaining the differences between the survival rates of elderly patients with a cervical spine or hip fracture and those with a wrist fracture.

      Whilst the authors rightly point out that the increasingly growing elderly cervical trauma population requires the same medical attention as other ‘major’ musculoskeletal injuries, they failed to identify the underlying factors that lead to relative high mortality rates in this particular group of patients. Simply comparing risk, odds or hazard ratios between specific trauma sub-populations will not assist orthopaedic and spinal surgeons in the everyday management of musculoskeletal injuries. I believe it is time to move away from correlation statistics and pursue the identification and management of true causal factors that have an impact on survival outcomes in elderly patients with cervical spine injuries.

      J.J. van Middendorp, MD, PhD, MClinEpid, Research Director of the Stoke Mandeville Spinal Foundation, Aylesbury, UK and Senior Research Fellow of the Harris Manchester College, University of Oxford, Oxford, UK

      References

      1 - Venkatesan M, Northover JR, Wild JB, et al. Survival analysis of elderly patients with a fracture of the odontoid peg. Bone Joint J. Jan 2014;96(1):88-93. PubMed: Venkatesan M, 2014

      2 - van Middendorp JJ, Albert TJ, Veth RP, Hosman AJ. Methodological systematic review: mortality in elderly patients with cervical spine injury: a critical appraisal of the reporting of baseline characteristics, follow-up, cause of death, and analysis of risk factors. Spine (Phila Pa 1976). May 1 2010;35(10):1079-1087. PubMed: van Middendorp JJ, 2010

      3 - Siu AL, Penrod JD, Boockvar KS, Koval K, Strauss E, Morrison RS. Early ambulation after hip fracture: effects on function and mortality. Arch Intern Med. Apr 10 2006;166(7):766-771. PubMed: Siu AL, 2006


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    1. On 2014 Jul 09, Mathias Wellmann commented:

      Comment regarding Kukkonen et al. Treatment of non-traumatic rotator cuff tears. A RANDOMISED CONTROLLED TRIAL WITH ONE-YEAR CLINICAL RESULTS, Bone Joint J 2014;96-B:75–81. PMID: 24395315

      Dear Authors,

      we read the study with great interest und discussed the clinical implications. We think the authors did a great job respecting formal aspects (prospectively randomized design, equivalent cohort size, homogeneous patient distribution). However, there are a few aspects of the study which are potentially misleading:

      1. The title of the study is misleading or to general at best. A more precise title would be: Treatment of small, well compensated non-traumatic supraspinatus tendon tears. We think a study title should be as clear as possible and should especially answer the question: What issue was studied? The study of Kukkonen et al. exclusively investigated patients with small (<10mm) supraspinatus tendon tears, which were well compensated regarding range of motion (full range of motion, inclusion criteria). In its present form the title of the study may lead to a transfer of the results to patients with decompensated full-thickness tears of the supraspinatus tendon. Such transfer is not valid and should be prevented using a more precise study title.

      2. All patients with an passive external rotation <30° and an elevation <120° were excluded from the study and the limitation of elevation and external rotation was defined as stiffness. However, a loss of elevation <120° is not a sufficient criterion to define shoulder stiffness. An adequate examination would have quantified passive glenohumeral abduction and external rotation (external rotation in comparison to the contralateral unaffected side). Further, the percentage of patients excluded because of shoulder stiffness should be indicated, since this is not a very common combination in patients with atraumatic rotator cuff tears. In the given form there is a risk that the study design systematically excludes patients with restricted range of motion caused by loss of strength and pain. This is a basic issue, since these are the typical patients, in which we think about rotator cuff refixation.

      3. The type of supraspinatus-tears for the patients, that were included in the study should be clearly defined (full thickness versus partial thickness tears). The authors use the term „supraspinatus tendon tear comprising <75% of the tendon insertion and documented with MRI“. Thereby it is unclear, if partial articular und bursal sided tears involving <75% of the tendon substance were also included in the study. In the results section the authors indicate the sagittal diameter of the tears treated by surgery. Does that mean, that all tears were full-thickness tears?

      4. It is unclear, if any of the patients had been treated by physiotherapy previous to the inclusion, or if this was an exclusion criterion as well. How did the authors deal with patients, that were randomized to be treated by surgery but did not agree to a surgical intervention.

      5. The authors did not perform a follow up MRI or even sonography to determine the rerupture rate of the rotator cuff repairs. This would have been a substantial information estimating the clinical success of rotator cuff repair. If further follow up investigations are planned in the study design, we strongly recommend to perform MRI scans.

      6. The Constant Score may not be the most helpful score with regard to outcome discrimination for a patient population with „ full range of motion“, since it strongly estimates range of motion (40 points) compared to pain (15 points) and the level of daily actvities (20 points). For such patients more detailed patient reported outcomes (PROs) should be beneficial.

      We recommend to revise the marked aspects to reach the highest possible scientific impact for this publication.

      Mathias Wellmann on behalf of the Shoulder committee of the AGA - Society for Arthroscopy and Joint Surgery


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    1. On 2014 Jan 17, Marcos Malumbres commented:

      I miss a reference to Bueno MJ, 2011; one of the first papers where the bidirectional networks between microRNAs and Myc were described.


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    1. On 2014 Feb 12, David Keller commented:

      None


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    2. On 2014 Feb 12, David Keller commented:

      Further arguments in support of PSA screening.

      Evidence in favor of PSA screening for prostate cancer detection was summarized in a review by Allan and colleagues (1): “Based on the best available trials, we concluded that prostate cancer screening, specifically PSA, does reduce prostate cancer mortality. The number needed to screen to prevent one prostate cancer death at nine and 14 years of follow-up were 1410 and 293, from the ERSPC and Göteborg studies, respectively.... In comparison, the number needed to screen with mammography to prevent one breast cancer death in women ≥50 years of age is 1235 and 614 for 7 and 13 years, respectively. The number needed to screen with fecal occult blood testing to prevent one colorectal cancer death is 617 over 12 to 18 years. Prostate cancer screening, similar to the other accepted cancer screening programs, does not modify overall mortality."

      Note that in the Goteborg study, 24% of the men invited to be screened never actually showed up to have a PSA drawn, yet they were included in the intention-to-treat analysis. If we subtract them from the results, then the number actually screened to prevent one death is reduced to 223. In the PLCO prostate cancer screening study, 52% of the “control” patients actually had PSA testing performed outside the study, and only 86% of patients in the screening arm were compliant with the PSA protocol. This severely contaminated data did not support PSA screening, which tells us little except to disregard any meta-analysis which includes PLCO.

      In my letter, I pointed out that clinicians can improve the specificity of PSA screening by the following technique: when an elevated PSA occurs, repeat it a few times at short intervals and discard all but the lowest PSA for comparison to the biopsy threshold. This simple technique can spare many men from undergoing prostate biopsies, reducing potential harms from screening. Arguments against PSA screening often cite patient worry as a potential harm, which actually represents failure by clinicians to communicate the indolent behavior of many prostate cancers. Men offered screening should be informed that prostate cancers exhibit a range of behaviors, and often do not result in metastases or death.

      Dr. Katz states that only 7% of men chose watchful waiting for localized prostate cancer in a recent registry, while 83% chose invasive treatments, despite the lack of convincing data to support the superiority of the latter. This again represents a failure of communication by the physicians involved. Patients are generally quite happy to avoid surgery when their clinician assures them it is not necessary or beneficial. We can increase the use of watchful waiting if we communicate effectively with our patients.

      Finally, I wish to correct an omission from the last paragraph of my letter, which should have read: “We need a large trial of PSA measured every 3 months during the first year (to establish a baseline PSA)....”

      1: Allan GM, Chetner MP, Donnelly BJ, Hagen NA, Ross D, Ruether JD, Venner P.Furthering the prostate cancer screening debate (prostate cancer specificmortality and associated risks). Can Urol Assoc J. 2011 Dec;5(6):416-21. doi:10.5489/cuaj.11063. PubMed PMID: 22154638; PubMed Central PMCID: PMC3235209.


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    1. On 2014 Jun 26, Amanda Capes-Davis commented:

      The authors use the Chang liver cell line as a model for human hepatocytes. Unfortunately, despite the name, Chang liver is cross-contaminated with HeLa, and so comes from adenocarcinoma of the cervix. A database of known cross-contaminated cell lines can be found at http://iclac.org/databases/cross-contaminations/.


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    1. On 2018 Jan 17, Rasmus Hertzum-Larsen commented:

      In the results section of the abstract I see: "Cytology coverage was higher among immigrant women compared to Spanish born (51.2 and 39% respectively)". But in figure 1 i see the opposite: 39% among immigrants, and 51.2% among spanish born. Which is correct?


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    1. On 2014 Jan 25, Ferenc Zsila commented:

      According to my comments outlined below, the peer-review procedure of this poorly written paper was seriously incomplete (page numbering refers to the PDF version).

      Ferenc Zsila M.D., Ph.D. Institute of Molecular Pharmacology, Research Centre for Natural Sciences Budapest, Hungary

      Missing experimental data (Materials and Methods, pp. 2-3.)

      Purity and fatty acid content of the HSA sample used are unknown. The source and chemical character (salt or free acid, racemic or not) of ibuprofen, warfarin, and digitoxin used in site probe studies are unknown. Experimental details of the site probe measurements (see on p. 7) are completely missing. There is not even a word to describe how the protein and LMF molecules were prepared for the docking procedures (p. 3). Docking type information are also missing (blind? targeted? rigid? flexible?). What are the parameters of the docking box used for the proteins? How much docking runs were performed? Where is the docking energy list? Where are the affinity constants calculated from the binding free energy values? How do they relate to the experimental values?

      Errors, speculations, and unsupported claims

      Page 1: "Based on these characteristics, with increasing amounts of PPIX in the blood, the probability of HSA-PPIX formation increases accordingly." It is a mere speculation which is not supported by research data. Hemopexin is the primary heme binding protein in the serum. "Methemalbumin is an abnormal component of plasma and has been found only in diseases associated with massive hemolysis, when hemopexin-binding capacity is exceeded." (Tolosano et al., Antioxid. Redox. Signal. 2010 (12) 305-320).

      Page 4: "When HSA is excited at 285 nm, it radiates strong intrinsic fluorescence at 334 nm." No emission band at 334 nm can be seen either in Fig. 1A or 1B. Fluorescence contribution of the bound PPIX is totally ignored. Origin and nature of the large emission peak centered around 430 nm remain obscure.

      Page 4: "To investigate the effect of TF on the binding of LMF to the (HSA-PPIX)-TF complex, steady-state fluorescence spectra of (HSA-PPIX), shown in Fig. 1A, and of (HSA-PPIX)-TF, displayed in Fig. 1B, were run and showed that the fluorescence intensity of the two systems became consistently weakened when increasing the LMF concentration." Just an opposite situation is shown in Fig. 1A and 1B: increase of the LMF concentration enhances the fluorescence intensity in both cases.

      In contrast to HSA, transferrin contains 8 Trp residues. It remains a mystery, how the fluorescence contribution of these residues was considered during evaluation of the emission spectra of (HSA-PPIX)-TF.

      Page 5: "Fig. 3 shows second-derivative fluorescence spectra of the (HSA-PPIX)-LMF and [(HSA-PPIX)-TF]-LMF complexes (inset). As can be seen, a negative band was observed at 310 nm and 316 nm in the (HSA-PPIX)-LMF and [(HSA-PPIX)-TF]-LMF spectra, respectively. These changes in the protein spectra should be assigned to the combination of environments of the aromatic residues in the protein and indicate that the Trp residue was in a relatively hydrophobic microenvironment." What Trp residue? There are 9 Trp in the [(HSA-PPIX)-TF]-LMF complex.

      Page 7: "The corresponding binding constants were evaluated and are listed in Table 3." These are not binding but quenching constants (cf. Table 1). No association constants (Ka) are shown in Table 3. HSA affinity constants as well as the amounts of the site probes added are unknown.

      Page 7: "Based on these results, it was concluded that ibuprofen had little effect on the binding of LMF to (HSA-PPIX)-TF while digitoxin removed LMF from the bindings site." Changing of the quenching constants shown in Table 3 contradicts to this claim. The Ksv value of [(HSA-PPIX) LMF] TF was reduced by an order of magnitude upon addition of both ibuprofen and digitoxin. The exact HSA binding location of digitoxin is unknown so it can not be used as a site probe. It may occur that these site probes bind to transferrin as well. Where are the controll experiments?

      Page 9: "In summary, this study provides useful information for the pharmacological and pharmacodynamic behavior of LMF and should be taken into account when calculating its dosage." This work deals with one aspect of the pharmakokinetic behavior of LMF (serum protein binding). No data are presented on the pharmacodynamic behavior of the drug.

      Confusing binding site designations

      Page 7: "In our previous work [18], we showed that PPIX occupied site I in the HSA and LMF bound to site IIA." As it is defined on page 1, site I corresponds to subdomain IIA ("Aromatic and heterocyclic ligands have been found to bind with two hydrophobic pockets in subdomains IIA and IIIA, namely site I and site II"). Therefore, according to the above sentence, both PPIX and LMF is bound in subdomain IIA.

      Page 7: "... we believe that the lower-affinity site of LMF, corresponding to the binding site, was switched in the presence of TF, causing LMF to bind to site III in HSA." No definition of site III is given.

      Page 9: "For the (HSA-PPIX)-TF complex in solution, the binding site of LMF to HSA-PPIX changed from Sudlow’s site IIA to Sudlow’s site IIIB with low affinity." No such site designations exist in the literature. Moreover, subdomain IIIB binding of LMF is very doubtful since it is not supported by experimental data.

      Wrong references

      Page 1: "The direct interaction of drugs with TF has been widely studied [9-12]." Ref. 11 is a drug-serum albumin and not a drug-TF binding study.

      Page 1: "LMF is very active against both Gram (+) and Gram (2) bacteria through inhibition of their DNA gyrase and is widely used for the clinical treatment of severe systematic infections, such as soft tissue infection, typhoid fever, bone and joint infections, prostatitis blood poisoning and sinusitis [13]." Ref. 13 is a spectroscopic study on the ion-association complex formation between fluoroquinolones and a synthetic dye (erythrosine). Thus, it does not cover the biological activities of lomefloxacin.

      Page 7: "In our previous work [18], we showed that PPIX occupied site I in the HSA and LMF bound to site IIA." Ref. 18 is not the authors' paper.

      Page 9: "The literature has numerous reports of LMF being located within an alpha-helix and a beta-sheet in the N-lobe of transferrin [46]." Ref. 46 is not about the LMF-transferrin interaction.


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    1. On 2014 Feb 28, Walter Vogel commented:

      This paper was the cover article of the February issue of TiPS and the subject of the lead segment of the February 2014 Cell Press Podcast: “On Cellular Symphonies and Symbiosis” in a segment titled: “How fine-tuning of transcription factor activity may open up new avenues for disease treatment,” where author Mark Leid was interviewed by the journal editor, Joanna Schaffhausen. Available on the Cell Press website http://www.cell.com and on iTunes https://itunes.apple.com/us/podcast/cell-podcast/id207189884. Released 27 February 2014.


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    1. On 2014 Jan 13, Amanda Capes-Davis commented:

      Please be aware that KB is NOT an oral squamous cell carcinoma (OSCC). The cell line is cross-contaminated, as shown by Gartler in 1967 (PMID 4864103). For a database of cross-contaminated or otherwise misidentified cell lines, see http://iclac.org/databases/cross-contaminations/.


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    1. On 2014 Jun 27, Andrea Manca commented:

      Beyond the unfortunate misprints for which we apologize and thank the commenter (90 mW instead of 90 W; 30 mW instead of 35 mW), our apparatus was set at the maximum power output for each diode (30 W x 3 diodes = 90 W), within the well-acknowledged therapeutic wavelength emission (904 nm) and for a treatment time of 10 minutes (600 seconds). The laser probe was in firm contact with the skin which allowed an optimal penetration (Prentice et al. 2005). In our sample only one trigger point (TP) had to be treated, since patients with a single TP in the upper trapezius muscle (in position TrP2) were preferentially recruited. This was done to avoid conflicting attributions of effects and sub-group analyses which would have reduced the statistical power. The commenter raised a concern about the power density. The power density measured by the commenter is 8.8 mW/cm2 (35 mW/4 cm2) which is higher than the 5 mW/cm2 recommended by the most recent guidelines for low level laser therapy treatment dosages (World Association for Laser Therapy-WALT, 2010). However, in our case the actual emitting area (2.35 cm2) was smaller than the contact surface of the probe (4 cm2) making the ratio between them even more favorable. In fact, the average output of 35 mW was spread over 2.35 cm2, resulting in a power density of 14.8 mW/cm2, which, is, again, higher than that recommended by WALT. The commenter defines such value of power density “as relatively low”. Basing on which criteria 8.8 or 22 mW/cm2 are rated as “relatively low power densities”, since in the cited WALT recommendations there is no indication on low or high power densities and only minimum requirements are stated? And how can the commenter state: “WALT recommendation for a TP is not 18 J, but 2-4 J per point” if no dosage specifications for trigger points are actually available in the cited most recent WALT recommendations? In summary, regarding the treatment doses for class 3B, 904 nm-GaAs low level laser therapy, the minimum requirements recommended by WALT are: peak pulse output > 1 Watt (here: 90 W); mean output > 5 mW (here: 35 mW), power density > 5mW/cm2 (here: 14.8 mW); irradiation time of 4 minutes per point or cm2 (here: 10 minutes); total dose 4 joules per point (here: 18 joules). All the recommended parameters were fully respected and treatment dosages delivered here were well above the minimum requirements. Moreover, assuming an emitting area of 2.35 cm2 and an average size of a TP in the upper trapezius of 0.16 cm2 (Sidkar et al. 2009), we are confident that the target was effectively irradiated by the laser beam with a definitely adequate power density. Then the conclusions of this trial are based on straightforward results which were obtained through appropriate procedures.

      References:

      Prentice W, Quillen W, Underwood F. 2005, “Therapeutic Modalities in Rehabilitation”, New York: McGraw-Hill 2005.

      Sikdar, S., Shah, J.P., Gebreab, T., Yen, R.-., Gilliams, E., Danoff, J. & Gerber, L.H. 2009, "Novel Applications of Ultrasound Technology to Visualize and Characterize Myofascial Trigger Points and Surrounding Soft Tissue", Archives of Physical Medicine and Rehabilitation, vol. 90, no. 11, pp. 1829-1838.

      WALT - World Association for Laser Therapy – Recommended dosages for low level laser therapy (2010). http://waltza.co.za/documentation-links/recommendations/dosage-recommendations/


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    2. On 2014 Feb 01, Jan Tunér commented:

      In the paper, the parameters are described: According to the acknowledged guidelines (WALT, 2004), delivery parameters were: wavelength 904 nm; pulse duration 200 ns; pulse frequency 1953 Hz; peak power 90 mW; average output 30 mW; power density 22.5mWcm2; treatment time 600 seconds; energy dose 18 J per session; spot size 4 cm2 and treatment frequency five times/week. Laser probe (head size: 4 cm2) was applied steady in skin contact with no pressure over the MTP. The 904 nm laser cannot possibly have a peak power of 90 mW. Let us accept this as a misprint for 90 watt. If so, the average output is 35 mW (not 30), which is reasonable for a TP. However, the “spot” is 4 cm2, so the 30 mW is spread over a large area, producing a power density which is very low. And in fact even lower than the one stated in the paper. Assuming that the peak power is 90 watt instead of 90 mW, the average output power can be calculated to 35 mW. Spot size is said to be 4 cm2. Then the power density will become 7.5 mW/cm2 (if 39 mW is used) or 8,8 mW/cm2 (if 35 mW is used). How are the stated 22.5 mW/cm2 calculated? Anyway, both 22 and 8 mW/cm2 are relatively low power densities. Further, WALT recommendation for a TP is not 18 J, but 2-4 J per point and certainly not one single TP. The conclusion of this study is based upon flawed parameters.


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    1. On 2014 Mar 25, Greg Finak commented:

      With manual gating still being the standard, we have to assume analysts doing the gating are experts, know the assay, and know what cell populations they're after. Starting from that premise, the normalization algorithm described does aim to emulate manual gating. I think that's pretty clearly described.

      However, your concern:

      if both datasets were gated by the same person, as seems likely. If that person is also the lead developer of the algorithm, a clear bias in favor of the algorithm becomes a real possibility.

      is unfounded. The the manual gating was not performed by the algorithm developers, nor were both data sets gated by the same person. The HVTN data set was gated by experts at the HIV Vaccine Trials Network, and the ITN was gated by experts at the Immune Tolerance Network.

      As to comparing manual gating generated by a sampling of individuals.. this has already been done.. see the FlowCAP paper, as well as a number of reviews by Maecker et. al. that show clearly that different analysts will give different results with higher C.V. than having data analyzed centrally. And if you're to have data analyzed centrally, then I'd argue you should use the best expertise possible. We started from that presumption here.

      Edit: I would also add that if you would like to scrutinize the manual gating more closely, you can grab the FlowJo workspaces from flowrepository.org, both data sets are now publicly accessible.


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    2. On 2014 Mar 23, Yannick Pouliot commented:

      One mild concern I have with this paper is the lack of details as to how the manual gating was performed. Given the authors' statement that a "... desirable outcome is to have low bias and low variability relative to the manual gates", what this really means is that the algorithm is trying to emulate the manual gating performance of a single individual if both datasets were gated by the same person, as seems likely. If that person is also the lead developer of the algorithm, a clear bias in favor of the algorithm becomes a real possibility.

      This sort of comparison would be much more informative if the algorithm were compared against manual gating results generated by a sampling of individuals with varying degrees of experience in the process and not involved in developing the algorithm.


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    1. On 2015 Jan 07, Jim Woodgett commented:

      The authors refer to a prior publication (PMID: 20939016) that correctly describes AR28 as a GSK-3alpha/beta inhibitor rather than a GSK-3beta inhibitor as described in the title and throughout most of the manuscript. Given the authors do not address specificity of AR28 in this publication, the Introductory comments seem unsupported: "While LiCl and BIO circumvent this problem by acting on GSK3β, downstream of the ligand/receptor binding, they are not ideal, with off target effects and toxicity (Davies et al., 2000, Meijer et al., 2003 and Liu et al., 2011)." It is also unusual in describing a novel inhibitor to not provide any details of the molecule. This inhibitor is also known as AZD2858 (PMID: 22142634), was developed by Astra Zeneca and is available from several commercial sources (e.g. Selleck Chemicals, Cayman Chemicals).


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    1. On 2014 Dec 20, Christopher Southan commented:

      Doubt has emerged (2Q2014) as to the drug target status of BACE2 http://cdsouthan.blogspot.se/2014/12/bace2-as-diabetes-target-or-maybe-not.html


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    2. On 2014 Jan 26, Christopher Southan commented:

      Our independent publication came out essentially back-to-back with "Asynchronous Evolutionary Origins of Aβ and BACE1” Moore DB, 2014. The two papers are complementary in coverage (Moore et.al. include a detailed analysis of APP evolution) and broadly convergent in their conclusions (details at http://cdsouthan.blogspot.se/2014/01/a-tale-of-two-targets-bace1-and-bace2.html including updates regarding TreeBase and the sequence acession number).

      APP evolution is also examined in "Origins of amyloid-β" http://www.ncbi.nlm.nih.gov/pubmed/23627794


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

      There are possible concerns with images in this paper.

      Fig 1e and f appear to be the same section, just rotated and/or with contrast adjusted. In addition, key findings of this study, the “crystal formations”, appear to be inserted objects into the image, at least one of which appears to be a 4-copy carbon copy (purple circles). http://imgur.com/ZcHzSYq

      Fig 1g, 1h and 1i “crystal formations” appear to be cloned, in some cases with sizes adjusted. They have remarkably similar features, shape, etc. http://imgur.com/UY82sIQ

      Authors and editors and Springer management contacted on June 15, 2016. To date, no response by any party.


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    1. On 2014 Aug 20, Claudiu Bandea commented:

      Just a few days after I posted the comment above on the remarkable study by Sauvageau et al. published in eLife (Sauvageau M, 2013), in which I questioned the interpretation and validity of some of the results, Bassett et al. published in the same journal an article outlining a series of highly relevant "considerations" when investigating the biological functions of lncRNA (Bassett AR, 2014). Interestingly, Bassett et al. expressed similar concerns about the study by Sauvageau et al., which should incite a response from the authors and eLife reviewing editor, Danny Reinberg.


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    2. On 2014 Aug 08, Claudiu Bandea commented:

      Multiple knockout mouse models reveal that some lincRNAs might be required for life and brain development

      In a recent series of mini-essays on genome functionality and ‘junk DNA’ prompted by Ford Doolittle’s article “Is junk DNA bunk? A critique of ENCODE” (1), I used the article by Sauvageau et al. (2) as an example of poor use of words in communicating scientific observations , which could lead to confusion and misrepresentations (3). In fact, I went so far as to suggest that some of the results in this particular study might be problematic. However, these allegations might be wrong and, therefore, it is important to bring them to the attention of the authors here, so they have the opportunity to respond.

      First, I would like to emphasize that the study by Sauvageau et al. is impressive. The problem, however, might be with the interpretation of the results and their integration into the existing body of knowledge, which are as important in advancing science as generating data, if not more. There might also be a problem with the absence of appropriate controls for the knockout mouse models, which questions the validity of some of the results.

      Briefly, to investigate the functional relevance of long intergenic noncoding RNAs (lincRNAs), Sauvageau et al. developed a collection of 18 lincRNA knockout mouse strains in which the locus was maintained transcriptionally active. In order to select the best candidates for functional lincRNAs, the authors “have implemented a generalized and logical lincRNA candidate selection process that leverages a collection of cell-based functional assays, RNA-sequencing data and computational analyses….”

      Remarkably, in their initial characterization of the 18 lincRNAs knockout strains, Sauvageau et al. found three strains that exhibited peri- or post-natal lethality and two additional strains with distinct developmental defects. Based on these findings the authors concluded that “This study demonstrates that lncRNAs play critical roles in vivo…” and entitled their article: “Multiple knockout mouse models reveal lincRNAs are required for life and brain development.”

      However, both the conclusion and the title of the study by Sauvageau et al. can be misleading. Factually, the results reported in the article indicate that 5 out of 18 lncRNAs included in study appear to play critical roles in vivo and, therefore, it should have been entitled something like: “Multiple knockout mouse models reveal that some lincRNAs might be required for life and brain development.”

      Moreover, based strictly on the results presented in the article, which showed that only 5 of the 18 lncRNAs were functional, and considering the strong bias introduced in the study by selecting lincRNAs that are most likely to be functional, a more appropriate scientific interpretation of the study would be that: “The results presented in this article indicate that most lncRNAs (i.e. 13 out of 18) do not appear to play critical roles in vivo….” It is possible that the authors will report in future articles results showing that some additional, or all the lincRNAs in their collection are functional; even then, the authors should be cautious about the broad interpretation of the results considering the bias of their collection toward putatively functional lincRNAs (therefore, the inclusion of a few random lincRNAs would have benefited the study).

      Whether the assertion about the broad interpretation of the results, which might be considered an 'innocent' case of ‘hype in science’ (4), resonate with the authors or with other readers remains to be seen: however, the allegation that the phenotypes observed in their study might be associated with untargeted genome alterations introduced inadvertently during the procedure of generating the knockout mice, rather than with the deletion of specific lincRNAs, questions the validity of the study, at least for the time being and, therefore, it should be of concern.

      Considering the well-recognized problems with generating knockout animal models (see, for example, Refs. 5-9), it is surprising that Sauvageau et al. did not discussed this issue in the context of their study, and that they did not include appropriate controls (e.g. duplicates) at least for some of the lincRNAs knockouts, preferably using mice with different genetic background. Although the data and observations presented by Sauvageau et al. might be correct, for the time being their validity remains questionable; therefore, it would make sense for the authors (and the editors) to add an explanatory note, both here at PubMed Commons and in the journal eLife.

      References

      (1) Doolittle WF. 2013. Is junk DNA bunk? A critique of ENCODE. Proc Natl Acad Sci USA., 110:5294-300. Doolittle WF, 2013

      (2) Sauvageau M. et al., 2014. Multiple knockout mouse models reveal lincRNAs are required for life and brain development. eLife (DOI: 10.7554/eLife.01749) Sauvageau M, 2013

      (3) Bandea CI. 2014. Everlasting confusion on ‘functional DNA’ and ‘junk DNA’ in the field of genome biology. PubMed Commons (National Library of Medicine; Bethesda, MD). Comment on: Doolittle WF, 2013

      (4) Maderspacher F. 2014. Hype in Halifax. Curr Biol. 14;24(8):R298-301. Maderspacher F, 2014

      (5) Wolfer DP, Crusio WE, Lipp HP. 2002. Knockout mice: simple solutions to the problems of genetic background and flanking genes. Trends Neurosci. 25:336-40. Wolfer DP, 2002

      (6) Crusio WE1, Goldowitz D, Holmes A, Wolfer D. 2009. Standards for the publication of mouse mutant studies. Genes Brain Behav. 8(1):1-4. Crusio WE, 2009

      (7) Eisener-Dorman AF, Lawrence DA, Bolivar VJ. 2009. Cautionary insights on knockout mouse studies: the gene or not the gene? Brain Behav Immun. 23:318-24. Eisener-Dorman AF, 2009

      (8) Striebel JF, Race B, Pathmajeyan M, Rangel A, Chesebro B. 2013. Lack of influence of prion protein gene expression on kainate-induced seizures in mice: studies using congenic, coisogenic and transgenic strains. Neuroscience. 15;238:11-8. Striebel JF, 2013

      (9) Nuvolone M et al. 2013. SIRPα polymorphisms, but not the prion protein, control phagocytosis of apoptotic cells. J Exp Med. 18;210:2539-52. Nuvolone M, 2013


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    1. On 2014 May 06, Serge Ahmed commented:

      This study is outstanding. Together with other studies, it confirms that sugar is a double reward. Sugar activates brain dopamine (DA) neurons twice: once during sweet tasting (via an initial polysynaptic brainstem pathway) and once after blood glucose absorption (via an activation of MCH neurons). The latter delayed activation of DA neurons plays a critical role in learned food preferences and may also contribute to maintain the ability of sweet taste to activate DA neurons.

      Rather surprisingly, this study also shows that concurrent optogenetic activation of hypothalamic MCH neurons during access to water sweetened with sucralose (a non-caloric sweetener) increases consumption of sweet water and also DA levels in the striatum. The time course of this effect is somewhat paradoxical, however, if one supposes that it mimics activation of MCH neurons by post-absorptive glucose. In fact, this effect is more consistent with a direct modulation of sweet palatability by MCH neurons. It would be interesting to know how glucose activation of MCH neurons during access to sweet water would affect consumption.


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    1. On 2015 May 13, Tim Smits commented:

      As already commented by James Coyne, there are serious issues with the statistics in this paper as well as with the overall level of academic scrutiny in the write-down of the methodology and findings. These have indeed been discussed in two Letters to the Editor Smits T, 2014 & Smits T, 2015. Though published, the journal has not yet warned its readers of these mistakes in the original article. Next to these two published letters, more concerns about the article are described in this blogpost http://persuasivemark.blogspot.be/2014/02/dont-get-all-psychotic-on-this-paper.html


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    2. On 2015 May 12, James C Coyne commented:

      This study compares a nurse-delivered cognitive behavior therapy to treatment as usual in a small, convenience sample of older psychotic patients from community care who averaged over 20 years of previous treatment. The treatment as usual is not adequately described or quantified in a way that allows interpretation of any differences between conditions. It cannot be determined whether any effects are due to specific elements of the intervention or to inadequacies in professional contact time, support, or expectations likely to be occurring in the community psychiatric care of patients who have been there over 20 years.

      But there are more basic problems. As detailed in letters to the editor Smits T, 2014 Smits T, 2015 and numerous blog posts, there are substantial discrepancies between findings reported in the abstract, in the narrative Results section, and in the tables and figures of this article. Just a sampling:

      For Table 2. The confidence intervals were suspiciously wide. The effect sizes seemed too large for what the modest sample size should yield. The table was inconsistent with information in the abstract. Neither the table nor the accompanying text had any test of significance nor reporting of means and standard deviations. Confidence intervals for two different outcomes were identical, yet one had the same value for its effect size as its lower bound.

      Figure 2 is mislabeled as a histogram and if results are to be believed, there are no significant pre-post differences between intervention and control group on any of the outcome variables. This is discrepant with what is reported in the abstract and narrative of the Results section.

      Figure 5 lacks any metric for the vertical lines.

      Their responses to letters about this article clearly indicate that the author Turkington D, 2014 and the statistical editor of the Journal < PMID:25816048 >are now aware of these problems.

      It is unclear why there has not been a retraction or correction issued.

      You can read more about the problems of this article and the response to criticism at my posts at PLOS Mind the Brain.

      Sordid tale of a study of cognitive behavioral therapy for schizophrenia gone bad http://blogs.plos.org/mindthebrain/2015/04/14/sordid-tale-of-a-study-of-cognitive-behavioral-therapy-for-schizophrenia-gone-bad/


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    1. On 2014 Jan 04, Dorothy V M Bishop commented:

      I was pleased to see that Professor Farthing took the opportunity to tackle the subject of research misconduct in his lecture. He cogently notes the nature of the problem and makes suggestions to deal with it. I thought his analysis was generally on-target, but I was concerned about his second suggested solution: enhanced monitoring and audit, and his failure to consider an additional approach, which is to change the incentive structure for researchers. The following points are taken from a blogpost I wrote on these topics (http://deevybee.blogspot.co.uk/2013/06/research-fraud-more-scrutiny-by.html).

      I agree we need to think about how to fix science, and that many of our current practices lead to non-replicable findings. I just don't think more scrutiny by administrators is the solution.

      So what would I do? The answers fall into three main categories: incentives, publication practices, and research methods.

      Incentives: Currently, we have a situation where research stardom, assessed by REF criteria, is all-important. Farthing notes that RAE/REF criteria have been devised to stress quality rather than quantity of research, which is a good thing, but it is still the case that too much emphasis goes on the prestige of journals (see http://deevybee.blogspot.co.uk/2013/01/journal-impact-factors-and-ref-2014.html).

      Instead of valuing papers in top journals, we should be valuing research replicability. This would entail a massive change in our culture, but a start has already been made in my discipline of psychology :see http://www.nature.com/news/psychologists-strike-a-blow-for-reproducibility-1.14232.

      Publication practices: the top journals prioritize exciting results over methodological rigour. There is therefore a strong temptation to do post hoc analyses of data until an exciting result emerges. I agree with Farthing that pre-registration of research projects is a good way of dealing with this. I'm pleased to say that here too, psychology is leading the way in extending research registration beyond the domain of clinical trials: http://blogs.lse.ac.uk/impactofsocialsciences/tag/registered-reports/

      Research methods: we need better training of scientists to become more aware of the limitations of the methods that they use. Too often statistical training is a dry and inaccessible discipline. All scientists should be taught how to generate random datasets: nothing is quite as good at instilling a proper understanding of p-values as seeing the apparent patterns in data that will inevitably arise if you look hard enough at some random numbers. In addition, not enough researchers receive training in best practices for ensuring quality of data entry, or in exploratory data analysis to check the numbers are coherent and meet assumptions of the analytic approach.

      Finally, before any new regulation is introduced, there should be a cold-blooded cost-benefit analysis that considers, among other things, the cost of the regulation both in terms of the salaries of people who implement it, and the time and other costs to those affected by it. My concern is that among the 'other costs' is something rather nebulous that could easily get missed. Quite simply, doing good research takes time and mental space of the researchers. Most researchers are geeks who like nothing better than staring at data and thinking about complicated problems. If you require them to spend time satisfying bureaucratic requirements, this saps the spirit and reduces creativity.

      I think we can learn much from the way ethics regulations have panned out. When a new system was first introduced in response to the Alder Hey scandal, I'm sure many thought it was a good idea. It has taken several years for the full impact to be appreciated. The problems are documented in a report by the Academy of Medical Sciences, which noted "Urgent changes are required to the regulation and governance of health research in the UK because unnecessary delays, bureaucracy and complexity are stifling medical advances, without additional benefits to patient safety"


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    1. On 2014 Jan 11, David Mage commented:

      The authors report an interesting study in regards to sustained hypoxia and respiratory neural control during a critical period of development in rats. However it may have no relation to the phenomenon of human sudden infant death syndrome (SIDS). It has been shown that human SIDS occur between birth and 3.5 years with a 4-parameter lognormal age distribution (Johnson SB) Mage DT, 2009. This distribution is continuous and has no discontinuities between fore and aft portions of the age distribution on either side of "a critical period of development." The SIDS community seems to have forgotten that the operative definiton of modern SIDS as being restricted to under one year from birth was made for research purposes only Willinger M, 1991 and the triple risk model for SIDS cited by these authors does not predict a 50% male excess for SIDS Mage DT, 2014.


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    1. On 2014 Jan 24, Tom Kindlon commented:

      I questioned the use of subjective outcome measures, particularly as primary outcomes, in trials of lightning process in a referenced comment on the feasibility study here: http://www.ncbi.nlm.nih.gov/pubmed/24304689#cm24304689_2383.

      Given the protocol uses subjective measures as primary outcomes, I thought I would highlight it here.


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    1. On 2014 Mar 06, David Keller commented:

      Cataract pre-ops are driven by the ophthalmologists

      The American College of Cardiology and the American Society of Anesthesiologists are in agreement that the routine pre-operative examination is not necessary for stable patients. That is good, but you will not see a decrease in the number of these exams until the ophthalmologists sign on to that agreement. Here is how it works in private practice: an elderly patient shows up in their internist's office one day, after skipping their routine follow-up appointments for way too long, perhaps to the point where their internist has been mailing them reminder letters and enlisting the patient's pharmacist to remind the patient to follow up soon. Finally, the patient shows up with a note from their ophthalmologist requesting certain specific blood tests, an EKG and "clearance" for the cataract procedure. If these instructions are not followed by the internist, the patient's cataract extraction will be postponed, and the internist may lose the patient to a more user-friendly PCP. To improve its impact, this article should be co-published in JAMA - Ophthalmology.


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    1. On 2014 Jan 26, Christopher Southan commented:

      Our independent publication "A tale of two drug targets: the evolutionary history of BACE1 and BACE2" Southan C, 2013 came out essentially back-to-back with this paper. The two are complementary in coverage and broadly convergent in their conclusions (details at http://cdsouthan.blogspot.se/2014/01/a-tale-of-two-targets-bace1-and-bace2.html).


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    1. On 2013 Dec 24, Hilda Bastian commented:

      An important initiative. There was animated discussion (and a fair amount of cringing) when this paper was presented at the Peer Review Congress earlier this year (see this blog post). Needing to gather, adequately describe and store the data we analyze in a way that others can use it has major implications for the daily life of many researchers.

      Having a spotlight shone on the adequacy of data stewardship is important, but there are some issues to keep in mind. It's in a very specific area of research. Some other fields have particular regulations about the retention, privacy and sharing of all, or some, data. See for example recent analyses of the availability of clinical trial data (Riveros C, 2013).

      The numbers of papers in this study at all dwindle in earlier years: 26 in 1991 compared with 80 in 2011. Data within particular categories (such as definitely lost in any one year) are correspondingly small.

      It was interesting that only 2.4% of studies had made their data available at the time of publication. (Those studies were excluded.)

      The authors practice what they preach: the full data are in Dryad and there's a manuscript in arXiv.


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    1. On 2016 May 10, Morten Oksvold commented:

      Please pay attention to the following report from ORI (Office of Research Integrity) before reading this article:

      https://ori.hhs.gov/content/case-summary-pastorino-john-g


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    1. On 2014 Feb 24, Eugene Koonin commented:

      A very interesting paper beyond doubt, demonstrating specific role of codon bias in translation regulation. The following previous publications provide complementary insights into the regulatory effects of codon usage: http://www.ncbi.nlm.nih.gov/pubmed/20403328 http://www.ncbi.nlm.nih.gov/pubmed/24012761


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    2. On 2014 Feb 04, Tobias von der Haar commented:

      That's interesting - you analysed rare codon clusters as a function of the protein motif, which would be related to folding. There is also evidence that rare codons are over-represented in low-expressed proteins, which could be related to the control mechanism we describe Neafsey DE, 2007. One might also expect rare codons to be over-represented near the 5'-end of messages (where they would exert control without significant ribosome queueing), but I don't think anyone has looked for this yet.


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    3. On 2014 Feb 03, Rafael Najmanovich commented:

      We have recently performed a large scale analysis of evolutionarily conserved rare codon clusters in protein families that may be of interest for readers of this paper: Chartier M, 2012.


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    1. On 2014 Jan 07, Aaron Liston commented:

      An important result shown in Figure 1, but not mentioned in the manuscript, is that poplar (Malpighiales) is sister to cacao (Malvales) and Brassicales (Arabidopsis, papaya) in the malvid clade, and not the fabid clade (Fabales, Rosales). This result has been reported in other studies of nuclear gene phylogeny, and conflicts with the widely utilized APG3 classification that is predominantly based on plastid genes.


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    1. On 2017 Jun 13, Christina Niederstadt commented:

      It would be enlightening to "abstract-only" or "mostly-just-abstract" -readers, if the abstract could contain information regarding the wheight-loss reasons or methods collected within the NWCR (bariatric surgery, anyone?)... (I do not say that I promote "abstract-only-reading" but it would help to decide on whether it would be worthwhile to order the full text of the article.)


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    1. On 2014 Feb 24, Zhongheng Zhang commented:

      An well written review that comprehensively summarized unusual signs of Px.


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    1. On 2013 Dec 30, Raphael Stricker commented:

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

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

      This editorial by Dr. Lantos was published together with an article by Wressnigg and colleagues from Baxter Bioscience in support of a new Lyme vaccine developed by Baxter Bioscience. Our published Letter to the Editor (http://www.ncbi.nlm.nih.gov/pubmed/24355028/) responded in part to Dr. Lantos.

      Both the Baxter Bioscience article and the Lantos editorial make short shrift of patient vaccine safety concerns, which Lantos describes as “largely unsubstantiated”. We note that the previous LYMErix vaccine sparked a class action lawsuit from patients who claimed that they were harmed by the vaccine, which was ultimately pulled from the market by the manufacturer. We also note that "by withdrawing LYMErix when it did, the manufacturer avoided releasing phase 4 post-marketing data that probably would have shown increased side-effects related to the vaccine. The data have never been disclosed."

      We conclude that patient trust in new Lyme vaccines will require that legitimate safety concerns regarding the previous vaccine be acknowledged and addressed. Because Lyme vaccines are given to a healthy population, our first priority is to make sure that they are safe.

      References

      1. Stricker RB. Lymerix® risks revisited. Microbe 2008;3:1-2.
      2. Smith P, Gaito A, Marks DH. Transcript of FDA Lymerix Meeting, Bethesda, MD, January 22, 2002. Available at: http://www.lymediseaseassociation.org/index.php?option=com_content&view=article&id=532:lymerix-meeting&catid=129:hhsfood-a-drug-administration-fda&Itemid=531
      3. Croke CL, Munson EL, Lovrich SD, et al. Occurrence of severe destructive Lyme arthritis in hamsters vaccinated with outer surface protein A and challenged with Borrelia burgdorferi. Infect Immun. 2000;68:658–63.
      4. Rose CD, Fawcett PT, Gibney KM. Arthritis following recombinant outer surface protein A vaccination for Lyme disease. J Rheumatol. 2001;28:2555–7.
      5. Latov N, Wu AT, Chin RL, Sander HW, Alaedini A, Brannagan TH. Neuropathy and cognitive impairment following vaccination with the OspA protein of Borrelia burgdorferi. Periph Nerv Syst. 2004;9:165–7.
      6. Alaedini A, Latov N. Antibodies against OspA epitopes of Borrelia burgdorferi cross-react with neural tissue. J Neuroimmunol. 2005;159:192–5.
      7. Souayah N, Ajroud-Driss S, Sander HW, Brannagan TH, Hays AP, Chin RL. Small fiber neuropathy following vaccination for rabies, varicella or Lyme disease. Vaccine 2009;27:7322-5.
      8. Marks DH. Neurological complications of vaccination with outer surface protein A (OspA). Int J Risk Saf Med. 2011;23:89-96.
      9. Molloy PJ, Berardi VP, Persing DH, Sigal LH. Detection of multiple reactive protein species by immunoblotting after recombinant outer surface protein A Lyme disease vaccination. Clin Infect Dis. 2000;31:42-7.
      10. Fawcett PT, Rose CD, Budd SM, Gibney KM. Effect of immunization with recombinant OspA on serologic tests for Lyme borreliosis. Clin Diagn Lab Immunol. 2001;8:79-84.
      11. Hanson MS, Edelman R. Progress and controversy surrounding vaccines against Lyme disease. Expert Rev Vaccines 2003;2:683–703.
      12. Nigrovic LE, Thompson KM. The Lyme vaccine: a cautionary tale. Epidemiol Infect. 2007;135:1–8.
      13. Nardelli DT, Munson EL, Callister SM, Schell RF. Human Lyme disease vaccines: past and future concerns. Future Microbiol. 2009;4:457-69.
      14. Smith P. Remarks to Vaccines and Related Biological Products Advisory Committee, Bethesda, MD, January 31, 2001. Available at: http://www.lymediseaseassociation.org/index.php?option=com_content&view=article&id=262:vaccine-remarks&catid=80:controversy&Itemid=76

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


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    1. On 2015 Sep 25, David Mage commented:

      Elder et al. do a thorough analysis of the possible causes of the Black-White infant mortality gap (B > W) and, per above, they show that if Black infants had the same risk factors as White infants then the gap between them would only be reduced by 25%. In our studies of sudden infant death syndrome (SIDS: (ICD-9 798.0; ICD-10 R95) [PMID 20049339, 24164639] we noted this Black infant excess. Given that SIDS is a unique disease because death is its first symptom, the excess Black death rate could not involve a deficiency in medical care of the B infants presenting with SIDS. We then used the tabulated infant mortality statistics for all ICD chapter causes of infant dearth < 1 year, wonder.cdc.gov, and found that B > W for all causes except neoplasms (ICD-10: C00-D48). We wondered at what age this deficit seen in other non-neoplasm codes for infant mortality would disappear and looked at older age ranges up to 65 years. The deficit does not disappear (except for a few years where cystic fibrosis is much higher for W than B) and in each and every age group the B death rate is greater than the W death rate {some genetic reasons not withstanding, such as sickle cell anemia with B > W). We reason that this B > W excess must be systemic and agree with Haider [Racial and ethnic infant mortality gaps and socioeconomic status. Focus; 2014;31 (1) Spring/Summer:18-20] that the poverty of the B population relative to the W population may be the shadow cast by the past history of the Plessy v. Ferguson legal fiction that ʺseparate but equalʺ education was constitutional and would cause no harm. The lingering effect of this past discrimination may be insidious if it resulted in the relative impoverishment of many of those discriminated against and their progeny that delays or reduces their access to adequate medical care. For example, the U.S. death rates from ICD-10 causes of medical errors Y40-Y69, Drugs, medicaments and biological substances causing adverse effects in therapeutic use, and Misadventures to patients during surgery and medical care, are higher for B than W at all ages up to 84 years.


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    1. On 2014 Jan 10, Luis Querol commented:

      This paper describes an amazing work and links the CD4 T cell responses against H1N1 with those against orexin. This paper has received a lot of mainstream media attention (see here for example) where it has been described as the demonstration that narcolepsy is an autoimmune disease. Although the study provides interesting data re-inforcing the autoimmune hypothesis of narcolepsy, it does not demonstrate so and it's not the first study to suggest the autoimmune hypothesis, as authors correctly point in the discussion. A brief comment summarizing the study and providing context to those mainstream media headlines has been published here


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    1. On 2015 Sep 09, Linda Rieswijk commented:

      da Silva RP, 2014 in the introduction of the manuscript it is stated that S-adenosylmethionine is abbreviated as AdoHcy. This is however confusing since in the sentence preceding this one it is stated that S-adenosylmethionine is abbreviated as AdoMet. I guess AdoHcy is the abbreviation for S-adenosylhomocysteine. This should be adjusted in the introduction.


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    1. On 2014 Jan 10, Farooq Rathore commented:

      Nobody can deny the importance of social media, but the doctor has to strike a balance between his professional demands and the urge to check the latest facebook post or reply to a tweet ASAP. All social media have the option of customization and if a physician chooses wisely he will be able to have latest knowledge and information from the social media at his finger tips ( literally)

      In addition doctors are humans too. We need to socialize and a little bit of socialization on FB, Twitter or G+ might not hurt if we keep a track of the time we need to spend of these social media sites


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    2. On 2013 Dec 22, William Brieger commented:

      Obviously social media like any other form of expression is an individual choice. The usual social media account by health professionals attracts a limited following of people with specific interests. Social media can be used to keep colleagues up to date on activities in their specific field. When attending professional conferences, physicians and other health workers can use social media to share what they are learning with colleagues who are unable to attend. Various privacy settings are available for those who want to control who reads their postings. Again, use of social media must have a purpose for individual users, and if it does not advance professional practice for an individual, there is no reason she/he should not use social media except among friends and family.


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    3. On 2013 Dec 21, Allison Stelling commented:

      First of all, thank you Anne Marie for linking to the pdf of your paper.

      I must say that I disagree with Decamp about the future and usefulness of social media as a means to distribute medical information. I do feel he is correct that no MD ought to be forced to participate if they do not feel so inclined. Those who are so inclined, however, must be rewarded and guided, not punished.

      Several of the phrases Decamp uses in his essay are quite telling ie, "On the contrary, the brevity, lack of control, and permanence of online information make engaging in such activities even more risky in the online realm." Such statements are loaded with fear- fear of loss of control of a conversation that is traditionally held between experts and bypasses any patient interaction. (Also, if one fears brevity, then one can get one's own blog where one can go on a bit.)

      This is an unwarranted fear that is eating away at the heart of American medicine. If you fear your public misunderstands you, educate them.

      Medicine is a public service, a public good; and as such must be publicly scrutinized (and funded, for that matter, but that is a different topic). Medicine and public health issues are a dialogue that must be had between the medical doctors, the public they serve, and the scientific researchers who lay the foundations for medical discoveries.

      The days of dictation and monologues delivered to an unresponding audience are gone. We need an educated and enthusiastic population to further our goals of cures. (I would settle simply for more accurate diagnostics!) And- even if the public is not permitted to speak during a particular conversation that they funded- they do have the right to view it and ask questions afterwards.

      Rapid dissemination of solid medical information is a crucial ingredient to my nation's- and the world's- future health. USA tax money pays for quite a percentage of foundational health research, and my nation's taxpayers have a fundamental right to the information and research for which they paid.

      Decamp also states that the "role of physician expertise is unclear." Perhaps it is not expertise that patients seek online from MDs, but comfort- and someone who will listen to them.

      As for the "mistakes" section- yes, MDs are human. They make mistakes. I've worked with many MDs in the course of my career, and the one prevalent flaw was an unwillingness to admit error. Over-confidence and an idealized image of perfection is haunting the medical community- remnants of a not-to-distant past wherein they were likened to "gods amongst men".

      We know very little about life and death, and the chemical differences that separate them. I would suggest it is high time the MDs drop the facade of certainty and confidence, and come into the light of collaborative discourse that social media enables. -Allison (https://twitter.com/DrStelling)


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    4. On 2013 Dec 21, Hilda Bastian commented:

      That's a useful list of reasons for value in social media for physicians. Further support for the "to learn" argument and finding good curators among peers comes from the growth of social media as a gateway to medical literature. James Colbert et al reported at the 2013 Peer Review Congress that for NEJM, Facebook and Twitter are both in the top 10 referring sites to the journal (at 6 and 10 respectively). Readers might also be interested in reports on the role of social media for journals and societies in dermatology (Amir M, 2014) and ophthalmology (Micieli R, 2012).


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    5. On 2013 Dec 21, Anne Marie Cunningham commented:

      Full free text pdf of this paper can be found here http://www.rcpe.ac.uk/sites/default/files/decamp_cunningham_curr_cont.pdf The RCPE journal is OA. They even let me retain copyright on this publication and licensed them to publish it. But for some reason PubMed doesn't link to the journal home page etc.

      Hope you enjoy- please leave us feedback!


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    1. On 2014 Mar 21, Pedro Reche commented:

      We have enhanced the EPISOPT site (http://imed.med.ucm.es/Tools/episopt.html).The server predicts epitope HLA I binding profiles, compute population protection coverage and select sets of epitopes providing a desired population protection coverage


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    1. On 2016 May 30, Heidi Schulz commented:

      According to HGVS guidelines, the p.Q238L mutation described as c.713del15 in the paper, should be named c.713_714+13del. The p.A357V variant mentioned in the paper has a MAF=0.02 in ExAc East Asians and has not been reported in patients with Best disease in the papers cited.


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    1. On 2014 Mar 14, Jonathan Eisen commented:

      Holly Ganz has written a post on the "microbiology of the Built Environment network" blog discussing this paper. See Dog hair and asthma


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    1. On 2016 Sep 26, Holger Schunemann commented:

      The Guideline Development Checklist is now shared with the Guideline International Network (GIN) (http://www.g-i-n.net/) and called the GIN-McMaster Guideline Development Toolbox (GET) or checklist and available in several languages in addition to English (Portuguese, Chinese, Spanish and Italian) on: https://cebgrade.mcmaster.ca/guidecheck.html


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    1. On 2014 Mar 26, Antonio Martinez-Gimeno commented:

      The results of this excellent RCT on the effect of hypertonic saline on infants with acute bronchiolitis can be easily added to current metaanalysis on the issue (Zhang L, 2013 and Chen YJ, 2014) Just download Review Manager 5.2, install it and introduce the previous data and the data from this study (along with the data from two other recently published RCT, Nenna R, 2014 and Sharma BS, 2013) and you will obtain an excellent update of each meta-analysis.

      Unfortunately, the authors of this study failed to include the actual numbers of hospital length of stay (group means and SD) in table 5 and that precludes its use in the meta-analysis update.

      It would be great if the authors could publicly provide these figures.


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    1. On 2014 Oct 17, Joe Newton commented:

      Your spatial-temporal correlation is especially suggestive for the pathophysiology expected in multiple neuropsychiatric diagnostic categories. Further work in animal models on measures of action potential speed/velocity are expected to reveal abnormalities in such neuropsychiatric categories. Best wishes, Joe Ray Newton


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    1. On 2014 Jan 02, Paul Whiteley commented:

      The authors are to be applauded for looking at this potentially important area of autism research. Combined with other research similarly indicating that a proportion of children on the autism spectrum may present with gut hyperpermeability: de Magistris and colleagues (2010): http://www.ncbi.nlm.nih.gov/pubmed/20683204 and de Magistris and colleagues (2013): http://www.ncbi.nlm.nih.gov/pubmed/23984403 an interesting pattern of gut-related pathology is emerging for at least some cases of autism (or should that be the autisms).

      Given that this cohort was (I think) drawn from the same participant group as that investigated by the same authors in other study: Chandler and colleagues (2013): http://www.ncbi.nlm.nih.gov/pubmed/23371507 it is a pity that similar values related to intestinal permeability were not reported for an asymptomatic (typically developing) control group as a comparator. Whilst the authors note that their special educational needs (SEN) group did not present with autism (I assume as reaching the diagnostic threshold for a diagnosis of autism) one wonders whether specific behaviours forming the diagnostic triad (or dyad depending on the criteria applied) may overlap and in turn, link autism and SEN participants?

      That also de Magistris and colleagues (2010) noted that use of a gluten- and casein-free (GFCF) diet seemed to affect intestinal permeability measurements also brings into play the question of whether similar dietary measures were included in any of the participant group of the current study and exerted an effect on the results obtained.

      Those issues aside, the emerging picture of gut hyperpermeability combined with features of a non-coeliac gluten 'sensitivity' in cases of autism as per Lau and colleagues (2013): http://www.ncbi.nlm.nih.gov/pubmed/23823064 and Ludvigsson and colleagues (2013): http://www.ncbi.nlm.nih.gov/pubmed/24068245 offers some new directions for autism research and practice.


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    1. On 2014 Nov 25, Harri Hemila commented:

      Virtamo J, 2014 analyzed post-trial mortality in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study, which included male smokers aged 50 to 69 years at baseline. In this new post-trial analysis, they calculated that post-trial relative mortality was 1.02 (95% CI, 0.98 to 1.05) for vitamin E recipients compared with nonrecipients. Unfortunately, Virtamo et al. ignored the strong evidence that the effects of vitamin E are not uniform over the ATBC Study participants.

      A previous analysis of the ATBC Study found that the effect of vitamin E on pneumonia incidence was significantly modified by three different measures of cigarette smoking exposure Hemilä H, 2004, DOI. Another analysis focusing on common cold incidence found significant modification of vitamin E effect by age, smoking and residential neighbourhood Hemilä H, 2006, DOI. The modifying factors on respiratory infections cannot be directly extrapolated to mortality, yet those findings led to an investigation on whether vitamin E effects on mortality might also be heterogeneous in the ATBC Study. During the 5-8 year intervention period of the ATBC Study, overall mortality was 2% higher in the vitamin E participants than in the no-vitamin E participants. However, if the effect of vitamin E is heterogeneous, then the 2% overall estimate might not be valid for a substantial proportion of the ATBC Study participants.

      In our analysis of all-cause mortality during the intervention period of the ATBC Study, we found that the combination of age and dietary vitamin C intake modified the effect of vitamin E supplementation to the extent that the heterogeneity over 6 subgroups was highly significant (P = 0.0005) Hemilä H, 2009, DOI. In 11,448 ATBC Study participants aged 50-62 years at the baseline who had dietary vitamin C intake above the median, vitamin E increased all-cause mortality by 19%. In contrast, in 872 ATBC participants aged 66-69 years who had vitamin C intake above the median, vitamin E reduced mortality by 41%. Vitamin E had no influence on mortality among those who had dietary vitamin C intake less than the median. The modifying effect of vitamin C was not explained by other substances in fruit and vegetables. The interaction between vitamins C and E is well documented Bruno RS, 2006, DOI, which may explain the role of vitamin C as a modifying factor for some vitamin E effects.

      Furthermore, in the younger ATBC Study participants (50-62 y at the baseline) who had vitamin C intake above average, vitamin E started to increase mortality only after a lag period of 3.3 years. There was no effect on mortality during the first 3.3 years of supplementation, but thereafter mortality increased in the vitamin E participants by 38% Hemilä H, 2009. The effect modification by supplementation-time is not easily explained by chance since the addition of the second vitamin E effect to start at 3.3 years improved the regression model significantly (P = 0.007). Thus, in addition to age and dietary vitamin C intake, the duration of vitamin E supplementation also modified the effect in this subgroup. The lag period may be explained by the fat solubility of vitamin E, since the body stores are changed slowly with changes in intake levels Handelman GJ, 1994, AJCN.

      Finally, the decrease in mortality in participants aged 66 and over by vitamin E implies that the survival time might also be influenced. A subsequent analysis found that among ATBC participants with dietary vitamin C intakes above the median who smoked less than a pack of cigarettes per day, vitamin E extended lifespan by 2 years at the upper limit of the follow-up age span Hemilä H, 2011, DOI.

      These subgroup findings invite the following questions. Given that mortality in the older ATBC Study participants was decreased by vitamin E, did the discontinuation of vitamin E at the end of the trial period lead to a corresponding increase in post-trial mortality in the oldest vitamin E recipients as compared with nonrecipients? Furthermore, given that after 3.3 years vitamin E started to increase mortality in the younger participants, did discontinuation of vitamin E lead to a corresponding decrease in post-trial mortality after a lag period? Because of the abovementioned subgroup findings, these questions are of obvious relevance and should have been investigated in the post-trial analysis of ATBC Study mortality. Virtamo et al. do not give any justification for dismissing the strong evidence of heterogeneity in the vitamin E effects on mortality.


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    1. On 2016 Apr 05, Marko Premzl commented:

      The third party data gene data set of eutherian ribonuclease A genes HG328835-HG329089 was deposited in European Nucleotide Archive under research project "Comparative genomic analysis of eutherian genes" (https://www.ebi.ac.uk/ena/data/view/HG328835-HG329089). The 255 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/


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    1. On 2014 Jan 14, Amanda Capes-Davis commented:

      Sounds like an exciting compound, but it may or may not be relevant to oral cancer. KB is known to be cross-contaminated and is actually HeLa, as shown by Gartler in 1967 (PMID 4864103). For a database of cross-contaminated or otherwise misidentified cell lines, see http://iclac.org/databases/cross-contaminations/.


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    1. On 2017 Oct 17, thomas samaras commented:

      Certainly most Western studies show that taller subjects have lower CHD than shorter ones. The reason for this is not related to inherent biological problems related to shorter height. In fact, shorter people following a good lifestyle and diet have been shown to have much lower risk of CHD. The evidence for this statement follows:

      1. Pre-Western people rarely experience Western type chronic diseases, including CHD. In fact, studies during the 20th C found a number of populations where there was no evidence of CHD or stroke. These populations included: Solomon Islands, Papua New Guinea, Kalahari Bushmen, Congo pygmies, and the island of Kitava. All these populations had males who averaged less than 5'4".

      2. In the early 1900s, the US and UK had very low levels of CHD. Yet, people were much shorter compared to today.

      3. Before 1970, US higher income people had higher rates of heart disease than working class people. After 1970, the situation reversed. In both cases working class people were shorter. The reason for this paradox may be increased overweight in shorter people and the consumption of fast foods, rich in animal protein and calories. Also improved diets based on medical advice may have helped the higher income people after 1970.

      4. When pre-Western populations transition to a more Western diet, they see a sharp rise in CHD.

      5. In the 20th C, Northern Europe had almost double the mortality from heart disease as shorter Southern Europe.

      6. Sardinia had the lowest CVD in Europe and its people were the shortest Europeans.

      7. A study of Western Sicilian centenarians found they were short and had no CVD risk factors.

      8. Women are shorter than men and have lower CHD mortality.

      If bigger size was an advantage in reducing heart problems, then why do Great Danes have 60 times the risk of heart failure vs. miniature Dachshunds? A study found that bigger dogs had more heart failure than smaller dogs. Smaller dogs have much smaller blood vessels and hearts. Their heart rates are also about 40% higher than big dogs.

      Part of the problem is that shorter people tend to be more overweight than taller ones. If tall and short people with the same BMI are compared, the taller will be relatively lighter than the shorter ones giving them a lower risk of CHD. Also, it is difficult to separate short people from a study who suffered childhood illness, malnutrition or experienced catch-up growth--all related to increased risk of adult heart problems. More information on the benefits of shorter height and lower CVD are discussed in the Indian Heart Journal, Samaras TT. 65(2013)66-71.


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    1. On 2014 Jan 25, Mones Abu-Asab commented:

      Have We Learned Anything from Tumor Heterogeneity?!

      Sullivan and Chandel wrote about an important topic in cancer biology namely the TCA aberrations and how cancer cells are able to circumvent these defects. However, the authors completely ignored the issue of heterogeneity in tumors and the challenges it poses when extrapolating from tissue culture model to in vivo tumors<sup>1-3</sup>. Additionally, the implications of heterogeneity for designing targeted therapies cannot be overemphasized since it has thus far proven to be the Achilles heel of targeted treatments of cancer<sup>1, 4</sup>. Zeroing in on mitochondrial metabolism for cancer therapy poses even bigger challenges than the targeting of cytoplasmic and nuclear metabolism. Intratumoral heterogeneity confers a selective advantage on a population of cells under many selective pressures targeting their proliferation and migration. Furthermore, the population of mitochondria within each cell is also heterogeneous—a phenomenon known as heteroplasmy that the cancer cell inherits by default. In cancer cells, there are not usually any normal mitochondria<sup>5</sup>. However, the damage of cancer mitochondria is also heterogeneous; each mitochondrion varies in the type of damage it harbors; this has thus far been confirmed by ultrastructural features. In this regard, mitochondria seem to be vulnerable organelles that vary in their sensitivity to insults; this fact extends beyond cancers to other pathologies as well such as age-related macular degeneration, bacterial septicemia, and adverse drug effects. Understanding the abnormal metabolic reactions within cancer cells is very important because it teaches us about the pathways diversity that can be generated in an allostatic environment; the new metabolic reactions confer the adaptive survival advantages upon cancer cells. Therefore, single-cell mitochondrial analyses from patients tumors are in order here if we want to reach an accurate understanding of cancer’s mitochondrial metabolism. Like other evolutionary events within any population, heterogeneity within a tumor arises by independent events within individual cells and their mitochondria. Thus, heterogeneities of tumor cells and their mitochondria permit resistance to treatment and survival in a persistently dynamic process. Fortunately, the tools for studying single cell models are here. Combining the microfluidic chip for single cell characterization<sup>6</sup> and Next Generation Sequencing (NGS), as well as other techniques, could supply us with needed data. If we are to target mitochondrial metabolism for cancer therapy, as Sullivan and Chandel have suggested, we need first to study the diversity of the mitochondrial population within a single cancer cell and determine the suitable universal targets that will not play “hide and seek” as the case has been with current targeted treatments<sup>1</sup>. Hopefully, this approach will bring us closer to applying a predictive paradigm of personalized medicine.

      References

      <sup>1</sup> Nathanson, D.A., et al., Targeted therapy resistance mediated by dynamic regulation of extrachromosomal mutant EGFR DNA. Science, 2014. 343(6166): p. 72-6.

      <sup>2</sup> Gerlinger, M., et al., Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med, 2012. 366(10): p. 883-92.

      <sup>3</sup> Horswell, S., N. Matthews, and C. Swanton, Cancer heterogeneity and "the struggle for existence": diagnostic and analytical challenges. Cancer Lett, 2013. 340(2): p. 220-6.

      <sup>4</sup> Abu-Asab, M.S., et al., Biomarkers in the age of omics: time for a systems biology approach. OMICS, 2011. 15(3): p. 105-12.

      <sup>5</sup> Davila, A.F. and P. Zamorano, Mitochondria and the evolutionary roots of cancer. Phys Biol, 2013. 10(2): p. 026008.

      <sup>6</sup> Sun, J., et al., A microfluidic platform for systems pathology: multiparameter single-cell signaling measurements of clinical brain tumor specimens. Cancer Res, 2010. 70(15): p. 6128-38.


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    1. On 2014 Apr 29, Amanda Capes-Davis commented:

      Although the authors refer to Hep2 as "larynx squamous carcinoma cells", the description is unfortunately not correct. Hep2 is cross-contaminated and is actually HeLa, from cervical carcinoma. For a list of known cross-contaminated or otherwise misidentified cell lines, see http://iclac.org/databases/cross-contaminations/.


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    1. On 2014 Jan 21, Serge Ahmed commented:

      Excellent review. The authors present the VTA as a unique brain hub that integrates a variety of humoral and neuronal signals to regulate the "drive" to eat palatable foods for pleasure, comfort and relief. They appreciate the difficulty of targeting this intricate brain region to selectively reduce the excessive pursuit of food reward without altering other life pursuits.


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    1. On 2014 Feb 08, Jenny Doust commented:

      An interesting trial which shows that moving to an absolute risk approach for cardiovascular disease prevention is probably more difficult than first thought. The study also shows two things not obvious in the abstract: 1) The problem of overprescribing to patients at low risk of a cardiovascular is a much larger problem than underprescribing to patients at high risk (in this study about 25% of the low risk patients were taking blood pressure or lipid lowering medication which was about 150 people, compared with about the same percentage of patients at high risk not taking either blood pressure or lipid lowering but this is 5 people) 2) The intervention was effective in reducing prescribing of blood pressure lowering medication to patients at low risk - see Figure 2.


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    1. On 2014 Nov 27, Guillaume Filion commented:

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


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    1. On 2013 Dec 23, Joseph Ana commented:

      I want to join Neil P. in his comments about the challenges that researchers, authors and indeed clinicians face in low Income countries when it comes to evidence based practice. Those same points came up in the last annual workshop of the Association of editors of scholarly publication in Nigeria (AESPN) in August this year. In addition, even though access and literature search online is spreading in LICs, the infrastructure is still at snail speed, relatively very expensive and unreliable because of perennial power shortage. What ever the current situation, Meyers's paper has helped to shine global light on the challenges with evidence based practice in LICs and PubMed has given us a unique opportunity to contribute to the discussion. A problem once identified is on its way to a solution. Congratulations.


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    2. On 2013 Dec 23, Neil Pakenham-Walsh commented:

      Thank you Sascha Meyer for drawing attention to the critical role of systematic reviews in low- and middle-income countries. The finding that only 5.7% of neonatal and 14.3% in neuropaediatrics Cochrane Reviews originate from middle and low-income countries is likely to be a reflection of several factors, including: 1. Most research is conducted in high-income countries, with a disproportionate focus on high-tech, high-cost, specialist medicine (and the benefits of such research are not accessible to the vast majority of the world's citizens)<br> 2. Health professionals and researchers in low-income countries often maintain 2 or 3 jobs simultaneously, and it may be difficult to invest the considerable (and often unremunerated) time to undertake a systematic review.<br> 3. Health professionals and researchers in low-income countries often may not have access to Ovid Medline, which is arguably essential for doing systematic reviews. (Ovid Medline provides more sophisticated search functions as compared with free PubMed.) Ovid regrettably has not joined HINARI, the WHO-publisher initiative that ensures free access to electronic journals, ebooks and databases in low-income countries. 4. It would be helpful if systematic reviews that are relevant to low-resources settings were made more easy to find through use of tagwords. HIFA profile: Neil Pakenham-Walsh is the coordinator of the HIFA2015 campaign and co-director of the Global Healthcare Information Network. He is also currently chair of the Dgroups Foundation (www.dgroups.info), a partnership of 18 international development organisations promoting dialogue for international health and development. He started his career as a hospital doctor in the UK, and has clinical experience as an isolated health worker in rural Ecuador and Peru. For the last 20 years he has been committed to the global challenge of improving the availability and use of relevant, reliable healthcare information for health workers and citizens in low- and middle-income countries. He is particularly interested in the potential of inclusive, transdisciplinary communication platforms to help address global health and international development challenges. He has worked with the World Health Organization, the Wellcome Trust, Medicine Digest and INASP (International Network for the Availability of Scientific Publications). He is based near Oxford, UK. www.hifa2015.org neil.pakenham-walsh AT ghi-net.org


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    1. On 2014 Feb 12, Jacob Jolij commented:

      This is an interesting and valuable contribution to the TMS-induced blindsight literature. Several studies thus far have claimed to find TMS-induced blindsight, or the ability to respond to visual stimuli that are suppressed from consciousness by stimulating the early visual cortex with TMS. The authors of this paper argue that in order to truly demonstrate unconscious processing, researchers should use bias-free measures of awareness, such as d'. I support this idea. In their discussion, the authors criticize several earlier studies that have not used such measures, including our demonstration of affective blindsight (Jolij J, 2005).

      I would like to note that we did report d' in our paper, albeit in the supplementary information. Detection sensitivity as measured with d' did drop to 0, whilst emotion discrimination sensitivity d' remained at 1.5 in the critical condition, where we presented stimuli for 16.7 ms. We therefore feel that the authors' (implicit) conclusion that our study did not provide sufficient evidence of unconscious processing because no bias-free measure was used is unwarranted.

      Interestingly, when inspecting the d'-analyses of our work I did notice that d'-values were above 0 for the 32 ms presentation time in our paper. I can therefore not exclude the possibility that there was 'weak conscious processing' in this condition. However, this would only strengthen the conclusion of our study: we claim that conscious processing block access to unconsciously processed information, something that has been found in other domains as well.


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    1. On 2014 Feb 17, David Keller commented:

      In their discussion of the harms of screening for lung cancer, Harris and colleagues discuss harms associated with earlier initiation of treatments which would have been started later or not at all without screening.

      The authors state that screening and earlier treatment delays death for only 20% of patients destined to die from lung cancer. This raises the question of why the other 80% of patients are being exposed to ineffective treatments and the associated harms. Is the problem that we are not able to identify which patients will be among the fortunate 20% to postpone death by being treated? If so, then studies should be done to learn which characteristics differentiate patients who benefit from these treatments (e.g. tumor stage, grade, patient functional status, genetic profile or other factors). Perhaps these treatments are given to the unfortunate 80% for the purpose of palliation of symptoms, with the knowledge that there will be no mortality benefit. If so, then the treatments are beneficial to the patient despite failing to prolong life.

      The authors state that the 80% of patients who are identified as having fatal cancers which cannot be treated to prolong life suffer harms from screening by virtue of their early diagnosis, in that they will have longer to live with the knowledge of their fate, causing anxiety and other psychological harms. However, other patients might strongly prefer to be informed as early as possible of their fatal diagnosis, in order to make better use of their remaining time alive and pain-free; for them, the earlier diagnosis afforded by screening is not a harm, but a benefit.

      To facilitate discussion, I respectfully request the person who found this comment "not helpful" to state their reason


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    1. On 2014 Mar 06, David Keller commented:

      Both sides now...

      I would like to learn the orthopedic surgeon's version of why he did not operate on this patient with an elevated c-reactive protein. Did the surgeon express concern about occult infection? If so, was an Infectious Diseases consultation obtained? What did the I.D. consultant recommend? Was the surgeon concerned about malignancy or auto-immune disease? Were those worries addressed fully? A surgeon who is not confident that the patient's medical condition has been optimized may be justified in postponing a non-urgent surgery.

      To facilitate discussion, I respectfully request the person who found this comment "not helpful" to state their reason


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    1. On 2014 Feb 03, David Simpson commented:

      This is an interesting approach, but I would have liked to see some attempt made to calculate false discovery rates. Something along the lines of the method reported by Qian et al. (J. Proteome Res. 2005, 4, 53–62) would have been great. Requiring a minimum Sequest XCorr score of 1.5 for identification acceptance is very permissive. A high false discovery rate would be a good explanation for the limited overlap reported in Figure 3.


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    1. On 2014 Jan 14, Amanda Capes-Davis commented:

      Just to clarify: the parental cell line, KB, is cross-contaminated and is actually HeLa. So derivatives of KB, including KB-3-1 and KCP-4, are not epidermoid carcinoma. For a database of cross-contaminated or otherwise misidentified cell lines, see http://iclac.org/databases/cross-contaminations/.


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    1. On 2013 Dec 27, guoan zhang commented:

      a good example of snp and cancer prevention,explaining gwas results is important.


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    1. On 2014 Mar 15, Valeria Fadda commented:

      Meta-analysis on novel oral anticoagulants vs warfarin for stroke prevention: re-expressing the results as risk difference

      In meta-analysis, the risk ratio (RR) and the risk difference (RD) are two commonly used outcome measures. Each of these indexes has its own advantages and disadvantages [1].

      The meta-analysis by Ruff et al. [2] adopted the outcome measure of RR. In particular, the values of pooled RR were estimated according to the random-effect model.

      We have re-analysed the results reported in Figure 1 of Ruff et al. [2] by expressing the results (event =stroke or systemic embolism) as RD instead of RR. In our re-analysis, the meta-analysis model was random-effect as implemented in the OMA software [3].

      Our results were the following (see Ruff et al.[2] for further details on these data sets): RE-LY (dabigatran vs warfarin): RD= -1.10% (95% confidence interval[CI]: -1.68% to -0.52%); ROCKET AF (rivaroxaban vs warfarin): RD= -0.52% (95%CI: -1.17% to 0.13%); ARISTOTLE (apixaban vs warfarin): RD = -0.59% (95%CI: -1.06% to -0.13%); ENGAGE AF-TIMI48 (edoxaban vs warfarin): RD = -0.58% (95%CI: -1.27% to 0.10%); overall (all new oral anticoagulants vs warfarin): RD =-0.70% (95%CI: -0.99% to -0.41%). Expressing this incremental benefit as RD is advantageous because this analysis provides an absolute estimate of the magnitude of the incremental improvement. This meta-analytical result (RD = -0.70%; 95%CI: -0.99% to -0.41%) is statistically significant, but has a small magnitude.

      To better interpret this absolute incremental benefit (i.e. a meta-analytical reduction of 0.70%) estimated from the overall analysis of these trials, a useful reference is given by the pre-specified non-inferiority margin that was used in the statistical power calculations of the pivotal trials comparing dabigatran, rivaroxaban, or apixaban with warfarin (RE-LY, ROCKET AF, and ARISTOTLE, respectively). These trials adopted a non-inferiority margin equal to half of the incremental benefit between warfarin and placebo (6 warfarin-vs-placebo trials) found in the meta-analysis by Hart et al. [4].

      As pointed out by Fadda et al. [5], while Hart and co-workers considered, as their outcome measure, only RR and not RD, a meta-analysis of the same trials based on RD can be helpful to interpret these findings. The result of this re-analysis is represented by a pooled RD for warfarin vs. placebo of -5.0% (95%CI: -7.5% to -2.4%; random-effect model). Halving this difference yields a margin, expressed as RD, of -2.5%

      References

      1. Walter SD. Choice of effect measure for epidemiological data. J Clin Epidemiol. 2000 Sep;53(9):931-9.

      2. Ruff CT, Giugliano RP, Braunwald E, Hoffman EB, Deenadayalu N, Ezekowitz MD, Camm AJ, Weitz JI, Lewis BS, Parkhomenko A, Yamashita T, Antman EM. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet. 2013 Dec 3. pii: S0140-6736(13)62343-0. doi: 10.1016/S0140-6736(13)62343-0. [Epub ahead of print]

      3. OMA software (Open Meta-Analyst version 4.16.12, Tufts University, U.S., url http://tuftscaes.org/open_meta/).

      4. Hart RG, Benavente O, McBride R, Pearce LA. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis. Ann Intern Med. 1999 Oct 5;131(7):492-501.

      5. Fadda V, Gatto R, Maratea D. Incremental benefit of warfarin over placebo in patients with atrial fibrillation (Comment), PubMed Commons, available at http://www.ncbi.nlm.nih.gov/pubmed/10507957#cm10507957_2944


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    1. On 2014 Jan 06, Paul Whiteley commented:

      As per the science and lay media interest in this research at publication, this paper potentially opens up a whole new world of investigations looking at the interplay between the gastrointestinal (GI) tract and brain in respect to lots of different behaviourally-defined conditions. That being said, mouse models of autism still have some way to go to 'mimic' the complexity that is autism (even the 'autisms' according to Whitehouse & Stanley 2013: http://www.ncbi.nlm.nih.gov/pubmed/23545020) and the often substantial risk of heightened comorbidity of various types that follow a diagnosis.

      Perhaps to some degree lost in the media translation of this research was the effect that B. fragilis administration seemed to have on gut barrier integrity (and in particular that B. fragilis "improves defects in GI barrier integrity and corrects alterations in tight junction and cytokine expression" p.1454). The notion of a triad of factors: gut barrier - gut microbiota - gut immune function is an important emerging concept in at least some autism research circles; these issues similarly being pursued in other research for example, linked to schizophrenia: Severance et al (2012) http://www.ncbi.nlm.nih.gov/pubmed/22446142

      That there may specific types of autism which carry various GI issues including those related to issues with gut flora: Williams et al (2011) http://www.ncbi.nlm.nih.gov/pubmed/21949732 is another emerging concept with some potentially important knock-on effects: Stilling et al (2013) http://www.ncbi.nlm.nih.gov/pubmed/24286462.

      Indeed, again drawing on other rodent models thought to reflect some of the complexity of autism, there is increasing understanding that GI issues may also for example, be present in the valproic acid (VPA) model as per the work from de Theije and colleagues (2013) http://www.ncbi.nlm.nih.gov/pubmed/24321212 and Kim and colleagues (2013) http://www.ncbi.nlm.nih.gov/pubmed/24386517.

      Further that those with genetic conditions which present with autistic symptoms such as 22q11.2 deletion syndrome might also experience similar GI issues including those related to intestinal permeability as per the work of Giardino and colleagues (2013) http://www.ncbi.nlm.nih.gov/pubmed/24344832 is testament to the fact that further research resources are required to probe this potentially very interesting gut-brain interface.


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    1. On 2016 Dec 08, University of Kansas School of Nursing Journal Club commented:

      Reviewers: Abigail Spare, Chelsea Gilmore, Haley Orlowski, Amy Toth, Kelley Ebeling, Nadia Grayfer, Mike Kelley, and Lauren Aks. [Team 2: KUSON Class of 2017].

      Background Introduction

      In our Development of a Microsystem Leader course, we have focused on several elements that enhance and maintain a healthy work environment. These elements include employee motivation, transformational leadership, and meaningful recognition. The article selected touched on many of these elements, and outlined the characteristics of both a transformational and authentic nurse leader from a historical perspective. This article met one of the requirements for the course as well as provided our group with a good understanding of these concepts. It also added a new perspective as to how transformational and authentic leadership was exemplified in the past. It took a closer look at both the character traits and practices of Matron Powell as a transformational and authentic leader through reported narratives. The article identified both the leadership qualities that set her apart from other nurse leaders, as well as her influence amongst the healthcare personnel and the patient population she served.

      Methods

      The article was found using CINAHL database. This qualitative paper uses secondary data analysis of existing narrative interviews done in the past guided by a natural enquiry that sought to understand the influence of Matron Powell in nursing practice. The data narrative was based on 136 nurses’ transcripts taken from the “Nurses Voices” archives at Kingston University and St. George’s at the University of London. The narrative data consisted of over 1000 face to face interviews of nurses who were trained and have worked at hospitals in London between the years of 1920 and 2000. These interviews were initially recorded, transcribed verbatim, and archived – describing many aspects of the nursing experience over the span of 80 years. Data was collected in several stages using an inductive approach that allowed the researchers to move from the reading of the complete narratives, to discovering similar trends and categories, and identifying overarching themes resulting from the leadership of Matron Powell (Harris, Bennett, Ross, 2014).

      Findings

      Matron Powell’s impact on St. George’s Hospital resulted in two overarching themes: innovation and open communication. The authors describe innovation as a “leading influence to improve standards of care” (p. 1633). This innovation began with changes driven by Matron Powell as she changed the way the health care team viewed the patient and their plan of care. She advocated for a change in hiring practices so that married women could continue to work as nurses. Matron Powell’s attitude about improving standards of care then began to spread to her staff nurses. An early kind of quality improvement project was used to study the effectiveness of team nursing by pairing an experienced nurse with an inexperienced assistant. The outcome was a success that led to the hospital wide implementation (Harris et al., 2014).

      The other theme was open communication, or the “ability to communicate at all levels” (pg. 1632). Many accounts spoke of Matron Powell’s ability to facilitate open communication with the nurses, health care personnel, and even the patients. Through communication she established a culture of mutual respect, camaraderie among the staff, and a general sense of teamwork. “Muriel Powell came in to talk to us in block and of course we all shot to our feet as one did and she said, ‘sit down we are all colleagues’” (pg. 1633). Even though her title gave her a substantial amount of power, she still saw herself as equals to her nursing colleagues. One narrative spoke of her ability to check on the patients and the care they were receiving without making the nurse feel inferior or in the wrong. Many of the interviews spoke very highly of Matron Powell, and this may contribute to some of the limitations of the research. Because all of the data studied had been from archives, there was no way to know why some former employees were interviewed and others were not. It is also limited by the lack of almost any negative comments. This hints at the idea that there may have been some bias in those who chose to participate in the interviews (Harris et al., 2014).

      Implications to Nursing

      The people interviewed told the story of Matron Muriel Powell’s career, influence, and legacy. They recognized the impact of this nurse’s leadership on nursing practice and patient outcomes. The effects of Powell’s leadership expanded beyond the lines of her profession and impacted the work environment of the whole hospital, demonstrating the need for nurse leaders. Matron Powell’s example is one to be examined and emulated in nursing practice. Her ability to lead was accompanied with vision, compassion, and friendliness, but she also stuck to her job with a firmness that many spoke of with respect (Harris et al., 2014). This can be replicated in our own nursing careers as we strive to become proficient nurses and front line leaders that will provide quality patient care in collaboration with the rest of our healthcare team.

      The history of nursing is incredibly intriguing. Being aware of our history and how it influences our nursing profession’s future helps to define the leaders that served as the pillars of our profession and draw from the characteristics that made them effective leaders and nurses. By appraising the example of Matron Powell, we can see specific qualities that made her an effective transformational leader who improved patient care, influenced and empowered nurses, contributed to the improvement of the work environment, and made a significant impact on the improvement of nursing by education at her time.

      Today there is a drive toward understanding the impact of nursing leadership on patient outcomes, worker’s satisfaction and motivation, and enhancement of a healthy work environment. The Institute of Medicine’s report on The Future of Nursing calls for nurses to occupy positions of leadership in the work environment, and contribute to the improvement of our healthcare system (IOM, 2011). Analyzing leadership in nursing from a historical perspective brings to light the results of what effective leadership can give to the improvement of nursing practice.

      References Harris, R., Bennett, J., & Ross, F. (2014). Leadership and innovation in nursing seen through a historical lens. Journal of Advanced Nursing, 70(7), 1629-1638. doi:10.1111/jan.12325

      Institute Of Medicine. (2011). Key messages of the report. The Future of Nursing: Leading Change, Advancing Health. Washington D.C.: The National Academies Press.


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    1. On 2016 Dec 05, Anne Carpenter commented:

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


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    1. On 2014 Apr 02, GREGORY CROWTHER commented:

      The following is an edited version of an entry in my personal blog (gregcrowther.com).

      Calculations of bees’ impact on strawberries’ market value

      This paper by Klatt et al. documents how strawberries benefit from pollination by bees, as opposed to pollination by wind or self-fertilization. It turns out that, on average, bee-pollinated strawberries are larger than others and also have fewer odd shapes, better color, and superior firmness. This detailed look at strawberry quality is a useful extension of past studies showing that insect pollination often boosts crop quantity (i.e., yield).

      In making their case for the agricultural importance of bees, Klatt et al. say that bee pollination accounts for at least $1.44 billion of the value of the $2.90 billion strawberry market in the European Union (EU). While I accept the take-home message that bees add a lot of value, I sure wish the authors had explained their calculations better.

      The $1.44 billion estimate is the sum of two factors: $1.12 billion in market value of the fresh berries, and another $0.32 billion corresponding to improved shelf life. Let’s consider each of these in turn.

      The figure of $1.12 billion is introduced in this section of the Results:

      "Bee pollination resulted in strawberry fruits with the highest commercial value (figure 1a). On average, bee pollination increased the commercial value per fruit by 38.6% compared with wind pollination and by 54.3% compared with self-pollination. Fruits resulting from wind pollination had a 25.5% higher market value than self-pollinated fruits. Pollination treatments were stronger than differences between varieties and thus had a main effect across all varieties (see table 2 for AICc and likelihood values). Our results suggest that altogether, bee pollination contributed 1.12 billion US$ to a total of 2.90 billion US$ made with commercial selling of 1.5 million tonnes of strawberries in the EU in 2009 [1]—but so far without consideration of the monetary value provided by enhanced shelf life (see below)."

      Figure 1 indicates that the mean value of 1000 wind-pollinated berries was ~$13.80 and the mean value of 1000 bee-pollinated berries was ~$22.40. The value of the wind-pollinated berries thus represents a ~38.6% DECREASE in value relative to the bee-pollinated berries; alternatively, the value of the bee-pollinated berries is a 62.9% INCREASE over the value of the wind-pollinated ones. A 62.9% increase takes us from $1.78 billion (the hypothetical value of strawberries only pollinated by wind) up to $2.9 billion, giving us the reported $1.12 billion boost from bees. The authors’ mention of a 38.6% increase when they meant a 38.6% decrease is not exactly a big deal, but initially made their math baffling to me and my students.

      Perhaps more significantly, the reported market values reflect the classification of strawberries into commercial grades by the first author. Ideally, the first author would have rated the berries while “blinded,” i.e., without knowing which ones came from which treatments (bees, wind, or self). The paper doesn’t mention blinding, so I fear that there was the potential for a pro-bee bias.

      Now for the $0.32 billion due to improved shelf life:

      "Bee pollination strongly impacted the shelf life of strawberries by improving their firmness (figure 2a). The firmness values of each treatment and variety were related to shelf life, measured as the number of days until 50% of fruits had been lost owing to surface and fungal decay (see the electronic supplementary material, S3). Higher firmness resulting from bee pollination potentially elongated the shelf life of strawberry fruits by about 12 h compared with wind pollination, and by more than 26 h compared with self-pollination. After 4 days in storage, only 29.4% of the wind-pollinated fruits and none self-pollinated fruit were still marketable, whereas, at the same time, 40.4% of the bee-pollinated fruits remained in a marketable condition. Thus, bee pollination accounted for a decrease of at least 11.0% in fruit losses during storage. These findings suggest that the value for bee pollination calculated in section 3a(i) has to be increased to accommodate this impact on the shelf life of strawberries. Hence, pollination benefits on the shelf life of strawberries potentially added another 0.32 billion US$ to the commercial value of strawberry pollination."

      Here it’s clear that the authors got $0.32 billion by multiplying 11% by $2.9 billion. What’s less clear is the meaning of “storage” (did the unspecified storage conditions simulate those typically used by strawberry farmers/distributors/vendors?) and the reason(s) why a duration of 4 days was used in this calculation (is this a typical time between harvesting and consumers’ purchases?).

      Such details aside, here’s a more general question relevant to both components of the $1.44 billion estimate. To what extent are commercial strawberries pollinated by bees in the wild?

      The calculations assumes that the study site — a field in Germany — is representative of most or all commercial strawberry farms in Europe. The study site was intentionally set up near well-established bee hives and nests; are most or all European strawberry farms situated similarly? Perhaps the answer is obvious to people with relevant expertise, but the paper doesn’t say. It’s worth noting that if only half of commercial strawberry fields enjoy bee pollination, the estimates of bees’ economic impact would need to be cut in half.

      Considering that the paper trumpets a billion-dollar claim in its abstract, more information on the calculations underlying that claim would have been helpful.


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    1. On 2014 Jan 24, Tom Kindlon commented:

      References:

      [1]. Crawley E, Mills N, Beasant L, Johnson D, Collin SM, Deans Z, White K, Montgomery A. The feasibility and acceptability of conducting a trial of specialist medical care and the Lightning Process in children with chronic fatigue syndrome: feasibility randomized controlled trial (SMILE study). Trials. 2013 Dec 5;14:415.

      [2]. Specialist Medical Intervention & Lightning Evaluation: Comparing specialist medical care with specialist medical care plus the Lightning Process for Chronic Fatigue Syndrome or Myalgic Encephalopathy (CFS/ME) ISRCTN81456207 http://www.controlled-trials.com/ISRCTN81456207 (last accessed: December 20, 2013)

      [3]. The Lightning Process Didn't Work For me. http://sallycats.hubpages.com/hub/The-Lightning-Process-Didnt-Work-For-me (last accessed: December 20, 2013)

      [4]. LP & ME What is the truth Identities withheld. http://groups.yahoo.com/neo/groups/MERSC-Viewpoint/conversations/topics/840?var=1 (last accessed: December 20, 2013)

      [5]. The Skeptic's Dictionary, From Abracadabra to Zombies, Phil Parker Lightning Process http://www.skepdic.com/lightningprocess.html (last accessed: December 20, 2013)

      [6]. Kewley AJ. Does Cognitive Behavioral Therapy or Graded Exercise Therapy Reduce Disability in Chronic Fatigue Syndrome Patients? Objective Measures Are Necessary. Clinical Psychology: Science and Practice 2013 20:321-322.

      [7]. Wiborg JF, Knoop H, Stulemeijer M, Prins JB, Bleijenberg, G. (2010). How does cognitive behaviour therapy reduce fatigue in patients with chronic fatigue syndrome? The role of physical activity. Psychological Medicine, 40(8), 1281–1287.

      [8]. White PD, Goldsmith KA, Johnson AL, Potts L, Walwyn R, DeCesare JC, Baber HL, Burgess M, Clark LV, Cox DL, Bavinton J, Angus BJ, Murphy G, Murphy M, O'Dowd H, Wilks D, McCrone P, Chalder T, Sharpe M; PACE trial management group. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet. 2011 Mar 5;377(9768):823-36

      [9]. Mason A. CBT and GET did not significantly reduce employment losses, overall service costs, welfare benefits or other financial payments. http://www.plosone.org/annotation/listThread.action?root=52797 (last accessed: December 20, 2013)

      [10]. Newton JL, Pairman J, Hallsworth K, Moore S, Plötz T, Trenell MI. Physical activity intensity but not sedentary activity is reduced in chronic fatigue syndrome and is associated with autonomic regulation. QJM. 2011 Aug;104(8):681-7

      [11]. Cockshell SJ, Mathias JL. Cognitive functioning in chronic fatigue syndrome: a meta-analysis. Psychol Med. 2010 Aug;40(8):1253-67.

      [12]. Loge JH, Ekeberg O, Kaasa S. Fatigue in the general Norwegian population: normative data and associations. J Psychosom Res 1998; 45:53-65.

      [13]. van Kessel K, Moss-Morris R, Willoughby E, Chalder T, Johnson MH, Robinson E. A randomized controlled trial of cognitive behavior therapy for multiple sclerosis fatigue. Psychosom Med. 2008 70:205-13

      [14]. Stouten B. Identification of ambiguities in the 1994 chronic fatigue syndrome research case definition and recommendations for resolution. BMC Health Serv Res. 2005 May 13;5:37.

      [15]. Goudsmit, EM., Stouten, B and Howes, S. (2008). Fatigue in myalgic encephalomyelitis. Bulletin of the IACFS/ME, 16(3), 3-10.

      [16]. Chalder T, Berelowitz G, Pawlikowska T, Watts L, Wessely S, Wright D, Wallace EP. Development of a fatigue scale. J Psychosom Res. 1993;37(2):147-53.


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    2. On 2014 Jan 24, Tom Kindlon commented:

      The validity of using subjective outcome measures as primary outcomes is questionable in such a trial

      Crawley and colleagues suggest dropping school attendance as a primary outcome from the full study, and replacing it with self-report outcomes "such as the SF-36 or the Chalder Fatigue Scale" and using "school attendance as a secondary outcome"(1). And indeed, this is what they have done with the full study which has two primary outcome measures: "Chalder Fatigue Scale at 6 months" and "SF 36 physical function short form at 6 months"(2). I question the wisdom of using self-report measures as primary outcomes for such a trial.

      The authors do not give much information about the details of the Lightning Process (they do mention it is "developed from osteopathy, life coaching and Neuro-linguistic programming (NLP))" but here are some descriptions from other sources (individuals who have undertaken a course) (note these are not descriptions from participants from the trial itself):

      (a) "It felt very naughty but I whispered to one of the woman (sic) sitting next to me 'how are you, is this working for you?'. She was reluctant to answer, to say anything but that she was doing well would be to go against the process because that is a negative thought. It was pointless asking really. Still I wanted it to work, but I was starting to worry about the fact that I was not only not feeling any better the effort of doing the course, not getting my normal rest was making me feel worse. But these were negative thoughts. I started to ruthlessly suppress them like I had been shown." (3)

      (b) “They tell you that you're not allowed to say that you're ill anymore or that you have any symptoms. They force you to ignore the symptoms because they say that the symptoms don't really exist. They force you to do activities even though it's making you really ill, but you're not allowed to say so.” (4)

      Another, more thorough, description can be found on the Skeptic's Dictionary website(5).

      I have seen many similar descriptions to these in discussions in many private fora. Here's one example: "So the first step in the process is to recognise when you’re in THE PIT. Maybe sometimes or all the time. It’s important to recognise what you say to yourself as you go into the pit. For example “I’m feeling really ill this morning”, “if I do this, then I’ll get exhausted”, “last time I did this I got really ill for days”, “I can never eat this” etc. This takes some practise but we were assured that you always say something in your head as you go into the pit. As soon as you spot one of your “pit” phrases you want to STOP yourself right away. So imagine you’re on the mat and you start to say “I feel really ill today”. Before you get to the end of this phrase you will interrupt with a very firm, loud “STOP” (yes, talk out loud to yourself!) and jump into the STOP position as described above. So you jump outside the mat, to your left. Now you’re here you have interrupted your bad thought patterns."

      In essence when one is doing the lightning process, both during the three days training and after, you are to declare yourself well. You are not to say (or think) you have symptoms and you are not to say (or think) you have limitations. In other words, patients are 'trained' to dismiss and deny their symptoms and illness. Patients are instructed not to “do” ME or CFS anymore. In such a scenario, subjective reports from the patient are no longer reliable. Hence the need for objective measures in such trials.

      To a lesser extent, it can also be argued that subjective measures are not ideal for all participants in this trial, including the control group. With graded activity-oriented therapies, which all the participants undertake (1), there may be response bias (6). This was seen in a review of three Dutch trials of graded activity-oriented cognitive behaviour therapy (CBT) for CFS. While the CBT participants reported improvements in fatigue (and also SF-36 physical functioning although that was not measured in all of the trials), no improvements in objectively measured activity were reported over the control group(7). Similarly a mediation analysis showed changes in physical activity were not related to changes in fatigue. A similar effect with CBT could be in PACE Trial, the largest such trial in the CFS field(8).

      Although participants who had undergone CBT reported improvements in scores on both the Chalder Fatigue Scale and SF 36 physical function subscale, no improvements were reported in the six minute walking distance compared to the group who had undergone no additional individual therapy (all participants had specialist medical care). Similarly, CBT did not significantly reduce employment losses, overall service costs, welfare benefits or other financial payments(9).

      Objective measures of physical activity are one type of objective measurement that could be employed. This could be used not just to measure the total quantity of activity but also to check the intensity of activity as people with ME/CFS may perform lower levels of more intensive activity(10). Tests of neuropsychological performance could also be used, given the impairments that have previously been reported(11). If necessary, a webpage could be created that could be accessed remotely.

      One particular problem with the 0-33 scoring method for the Chalder fatigue scale is that patients can give unusually low, or artificially good, scores.

      The scale consists of 11 questions. For each question (e.g. "Do you have less strength in your muscles?"), patients have to say whether they have the symptom: "Less than usual" (score of 0); "No more than usual" (score of 1); "More than usual" (score of 2) or “Much more than usual” (score of 3). So healthy people should score around 11 and indeed in the only population study I can recall that gave data for a healthy (no disease/current health problem) group, the mean was 11.2 (12).

      However, some unusual scoring is possible. This was seen in a multiple sclerosis trial, of a similar CBT intervention to the graded activity-oriented CBT used in CFS (13). Participants in the CBT leg of the trial entered with a Chalder fatigue scale score of mean (sd): 20.94 (4.25). Two months after therapy, the mean (sd) was 7.90 (4.34) i.e. this groups suffering from multiple sclerosis had a much better score than one sees in healthy people!

      Such averages could also hide non-responders or, possibly more seriously, people who deteriorated, depending on how the data was analysed. For example, if two participant deteriorated and ended up with a Chalder fatigue scale scores of 32, but 8 others had an average score of 2, this would give an average score of 8, again giving the impression that this group had less fatigue than healthy people. This issue of supranormal scoring with likert scoring (0-3) can be dealt with by utilising the commonly used bimodal scoring method for the Chalder fatigue scale. However, both it and likert scoring suffer from ceiling effects in CFS populations so other scales are likely preferable (14,15). If the Chalder fatigue scale is used, the original developers of the scale suggested, based on their analyses, that "it would probably be more useful to have two scores, one for physical fatigue and one for mental fatigue"(16).

      (Message has reached word limit - references are reply)

      Competing interests: I am the Assistant Chairperson and Information Officer for the Irish ME/CFS Association. All my work for the Association is voluntary.


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    1. On 2016 Aug 23, Ben Goldacre commented:

      This trial has the wrong trial registry ID associated with it on PubMed: both in the XML on PubMed, and in the originating journal article. The ID given is NCT009176. We believe the correct ID, which we have found by hand searching, is NCT00917631.

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

      Many thanks,

      Jessica Fleminger, Ben Goldacre*

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

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


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    1. On 2014 Jun 17, Pavel Baranov commented:

      This PubMed record is wrong. We informed NLM on the Dec 6, 2013.


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    1. On 2014 Nov 27, Jürgen Hänggi commented:

      Dear community

      a study recently published by our group questioned the sex effects reported here. We also conducted two very interesting between sex comparisons in order to tract down whether increased interhemispheric connectivity in women and increased intrahemispheric connectivity in men might be confounded by differences in brain size. One comparison is called "extreme group comparison" and compared small female brains with large male brains. This comparison revealed that the effect under question became much stronger because the difference in brain size between these two groups became stronger as well. The other comparison has been called "control group comparison" and used men with small brains who were compared with women with large brains. This comparison shows that the "apparent sex effect" disappeared because these two groups did not differ in brain size any longer. Although both comparisons involved women and men, the first comparison showed a positive result, whereas the second comparison provided a negative finding. These comparisons alone provide strong evidence that clearly contradicts "increased interhemispheric connectivity in women and increased intrahemispheric connectivity in men". The hypothesis of neuronal interconnectivity as a function of brain size represents a general and fundamental organization principle of the human connectome that is sex-independent and that might be applied also to non-human animals as suggested by our cross-species comparison.

      Our study can be found here

      http://journal.frontiersin.org/Journal/10.3389/fnhum.2014.00915/full

      Further discussion with respect to the effect size as well as comparisons of small, medium and large brain size groups and a network-based statistical analysis similar to the analysis conducted in the study under question can be found here

      http://www.juergenhaenggi.ch/index.php?option=com_content&view=category&layout=blog&id=58&Itemid=136

      A critical discussion of the problem of overpowered studies and its associated "trivial effects" can be found here

      http://www.sciencedirect.com/science/article/pii/S1053811912003990


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    2. On 2014 Nov 01, Jürgen Hänggi commented:

      None


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    3. On 2014 May 29, Gerard Ridgway commented:

      This paper reports no effect sizes. An illustrative example based on converting from t and degrees of freedom to an estimate of Cohen's d can be found here: http://figshare.com/articles/Illustrative_effect_sizes_for_sex_differences/866802


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    4. On 2013 Dec 05, Allison Stelling commented:

      This paper has generated quite a lot of commentary in the press. Here's a sampling of some of the coverage thus far, mostly from the discussion occurring on PubPeer at https://pubpeer.com/publications/3CFCCE950D22E7560E9B07C8B63979:

      https://theconversation.com/are-men-better-wired-to-read-maps-or-is-it-a-tired-clich-21096

      https://theconversation.com/new-insights-into-gendered-brain-wiring-or-a-perfect-case-study-in-neurosexism-21083

      (These links are in Peer 0's post, please see: https://pubpeer.com/publications/3CFCCE950D22E7560E9B07C8B63979/comments/4381)

      I personally don't buy fMRI in general to measure anything other than water nuclei in tissues. The physical correlates for "activity" seem murky at best and I tend to take any interpretation other than 'bulk tumor mass' with a grain of salt.


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    1. On 2013 Dec 09, John Cannell commented:

      The authors report that immune system dysregulation is common in autism spectrum disorder (ASD). The question is why does this immune dysregulation occur and what has caused such dysregulation to skyrocket in recent decades?

      Vitamin D deficiency produces very similar immune dysregulation to what the authors reported.

      Prietl B, 2013

      Kamen DL, 2010

      Yang CY, 2013

      Baeke F, 2010

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

      Gong ZL, 2014

      Meguid NA, 2010

      Mostafa GA, 2012

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

      DeLuca GC, 2013

      Eyles DW, 2013

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

      Cannell JJ, 2010

      Cannell JJ, 2008

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

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

      Kočovská E, 2012

      As the authors point out, immune dysregulation is common in ASD. The question is why now and what is causing it?

      John J Cannell, MD

      Vitamin D Council

      http://www.vitamindcouncil.org


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    1. On 2017 Mar 25, Anthony Gitter commented:

      An open source implementation of the Multi-PCSF algorithm presented in this manuscript is now available under the BSD-2-Clause license. https://github.com/agitter/MultiPCSF contains the latest version, and https://doi.org/10.5281/zenodo.438043 contains an archived copy of the initial release.


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    1. On 2014 Mar 06, David Keller commented:

      Is that a T-wave inversion, or are you just glad to see me?

      DEXA bone densitometry causes a small risk of harm due to ionizing radiation exposure, so I adhere to the recommended guidelines. The USPSTF recommends that routine DEXA screening begin at age 60 for women at increased risk for osteoporotic fractures, and at age 65 for women at average risk. I think your internist jumped the gun by ordering your first scan at age 50. On the other hand, I support her decision to obtain an "unnecessary" ECG, since this test causes no direct harm to the patient and is inexpensive. If the patient has a false-positive abnormality on ECG, it is better to learn about it when she is asymptomatic, rather than in the ER when she is presenting with an acute aortic dissection.

      To facilitate discussion, I respectfully request the person who found this comment "not helpful" to state their reason


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    1. On 2014 Aug 13, Jim Woodgett commented:

      From the Discussion: "Finally, although numerous specific inhibitors for GSK3β were tested, we cannot entirely rule out that nonspecific GSK3α inhibition may have partly contributed to the observed biological effect. However, the relative contribution of GSK3α in DM-induced EPC dysfunction is unlikely to be significant but remains to be elucidated."

      None of the tested inhibitors (AR-A014418, CHIR98014, 6-bromoindirubin-3-oxime, GSK peptide inhibitor or LiCl) are specific for GSK-3beta (over GSK-3alpha), these inhibitors fail to show any degree of isoform specificity and are essentially equipotent in blocking each. GSK-3alpha has been implicated in insulin signalling (e.g. PMID 18781825). It isn't clear whether GSK-3alpha activity is increased in diabetic patients but the mechanisms by which the beta isoform are activated (reduced serine 9 phosphorylation) also act on the alpha isoform (serine 21). It would be interesting to test this directly. As it stands, the conclusions of this current analysis are entirely consistent with combined roles for both isoforms - especially given that the two kinases are entirely redundant with respect to Wnt signalling and are expressed at similar levels in endothelium.

      It's also worth noting that GSK-3 is known to regulate protein translation as well as transcription (via eiF2B, TSC1 and other mechanisms).


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    1. On 2017 Oct 31, Morten Oksvold commented:

      Please note that this article contains unreliable data, and should not be cited. The central ethical review board in Sweden found research misconduct in six articles by Macchiarini, including this one.

      Please see the report from the Central ethical review board in Sweden: http://www.epn.se/media/2516/pressmeddelande-o-12-2016eng.pdf https://drive.google.com/file/d/0By2HqPi4t2RbYzZweVRieVVMajhJQUM0cmFMekwyRVJTUFVr/view

      This information was provided by Leonid Schneider (forbetterscience.com).


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    1. On 2015 Sep 25, Amanda Capes-Davis commented:

      The International Cell Line Authentication Committee (ICLAC) has just released a case study on RGC-5 at http://iclac.org/case-studies/rgc-5/.

      The RGC-5 cell line was originally thought to be established from rat retinal ganglion. However, a number of journal articles have now shown that RGC-5 is misidentified and is actually 661W, a mouse photoreceptor cell line.

      Eye research journals have responded to this problem by setting policies that raise awareness regarding RGC-5 and the broader problem of misidentified cell lines. Food research is another important area where cell line models are widely used and misidentified cell lines are commonly encountered. A list of known misidentified cell lines is available at http://iclac.org/databases/cross-contaminations/.


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    1. On 2013 Dec 04, Hilda Bastian commented:

      This is a non-systematic review with unclear inclusion criteria, limited search strategy, and unclear methods for selection of studies. It includes reviews, primary studies and some animal studies. Important randomized trials in the area of dietary prevention of colorectal cancer have not been included. The conclusions of this paper are more positive about the potential for dietary prevention of colorectal cancer than conclusions from the National Cancer Institute.

      Reviews of randomized trials not considered in this paper include: randomized trials have not shown a benefit of dietary or supplemented fiber (Asano T, 2002); and a combined analysis of 3 large randomized trials showing no clear effect of folate supplementation (Figueiredo JC, 2011).

      The authors point out that their conclusions are largely based on non-randomized studies. Moorthy D, 2013 shows the extent to which results from epidemiological studies of nutrition can vary from randomized trial results. This blog post addresses aspects of the history of diet and the development of colorectal cancer.


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    1. On 2013 Dec 06, John Cannell commented:

      I congratulate the authors on an important article.

      It is of intrest that whatever is causing the latitudinal differences in incidence rate in schizophrenia is so strong that it obviates the role of all known modern public health, early diagnosis, and modern treatment methods for schizophrenia.

      Kinney DK, 2009

      John Cannell, MD

      Vitamin D Council

      http://www.vitamindcouncil.org/


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    1. On 2014 Mar 05, David Reardon commented:

      Dear Dr. Räisänen,

      I recently read your paper on fear of childbirth as predictive of post-partum depression.

      I have a couple questions and observations.

      First, while you did examine history of pregnancy loss, including both miscarriage and termination, it seems that additional segregation of the findings relative to exposure to pregnancy loss would be very beneficial.

      For example, in Table 2, you found higher rates of adverse perinatal outcomes associated with postpartum depression. The confounding factor here is that a history of pregnancy loss is itself a predictor of adverse perinatal outcomes. For example, the Finland data set has shown that induced abortion is associated with most of the adverse outcomes you list, and that there is a dose effect, with more abortions associated with more problems. (See: Birth outcomes after induced abortion: a nationwide register-based study of first births in Finland. Klemetti R, Gissler M, Niinimäki M, Hemminki E. Hum Reprod. 2012 Nov;27(11):3315-20. doi: 10.1093/humrep/des294. Epub 2012 Aug 29.)

      With this information in mind, it would be very helpful if you could provide an expanded version of Table 2, showing 8 columns rather than 4, adding as "A history of pregnancy loss" or perhaps "A history of termination" as another breakdown. (To check for a dose effect, you might also consider a breakdown with "Number of terminations" with columns for 0, 1, 2 or more.)

      Regarding your "fear of childbirth" variable, it would also be most helpful if you provided an analysis of whether women treated who had a fear of childbirth were significantly more likely to have had one or multiple prior pregnancy losses (miscarriage or induced abortion).

      Based on clinical experience and self reports, it appears that women who have had a history of pregnancy loss may be significantly more likely to have fears surrounding childbirth. For example, some women with unresolved issues related to a past abortion report intense fear that they will be "punished" by God with an adverse outcome of a subsequent wanted pregnancy. While I know this to be true in isolated cases, I do not know of any studies which have examined whether this reported association between pregnancy loss and fears regarding childbirth are statistically significant. It appears you data could shed light on this question.

      Thank you for any additional information you can provide.


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    1. On 2014 Jan 07, Stanley Lazic commented:

      An excellent point and discussed in Lazic SE, 2013 and references therein.

      Also, it is not clear why the dorsal and medial glomerulus have different n for what appears to be same animals. These discrepancies occur for all histological data (e.g. Fig4 panel (i) has n=23 and n=16 for dorsal while panel (j) has n=16 and n=19 for ventral).


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    2. On 2013 Dec 03, Gonzalo Otazu commented:

      The statistical tests in the paper, both for the behavioral measurements as well as for the size of the M71 glomeruli , use as n, number of samples, the number of F1 and F2 individuals. This would be fine if the individuals were actually independent samples. However, they arise from a presumably small number of FO males. The numbers of FO males are not given in the paper. This is a major concern given that there is a lot of variability in the levels of expression of olfactory receptors in these mice that might be inheritable. As an example, for Figure 1a, the authors compared 16 F1-Ace-C57 mice with 13 F1-Home-C57 mice and find a p value of 0.043, with 27 degrees of freedom . But these 29 mice could have been originated from a very small number of FO mice. The actual n that should be used for the statistics in the whole paper are not the individual number of F1 or F2, but it should be the number of founding F0, for both groups. So the actual p values are larger than reported. Without the information about the size of the F0 populations used in each figure panel, it is hard to interpret the results.


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    1. On 2014 Mar 30, M Felix Freshwater commented:

      I would appreciate the authors answering these questions: 1. They wrote: "The study protocol conformed to the ethical guidelines of the Declaration of Helsinki." Can they share with readers the name of the institutional whose review board approved the study? 2. Can they share with readers the trial registry and registration number for this study, which is a requirement of the Declaration of Helsinki? 3. Can they describe their randomization method? 4. Figure 1 is described as a preoperative view of the TOCTR, yet there are obvious suture marks and a scar that extends proximal to the wrist crease. Can the authors explain this and tell readers how many patients in each group were having repeat carpal tunnel surgery as the patient in figure 1 appears to have had? 5. Can the authors explain why the median nerve is shown as being lifted out of the wound in figure 2? Is this a routine part of their TOCTR procedure? If so this stretching of the nerve could be the etiology of the differences in their results. 6. They describe their MACTR incisions as being 2 cm. long while they describe their TOCTR incisions as “extended 2-4 cm proximally towards the wrist crease”. Figure 3 shows that the TOCTR incision extends an additional 2-4 cm. proximal to the wrist crease. Since both types of incisions began at Kaplan’s line, it appears that what they were comparing were the pain and appearance of a 2 cm scar vs. the pain and appearance of a 4-8 cm total length scar. I think that their findings were a foregone conclusion. What was the purpose of studying pain and appearance in two groups of scars whose length was twice to four times different?


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    1. On 2013 Dec 09, John Cannell commented:

      The authors report that immune system dysregulation is common in autism spectrum disorder (ASD). The question is why does this immune dysregulation occur and what has caused such dysregulation to skyrocket in recent decades?

      Vitamin D deficiency produces very similar immune dysregulation to what the authors reported.

      Prietl B, 2013

      Kamen DL, 2010

      Yang CY, 2013

      Baeke F, 2010

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

      Gong ZL, 2014

      Meguid NA, 2010

      Mostafa GA, 2012

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

      DeLuca GC, 2013

      Eyles DW, 2013

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

      Cannell JJ, 2010

      Cannell JJ, 2008

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

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

      Kočovská E, 2012

      As the authors point out, immune dysregulation is common in ASD. The question is why now and what is causing it?

      John J Cannell, MD

      Vitamin D Council

      http://www.vitamindcouncil.org


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    1. On 2013 Dec 12, Ron Burk commented:

      I wonder if the study had controlled for light exposure if it would have found what separated those who experienced benefits from those who don't. My suspicion is that AIs (whose side-effects closely mimic RA) have the same (poorly understood) relation to melatonin as RA does, and they are effectively inducing a form of RA. My hypothesis is that decreased estrogen in the pineal gland decreases the effectiveness of light-induced melatonin suppression, leading to auto-immune effects, providing a unified explanation for the joint pain of AIs and perimenopause. The solution being to get the patient's eyes into bright outdoor sunlight for as many hours each day as possible and try to restore a normal melatonin cycle. Burk R, 2008


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    1. On 2014 Jul 13, David Keller commented:

      I concur that the USPSTF "got it wrong" with their blanket recommendation against PSA screening, and I would add that I also disagree with their recommendation against carotid artery screening, and their inconclusive report regarding the evidence that multivitamins reduce cancer rates in men.

      The USPSTF is tasked with producing or updating a large number of recommendations each year on a wide variety of topics; it is difficult to imagine how one committee of part-time volunteer primary care physicians can provide definitive answers to such a spectrum of difficult questions. Perhaps this is why many clinicians disagree with these recommendations and do not adhere to them.

      Click the following link for a rebuttal of the USPSTF blanket recommendation against PSA screening:

      http://www.ncbi.nlm.nih.gov/pubmed/24394929#cm24394929_2707

      Click the following link for a rebuttal of the USPSTF recommendation against carotid artery screening for asymptomatic persons:

      http://www.ncbi.nlm.nih.gov/pubmed/25003392#cm25003392_5218

      Click the following link to read why the USPSTF should have recommended that men consider taking a multivitamin supplement:

      http://www.ncbi.nlm.nih.gov/pubmed/24887626#cm24887626_4774

      The following link argues against the USPSTF's condemnation of breast self-examination:

      http://www.ncbi.nlm.nih.gov/pubmed/19920272#cm19920272_5419

      Rather than expecting one committee to be able to arrive at the correct answer on such a wide variety of topics, it would make more sense to have several separate committees, each with a different focus of expertise. For example, one committee should be devoted solely to the issue of prostate cancer screening, and (unlike the current USPSTF) it should include urologists, which seems like an obvious necessity. There should be another separate committee devoted to the question of screening for asymptomatic atherosclerosis, with carotid ultrasound or otherwise, and it could include experts on atherosclerosis.

      The many varied questions addressed by the USPSTF demand a greater degree of focus and specialization than any one committee can realistically provide, particularly since they serve as part-time volunteers.


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    1. On 2014 Jan 24, guoan zhang commented:

      this study showed hypercholesterolemia could promote ER-positive breast cancer cells growth and metastasis. and suggested new treatment for breast cancer patients with hypercholesterolemia. it seems that after breast cancer emerge,hypercholesterolemia enhanced the survival of ER-positive breast cancer colony, and this maybe one reason for the link between hypercholesterolimia and er-positve breast cancer.


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    1. On 2014 Jul 02, Valeria Fadda commented:

      Gastrointestinal adverse events of bisphosphonates

      Valeria Fadda HTA Unit, Area Vasta Centro Toscana, Regional Health System, Via San Salvi 12, 50100 Firenze (Italy)

      In the paper by Tadrous et al. [1], the gastrointestinal safety of bisphosphonates in primary osteoporosis has been assessed. In particular, the safety end-point has been compared for individual agents (i.e. alendronate, zoledronate, risedronate or etidronate) versus placebo; some head-to-head comparisons between active agents were studied too. The original analysis by Tadrous et al. expressed these outcomes according to the outcome measure of odds-ratio (OR). However, since the outcome measure of risk difference (RD) is preferable for analyses aimed at equivalence testing, we have repeated the meta-analysis by Tadrous using RD in substitution for OR. Our results are shown in Figure S1.


      Figure S1. Standard pair-wise meta-analysis of the incidence of gastrointestinal adverse events: Forest plot of risk differences for a series of comparisons involving alendronate, risedronate, etidronate, zoledronate, and placebo (data of 103 study arms from 51 randomized trials). The horizontal bars indicate the two-sided 95% confidence interval for RD of individual trials (solid squares) or of subgroup meta-analysis (yellow diamonds). Abbreviations: AE, adverse event; RD, risk difference; P, placebo; A, alendronate; R, risedronate; E, etidronate; Z, zoledronate; Ev, events; Trt, number of patients in the treatment groups; Ctrl, number of patients in the control groups.

      This figure is available at url http://www.osservatorioinnovazione.net/papers/figures1fromtadrous.jpg


      References

      1. Tadrous M, Wong L, Mamdani MM, Juurlink DN, Krahn MD, Lévesque LE, Cadarette SM. Comparative gastrointestinal safety of bisphosphonates in primary osteoporosis: a network meta-analysis. Osteoporos Int. 2014 Apr;25(4):1225-35. doi: 10.1007/s00198-013-2576-2


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    1. On 2014 Feb 13, masahito ikawa commented:

      pCAG-EGxxFP, pCAG-EGxxFP-Cetn1, and pX330-Cetn1/1 plasmids are available from Addgene (http://www.addgene.org/Masahito_Ikawa/).


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    1. On 2015 Sep 30, John Quackenbush commented:

      My colleagues and I have conducted an expanded analysis of the CCLE and CGP/GDSC data, including additional data that these groups have released since 2012. Our goal in doing this analysis was to address some questions that people had raised about how we measured correlation between reported drug response. For example, one would expect highly targeted therapies may have many non-responsive cell lines representing phenotypic noise where one might not expect correlation. Could smarter filtering of the phenotype data uncover missed correlations? Would binary characterization of the cell lines as either responsive or nonresponsive improve the observed correlation? Would other correlations metrics better measure drug response correlations? The results largely support our initial findings of a general inconsistency and suggest the need for standardization of how drug response is measured.

      Our updated analysis is available on the bioRXiv. We welcome comments as we move this work to publication.


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    1. On 2014 Mar 04, David Keller commented:

      The quantum treatment discontinuity at 190 mg/dL lacks biological plausibility

      The case of the 57-year-old white man in Table 2 illustrates a peculiar aspect of the new lipid treatment guidelines: his recommended treatment is high-intensity statin therapy if his LDL is greater than or equal to 190 mg/dL, but if his LDL is below 190 mg/dL, then no treatment is recommended. It seems odd that an LDL of 189 mg/dL is not considered high enough to warrant any statin therapy at all, but if his LDL is 1 point higher, it triggers the need for maximum-dose statin therapy. The true variation of cardiovascular risk with LDL seems unlikely to exhibit this sort of quantum jump discontinuity. Cardiovascular risk seems more likely to be a smooth, continuous and monotonically increasing function of LDL, and amelioration of this risk would therefore justify a range of statin doses, starting with low dose statins to treat mild LDL elevations, medium dose statins to treat moderate LDL elevations, and high dose statins to treat severely elevated LDL levels of 190 mg/dL or higher. This is how clinicians have historically treated patients for hyperlipidemia. If the data does not exist to support this range of treatments, it may be because mild and moderate LDL elevations do not cause enough adverse events fast enough to generate statistically significant results over the course of a clinical trial for this category of patient. Guideline-issuing organizations should revisit evidence-based guidelines which include recommendations that lack biological plausibility. Since biological variables are generally continuous, while data points from major clinical trials are discrete, interpolation and curve-fitting should be permissible in evidence-based guidelines, in order to avoid the kind of quantum discontinuity encountered in this case.

      To facilitate discussion, I respectfully request the person who found this comment "not helpful" to state their reason


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    2. On 2014 Feb 23, David Keller commented:

      None


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    3. On 2014 Feb 23, David Keller commented:

      None


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    4. On 2014 Feb 18, David Keller commented:

      Error in Table 2, Case Examples: "White man with high cholesterol"

      In Table 2 of this review of the 2013 ACC-AHA cholesterol treatment guidelines, statin therapy was not recommended for a 57-year-old white man with total cholesterol (TC) of 255 mg/dL, HDL cholesterol of 45 mg/dL, no triglyceride (TG) or LDL levels specified, and no other coronary risk factors or contraindications to statin therapy specified. The new guidelines recommend high-intensity statin therapy for this man if his LDL cholesterol level is at least 190 mg/dL, which is entirely possible. The Friedewald equation, valid for TG levels under 200 mg/dL, states that TC = HDL + LDL + TG/5 (1). By plugging his HDL and total cholesterol levels into the Friedewald equation, we find that if his triglyceride level is 100 mg/dL or less, his LDL cholesterol would be 190 mg/dL or higher. The new guidelines recommend high-intensity statin therapy for primary prevention in patients whose LDL is at least 190 mg/dL, barring contraindications which this patient is not said to have. Since it cannot be determined whether his LDL is higher or lower than the 190 mg/dL threshold for treatment, we cannot determine whether he requires statin therapy with the information given. This case illustrates that the new evidence-based guidelines emphasize the paramount role of LDL cholesterol levels in treatment decisions, and that statins are the treatment of choice for preventing cardiovascular events. Table 2 presents only HDL and total cholesterol levels for each patient, which was formerly sufficient information when treatment decisions were based on the TC/HDL ratio, but not under the new guidelines.

      1. Fukuyama N et al. Validation of the Friedewald Equation for Evaluation of Plasma LDL-Cholesterol. J Clin Biochem Nutr. 2008 July; 43(1): 1–5.

      To facilitate discussion, I respectfully request the person who found this comment "not helpful" to state their reason


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    1. On 2013 Nov 28, Ryan Madanick commented:

      Phenomenal piece, and thank you for also citing the infamous "Parachute" article.


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    1. On 2013 Dec 08, George McNamara commented:

      Brief comments (pretty obvious I was not one of the reviewers):

      • metal-dielectric coated is similar to metal enhanced fluorescence ... 164 papers in PubMed for http://www.ncbi.nlm.nih.gov/pubmed/?term="metal+enhanced+fluorescence" of which 28 mention distance http://www.ncbi.nlm.nih.gov/pubmed/?term="metal+enhanced+fluorescence"+distance (search on Dec 8, 2013). I was surprised at the lack of references to Lakowicz and colleagues, who have published extensively in this field: 109 references for metal enhanced fluorescence lakowicz

      • The MEF/RDE (metal enhanced fluorescence / radiative decay engineering ... same thing, different acronyms) depends on DISTANCE and "intrinsic" quantum yield. Lakowicz MEF/RDE papers show biggest benefit for fluorophores with low intrinsic QY, like Rose bengal (and possibly flavins as in Fu). Elsayad used Alexa Fluor 488 (QY ~0.92 in water), so could have had a lot bigger enhancement factors by using Lakowicz-style fluorophores. Payoff: molecules diffusing in solution away from the silver islands would emit very little (though may generate copious oxygen radicals), so minimal background (re: Le Moal).

      • for a 'spectrally" titled paper, their figures had almost free of spectral results ... their Fig 4c X-axis was 21 data points over 520-540 nm (21 data points is 1 nm interval, which does not make sense if this was Zeiss LSM710 Quasar (confocal), whose smallest interval is 1.9 nm - see last paragraph of methods). Also, would have been better to see more emission spectra range (ex. to 560 nm) for Alexa Fluor 488. .

      • Fig 4cY-axis had a range of 0.95 to 1.15. Not impressive compared to Le Moal 2007 ( http://www.ncbi.nlm.nih.gov/pubmed/17172306 )

        we found the fluorescence signal emitted by a molecular cyanine 3 dye layer to be amplified by a factor ~30 when fluorophores are separated by a proper distance from the substrate. We then adapted our model to the case of homogeneously stained micrometer-sized objects and demonstrated mean signal amplification by a factor ~4. Finally, we applied our method to fluorescence imaging of dog kidney cells and verified experimentally the simulated results.

      • another quantitative example: See page 12 and 14 of Fu ... Lakowicz - note Y-axes ( http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3087598/ ). They don't mention quantum yields of their fluorophores, flavin(s) are probably low (see next bullet).

      • optics: Fig 1 shows objective lens from above. Text refers to 1.4 NA objective lens. No mention of coverglass on that side, or distance from that coverglass to the top of the cell (side away from the dichroic/silver islands surface). For live cells this would need to be aqueous. Staudt ... Hell 2007 ( http://www.ncbi.nlm.nih.gov/pubmed/17131355 , fig 6) a nice graph showing that an aqueous "gap" of 20 um results in collecting 20% of signal relative to at the coverglass (1.0 Airy unit confocal). So Elsayad's fig 4C would be compressed five fold.

      Plan T: TIRF is also distance dependent. If their scheme is useful, I suggest could do plain glass surface with "dual view" TIRF with two emission bands (say 520-530 nm and 530-560 nm, with respect to their fig 4C and my knowing AF488's emission spectra), and simply ratio those ... See also Brunstein ... Oheim for combined TIRF + SAF benefits ( http://arxiv.org/ftp/arxiv/papers/1302/1302.1615.pdf ).

      Plan V: Vutara SR-200 fluorescence nanoscope is rated as 20x20x50 nm precision localization (www.vutara.com, FPALM, also single molecule tracking of sparse non-blinking fluorophores - see also Zeiss PALm, Nikon STORM and Leica GSD, and many academic lab variants, including iPALM, ref 15 of Elsayad et al). However, this assumes a modest performance fluorophore. For easy math, a 100x more photons fluorophore would be a sqrt(100) = 10x improvement, so 2x2x5 nm, a lot better than these folks can do. [prices should be considered as "rough ballpark" for US market and without negotiations, end of year discounts, or post-warranty service contracts). Also SR-200 is around $300K vs Zeiss LSM710 is ~$600K nicely loaded (they used a 710). The 710's Quasar detector is a "standard" 32-channel PMT ... the LSM780 has a GaAsP version with ~2x higher QE, say $700K. See also Tables 1 and 2 of Ram et al 2008 ( http://www.ncbi.nlm.nih.gov/pubmed/18835896 ) ... multifocal imaging ~20 nm Z (precision localization) single QDot ... live time series, one objective lens (2 or 4 cameras).

      Plan B: (or "issue B"): Bailey et al published standing wave excitation - in 1993 - that used 2 objective lenses (and 20 years earlier means earlier generation of fluorophores, objective lenses, filters, detector) that did pretty nicely ( http://www.ncbi.nlm.nih.gov/pubmed/?term=8232536 ). Too bad never offered commercially (since then carried on in 4pi, iPALM etc).

      These "plans" are not the only alternatives possible and Elsayad et al do reference a few alternatives.

      Ref 22: spectra web site reference of http://www.fluorophores.tugraz.at ... list at http://www.fluorophores.tugraz.at/substance/ ... login required. Around 90% of spectra are from PubSpectra, for example, AF488 http://www.fluorophores.tugraz.at/substance/618 "quantum yields" tab. I would have cited Carl Boswell and my PubSpectra dataset (open access, no registration, no legalese - data are not copyrightable) http://works.bepress.com/gmcnamara/9/ and http://www.ncbi.nlm.nih.gov/pubmed/?term=16969821


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    1. On 2015 Jan 07, Seyed Moayed Alavian commented:

      Dear Authors, Thanks for your valuable study. I think the pazzel is more complicated in affect of obesity on HBV infected patients.Th diabetes mellitus is a key variable in progression of liver disease and increase the chance of hepatocellular carcinoma in these high risk group patients. Yours Alavian SM


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    1. On 2014 Feb 15, Andrea Messori commented:

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

      Relative risk (RR) and risk difference (RD) have different advantages and disadvantages [see Walter (2000) for further discussion]. In the paper by Kawalec and co-workers (2014), the analysis focused on the induction of remission is the one endowed with the main therapeutic implications. To better explore this data set (end-point = induction of remission), we have re-analyzed the results from the various trials by using both RR and RD as outcome measures for the meta-analysis. Our results are shown in a figure that can be downloaded from the following link: www.osservatorioinnovazione.net/papers/kawalec-reanalysis.pdf .

      The analysis based on RDs is advantageous because the outcome measure is an absolute one and permits us to interpret the clinical significance of these findings using the number need to treat.

      FIGURE LEGEND: The meta-analysis shown in this figure re-examined the same information previously reported by Kawalec et al. (data set: induction of remission). Our figure shows the Forest plot with the values of RR (Panel A) or RD (Panel B) for individual trials (solid square with 95%CIs indicated by horizontal bars) and for some trial subgroups (diamonds in yellow). The pooled rates for the entire data-set are shown as blue diamonds. I2 is a measure of heterogeneity. Statistical calculations were performed by the OMA software (Open Meta-Analyst version 4.16.12, Tufts University, U.S., url http://tuftscaes.org/open_meta/). Abbreviations: Ev, number of events; Trt, number of patients receiving treatment.

      REFERENCES:

      -Kawalec P, Mikrut A, Wiśniewska N, Pilc A. Tumor necrosis factor-α antibodies (infliximab, adalimumab and certolizumab) in Crohn's disease: systematic review and meta-analysis. Arch Med Sci. 2013 Oct 31;9(5):765-79.

      -Walter SD. Choice of effect measure for epidemiological data. J Clin Epidemiol. 2000 Sep; 53(9):931-9.


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    1. On 2013 Dec 17, L. Miguel Martins commented:

      A very elegant data analysis workflow! See figure entitled "Extended Data Figure 3: Overview of data analysis workflow". This paper provides a very useful resource to scientists characterising the pink1-parkin pathway.


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    1. On 2014 Jan 21, Serge Ahmed commented:

      An excellent perspective article. I particularly liked the section entitled "Uniqueness of dietary choice" which lists several reasons why food choice is "a unique choice problem."


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    1. On 2014 Jan 08, Daniele Focosi commented:

      Anelloviruses and immune competence.

      We read with interest the recent article by De Vlaminck et al showing marked human plasma virome compositional dynamics in 96 heart and lung transplant recipients (De Vlaminck et al., 2013). Since most fluctuations in plasma virome were due to expansions and contractions of members of the family Anelloviridae, specifically torquetenovirus (TTV) species, these authors suggested that levels and fluctuations of these viruses in plasma might serve as indicators of immune system functionality These findings and hypotheses are not unexpected to us. In 2008, using a quantitative real-time PCR assay targeting conserved TTV genome regions, we reported very similar dynamics in myeloma and lymphoma patients receiving high-dose chemotherapy supported by autologous hematopoietic stem cells transplantation. Here we found a clear correlation between peaks of TTV viremia and expansion of senescent CD8+CD57+ T lymphocytes, which are known to soothe immune responses and are associated with CMV infections (Maggi et al., 2008 ). We then demonstrated that the time needed for TTV viremia to return to baseline levels after the peak that inexorably followed conditioning predicts how long is the time for recovery of the immune system function, and hence we proposed TTV viremia as a surrogate marker of functional immune competence (Focosi et al., 2010 ). We finally confirmed the preeminent role of hematopoietic cells in controlling plasma TTV viremia in fully myeloablated recipients of haploidentical stem cell transplantations (Maggi et al., 2010). We also found TTV viremia kinetics similar to those reported by De Vlaminck et al in 114 kidney and pancreas transplant recipients followed-up for 1 year (Focosi et al., 2013; manuscript in preparation). CMV positive (donor or recipient) transplant cases were treated with anti-CMV prophylaxis, valganciclovir. Here again we found that the hematopoietic cells played a pivotal role in regulating plasma TTV viremia, and demonstrated a massive drop of TTV viremia in the immediate days after lympho-depleting induction regimens. TTV viremia rebounded after day 7, peaked at month 3-6 to decline thereafter during maintenance immunosuppression. Interestingly, although statistical limitations did not allow to demonstrate a correlation between TTV viremia levels and graft rejections, we found a positive association with CMV reactivations. In their paper, De Vlaminck et al. used shotgun sequencing to determine human virome composition in cell-free plasma DNA and concluded that this data offer a potential application to monitor the effect of pharmacological treatment and predict immunocompetence. Shotgun sequencing is a powerful technique but is time-consuming, expensive, and poorly apt for routine diagnostics. In our papers we have instead shown that a fast and cheap quantitative, TTV-universal real-time PCR can provide an estimate of immunocompetence and be a simple and practical tool for tailor-made maintenance immune suppression. In conclusion, although we should be aware that the factors that can impact on TTV viremia levels and complexity are numerous (including polymorphisms in innate immunity genes and superinfections with different TTV genotypes) and largely uninvestigated, we totally agree with De Vlaminck et al that replication of TTV in humans is a promising marker to monitor functional activity of immune system. We declare that we don’t have any conflict of interest related to this comment.

      Dr. Fabrizio Maggi, MD<sup>1,2,*,#</sup> Dr. Daniele Focosi, MD<sup>3,*</sup> Prof. Mauro Bendinelli, MD, PhD<sup>3</sup> Prof. Ugo Boggi, MD, PhD<sup>3</sup> Prof. Mauro Pistello, PhD<sup>3</sup>

      <sup>1</sup> Virology Section, Pisa University Hospital, Pisa, Italy <sup>2</sup> Chair, Anelloviridae Study Group, International Committee on Taxonomy of Viruses <sup>3</sup> Department of Translational Research, University of Pisa, Pisa, Italy

      <sup>*</sup> both authors contributed equally to this manuscript. <sup>#</sup> corresponding author : Virology Section, Pisa University Hospital, via Paradisa 2, 56124 Pisa, Italy. E-mail: fabrizio.maggi63@gmail.com. Phone : +39 050 997055

      References : 1. De Vlaminck, I., Khush, K.K., Strehl, C., Kohli, B., Luikart, H., Neff, N.F., Okamoto, J., Snyder, T.M., Cornfield, D.N., Nicolls, M.R., et al. (2013). Temporal response of the human virome to immunosuppression and antiviral therapy. Cell 155, 1178-1187. 2. Focosi, D., Macera, L., Santi, M., Vistoli, F., Pistello, M., Scatena, F., Maggi, F., and Boggi, U. (2013). TTV kinetics as a novel marker of functional immune deficiency. Paper presented at: European Society for Organ Transplantation (ESOT) (Vienna). 3. Focosi, D., Maggi, F., Albani, M.M., L, Ricci, V.G., S, Di Beo, S.G., M, Antonelli, G., Bendinelli, M.P., M, and Ceccherini-Nelli, L.P., M (2010 ). Torquetenovirus viremia kinetics after autologous stem cell transplantation are predictable and may serve as a surrogate marker of functional immune reconstitution. J Clin Virol 47, 189-192. 4. Maggi, F., Focosi, D., Albani, M., Lanini, L., Vatteroni, M.L., Petrini, M., Ceccherini-Nelli, L., Pistello, M., and Bendinelli, M. (2010). Role of hematopoietic cells in the maintenance of chronic human torquetenovirus plasma viremia. J Virol 84, 6891-6893. 5. Maggi, F., Focosi, D., Ricci, V., Paumgardhen, E., Ghimenti, M., Bendinelli, M., Ceccherini-Nelli, L., Papineschi, F., and Petrini, M. (2008 ). Changes in CD8+57+ T lymphocyte expansions after autologous hematopoietic stem cell transplantation correlate with changes in torquetenovirus viremia. Transplantation 85, 1867-1868.


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    1. On 2014 Feb 06, Tim Andrews commented:

      In our article, we reported that in our functional MRI experiment, there was “an interaction between condition and orientation, F(2,46)=3.03, p<.05” (p.132) in the case of the same-identity faces. We should have instead reported that “there was a trend toward an interaction between condition and orientation, F(2,46)=3.03, p=.058.”


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    1. On 2016 Sep 16, Christian Rück commented:

      Thank you for pointing out the typo in the abstract. We have contacted PLoS to correct this. The correct number is indeed NCT00564967.

      Best regards,

      Christian Rück | Associate Professor, MD. PhD Dept. of Clinical Neuroscience | Karolinska Institutet Karolinska University Hospital Huddinge | M46 | SE-141 86 Huddinge | Sweden rucklab.com @christianruck


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    2. 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 NCT0056496. We believe the correct ID, which we have found by hand searching, is NCT00564967.

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

      Many thanks,

      Jessica Fleminger, Ben Goldacre*

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

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


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    1. On 2014 Apr 05, Allison Stelling commented:

      The problem lies in the tests themselves.

      The pathologists can only be as right as the tests themselves. Immunohistochemistry and standard H&E staining both have a notorious and disturbing amount of inter-observer variability. The entire American medical enterprise is far, far too focused on "cures" rather than the underlying "causes", which results in high percentages of misdiagnoses- not because the pathologists are doing the tests wrong, but because the tests themselves are highly inadequate.

      It's somewhat akin to having the world's deadliest arsenal but no map of the enemy territory. I'm working on this from my end with Raman and IR tissue mapping and analysis, should be far more accurate, reliable, and cheaper than anything that uses dyes or labels to sense disease phenotypes. (Esp. when combined with other non-destructive, optical methods.)

      For a recent overview of the complexities of brain tumor diagnostics as an example, see Figure 1 in this lovely article on the field: "Refined brain tumor diagnostics and stratified therapies: the requirement for a multidisciplinary approach." Riemenschneider MJ, Louis DN, Weller M, Hau P.

      (Note: I put this comment on the PLoS website when this article was first published [Posted by antistokes on 20 Nov 2013 at 13:40 GMT ], but thought I would place it in Commons as well.)


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    1. On 2013 Nov 22, Chris Carter commented:

      Heparan sulphate is also a receptor for a large number of viruses , bacteria and parasites, many of which have been implicated in these diseases : reviewed in Chen Y, 2008: Pathogen binding to these receptors will also impinge upon their functions described in the abstract above.


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    1. On 2014 Aug 05, David Keller commented:

      Women sometimes refuse mammography due to the pain it causes - how should they be screened?

      In her reply to my letter (1), Dr. Hwang did not address my suggestion of using MRI to screen women who refuse compression mammography due to the pain it causes, or their wish to avoid ionizing radiation to their breasts. I pointed out that these issues affect mainly younger women who are sent for mammograms, due to their higher breast content of glandular tissue.

      Dr. Hwang wrote: "Most breast cancer screening guidelines recommend against mammographic screening in women younger than 40 years owing to the low breast cancer incidence in this population”

      To clarify, I agree, and I support the American Cancer Society recommendation that routine annual screening mammography should begin at age 40 (2).

      Dr. Hwang wrote: “Furthermore, it has been clearly demonstrated that premenopausal women experience MRI changes with the menstrual cycle, which can often lead to false-positive MRI findings."

      I agree again, and menstrual cycle variations in breast imaging characteristics (in both MRI and mammography) can and should be mitigated by the proper timing of the examination. A European guideline states: "The optimal time in pre-menopausal women to perform a breast MRI is between the 5th and 12th day after the start of the menstrual cycle during week 2 of the menstrual cycle" (3).

      Most importantly, I would like to know what Dr. Hwang recommends be done to screen women who refuse mammography. If not MRI, what would she suggest?

      References

      1: Keller, DL. In Defense of Screening for Breast Cancer With Magnetic Resonance Imaging. JAMA Intern Med. 2014;174(8):1417. doi:10.1001/jamainternmed.2014.810.

      2: American Cancer Society website, accessed on 8/4/2014 at the following URL: http://www.cancer.org/cancer/breastcancer/moreinformation/breastcancerearlydetection/breast-cancer-early-detection-acs-recs

      3: Mann RM, Kuhl CK, Kinkel K, Boetes C. Breast MRI: guidelines from the European Society of Breast Imaging. Eur Radiol. 2008 Jul;18(7):1307-18. doi: 10.1007/s00330-008-0863-7. Epub 2008 Apr 4. PubMed PMID: 18389253; PubMed Central PMCID: PMC2441490.


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    1. On 2014 Jan 13, Sergei Jargin commented:

      This is a continuation of: Jargin SV. Overestimation of Chernobyl consequences: poorly substantiated information published. Radiat Environ Biophys. 2010;49(4):743-5; author reply 747-8. PMID: 20640449


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    1. On 2013 Dec 01, James C Coyne commented:

      This study is the largest ever evaluation of the Penn Resiliency Program for Children and Adolescents, with more participants than all past studies combined.

      Results are disappointing and may even be less than reported. Read more at http://blogs.plos.org/mindthebrain/2013/11/25/positive-psychology-in-the-schools-the-uk-resilience-project/ .

      Intervention does not seem distinctly positive psychology, with elements of cognitive therapy of Beck and Ellis' rationale emotive therapy dominating. Why would the authors have expected effects if samples were low in depressive symptoms at baseline?

      Such investments of public resources and such demands on student time should have better prior evidence to be justified.


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    1. 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/CNVannotator/.


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    1. On 2014 Jan 24, guoan zhang commented:

      a new mechanism underlying BRAF V600E-promoted NIS silencing in thyroid cancer by Xing M, one of the leader in the area of thyroid cancer study.see Xing M, 2013


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    1. On 2016 Aug 30, A Dahan commented:

      We agree, the clinicaltrial.gov registration number is indeed NCT01631149.This will be corrected in the journal. Many thanks, Albert Dahan MD PhD


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    2. 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 NCT01361149. We believe the correct ID, which we have found by hand searching, is NCT01631149.

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

      Many thanks,

      Jessica Fleminger, Ben Goldacre*

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

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


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    1. On 2014 Feb 05, Peter Uetz commented:

      Neither the title nor the abstract says which species is studied here. Only digging in the text reveals it is yeast, Saccharomyces cerevisiae.


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    1. On 2016 Feb 05, Kristina Hanspers commented:

      The graphical abstract for this publication is available as a pathway in the "Open Access Publication" Collection at WikiPathways: http://wikipathways.org/index.php/Pathway:WP3299. This pathway can be used for data visualization or for network analysis in tools like Cytoscape and PathVisio.


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    1. On 2014 Aug 30, Michelle Lin commented:

      Great landmark publication about TTM. A week-long discussion with ALiEM-Annals of EM journal club discussed the nuances of the study. It also featured the first author, Dr. Nielsen, in a videocast with our discussants.

      http://www.aliem.com/aliem-annals-em-journal-club-targeted-temperature-management/


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    1. On 2014 Jun 12, Gordon Warren commented:

      This is not a meta-analysis and does not claim to be.


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    2. On 2013 Nov 18, James C Coyne commented:

      Yikes, this is a really badly conducted and interpreted meta analysis. Thanks, Hilda Bastian, for calling this to our attention and offering alternative references.


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    3. On 2013 Nov 18, Hilda Bastian commented:

      The conduct and reporting of this systematic review falls so far short of the standards and criteria covered by PRISMA for reporting (Moher D, 2009) and quality appraisal tools such as AMSTAR, that this review does not meet current expectations of a systematic review.

      While conclusions about effectiveness are made, result data from the primary studies are not provided, nor are methods of data extraction and analysis discussed. Despite the large number of included trials, no meta-analyses of suitable data were performed and no reason for this was given.

      What constituted exercise was not specified and the reason for excluding studies prior to 2000 is not given. The reasons for inclusion and exclusion of studies are not entirely clear: for example, studies were excluded because of concomitant drug therapy, which, while a reasonable criterion, was not included in their list. A full list or explanation of exclusions is not provided.

      The search strategy as reported appears to be simplistic and does not include adequate search terms or key databases such as PEDRO. The number of studies for the stages in PRISMA’s flow diagram are not provided (duplicates removed, records screened). The quality of included studies is not assessed.

      If you are interested in reading a systematic review on this question, consider Umpierre D, 2011 - see the DARE critical appraisal.


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    1. On 2015 Oct 15, Christopher Southan commented:

      We now have an updated database publication at www.ncbi.nlm.nih.gov/pubmed/26464438


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    2. On 2014 Nov 18, Helen E Benson commented:

      Details of the latest IUPHAR/BPS Guide to PHARMACOLOGY (GtoPdb) release can be found on the blog maintained by the curation team.


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    1. On 2014 Mar 04, Dale D O Martin commented:

      After reading this paper, it appears to be quite thorough and well presented. Their results are very interesting. There are a few typos in the figures, but they do not take anything away from the data presented.


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    1. On 2013 Nov 16, Ellen M Goudsmit commented:

      The authors do not define ME and assume equivalence with CFS which is defined more broadly and covers a heterogeneous population. The assumption of equivaleance has yet to be validated. In light of the literature on ME, I note that evidence of differences between this disease and MS have not been discussed, e.g. type and distribution of UBOs on MRI cf Posner, reproduced in the textbook on ME by Hyde, B. Many findings on CFS are inconsistent due to the heterogeneity of the samples so data should be interrpeted with caution. My study comparing 50 patients with ME, 50 with MS and 50 healthy controls showed no differences between the patients groups on a neuroticism scale. Both had higher scores than healthy controls and this was almost certainly due to the inclusion of somatic symptoms to assess neuroticism.


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    1. On date unavailable, commented:

      None


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    2. On 2014 Aug 05, Michael Baudis commented:

      Thanks for the notes, and your usage of our resource. Regarding the other comments, you are obviously perfectly right that one has to do a critical evaluation of the data, beyond what we can provide.

      But regarding the specific criticism about the DCIS data, I am not sure if I can find real issues:

      • For Progenetix, by accepting only publication derived data, we rely on the peer review process running due course - there will be errors, but limited through standard operating procedures inherent to the process.
      • All the 76 samples, as far as I can follow this up without producing a review of the field, had been labeled as DCIS in the papers or supporting information; so the number stands. Frequently the DX contained addl. specifications (e.g."poorly differentiated").
      • Most importantly, for the analysis results it doesn't matter if the clinical diagnosis was incomplete due to needle biopsy (i.e. if the patient had an undetected infiltrating component) as long as the profiling was derived from the DCIS cells. Also, in hindsight and with some thousands of IDC available through www.progenetix.org and www.arraymap.org, the CGH profiles overall support the DCIS statements.

      However, we are absolutely delighted about community support in improving our annotations! So if you have clear per sample corrections (and there will be plenty of opportunities I guess) - just help us through providing specific comments.

      Best,

      Michael.


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    3. On 2014 Aug 05, Swapnil Rane commented:

      It is fantastic effort on part of the authors to provide such a resource. However, I noticed few problems on running a sample query. I searched for ductal carcinoma in situ cases in this database and initially I was very happy to see copy number information on 76 cases. But on looking at the 5 papers from which the query sourced the information, only two of them seemed valid sources. The remaining three papers according to me are not valid, as they either do not report the CNA in DCIS separately from the coexisting IDC or the technique itself by which samples were obtained(FNAC) for genetic analysis did not differentiate between DCIS and IDC. Even if I took into account only those two papers which exclusively report on DCIS and the pure DCIS cases from other three papers, the total number of cases does not exceed 43.... How did they reach a number of 76?.. Atleast, the database should annotate that the data is derived from mixed cohort of pure DCIS and DCIS with coexiting IDC. While I have not run any other query on the resource and it is possible that this glitch is only seen for this particular query, but it has made me sceptical about the reliability of the information provided by any such resource. It seems we cannot take any information at face value, no matter how reliable the source might seem to be!!


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    1. On 2014 Mar 14, Jonathan Eisen commented:

      The first author of the paper, Rachel Adams, wrote a post about this paper for the "microbiology of the built environment network" (microBEnet) blog. See Fungi on residential surfaces: sinks are sources, other surfaces are sinks


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    1. On 2014 Mar 29, Sergio Stagnaro commented:

      None


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    2. On 2014 Mar 25, Abdalla Elhwuegi commented:

      This review state that EDRF was discovered by Moncada, which is not the case. It is well known that EDRF was discovered by Furchgott and Zawadzki.


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    1. On 2016 Jun 01, David C. Norris commented:

      One must lament that our toxic politics did not countenance a proper nomination and Senate confirmation process for Dr Berwick. This would have given national audience to his passionate and infectious faith in the promise of healthcare improvement, stimulating meaningful debate on its moral and scientific basis at a most fortuitous time. In this JAMA Viewpoint, Berwick assays our healthcare politics for the activity of numerous paralytic toxins responsible for this and other lamentable lost opportunities. Of these toxins, I wish to address specifically the "Suspicion of Science" Berwick invokes, since it strikes at the heart of the medical profession's capacity to elevate our politics to a higher form – through persuasion.

      One hardly need invoke the lay public's suspicion of Science (capitalized and singular, if you will)<sup>1</sup> to account for the medical profession’s credibility gap as it now endeavors to appeal – so often in the name of cost containment, of all things – to the several sciences that fall under the heading of comparative effectiveness. Indeed, this invocation risks seeming to absolve Medicine of the responsibility to scrutinize its own professional norms and practices for modifiable factors that widen this gap. Such self-scrutiny is entirely in the spirit of the remainder of Berwick's argument, being essential to the professional mobilization he so rightly calls for.

      It would surprise few laypersons to learn of clinical medicine's troubled relationship with elementary scientific behaviors and modes of thought, as demonstrated for example by the fact that Braithwaite's excellent piece<sup>2</sup> on there-is-no-evidence-to-suggest was rightly judged necessary to publish in this same journal in 2013. Laypersons enjoy a ready access to a wide variety of subtle observations and distinctions that would alarm the Profession if appreciated more fully. In particular, alert laypersons perceive the contrast between the powerful sciences underlying medical technology, and the pervasive disorder in a clinical practice from which scientific method is largely absent.<sup>3</sup> It may well be the expression of a uniquely American genius that, regardless of what obtains abroad, until Americans routinely experience medical practice as a profound application of scientific method to optimizing their care as individuals, they will harshly censure as premature any attempt by this profession to invoke the sciences in the service of global optimizations like cost containment.

      [1] Kitcher P. Science in a Democratic Society. Amherst, NY: Prometheus Books; 2011.

      [2] Braithwaite RS, 2013

      [3] Weed LL, Weed L. Medicine in Denial. Charleston, SC: CreateSpace; 2011.


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    1. On 2014 Nov 26, Harri Hemila commented:

      Ludwig M, 2013 write in their background section that vitamins and zinc are not effective against the common cold when systematically reviewed. This is not correct.

      A systematic review on vitamin C and the common cold showed that vitamin C administration reduced common cold incidence by 52% (95%CI: 36% to 65%) in people who were under short term heavy physical activity Hemilä H, 2013. In addition, regular administration of 1 g/day vitamin C shortened the duration of colds in adults by 8% (95%CI: 3% to 12%) and in children by 18% (95%CI: 9% to 27%) Hemilä H, 2013. Ludwig et al. specifically refer to the Karlowski et al. (1975) study. Karlowski TR, 1975 found that 6 g/day of vitamin C was twice as effective as 3 g/day, indicating dose dependency in the high dose region, see Hemilä H, 1996, Hemilä H, 1999.

      A systematic review on zinc lozenges found 13 placebo-controlled trials Hemilä H, 2011. There was substantial heterogeneity between the studies, but the heterogeneity was explained by the dose of zinc and the zinc salt that was used. On the basis of 3 RCT:s, high dose zinc acetate lozenges shortened the duration of colds by 42% (95%CI: 35% to 48%).

      There is strong evidence that vitamin C and zinc acetate lozenges have an effect on the common cold.


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    1. On 2014 Nov 19, Helen E Benson commented:

      The chemokine receptor family page on the IUPHAR/BPS Guide to PHARMACOLOGY can be found here.


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    1. On 2014 Jan 09, David Mage commented:

      Randall et al. studied serotonin receptor binding in a non-probability (convenience) sample of case infants dying suddenly and unexpectedly without explanation (SIDS) and control infants dying of known causes, from San Diego County, CA. As pointed out previously to some of these same authors Mage DT, 2010 their results do not apply to any populations not probability sampled for this study and therefore statistical testing for significant differences between their cases and controls has no theoretical statistical basis and may lead to meaningless results. The authors' reply (op. cit.) leads one to believe that they think they are excused because they know of no "reason to believe that the levels of serotonin in brainstems of SIDS and non-SIDS in San Diego would be different than in infants elsewhere." Here are a few such reasons that may be relevant: 1) All cases and controls were autopsied at the San Diego County Medical Examiner's Office. It is well known that different pathologists independently looking at the same cases without any discovered obvious prima facie cause of death can give different causes of death by SIDS and non-SIDS such as positional asphyxia Emery JL, 1972 , Kim SY, 2012. Consequently their case definitions of SIDS may not apply elsewhere where different operative decisions for choice of cause of death are made by different medical examiners; 2) Serotonin does not cross the blood brain barrier, so all cerebral serotonin must come from its precursor dietary tryptophan (TRY). Because the infants' TRY in utero comes from their mothers' diet during pregnancy and after birth from their own diet it may make a big difference if they are breast fed or given milk formula as breast milk has higher TRY content than ordinary formula, that can be enriched in TRY (Young SN, 2007). The authors noted the higher percentage of Hispanic ethnicity and lower percentage of African Americans compared to the U.S. infant population. Consequently the frequency of breast feeding and the dietary carbohydrate intake of the Hispanic nursing mothers during and after pregnancy can be quite different in San Diego County compared to the rest of the U.S.; 3) Hispanic ethnicity mothers in San Diego may wean their infants at different ages than other non-Hispanic mothers and the infants' diets after weaning may also differ between Hispanic and non-Hispanic ethnicities; 4) Because the cause of SIDS is unknown, there may be yet unknown SIDS risk factors that vary between their cases and controls and all other cases and controls not sampled. In summary the authors' conclusions strictly apply to only those cases and controls they measured. The statistical testing and confidence intervals they report do not apply to all the other cases and controls that were not in the sample frame from which their cases and controls were chosen because they had no known finite probability of selection for this study.


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    1. On 2014 Nov 27, Guillaume Filion commented:

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


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    1. On 2014 Feb 03, George McNamara commented:

      Prof. Couchman's editorial for this issue included this paragraph on PubMed Commons:

      "However, undaunted, PubMed Commons has been launched, at least in trial format (as of October 2013). This allows anyone with an account to add comments to any article that is lodged with PubMed. This therefore includes JHC content. It will be interesting to see how this feature evolves. Naturally, the aim is constructive discourse and the rules make clear what constitutes unacceptable activity, which may be removed. The question is whether added comments will be useful or subject to misuse and, indeed, if this commentary is “peer” reviewed. Will comments be applied to papers by contributors with real expertise in the area? In addition, will authors of papers that are listed in PubMed check regularly to see who is attaching comments and respond? I have to confess that I am not sure this will be a high priority for me."

      John and readers - I have used PubMed Commons to comment on several papers, including updates on some of my own. At this point, evolution is not needed here - use is!

      With respect to the reproducibility in the title, it is the responsibility of the authors to provide full and correct details on what they did to generate the data, and calculate the statistics, that went into their work. It is unrealistic for peer reviewers to go through the manuscript or data to look for bad data or bad judgement. These are things the authors should deal with as they are doing their experiments, presenting/discussing their data in their lab meetings, at department seminars, retreats, poster sessions (would help if scientists visited posters at poster sessions), before the work is packaged into a manuscript.

      I also recommend that all journals should encourage - even demand - that all the data that underlies a peer reviewed manuscript be available as Open Data in a public repository(ies). Having all the data available lets anyone check it out. GenBank has been "standard of care" for DNA sequence data for years.

      For another recent editorial on this topic, see M. McNutt 2014 Reproducibility. Science 343(6168):229. doi: 10.1126/science.1250475. http://www.ncbi.nlm.nih.gov/pubmed/24436391


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    1. On 2014 May 07, David Keller commented:

      Just leave them alone

      Agitated elderly demented long-term care patients become more agitated when they are given the quiet presence of an unfamiliar research assistant, and even more agitated when the research assistant massages their feet. The best thing to do for agitated elderly demented long-term care patients, if you are an unfamiliar research assistant, appears to be to simply leave them alone.


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    1. On 2015 Oct 27, Lydia Maniatis commented:

      Perceived slant can be in any direction, not only around the horizontal.


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    2. On 2015 Aug 13, Lydia Maniatis commented:

      The authors' claim here, that foreshortening is a "cue" to slant, is logically untenable. They define foreshortening as the change in the ratio of width to length (compression), i.e. the difference in the proportions of the object and the proportions of the projection of the object. More specifically, for each of their stimuli, they define this change with respect to a single one of the actually infinite number of 3D object shapes that could have produced the given projection (with some wiggle room since they are assuming orthographic and not perspective projection). But the viewer does not have access to this one object, and thus does not have access to the change in aspect ratio that the investigators have in mind. The shape of the object must be inferred from the projection, on the basis of shape constraints. Having been inferred, the degree of slant/foreshortening then follows as a secondary inference. It is in no way present as a cue in the stimulus/projection.

      The reason that the investigators' predictions for the slant of single shapes were confirmed is that the 3D object on which they based their definition of foreshortening was the most regular shape that could have produced the given projection, that is, the 3D shape possessing the characteristics preferred by the visual system when interpreting a projection. If the visual system were partial to skew symmetrical rather than symmetrical shapes, then the stimulus would have been perceived as fronto-parallel with no foreshortening, and the prediction would have failed. Again, foreshortening is not a feature of the 2D stimulus.

      The investigators' proposed dichotomy between single shapes and "textures" with respect to the role of the "foreshortening cue" is also false, and results from their failure to appreciate the role of shape constraints. The textures to which they refer were composed of rectangles subjected to orthographic projection. They were compressed/foreshortened, but the compressed projections were similarly rectangular, and thus would not have caused the visual system of the observer to infer a different shape (i.e. the shape based on which the investigators calculated the predicted degree of foreshortening), and thus a non-fronto-parallel orientation plus foreshortening. Rectangles just don't slant, even if they happen to be orthographic projections of taller rectangles.

      Also, the discussion by Ivanov et al seems to take it for granted that the direction of foreshortening is from top to bottom as happened to be the case for their stimuli (since they treat it as a given), but the visual system may infer foreshortening in any direction, it just depends on the shape of the projection and what is required to regularise it as much as is consistent with the projection.


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    1. On 2017 Oct 06, Peter Gøtzsche commented:

      The authors compared inhalers with combination drugs (a steroid plus a long-acting beta-2 agonist), with placebo and write in their abstract that the number needed to treat to prevent one death with fluticasone/salmeterol was 42 (1). They explain, just before Objectives, that the largest randomised trial of combination therapy (TORCH) demonstrated a significant reduction in mortality versus placebo (P = 0.052) and that they wished to see whether other combined inhalers had a similar effect. Just above “Implications for research,” we are told that “whether a combination is better than the two components taken separately was not addressed in this review,” and under “Authors’ Conclusions” the authors advocate that the combination should be compared with its two components.

      This information is misleading. Firstly, the review authors overlook that the TORCH trial (and several other trials) was designed to answer what they call for in future research, namely whether the combination was better than any of its components.

      Secondly, the authors give the readers the impression that the combination reduces mortality. However, the fact is that the steroid contributes absolutely nothing to the mortality benefit. The primary outcome in the TORCH trial was total mortality (2). GlaxoSmithKline randomised 6184 patients to four groups: placebo; salmeterol; fluticasone; and both drugs together. By definition, this design is factorial. It is powerful, as it allows the investigators to study three research questions with a sample size that would usually only allow one question to be answered. Such a trial can tell us whether the two drugs are effective, and whether the combination is better than any of its components. However, the analysis in the TORCH trial included only half of the patients, thereby spoiling the advantage of the factorial design, although the published trial protocol stated that a factorial analysis was to be performed (3).

      Nowhere in the 15-page trial report is the factorial analysis to be found, and the abstract of the TORCH trial gives the readers the clear impression that the combination was better than any of its components, which is the result the authors of the Cochrane review quoted.

      The authors of a letter to the editor used a factorial analysis and showed that the effect of the combination was entirely due to salmeterol (4); the hazard ratio for fluticasone was 1.00 (0.87 to 1.15), p = 0.99. In other similar trials, both GlaxoSmithKline and AstraZeneca did not perform a factorial analysis (5).

      1 Nannini LJ, Poole P, Milan SJ, et al. Combined corticosteroid and long-acting beta2-agonist in one inhaler versus placebo for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2013;11:CD003794.

      2 Calverley PM, Anderson JA, Celli B, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007;356:775–89.

      3 Gøtzsche PC. Questionable research and marketing of a combination drug for smoker’s lungs. J R Soc Med 2014;107:256-7.

      4 La Vecchia C and Fabbri LM. Prevention of death in COPD. N Engl J Med 2007;356:2211–2.

      5 Suissa S, Ernst P, Vandemheen KL, et al. Methodological issues in therapeutic trials of COPD. Eur Respir J 2008;31:927–33.


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    2. On 2017 Aug 24, Peter Gøtzsche commented:

      None


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    1. On 2017 Jul 13, WALTER LUKIW commented:

      As originally reported by the authors, we find miRNA-168a abundant in dietary plant(s) and in the systemic circulation (and other really, really, really interesting places) of animals who consume these plants as part of their diet (unpublished observations); in our hands RT-PCR is a very easy but very inconsistent method to detect ANY type of microRNA abundance anywhere from any biological fluids or tissues, either plant or animal; we use RNA-sequencing, miRNA array-based (microfluidic hybridization) approaches, LED-Northerns, regular Northern dot blots and yes, RT-PCR - although RT-PCR approaches clearly yield the most inconsistent results.

      Walter J. Lukiw BS, MS, PhD Professor of Neurology, Neuroscience and Ophthalmology Bollinger Professor of Alzheimer’s disease (AD) LSU Neuroscience Center, Louisiana State University Health Sciences Center 2020 Gravier Street, Suite 904 New Orleans LA 70112 USA TEL 504-599-0842 EMAIL wlukiw@lsuhsc.edu


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    1. On 2013 Dec 24, Kenneth Witwer commented:

      Along with the study mentioned by M Mangan, some other primary publications on the topic are noted in this comment.


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    2. On 2013 Nov 16, M Mangan commented:

      This article is an important attempt to replicate the outcomes published in a previous article: Zhang L, 2012. This follow-up work was unable to obtain the same results as the original claims, and should be considered in comparison with that prior paper.

      For more detail on this story you should also see this explanation from the publisher about this work: Anonymous, 2013.


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    1. On 2013 Nov 16, M Mangan commented:

      This editorial provides an interesting explanation for why this journal chose to publish an article that generated a negative result, which was an attempt to replicate previous work. It provides an interesting discussion of the philosophy of replicating work and of publishing replications, which not all journals will elect to do, apparently. The replication article they published this one: Dickinson B, 2013.

      The new article described the inability to replicate the claims from this prior article: Zhang L, 2012.


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    1. On 2016 Aug 31, Pavel Nesmiyanov commented:

      Authors say "Of note, however, the chemotherapeutic pressure selected an evolutive conversion of some non-SP cells into SP cells over-expressing both ABCG2 and the stem cell marker BMI-1 [45]." However, ref.45 doesn't support this statement.


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    1. On 2013 Dec 18, Meghan Lane-Fall commented:

      The I-PASS curriculum referenced in this article can be accessed via the AAMC's MedEdPortal. On this site, the six components of the I-PASS curriculum along with supporting documents can be accessed without charge after registration: https://www.mededportal.org/


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    1. On 2016 Jan 23, Eric Gamazon commented:

      Reference #60 should be:

      Gamazon ER, Im HK, Liu C, Members of the Bipolar Disorder Genome Study (BiGS) Consortium, Nicolae DL, and Cox NJ. The convergence of eQTL mapping, heritability estimation and polygenic modeling: Emerging spectrum of risk variation in bipolar disorder. arXiv, arXiv:1303.6227, 2013. http://arxiv.org/abs/1303.6227


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    1. On 2016 Aug 30, Ben Goldacre commented:

      This trial has the wrong trial registry ID associated with it on PubMed: both in the XML on PubMed, and in the originating journal article. The ID given is NCT00123456. This trial ID does not appear in ClinicalTrials.gov.

      We have contacted the corresponding author on the study to ask them for the correct trial ID on 18/08/2016, but received no reply. We have also searched manually for this trial on ClinicalTrials.gov and found no matching study. We therefore believe that this trial may not have been registered on ClinicalTrials.gov.

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

      Many thanks,

      Jessica Fleminger, Ben Goldacre*

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

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


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    1. On 2014 Apr 05, Jonathan Eisen commented:

      I believe some of the claims in this paper regarding the connection between ethnicity and the microbiome and the mechanisms behind such connections are not justified.

      For example, in the discussion the authors write "Our data demonstrates that ethnicity exerts a selection pressure on the oral microbiome, and that this selection pressure is genetic rather than environmental, since the two ethnicities that shared a common food, nutritional and lifestyle heritage (Caucasians and African Americans) demonstrated significant microbial divergence. "

      I see no evidence presented here of ANY genetic component to the microbiome differences reported here.

      I and others have written blog posts critiquing this paper and the claims (such as the one mentioned above) by the authors in press releases associated with the paper. For more detail see

      http://phylogenomics.blogspot.com/2013/11/short-post-bad-taste-in-my-mouth-for.html

      and

      http://phylogenomics.blogspot.com/2014/03/guest-post-by-jay-kaufman-bad-taste.html


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    1. On 2013 Nov 15, Rolando Garcia-Milian commented:

      Interesting paper though I would add "in a murine model of inflammation-associated colorectal cancer" to the title. The specific organism that was studied should be part of the title.


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    2. On 2013 Nov 15, Morgan Langille commented:

      Really great paper showing the first instance that their is a causal relationship between the microbiome and colorectal cancer and not just correlation.


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    1. On 2013 Nov 08, Allison Stelling commented:

      The molecular characterization for glioblastoma section of this paper was a bit weak; unfortunately due to a paucity of work in this field. I realize the whole field is desperate for cures for this rather frightening class of brain tumor. However, its very heterogeneity renders it a formidable foe. We need better maps of this undiscovered molecular territory if we are to even hope for a targeted strategy with chemotherapies. Genetic and morphological information gives me a few pieces of the picture, but I need to know the spatially resolved biochemistry to mount an effective chemical attack.

      The authors state in their neurosurgery section "In inoperable tumors, stereotactic biopsy may be performed for histologic diagnosis, but the limited amount of tissue acquired may preclude full molecular characterization."

      Optical methods like Raman and infrared spectroscopy can help to directly address this issue, since they are (a) non-invasive and (b) you can get reliable phenotype information about the biochemistry from quite small tissue samples (for example, ratios of lipids to proteins) fairly rapidly (see my paper Stelling AL, 2013; as well as recent work on skin cancer Kong K, 2013 for more).

      On a final note: I've chatted with a few neuropathologists. Even when the entire brain hemisphere with the tumor in it is removed, there's still recurrence. I strongly suspect after the cancerous cells are present (after they have evolved from the stem cells etc), they leave behind carcinogenic contamination. There's some studies on the extracellular matrix of gliomas pointing to a role for these structural proteins and sugars in progression and recurrence as well. (See Payne LS, 2013 for a recent review.)


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    1. On 2014 Jun 11, Jorge H Ramírez commented:

      Linked editorial related to the original research paper published in the BMJ (Nov 5, 2013) by Bird and colleagues.

      Additional rapid responses by this author (available in the website of the BMJ):

      November 15, 2013 | Comments about the rapid response “Prevention of hypotension and first dose phenomenon due to postsynaptic alpha-2 blockers”. URL: http://www.bmj.com/content/347/bmj.f6320/rr/672217

      May 16, 2014 | Expression of concern about tamsulosin: at least 78.4% of the studies are unpublished. URL: http://www.bmj.com/content/347/bmj.f6320/rr/698284

      June 6, 2014 | Correction: "Expression of concern about tamsulosin: at least 78.4% of the studies are unpublished" URL: http://www.bmj.com/content/347/bmj.f6320/rr/700980

      Expression of concern is also available via Figshare: http://dx.doi.org/10.6084/m9.figshare.1094338 URL:http://figshare.com/articles/Expression_of_concern_about_tamsulosin_over_three_quarters_of_human_studies_are_unpublished/1094338


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    1. On 2014 Jul 13, Jorge H Ramírez commented:

      PubMed Commons comment

      I would like to make the following remarks about this study.

      • The sample size (n=383567) and time of patient follow-up (16 weeks, interquartile range 5-50 weeks) of Bird ST, 2013 study is clearly superior to the registered (published and unpublished) previous studies of tamsulosin (n=83201; median time of follow-up=6 weeks, interquartile range 2-12 weeks).1,2

      • "The available scientific evidence supports the association of tamsulosin with serious adverse cardiovascular drug reactions, probably more than any other pharmacological effect attributed to this drug. I urge doctors to reconsider the use of tamsulosin as a first line treatment in patients with lower urinary tract symptoms."1

      • Tamsulosin is not uroselective.1,2

      • Over three quarters of tamsulosin studies are unpublished.1,2

      References

      1. Ramirez JH. Re: Tamsulosin treatment for benign prostatic hyperplasia and risk of severe hypotension in men aged 40-85 years in the United States: risk window analyses using between and within patient methodology (May 16, 2014) http://www.bmj.com/content/347/bmj.f6320/rr/698284

      2. Ramirez, Jorge H (2014): Expression of concern about tamsulosin: over three quarters of human studies are unpublished. figshare. http://dx.doi.org/10.6084/m9.figshare.1094338


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    1. On 2014 Jan 09, B Martini commented:

      In their recent article (1), The Brugada brothers reported that “Martini et al had published a series of patients with idiopathic ventricular fibrillation and, upon retrospective analysis, one had an electrocardiogram (ECG) with similar characteristics. However, in contrast to the report in JACC, their patients had structural heart disease with no evidence for a hereditary disorder”. This statement is again a personal interpretation of the contribution of Italian and Japanese Colleagues who published the syndrome 5 years before the Brugada article (1-4). It is not true that only 1 patient had the discussed ecg, and that there was no evidence of hereditary disorder. We have recently re-discussed and documented all the true history (5). Moreover also the “recently discovered” depolarization theory was fully proposed and demonstrated in those early articles. We wrote and still believe that all these patients have some underlying heart disease, and that there is not a distinguished functional syndrome, different from an organic one.<br> I personally have an high respect for the Brugada contribution to the syndrome, but the repeated authorital attempts to erase the true history of the discover, do not further enhance the importance of their contribution.

      1. Brugada P,Brugada J, Roy D. Brugada syndrome 1992–2012: 20 years of scientific excitement, and more. Eur Heart J 2013 in press

      2. Nava A, Canciani B, Schiavinato, M. L, Martini B: La repolarisation precoce dans le precordiales droites: trouble de la conduction intraventriculaire droite? Correlationse l'electrocardiographie- vectorcardiographie avec l'electro-physiologie. Mises a Jour Cardiologiques 1988;17:157-159

      3. Martini B, Nava, A, Thiene, G, et al: Ventricular fibrillation without apparent heart disease: description Of six cases. Am. Heart J. 1989; 118: 1203-1209

      4. Aihara, N, Ohe, T, Kamakura S, et al: Clinical and electro physiologic characteristics of idiopathic ventricular fibrillation. Shinzo 1990;22 (suppl. 2). 80-83

      5. Martini B, Wu J. Nava A. A rare lethal syndrome in search of its identity: Sudden death, right bundle branch block and ST segment elevation. In Wu J, Wu J Editors: Sudden Death. Nova Biomedical New York, pp.1-39


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    1. On 2014 Aug 05, Andrew Sharp commented:

      A recent paper (PMID: 25079557) that performed DNA methylation analysis of developing embryos made some interesting observations that are potentially relevant to our findings in this paper. A quote from this paper: "...we found that SINEs and LINEs with different evolutionary ages showdifferent demethylation patterns (Fig. 4a–d and Extended Data Fig. 10d–f). For example, both LINE-1 (L1) and LINE-2 (L2) belong to the LINE family of transposable elements, with L1 being evolutionarily younger than L2 (ref. 25).The younger L1 shows a higher methylation level than L2 in oocytes, whereas they show a comparable level of methylation in sperm. More importantly, we found that during the genome-wide demethylation process, the evolutionarily younger L1 retains higher levels of residual methylation than L2. L1 was also remethylated to a higher methylation level after implantation (Fig. 4d)."

      I think it is an interesting idea that this differential demethylation/remethylation might potentially explain the association of younger LINEs with the spread of X inactivation?


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    1. On 2014 Nov 17, Pavel Baranov commented:

      Due to a software error in an earlier version of the browser, the data in Figure 1 are not represented correctly. Apologies. The correct image is published here.


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    1. On 2017 Apr 28, Robert Badgett commented:

      Regarding recommendations of the International Committee of Medical Journal Editors for trial registration:

      • The initial registration of this trial was on April, 27, 2010 and states the the study was executed earlier from May, 2009 through October, 2009.
      • The initial April, 2010 registration indicates that the primary outcome was "Difference in pain intensity as measured on the Visual Analog Scale (VAS)." The July, 2013 version changes to "Percentage of Participants With Reduction in Pain Intensity".


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    1. On 2014 Sep 13, Vahid Rakhshan commented:

      The formatted version of this unpublished letter to the editor can be found at this address (LINK).

      I read with interest the valuable article of Ferreira et al. [PMID: 24182586]. Although it was a very good research, few points were unclear to me.

      1. Gold standard preparation was extremely vague (P.699). The numbers of examiners, their calibration/training/inter-rater agreements, and the number of assessments per each skull were not mentioned. Measuring the bone defects might first appear as an easy task and not needing detailed clarification. However (A) the gingival bone margin does not exist in dehiscence (Figure 1) and evaluator needs to guess from where to measure the distance. (B) If there were irregularities in the bone defect, which distance would be measured? The longest one? Or the shortest one? Or the vertical one? What about horizontally expanded defects? (C) The distances do not seem perfectly vertical and similar in Figure 1. The angle of the gauge can affect the measured length as well. Therefore calibration and inter-rater agreement are critical.

      2. I wonder how the evaluators could certainly identify the bone “marrow” absence by the naked eye for fenestration diagnosis (P. 699).

      3. It is stated that “the level of agreement proved that…” and also “the assessments do reflect reality” (P.701). These two strong conclusions were made based on agreements between 0.47 and 0.76.

      4. Surprisingly, there was absolutely No P value reported for any test/correlation/kappa, which disallows any generalizations/validations. So how statistically unsubstantiated kappa values can prove anything?

      5. There is mention of a chi-square used on sagittal and axial reconstructions (P.701). However, there are no P values or results for chi-square reported throughout the study.

      6. In the last paragraph of the Results, the sensitivity / specificity / accuracy of sagittal reconstructions were stated but none was stated for axial reconstructions. Yet immediately after that part (after a semicolon), the authors concluded that the sagittal reconstructions performed better than axial. How did they do so without any comparisons?

      7. Perhaps the authors had used the previous paragraph that stated agreements with the gold standard. The agreements for sagittal and axial reconstructions were 78.5% and 73.3%, respectively. I would much appreciate to know how the authors compared these two without (A) first identifying whether or not these two agreements were significant; and (B) whether or not there was a statistically significant difference between these two correlation coefficients? The authors needed to run a t-test between the two agreements to see if the 78.5% was significantly greater than 73.3% or the difference was not reliable (statistically non-significant).

      8. K=0.4509 and K=0.3131 are considered 78.43% and 73.33% agreement, respectively (P.701). I think it is not correct and they respectively mean 45.09% and 31.31% agreements.

      9. Making decisive conclusions from a report without any P values or confidence intervals should be avoided. The findings were not substantiated statistically, and thus should be approached cautiously.

      10. The conclusions of text and abstract contradict completely. The abstract concludes “There was no difference in the performance of the axial and sagittal reconstructions.” The text concludes “The sagittal section is more reliable than the axial section, mainly in the middle third.” Which conclusion to take home?


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    1. On 2014 Sep 13, Vahid Rakhshan commented:

      The formatted version of this unpublished letter to the editor with tables can be found at this address (LINK).

      Sufficient test powers are necessary for validating non-significant results

      1. The sample size was not based on power calculations. This might be justified partly by difficulty of finding surgery patients. However, compounded with next issues, this might become serious.

      2. Except one, no pairwise comparison was significant. It is why the power becomes serious. Given the rather small sample size (2×13 for each t-test), it was possible that many of those non-significant results were merely type II errors (false negative results).

      3. No exact P values had been reported for the comparisons. It was only stated that “P>0.05”. Reporting P values is necessary to distinguish non-significant cases like P=0.053 [which are still pointing to some difference] from cases like P=0.999.

      4. When it comes to interclass correlations, only correlation coefficients had been reported. It was not mentioned whether those coefficients were significant or non-significant (even as any “P>0.05” or “P≤0.05” statements). The statistical significance is needed to verify if a correlation result is generalizable to the population. No matter how big is a correlation coefficient, unless it is not verified statistically (P≤α), it remains unsubstantiated and should not be used as a finding.

      5. The authors have stated as a limitation, “the few subjects (6) with Le Fort advancement surgery”. However, their serious (and ignored) limitation was their lack of power calculations, even a post-hoc one. Certain studies [like this one] might favor the absence of significant differences between a new approach and the gold standard (i.e. P>0.05). Power calculations are extremely essential, especially in such studies. Without a sufficient power, the non-significant results are not reliable as they can be simply false negative errors.

      6. The Discussion/Conclusion/Abstract are full of strong conclusions regarding the proper accuracy of evaluated programs. In this design with unknown/low power and many non-significant results, I could not be so sure about the accuracy of the programs.

      7. The sample size (2×13) seemed rather small for a paired t-test. Authors might need to justify using a parametric test in this sample via proper normality assessments.

      8. In Tables II–V [last columns], the “(maximum error)” was calculated incorrectly for some rows (Table I of this letter).

      9. The 95%CIs are critical and also used for authors’ interpretations. At first look, some of the 95%CIs did not accord with the reported means. For example, in Table II, the mean error for “Stomion Superior” is +0.10±0.004 (minimum: –0.30, maximum: +1.02). However, its 95%CI was –0.36 to +0.13, which did not accord with the given information. Or, in the case of “Bridge of Nose” in Table V, the 95%CI was not even around the mean (mean = –0.063, CI= –0.20, –0.57)! Hence, I re-calculated the CIs using the provided means, SDs, and n=13, based on two distributions: normal and t (Tables II–III). The t distribution produced completely different CIs, while the normal distribution provided some similarities to the original report. However, even in that case, many original CIs were extremely different from CIs calculated using means/SDs. I think many calculated CIs are seriously erroneous. Any clarifications are appreciated.

      Table I. The corrected “(maximum error)” values alongside the originally reported incorrect ones. Both columns show the original 95%CIs on the left of each column (exactly the same in both columns and borrowed from Nadjmi et al). On the right side of each column, stands the “(maximum error)” within the parentheses block. In the left column, this value is incorrectly calculated (in red font). The corrected one is visible in the right column.

      Table II. The 95% confidence intervals (based on normal distribution) for the means reported in Tables II to IV of Nadjmi et al. Only the rows in bold blue font comprise original CIs matching my CIs from means and SDs. The rest of original CIs were inconsistent with the mean/SD (highlighted in yellow). Moreover, of those questionable original CIs (highlighted in yellow), some were strangely different from what they should be according to the reported means and SDs. They are written in red bold font.

      Table III. The 95% confidence intervals for the means reported in Tables II to V of Nadjmi et al.1 calculated based on the t distribution. None of these CI values were similar to the CI values reported by Nadjmi et al.


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    1. On 2014 Apr 03, David Geter commented:

      The reference within of Gollapudi et al., 2011 detailing the dose-response of phenobarbital in CD-1 mice is now published as: Geter DR, V Bhat, BB Gollapudi, R Sura, S Hester. (2014). Dose-response modeling of early molecular and cellular key events in the CAR-mediated hepatocarcinogenesis pathway. Toxicological Sciences. 138(2):425-45. PubMed ID: 24449422.


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

      This study, along with another study in the same area, was discussed on May 27th and June 3rd 2015 in the open online nephrology journal club, #NephJC, on twitter.

      Introductory comments are available at the NephJC website. The discussion was quite animated, with more than 50 participants, including nephrologists, fellows and residents.

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

      The highlights of the tweetchat were:

      • The participants thought true diuretic resistance requires higher doses and correct combinations of diuretics (e.g. furosemide, metolazone and spironolactone), and were hence not convinced with the data presented. Similar concerns were expressed about the severity of heart failure, and the low rate of device usage (e.g. defibrillators)

      • Given the negative outcomes from a similar trial with ultrafiltration, CARESS-HF, the discussants were not impressed with the hypothetical increased sodium removal compared with diuresis.

      • However, there was unanimity that peritoneal dialysis is a promising approach, and that this should be tested in a properly designed randomized trial. There was much discussion around possible inclusion criteria, comparators (standard care or left ventricular assist devices) and feasibility of arranging peritoneal dialysis. One such trial is already underway in UK and those results will be keenly followed.

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


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    1. On 2014 May 22, David Goldfarb commented:

      This article was selected as CJASN's electronic journal club (eJC) for January 2014. The discussion can be accessed (with a free log-in for the American Society of Nephrology) at: http://ejc.cjasn.org/phpBB3/EJCArchives.php


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    1. On 2013 Dec 02, MARK VRABEL commented:

      Thanks for writing this, Jon -- Blair told me about it. In addition to the 47 references in your article, there are several Cochrane systematic reviews on antiretroviral therapy, topical microbicides, etc. for HIV prevention, such as PMID 23633367, 22786505, and 22696373.


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    1. On 2013 Nov 05, Allison Stelling commented:

      The ECM section of this paper ((c) Tumor-stromal extra-cellular matrix-ECM-dependent interactions) lends weight to the idea that the ECM constituents of cellular secretions themselves may constitute a viable biomarker for "tumor-like" microenvironments.

      Further physiochemical investigations into the unique biochemical phenotypes generated by tumor cells may be quite helpful for addressing issues with drug delivery, and provide new targets for drug design. (For example, the degree of cross-linking seen between collagens in the matrix would alter the density, possibly things like polarity/ability to H-bond, etc.)


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    1. On 2014 Jul 30, Jim Woodgett commented:

      This compound was not tested in vitro against GSK-3alpha. Given the virtual identity in the active (ATP binding) site of these two isoforms, it is extremely probable that these compounds also inhibit GSK-3alpha with very similar potency to GSK-3beta. The authors also measured the effect of compound 21 (in comparison to LiCl) on tau phosphorylation in brains of mice. Notably, GSK-3alpha also phosphorylates tau and the observed effects are likely a result of combined inhibition of these related kinases.


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    1. On 2014 Jan 08, Brett Snodgrass commented:

      Dear Authors,

      Thank you for the excellent article.

      The vessels you report are consistent with those reported by Wearn. http://bit.ly/JTWearn

      Whether the definition "Fistula" is applied depends on how that term is defined. Strictly speaking it is not a "true fistula," as the connection is likely a normal structure, a vessel of Wearn. http://bit.ly/JTWearn

      The vessels described by Wearn are distinct form those described by Thebesius. http://bit.ly/Thebesius

      For additional commentary, please see https://twitter.com/BrettSnodgrass1/status/412316776702021632

      Comments and suggestions are welcome.

      Thank you kindly.


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    1. On 2014 May 23, Leonid Teytelman commented:

      Indeed, using MNase may be the solution. Please see Kasinathan S, 2014 "High-resolution mapping of transcription factor binding sites on native chromatin".


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    2. On 2014 May 22, L. Norton commented:

      Nice work. Background is certainly an issue in ChIP-Seq studies and I think one way to deal with this is to examine gene expression of the proposed targets following knock-down of the transcription factor. Although this is not a perfect solution, after doing these experiments it becomes apparent that very few ChIP-Seq binding events are 'functionally significant' in a way that we expect (i.e. effect transcription). As a side note, I wonder if you or anyone else has examined the impact of sonication vs. MNase digestion on this phenomenon?


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    3. On 2014 Apr 10, Leonid Teytelman commented:

      Below are other publications reporting the expression-associated ChIP artifact.

      Fan X, 2009 "Where Does Mediator Bind In Vivo?" (Work in S. cerevisiae questioning reports of pervasive genome-wide binding of the Mediator complex.)

      Waldminghaus T, 2010 "ChIP on Chip: surprising results are often artifacts" (Work in E. coli; also see arising correspondence Schindler D, 2013.)

      Park D, 2013 "Widespread Misinterpretable ChIP-seq Bias in Yeast" (Analysis very similar to ours.)

      Kasinathan S, 2014 "High-resolution mapping of transcription factor binding sites on native chromatin" (Questions specificity of standard ChIP in S. cerevisiae and at HOT regions of Drosophila. This work possibly provides a solution to the artifact with a modification of the ChIP technique.)


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