On 2017 Sep 18, Clive Bates commented:

A couple of great quotes from this report:

[Linda] Bauld commented “In the UK, regulators endeavour to balance the benefits of e-cigarettes (to help adults quit tobacco smoking) with any potential risks (protecting young people). Our evidence from a number of surveys is reassuring. Although some young people who do not smoke tobacco cigarettes are experimenting with e-cigarettes, this is not leading to regular e-cigarette use. Most experimentation and regular use of e-cigarettes is by young people who already smoke tobacco cigarettes. Importantly, smoking among adolescents is continuing to decline.”

...

John Britton (Nottingham University, Nottingham, UK) added “This study demonstrates again that experimentation with e-cigarettes among young people in the UK rarely leads to uptake of smoking. The findings should therefore help to reassure those who worry that the availability of e-cigarettes is increasing uptake of smoking. Combined with overwhelming evidence that e-cigarettes are helping thousands of UK smokers to quit smoking each year, this is excellent news for public health.”

On 2017 Sep 18, Clive Bates commented:

The Portland State University researchers display little awareness of the deep flaws in their 2015 attention-grabbing "Hidden Formaldehyde" NEJM paper - see Jensen RP, 2015 for the study and comments. Nowhere in the present paper do they check whether their operating conditions are a realistic proxy for user experience and therefore whether their findings have any real-world relevance. They dismiss the controversy over their previous paper as just differences in standardisation.

However, a major challenge is the lack of standardized analytical protocols. This issue has led to wide variations in interlaboratory results and has contributed to the dichotomy in the literature about electronic cigarettes and their potential health effects.

No, this diagnosis is incorrect. The wide variation is between researchers who use the products in unrealistic conditions and researchers who recognise the human use control feedback created by dry-puff conditions and so measure the products in realistic conditions. These authors are in the former category.

Creating a realistic proxy for human use does not appear to have influenced their choice of equiment settings. This was determined by:

Wattage settings of the battery unit used were 10 W and 15 W. These conditions were chosen to produce amounts total HCHO that could enable them to be conveniently distinguished, with the intent to produce a comparison between various sampling and analytical methods.

There are no human use considerations at all, as far as I can see. If they don't check for conditions that breach plausible human use, the whole work is unreliable as any sort of guide to e-cigarette health risks or for regulatory policy - just like the last one.

On 2018 Feb 04, Sin Hang Lee commented:

The medical profession, including medical schools and hospitals, is now a part of the health care industry, and implementation of editorial policies of medical journals is commonly biased in favor of business interests. PubMed Commons has offered the only, albeit constrained, open forum to air dissenting research and opinions in science-based language. Discontinuation of PubMed Commons will silence any questioning of the industry-sponsored promotional publications indexed in PubMed.

On 2017 Sep 21, Sin Hang Lee commented:

The narrative review titled “To test or not to test? Laboratory support for the diagnosis of Lyme borreliosis” by Dessau and colleagues[1] is a position paper of the authors. It is not a systematic review. A systemic review typically involves a detailed and comprehensive plan and search strategy derived a priori, with the goal of reducing bias by identifying, appraising, and synthesizing all relevant studies on a particular topic.[2] The gross biases in this position paper are:

1.Dessau and colleagues recognized “Lyme borreliosis (LB) is a tick-borne infection caused by Borrelia burgdorferi sensu lato.”, namely a bacterial infectious disease. However, the authors proposed using objective signs of clinical presentations to diagnose borreliosis[1], but failed to mention that the European Centre for Disease Prevention and Control requires detection of the pathogen’s nucleic acid in a clinical specimen and confirmation by DNA sequencing for diagnosis of any emerging infectious diseases, such as Ebola.[3] According to an official publication of the United States Centers for Disease Control and Prevention, the state of the art in diagnosing infectious diseases is by molecular approaches[4], in particular by 16S rRNA gene analysis for bacterial infectious diseases, such as anthrax.[5]

2.Dessau and colleagues stated that “clinicians are advised to avoid serological testing whenever the clinical symptoms are not indicative of LB according to the case definitions”. However, the case definitions which were written by some of the authors of the current position paper are “for reliable epidemiological studies and are of great value in clinical management[6]”, not for reliable diagnosis of Lyme borreliosis. In fact, in another recet review, two of the co-authors (Strle and Hovius) of the current narrative review stated on record that “Demonstration of borrelial infection by laboratory testing is required for reliable diagnosis of Lyme borreliosis, with the exception of erythema migrans.” [7] Therefore, at least two of the co-authors of this position paper[1] are advancing an agenda of managing clinical patients of Lyme borreliosis, an infectious disease, without a reliable diagnosis against their own beliefs.

3.The statement “Laboratory testing for antibodies to B. burgdorferi in serum is necessary for diagnosing suspected manifestations of LB such as Lyme carditis, borrelial lymphocytoma, Lyme arthritis, acrodermatitis chronica atrophicans and possibly other rare LB manifestations” while omitting direct DNA testing of blood for the diagnosis of spirochetemia is biased. At least two of the co-authors of this position paper knew and stated that the early stage of Lyme borreliosis infections “can be treated successfully with a 10–14 day course of antibiotics”, “serodiagnostic tests are insensitive during the first several weeks of infection” and if untreated “within days to weeks, the strains of B. burgdorferi in the United States commonly disseminate from the site of the tick bite to other regions of the body.”[7] Sensitive 16S rRNA gene analysis for the detection of Lyme borreliae in blood samples has been known since 1992.[8-12] Continued suppression of using direct DNA testing for the diagnosis of early Lyme borreliosis infections is no longer acceptable.

4.The authors of this position paper emphasized “an immune response with clinical findings, such as skin lesions, neurological signs, cardiac involvement (e.g. AV block), or arthritis involving the large joints”, but avoided mentioning that cardiac involvements may be due to myocarditis caused by spirochetes invading the myocardium.[13] The authors focused on management of the immune response in the cases of chronic Lyme neuroborreliosis because “there is no convincing evidence that B. burgdorferi produces any toxin.” It is well known that Treponema pallidum, the spirochetes causing neurosyphilis, also lacks a lipopolysaccharide endotoxin. However, it possesses abundant lipoproteins which induce inflammatory processes.[14] Would these authors recommend not to treat patients suffering from neurosyphilis with antibiotics?

In summary, this narrative review by Dessau and colleagues contains serious scientific biases and should not be used as materials to influence public health policy decisions or as guidelines to direct clinical practice.

References

[1] Dessau RB, van Dam AP, Fingerle V, Gray J, Hovius J, Hunfeld KP, Jaulhac B, Kahl O, Kristoferitsch W, Lindgren PE, Markowicz M, Mavin S, Ornstein K, Rupprecht T, Stanek G, Strle F. To test or not to test? Laboratory support for the diagnosis of Lyme borreliosis. Clin Microbiol Infect. 2017 Sep 5. pii: S1198-743X(17)30488-3.

[2] Uman LS. Systematic reviews and meta-analyses. J Can Acad Child Adolesc Psychiatry. 2011;20:57-9.

[3] http://ecdc.europa.eu/en/healthtopics/ebola_marburg_fevers/EVDcasedefinition/Pages/default.aspx

[4] CDC. State of the Art. Molecular Approaches to Diagnosing and Managing Infectious Diseases: Practicality and Costs https://wwwnc.cdc.gov/eid/article/7/2/70-0312_article

[5] Sacchi CT, et al. Sequencing of 16S rRNA gene: a rapid tool for identification of Bacillus anthracis. Emerg Infect Dis. 2002 Oct;8(10):1117-23.

[6] Stanek G, Fingerle V, Hunfeld KP, Jaulhac B, Kaiser R, Krause A, Kristoferitsch W, O'Connell S, Ornstein K, Strle F, Gray J. Lyme borreliosis: clinical case definitions for diagnosis and management in Europe. Clin Microbiol Infect. 2011;17:69-79.

[7] Steere AC, Strle F, Wormser GP, Hu LT, Branda JA, Hovius JW, Li X, Mead PS. Lyme borreliosis. Nat Rev Dis Primers. 2016 Dec 15;2:16090.

[8] Marconi RT Garon CF . Development of polymerase chain reaction primer sets for diagnosis of Lyme disease and for species-specific identification of Lyme disease isolates by 16S rRNA signature nucleotide analysis. J Clin Microbiol . 1992;30:2830–2834.

[9] Cyr TL, et al Improving the specificity of 16S rDNA–based polymerase chain reaction for detecting Borrelia burgdorferi sensu lato–causative agents of human Lyme disease. J Appl Microbiol . 2005;98:962–970.

[10] Santino I, et al. Detection of Borrelia burgdorferi sensu lato DNA by PCR in serum of patients with clinical symptoms of Lyme borreliosis. FEMS Microbiol Lett . 2008;283:30–35.

[11] Lee SH, et al. Early Lyme disease with spirochetemia - diagnosed by DNA sequencing. BMC Res Notes. 2010 Nov 1;3:273. doi: 10.1186/1756-0500-3-273.

[12] Lee SH, et al. DNA sequencing diagnosis of off-season spirochetemia with low bacterial density in Borrelia burgdorferi and Borrelia miyamotoi infections. Int J Mol Sci. 2014 Jun 25;15(7):11364-86.

[13] Muehlenbachs A, et al. Cardiac Tropism of Borrelia burgdorferi: An Autopsy Study of Sudden Cardiac Death Associated with Lyme Carditis. Am J Pathol. 2016;186:1195-205.

[14] https://www.ncbi.nlm.nih.gov/books/NBK7716/

Conflicts of Interest: Sin Hang Lee, MD is the director of Milford Molecular Diagnostics Laboratory specialized in developing DNA sequencing-based diagnostic tests.

On 2018 Feb 04, Sin Hang Lee commented:

The medical profession, including medical schools and hospitals, is now a part of the health care industry, and implementation of editorial policies of medical journals is commonly biased in favor of business interests. PubMed Commons has offered the only, albeit constrained, open forum to air dissenting research and opinions in science-based language. Discontinuation of PubMed Commons will silence any questioning of the industry-sponsored promotional publications indexed in PubMed.

On 2018 Jan 14, Sin Hang Lee commented:

The review by Mohsen and colleagues, titled “Major findings and recent advances in virus-like particle (VLP)-based vaccines”, correctly pointed out that bacterial or viral nucleic acids are probably the real active adjuvants through activation of various toll like receptors (TLRs) in the antigen-presenting cells (APCs) to boost innate immune responses in VLP-based vaccinations, as illustrated in Fig. 5 of the review article. However, in Section “HPV VLP-based vaccines” the authors merely mentioned the facts that Gardasil® is adjuvanted with amorphous aluminum hydroxyphosphate sulfate (AAHS) and that Cervarix® contains an aluminum hydroxide-based AS04 adjuvant which carries TLR4 agonist 3-0-descyl-4'-monophosphoryl lipid A (MPL)- a moiety of the cell wall lipopolysaccharide of Salmonella Minnesota. Since HPV vaccination is now being carried out in large scale, additional discussion on these two VLP-based vaccines is warranted.

In spite of the fact that VLPs are more immunogenic than the same epitopes displayed repetitively on a flexible polymer, both aforementioned VLP-based HPV vaccines still need special proprietary aluminum salt adjuvants to boost the immune responses of the host to reach sustained high levels of genotype-specific anti-HPV L1 antibodies for protective efficacy. Immunization with HPV L1 VLPs formulated with AAHS elicited a significantly stronger immune response with higher peak antibody titers both at four weeks post vaccination (12.7 to 41.9-fold higher) as well as in the persistent phase at week 52 (4.3 to 26.7-fold higher) than that with HPV L1 VLPs alone. [1] The AS04 formulation Cervarix® elicited an increased frequency (2.2-5.2-fold) of HPV L1 VLP specific memory B cells when compared with the aluminum salt only formulations. [2]

However, aluminum salts do not activate TLRs. They simply bind and carry the TLR agonists into the APCs. The addition of TLR agonists as adjuvant to a vaccine product is a logical choice to enhance innate immune response needed for effective vaccination. The TLR4 agonist MPL bound to aluminum hydroxide (AS04) is used in licensed vaccines against hepatitis B and human papilloma virus (Cervarix®). The effect of other TLR agonists, including TLR9 agonist CpG ODN which is known to enhance the antibody response in mice to hepatitis B antigen formulated with aluminum hydroxide, on the immune response to aluminum-adjuvanted vaccines has been investigated, but this has not yet led to licensed products. [3]

To function as an effective adjuvant in vaccination, a TLR agonist molecule either in the form of MPL or in the form of a nucleic acid must bind the cationic aluminum salt loosely or partially so that part of its linear molecule can make contact with the TLR [4]. If a bacterial or viral nucleic acid is used as the TLR9 agonist, the agonist molecule must be rendered resistant to nuclease attack, thus increasing its in vivo half-life [5].

Although both AS04 and AAHS are commonly labeled as special proprietary “vaccine adjuvants” and both prepared by partial ligand exchange of a phosphate group for a hydroxyl group on aluminum hydroxide, there is a big difference between these two “adjuvants” in that for AS04 the phosphate group is TLR4 agonist MPL while for AAHS the phosphate group is an inorganic anionic phosphate which is immunologically inert. When AAHS is used as an adjuvant in formulation of recombinant hepatitis B vaccine (Merck), some of the hydroxyl groups on the AAHS are exchanged for the phosphate groups of the phospholipid-containing hepatitis B surface antigen [6] that the phospholipid moiety of the viral surface antigen actually serves as TLR4 agonist [7]. However, for Gardasil® formulation with AAHS there is no disclosed TLR agonist.

In compliance with good manufacturing practice for vaccine production, the HPV VLPs have been rendered free of packaged DNA [8, 9]. However, Gardasil® does contain recombinant HPV L1-specific DNA fragments [10, 11], and at least some of these viral DNA fragments bound to the AAHS particles have assumed non-B topological conformations [12], thus rendered resistant to nuclease degradation after being transfected into APCs. These viral DNA fragments bound to AAHS in non-B conformations can serve as potent long-acting TLR9 agonist.

In theory, the major difference between Cervarix® and Gardasil® in the mechanism of stimulating immune response seems to be that Cervarix® depends on using an MPL bound to cationic aluminum to activate the TLR4 located on the surface of innate immune cells [13] while Gardasil® uses HPV L1 gene DNA fragments also bound to cationic aluminum to activate the TLR9 located in the endosome of the immune cells [13]. In general, TLR4 activation by MPL (AS04) induces cytokine cascades of both Th1 and Th2 type responses with a probably preferential bias toward induction of a Th2 phenotype while TLR9 activation favors induction of pro-inflammatory and Th1 cytokines (for example, IL-6, IL-1, TNFα, IFNγ and IL-12). [14] However, Cervarix® may contain HPV L1 DNA fragments as well, and both the DNA and MPL molecules may attach side-by-side to the same cationic aluminum; the juxtaposition of these two linear molecules may change the shape of the DNA and interfere with conventional PCR amplification for DNA detection. In addition, TLR9 activation may be effected by more than one category of agonists. Therefore, additional research on TLR activation is needed for further improvement of safety and efficacy in HPV vaccination.

References

[1] Ruiz W, et al. Kinetics and isotype profile of antibody responses in rhesus macaques induced following vaccination with HPV 6, 11, 16 and 18 L1-virus-like particles formulated with or without Merck aluminum adjuvant. J Immune Based Ther Vaccines. 2005;3:2.

[2] Giannini SL, et al. Enhanced humoral and memory B cellular immunity using HPV16/18 L1 VLP vaccine formulated with the MPL/aluminium salt combination (AS04) compared to aluminium salt only. Vaccine. 2006;24:5937-49.

[3] Hogenesch H. Mechanism of immunopotentiation and safety of aluminum adjuvants. Front Immunol. 2013;3:406.

[4] Tagliabue A, Rappuoli R. Vaccine adjuvants: the dream becomes real. Hum Vaccin. 2008;4:347-9.

[5] Aebig JA, et al. Formulation of vaccines containing CpG oligonucleotides and alum. J Immunol Methods. 2007;323:139-46.

[6] Egan PM, et al. Relationship between tightness of binding and immunogenicity in an aluminum-containing adjuvant-adsorbed hepatitis B vaccine. Vaccine. 2009;27:3175-80.

[7] Wong-Baeza C, et al. Nonbilayer Phospholipid Arrangements Are Toll-Like Receptor-2/6 and TLR-4 Agonists and Trigger Inflammation in a Mouse Model Resembling Human Lupus. J Immunol Res. 2015;2015:369462.

[8] Frazer IH. Eradicating HPV-Associated Cancer Through Immunization: A Glass Half Full…. Viral Immunol. 2018 Jan 3. doi: 10.1089/vim.2017.0119.

[9] Mach H, et al. Disassembly and reassembly of yeast-derived recombinant human papillomavirus virus-like particles (HPV VLPs). J Pharm Sci. 2006 Oct;95(10):2195-206.

[10] Lee SH. Detection of human papillomavirus (HPV) L1 gene DNA possibly bound to particulate aluminum adjuvant in the HPV vaccine Gardasil. J Inorg Biochem. 2012;117:85-92.

[11] FDA Information on Gardasil – Presence of DNA Fragments Expected, No Safety Risk. http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm276859.htm

[12] Lee SH. Melting profiles may affect detection of residual HPV L1 gene DNA fragments in Gardasil®. Curr Med Chem. 2014;21:932-40.

[13] O'Neill LA, et al. The history of Toll-like receptors - redefining innate immunity. Nat Rev Immunol. 2013;13:453-60.

[14] Dowling JK, Mansell A. Toll-like receptors: the swiss army knife of immunity and vaccine development. Clin Transl Immunology. 2016;5(5):e85.

Conflicts of Interest: Sin Hang Lee, MD is the director of Milford Molecular Diagnostics Laboratory specialized in developing DNA sequencing-based diagnostic tests.

On 2018 Jan 13, Sin Hang Lee commented:

None

On 2017 Sep 18, Clive Bates commented:

The paper provides a very unsatisfactory contribution to the literature on e-cigarettes and harm reduction, from which no useful policy conclusions can be drawn.

CONCLUSIONS: E-cigarette use, which is common in adults with or at risk for COPD, was associated with worse pulmonary-related health outcomes, but not with cessation of smoking conventional cigarettes. ​

But it turns out that e-cigarette use was associated with more intensive smoking in the past.

E-cigarette users had a heavier conventional cigarette smoking history and worse respiratory health, were less likely to reduce or quit conventional cigarette smoking, had higher nicotine dependence, and were more likely to report chronic bronchitis and exacerbations.

This likely explains the difference in respiratory health and why more heavily dependent users may find it harder to quit. In other words, it is nothing to do with e-cigarettes, the use of which is probably just a marker of more intensive smoking, higher dependency and greater difficulty quitting - not caused by e-cigarette use. It is the smoking history that matters.

From this the authors add to their conclusion:

Although this was an observational study, we find no evidence supporting the use of e-cigarettes as a harm reduction strategy among current smokers with or at risk for COPD.

​It is literally true that they "find no evidence...", but that is because this study is completely ill-suited to drawing any policy conclusions about e-cigarettes and COPD. Despite hinting at the limitations of cross-sectional data, the authors draw a negative-sounding conclusion without addressing the key question of how respiratory health changes for a given smoker who uses e-cigarettes to quit or cut down once they are ill from smoking or as a way of preventing COPD.

For respiratory physicians wondering what to do in the interest of their patients, Polosa R, 2016 Evidence for harm reduction in COPD smokers who switch to electronic cigarettes might be more useful.

A whole new level of over-interpretation is achieved in the press statements that accompany this paper.

"The data further suggest that there's no clear benefit of e-cigarettes as a harm-reduction strategy in this population of smokers with or at-risk for COPD."

This effortlessly moves from a no-evidence-of-effect (the paper) to evidence-of-no-effect (the press statement). I'm sure the authors will be embarrassed by that.

On 2017 Nov 04, Arnaud Chiolero MD PhD commented:

I fear that we will not survive. But this is not new - evidence has never matched public health and clinical practice.

On 2017 Sep 13, Francesco Brigo commented:

Very nice study. Congratulations! This has reminded me about the recent exhumation of the body of Salvador Dalì. According to forensic experts, his moustache was still inact, pointing to 10-past-10, just as he wanted. Francesco Brigo, University of Verona, Italy

On 2017 Oct 02, Donald Forsdyke commented:

VIRAL REPRODUCTIVE ISOLATION WITHIN A COMMON HOST CELL

This otherwise admirable article (Hunter P, 2017) begins with the curious assertion that, "since they depend on their host for replication," then viruses cannot "be categorized as species on the basis of reproductive isolation." The latter prevents recombination between organisms and so forms the most generally accepted definition of species. Virus species whose members share a common host cell, and depend on that cell for their replication, are still able to retain their species individuality. Their members do not mutually destroy each other by recombinational blending of their genomes. They are reproductively isolated from each other.

When we compare two viral species that have a common host cell, with two viral species that, even within a common host, do not share a common cell, we would expect to observe a fundamental difference related to their reproductive isolation mechanisms. If that difference is found to apply to other viral pairs that occupy a common host cell, then a fundamental isolation mechanism has been identified.

Such a difference was first related to the base compositions of insect viruses (1), a then to the base compositions of herpes viruses (2). A more extreme example arose from studies of retroviruses that share a T-lymphocyte host. The AIDS virus (HIV1) and human T cell leukaemia virus (HTLV1), can be assumed to have evolved from a common ancestor. Differentiation of members of that ancestral species within a common host cell into two independent populations would have required some mechanism to prevent their blending. Thus, we see today a wide divergence in base compositions. HIV1 is one of the highest AT-rich species know. HTLV1 is one of the highest GC-rich species known (3). There is high differentiation of chromosomal nucleic acids.

In these viruses there has been no opportunity for other reproductive isolation mechanisms to supersede chromosomal mechanisms. Diffusible cytoplasmic products make the subsequent evolution of genic incompatibilities less likely, and being in a common host cell there is no equivalent of prezygotic isolation as conventionally understood (4).

1. Wyatt GR (1952) The nucleic acids of some insect viruses. J Gen Physiol 36:201-205. WYATT GR, 1952
2. Schachtel GA et al. (1991) Evidence for selective evolution of codon usage in conserved amino acid segments of human alphaherpesvirus proteins. J Mol Evol 33:483-494. Schachtel GA, 1991
3. Bronson EC, Anderson JN (1994) Nucleotide composition as a driving force in the evolution of retroviruses. J Mol Evol 38:506-532. Bronson EC, 1994
4. Forsdyke DR (1996) Different biological species broadcast their DNAs at different (G+C)% wavelengths. J Theoret Biol 178:405-417. Forsdyke DR, 1996% "wavelengths".")

On 2018 Feb 01, Joe G. Gitchell commented:

Readers may find this correspondence responding to the Kostygnia et al paper (https://www.ncbi.nlm.nih.gov/pubmed/27077338) of interest, too:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5105003/

On 2017 Sep 27, Donald Forsdyke commented:

"CLOSE TO SELF" AND "NEAR SELF"

A major conclusion of this elegant modeling study is that "TCR selection against self-peptides has a minimal influence on the recognition of peptides which are 'close' to self." Thus, "TCR negative selection by host peptides has only a weak suppressive effect on detecting peptides which closely resemble self." This agrees with a somewhat less elegant modeling study that invoked lymphocyte clones selected for anti-"near-self" immune reactivity. These would normally have escaped negative selection (i.e. would have been positively selected; 1). The "near-self" viewpoint contrasted with the then prevailing "altered self" viewpoint (2). However, whereas George et al. (2017) regard their study as "empirical," the earlier study (1) arose from consideration of alloreactive phenomena and recognized implications for cancer immunotherapy in keeping with an "overall objective of optimizing CRL therapy" (3, 4). Full historical reviews are available (5, 6).

1. 1.Forsdyke DR (1975) Further implications of a theory of immunity. J Theor Biol 52: l87-l98.Forsdyke DR, 1975

2. 2.Forsdyke DR (2005) "Altered-self" or "near-self" in the positive selection of lymphocyte repertoires? Immunol Lett 100: 103-106.Forsdyke DR, 2005

3. 3.Forsdyke (1977) Grant application

4. 4.Forsdyke DR (1999) Heat shock proteins as mediators of aggregation-induced "danger" signals: implications of the slow evolutionary fine-tuning of sequences for the antigenicity of cancer cel1s. Cell Stress Chaperone 4: 205-210.Forsdyke DR, 1999

5. 5.Forsdyke DR (2012) Immunology (1955-1975): The natural selection theory, the two signal hypothesis and positive repertoire selection. J Hist Biol 45: 139-161.Forsdyke DR, 2012

6. 6.Forsdyke DR (2015) Lymphocyte repertoire selection and intracellular self/not-self discrimination: historical overview. Immun Cell Biol 93: 297-304.Forsdyke DR, 2015

On 2017 Sep 13, Haibao Tang commented:

No major flaws in "Identification of individuals by trait prediction using whole-genome sequencing data"

For a complete discussion, please also read authors' response to Erlich's critique:

http://www.biorxiv.org/content/early/2017/09/11/187542

Abstract

In a recently published PNAS article, we studied the identifiability of genomic samples using machine learning methods [Lippert et al., 2017]. In a response, Erlich [2017] argued that our work contained major flaws. The main technical critique of Erlich [2017] builds on a simulation experiment that shows that our proposed algorithm, which uses only a genomic sample for identification, performed no better than a strategy that uses demographic variables. Below, we show why this comparison is misleading and provide a detailed discussion of the key critical points in our analysis that have been brought up in Erlich [2017] and in the media. We also want to point out that it is not only faces that may be derived from DNA, but a wide range of phenotypes and demographic variables. In this light, the main contribution of Lippert et al. [2017] is an algorithm that identifies genomes of individuals by combining DNA-based predictive models for multiple traits.

On 2017 Sep 08, Yaniv Erlich commented:

Major flaws in "Identification of individuals by trait prediction using whole-genome"

Check the following bioRxiv link for a full explanation on the methodological problems in this paper: http://www.biorxiv.org/content/early/2017/09/06/185330

Abstract

Genetic privacy is an area of active research. While it is important to identify new risks, it is equally crucial to supply policymakers with accurate information based on scientific evidence. Recently, Lippert et al. (PNAS, 2017) investigated the status of genetic privacy using trait-predictions from whole genome sequencing. The authors sequenced a cohort of about 1000 individuals and collected a range of demographic, visible, and digital traits such as age, sex, height, face morphology, and a voice signature. They attempted to use the genetic features in order to predict those traits and re-identify the individuals from small pool using the trait predictions. Here, I report major flaws in the Lippert et al. manuscript. In short, the authors' technique performs similarly to a simple baseline procedure, does not utilize the power of whole genome markers, uses technically wrong metrics, and finally does not really identify anyone.

On 2017 Sep 19, Helmi BEN SAAD commented:

The exact names of authors are: Ben Khelifa M, Ben Salem H, Sfaxi R, Chatti S, Rouatbi S, Ben Saad H"

On 2017 Sep 22, Ryan Jajosky commented:

After asking the FDA for clarification, I was directed to the FDA's Blood Products Advisory Committee Transcript... which states the following "Babesia microti is among the most frequently transfusion transmitted infections reported to FDA, with associated fatalities, for which no donor testing is available."

https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/BloodVaccinesandOtherBiologics/BloodProductsAdvisoryCommittee/UCM449523.pdf

The FDA has labelled the page number 9 (which corresponds to digital page number 11).

So, this statement may have been misinterpreted to mean that "Babesia is the most common transfusion transmitted infection in the United States".

On 2017 Sep 09, Clive Bates commented:

The authors of the original study Jensen RP, 2015 should now correct or retract their findings. The key weakness in their work was an attention-grabbing calculation of formaldehyde-related excess cancer risk. It was this that gained the authors world wide media coverage.

The problem for the authors is that cancer is a human condition and their calculation is based exposures measured by a lab machine in conditions that no humans would be able to tolerate.

It is thus a wholly flawed and misleading paper. Yet it has been cited 141 times as of - 9 Sept 2017, and continues to mislead and contaminate the literature with its baseless assertions about formaldehyde exposure and cancer risk.

On 2017 Oct 27, Thomas Jové commented:

I would like to point out that the right citation for the localisation of the Pc promoter from the IntIA Vibrio cholerae integron is PMID24614503 (Krin et al., 2014) and not PMID22287520 (Baharoglu et al., 2012) as stated in the discussion section of our paper. Our apologies for the inconvenience.

On 2017 Sep 25, Franz Schelling commented:

What appears rather strange is, besides, this fact: The massive changes found to affect the MS lesions' central veins themselves as well as their perivascular spaces are hardly anywhere taken into account

On 2017 Sep 25, Franz Schelling commented:

It is a pity this study offers no explanation for the following: (a) the prominent involvement of the inner cerebral veins (Zeng ea 2013); (b) the abrupt respectively gradual destruction of large subependymal collecting veins (Adams 1989); (c) the extension of these changes on certain segments of mainly the cerebral hemispheres' periventricular veins, first shown by Charcot in 1866, explicitly pointed out by Bruce in 1911, traced in 3D reconstructions by Putnam Adler in 1937 and the most thoroughly and comprehensively by Fog in 1964/5; (d) the absence of any evidence regarding a vein-dependent development of the lesions affecting the spinal cord in MS; and, above all, (e) the lesion dynamics revealed at http://www.msdiscovery.org/news/news_synthesis/322-more-meets-eye. References on request.

On 2017 Sep 18, David Hubbard commented:

Reposted from ResearchGate A new model of MS pathogenesis is reviewed in which the primary mechanism is not immunopathology but instead blood-brain barrier disruption and hypoperfusion: “The focus on the peripheral immune system alone may be limiting our understanding of the disease and the success of developing therapies.” The authors note that all current immunomodulatory therapies act on downstream immune-mediated pathology and provide no treatment for progressive disease or cure. A review of research demonstrates that BBB disruption is present at the earliest stages of disease, preceding symptoms, enhancing lesions, or other MRI changes. Global hypoperfusion is present before any grey matter volume loss and is out of proportion to reduced metabolic demand associated with axonal loss. They propose that oxidative stress secondary to chronic hypoxia causes oligodendrocyte degeneration and selective myelin loss which then leads to immune cell infiltration secondarily.

Finally, the diagnosis and treatment of MS shifts from suppressing T-cells and to perfusing oligodendrocytes.

On 2017 Sep 14, Alessandro Rasman commented:

Giampiero Avruscio MD and Alessandro Rasman

We read with interest the paper from Spencer et al. titled "Vascular pathology in multiple sclerosis: reframing pathogenesis around the blood-brain barrier" (1). Nice review but no mention of pressure, flow, gradient, G-lymphatics. And we find it really curious that the authors are now acting as though it's a surprise there is a vascular pathogenesis in MS. We know the blood brain barrier breaksdown occurs before demyelination. There’s a paper on this from 1990 (2). This ain't new.

References: 1. Spencer, Jonathan I., Jack S. Bell, and Gabriele C. DeLuca. "Vascular pathology in multiple sclerosis: reframing pathogenesis around the blood-brain barrier." J Neurol Neurosurg Psychiatry (2017): jnnp-2017. 2. Kermode, A. G., et al. "Breakdown of the blood-brain barrier precedes symptoms and other MRI signs of new lesions in multiple sclerosis: pathogenetic and clinical implications." Brain 113.5 (1990): 1477-1489.

On 2017 Sep 08, Harald HHW Schmidt commented:

This is a poorly reviewed paper. I cannot detect any evidence that this peptide is specific for sGC nor that it would act via sGC-alpha1 to induce apoptosis.

On 2017 Sep 01, Daniel Corcos commented:

Maybe women who did not find believable the statements about overdiagnosis showed good judgement. Overdiagnosis only accounts for a small part of excess cancers observed after mammography screening.

On 2017 Sep 30, Alessandro Rasman commented:

Very interesting study. It is important now to test it on humans because there are doubts about the utility of the EAE model in the MS (1). References: 1. Behan, Peter O., and Abhijit Chaudhuri. "EAE is not a useful model for demyelinating disease." Multiple Sclerosis and Related Disorders 3.5 (2014): 565-574.

On 2017 Sep 20, christian lino cardenas commented:

Hdac9 gene encode different isoforms. it would be interesting to know which isoform miR-182 is targeting and whether such interaction occurs in humans.

On 2017 Aug 31, Varshil Mehta commented:

Great work team!

On 2017 Nov 28, Natalie Clairoux commented:

Free version of this article available at https://papyrus.bib.umontreal.ca/xmlui/handle/1866/19536

On 2017 Sep 15, Anna Selva commented:

Thank you. We are glad this strategy have been added to ISSG Search Filters Resource. It will help its diffusion to potential users.

On 2017 Sep 05, Kath Wright commented:

I agree this is a useful addition to the literature. It's been added to the issg Search Filter Resource at https://sites.google.com/a/york.ac.uk/issg-search-filters-resource/filters-to-identify-studies-of-public-views-and-patient-issues

On 2017 Sep 15, Anna Selva commented:

Thank you. The copy-paste version is available under request. Please, contact the corresponding author and we will provide it to you.

On 2017 Sep 03, Hilda Bastian commented:

This is a useful addition on an important topic, and is a good resource for other similar search strategies. Given it is such a long search strategy, it would be useful if the authors could provide a cut and paste version. Small point: the KiMS search strategy cited with reference number 27 in the article is actually at reference number 28 (Wessels M, 2016).

On 2017 Sep 03, Honglin Jia commented:

A recent report about RON4 in T.gondii should be refered. Wang et al., The moving junction protein RON4, although not critical, facilitates host cell invasion and stabilizes MJ members.Parasitology.

On 2017 Oct 06, Susan Altfeld commented:

We thank Dr. Mages for his interest in our work; however, we do not agree with his assessment. While it would have been more precise to talk about “non-Hispanic Black mothers” and “Hispanic mothers”, the authors of the paper we were citing (Colson, Willinger, Rybin et al., 2013) themselves refer to “non-Hispanic Black infants” and “Hispanic infants” in their study (most likely adhering to the NCHS standard of attributing mother’s race-ethnicity to the infant.) We are aware of the difference between race and ethnicity, but are not sure what point Mages was trying to make, as combining the two in demographic categories (e.g. “non-Hispanic black”) is standard practice in reporting epidemiological data (hence the common use of the term “race/ethnicity”.) The focus of our commentary was not racial/ethnic differences in SUID rates, but on the need for a more nuanced, harm reduction approach to safe sleep messaging. Many caregivers, of diverse backgrounds, have failed to adhere to abstinence messages regarding infant sleep and new approaches are needed to impact caregiver knowledge and behavior.

On 2017 Oct 01, David Mage commented:

Altfeld et al., PMID: 28838726, made an excellent study of the recent efforts to reduce sleep-related infant deaths in the U.S. However, they made both an explicit error and an implicit error that needs to be called to the readers’ attention:

Explicit Error: On page 2, they refer to “mothers of non-Hispanic Black infants” and “mothers of Hispanic infants.” [NB: Hispanic is an ethnicity and not a race] Apparently, the authors did not read carefully their references [1, 2, 21] and the Technical Notes cited therein. The CDC and NCHS both explicitly state that their cited racial data are either the mother’s self-identified race if monoracial, or “To provide uniformity and comparability of these data [to census data, per OMB requirement], multiple race [of mother] is imputed to a single race.” (see NCHS Technical Notes). The authors of reference 21 conducted an evening at-the-door survey of parents of recently born infants, and “Participants were asked: ‘Which of the following best describes [your, or] the mother's race or ethnic background?’ They were then read a list but also given the option to name one that was not listed.” The mother answered 84% of the time and 16% of the time another adult person responded for her;

Implicit Error: The authors seem to have forgotten that the father of an infant often plays a role in the determination of the race of the infant. I used the word “often” instead of always because “Tis a wise child that knows its own father.” [Puddn’head Wilson, Mark Twain] {Old Burlesque joke: Enter little redhaired boy. Clown: What lovely red hair you have. Do mommy and daddy have red hair too? Little Boy: No --- But we do have a milkman with red hair. (audience laughs) Exit boy.} Therefore, implicitly, the self-identified race of the mother is the same race as the infant if, and only if, the mother is monoracial, and the father (either known or unknown) is the identical race as the mother.

On 2017 Dec 03, Donald Forsdyke commented:

REDESIGNATING SELF AS NOT-SELF MARKERS

A cell's altruistic service to the population of cells that comprise its host organism may be compromised by a foreign pathogen or by a mutated driver cancer gene (both deemed "non-self"). Such intracellular compromising agents can first be addressed by internal sensing and auto-destructive mechanisms. Should one of these fail, then external sensing and destructive mechanisms, involving reactions with specific predatory T cells, may come into play. A compromised cell has the option of displaying peptides as pMHC complexes to see if they are recognized by members of T cell populations that, following thymic surveillance and deletion of nascent strongly self-reacting T cells, are programed to eliminate cells displaying non-self markers.

While such markers may arise from foreign proteins or mutated self proteins, Mishto and Liepe note that the scope of markers ("the antigenic landscape") can be greatly increased by redesignating potential self markers (unspliced peptides in pMHC complexes) as non-self (1). This creation of foreign from self is achieved by splicing and trimming non-contiguous peptides to create novel peptides that would not have passed thymic filters and so would be seen as non-self. Two corollaries of this are that such peptide splicing must not occur in the thymus and that, to militate against autoimmunity, extra-thymic specific splicing of separate protein segments would not occur randomly in uncompromised cells.

Thus, some elements of an internal sensing mechanism within a compromised cell would be needed to foster an extension of the antigenic landscape. The growing evidence for such a mechanism in the antigen presentation pathway (intracellular self/non-self discrimination) is presented elsewhere (2). I agree that "the unexpectedly large frequency and amount of … spliced peptides may … have profound implications for the concept of self/nonself peptide presentation" (3).

1.Mishto M, Liepe J. (2017) Post-translational peptide splicing and T cell responses. Trends in Immunology 38:904-915 Mishto M, 2017

2.Forsdyke DR (2015) Lymphocyte repertoire selection and intracellular self/not-self discrimination: historical overview. Immunology and Cell Biology 93:297-304. Forsdyke DR, 2015

3.Liepe J et al. (2016) A large fraction of HLA class I ligands are proteasome-generated spliced peptides. Science 354:354-358.Liepe J, 2016

On 2017 Oct 28, Daniel Weiss commented:

Karter et. al describe a tool to predict the risk of hypoglycemia in persons with Type 2 Diabetes. This tool confirms obvious, well-established clinical observations: sulfonylureas and insulin are associated with an increased risk of hypoglycemia. Three points are worth clarifying.

First, this tool was developed in the Kaiser Permanente of Northern California health care system where practitioners have a very limited choice of agents for Type 2 Diabetes. In that system and the Veterans Health Administration, the usage of drugs that do not tend to cause hypoglycemia is restricted due to cost. Yet, glucagon-like peptide-1 (GLP-1) receptor agonists have been available since 2005 and the first sodium-glucose cotransporter-2 (SGLT2) inhibitor was approved in 2013. Although less effective, dipeptidyl peptidase-4 (DPP-4) inhibitors have been around since 2007. All these drug classes cost more than sulfonylureas but none put patients at risk for hypoglycemia.

In large part, because of that risk of hypoglycemia, the American Association of Clinical Endocrinologists algorithm (1) for pharmacotherapy of Type 2 Diabetes judges sulfonylureas as the worst option. Indeed, the annual rate of hypoglycemia was lowest in the Group Health Cooperative patients where sulfonylureas were used less frequently.

Second, the authors fail to account for the type of insulin prescribed. They lump all insulins together. And they discuss skipping meals as a cause of hypoglycemia. All insulins are not the same. For example, NPH insulin is associated with a greater risk of hypoglycemia than is insulin glargine in head to head trials (2). And the pharmacokinetics of NPH insulin are such that insulin levels often peak when the patient is not eating. Well-designed insulin regimens allow patients to skip meals with no problem.

Third, in their lengthy discussion on steps to reduce the risk of hypoglycemia, the authors fail to even mention choosing effective agents that do not cause hypoglycemia such as GLP-1 receptor agonists or SGLT-2 inhibitors. And some of these newer agents have now been demonstrated to reduce cardiovascular events and mortality.

The authors focus on population approaches, not the best care for the individual patient in the exam room.

Conflict of Interest Disclosures: This commenter receives clinical research funding and speaker honoraria from multiple pharmaceutical companies that market medication for diabetes.

1. Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus Statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the Comprehensive Type 2 Diabetes Management Algorithm - 2017 Executive Summary. Endocr Pract. 2017;23(2):207-238.
2. Riddle MC, Rosenstock J, Gerich J, Insulin Glargine Study I. The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care. 2003;26(11):3080-3086.

On 2017 Sep 02, David Keller commented:

More evidence that light-to-moderate ethanol consumption reduces all-cause mortality, primarily by reductions in cardiovascular events. Now, we need randomized controlled trials of ethanol

This large study paid careful attention to the drinking history and pattern of ethanol consumption of its subjects, eliminating many of the objections raised to prior studies which have reached the same conclusions. I, for one, am as convinced as can be, given the observational nature of all such studies, that light-to-moderate consumption of ethanol is probably beneficial, especially in persons at higher than average risk of cardiovascular (CV) events. The time has come to conduct interventional trials, with subjects randomized to receive capsules of ethanol at bedtime or placebo, to compare outcomes when ethanol is prescribed to patients with evidence of atherosclerotic vascular disease (ASVD), or at high risk thereof. If these most-likely-to-benefit patients do benefit, the next trial could expand to include subjects at average CV risk. Ethanol remains the agent most likely to benefit those with ASVD which cannot be prescribed, because it has never been studied as a medicine, rather than an addiction.

On 2017 Aug 23, Mick Watson commented:

Quite remarkable that this review fails to cite our prior review on exactly the same subject:

http://journal.frontiersin.org/article/10.3389/fgene.2017.00023/full

On 2017 Aug 29, Marcus de Jong commented:

With great interest, but also with significant apprehension, we read the article by Yamanaka et al. recently published on-line ahead of print in Neurosurgical Review, entitled "Trilateral retinoblastoma: A systematic review of 211 cases."

We have had a long-time interest in retinoblastoma, including trilateral retinoblastoma, and we became worried about the fact that the authors allegedly have included 211 patients with trilateral retinoblastoma in their statistical analysis. We have reason to believe that this number, and consequently, the presented results may not be correct. In 2014, we published a systematic review and meta-analysis on trilateral retinoblastoma in Lancet Oncology, based on strict adherence to the PRISMA Statement (de Jong et al. [1]). We also contacted authors to resolve any equivocal issues. In particular, we meticulously matched patients between reports to prevent including any patients twice in our analysis. Many patients with trilateral retinoblastoma appear in the literature two or more times over the years; in the extreme case, one patient features in five different reports over 12 years. Resolving duplications and consolidating the sequential reports by each patient, we ended up with 174 unique individuals with trilateral retinoblastoma (see the attached table from the online supplement of our article).

Naturally, a number of trilateral retinoblastoma cases included in Yamanaka et al.'s paper have been published after acceptance of our paper. These are Andrade et al. [2] with 1 case, De Ioris et al. [3] with 2 new cases, and Pham et al. [4] with 3 cases, amounting to a total difference of 6 unique patients.

However, we included several articles that Yamanaka et al. have not ascertained during their research: De Jong et al. [5], Duncan et al. [6], Dunst et al. [7], Gururangan et al. [8], Jin et al. [9], Lim et al. [10], Mauger et al. [11], Onadim et al. [12], Popovic et al. [13], White et al. [14], and Zimmerman et al. [15]. These amount to a total of 18 unique cases.

We became very concerned after noting that, correcting for new cases and articles not included by Yamanaka et al., the difference in the number of patients between the two articles is no less than 49 (our 174 - 18 not included by Yamanaka et al. = 156 in De Jong et al. [1] versus their 211 - 6 newly reported = 205 in Yamanaka et al. [16]). Because Yamanaka et al. have not provided a patient-by-patient table of their cases unlike we did, we are limited to this numerical comparison and cannot verify case by case their unique cases.

In summary, we have reason to believe that Yamanaka et al. have not accounted for the fact that trilateral retinoblastoma patients have often been published in more than one paper. Although the results of the meta-analysis by Yamanaka et al., in general, show results that appear largely similar to those that what we published, the unexplained and large difference in the number of patients suggests to us that most, if not all, percentages and p-values from the meta-analysis by Yamanaka et al. do not reflect reality. There is also no way of knowing whether a particular statistic is correct or not.

To solve this issue, we ask Yamanaka et al. to clarify this crucial aspect of their meta-analysis, ideally by providing a patient-by-patient list of the 211 cases to verify their uniqueness to be attached to their paper. Hopefully the authors can provide a valid explanation that completely resolves our concerns. Otherwise, we are afraid that the statistical results of this paper will be misleading and cannot be trusted, and then perhaps the paper in the present form should be retracted in order to correct the literature and to avoid wrong interpretations in clinical practice of managing children with trilateral retinoblastoma.

Marcus de Jong,

on behalf of the authors of de Jong et al. [1]

References

1.de Jong MC, Kors WA, de Graaf P, et al (2014) Trilateral retinoblastoma: A systematic review and meta-analysis. Lancet Oncol 15:1157–1167. doi: 10.1016/S1470-2045(14)70336-5

2.Andrade GC de, Pinto NP de C, Motono M, et al (2015) Trilateral retinoblastoma with unilateral eye involvement. Rev Assoc Med Bras 61:308–10. doi: 10.1590/1806-9282.61.04.308

3.De Ioris MA, Valente P, Randisi F, et al (2014) Baseline central nervous system magnetic resonance imaging in early detection of trilateral retinoblastoma: pitfalls in the diagnosis of pineal gland lesions. Anticancer Res 34:7449–54.

4.Pham TTH, Siebert E, Asbach P, et al (2015) Magnetic resonance imaging based morphologic evaluation of the pineal gland for suspected pineoblastoma in retinoblastoma patients and age-matched controls. J Neurol Sci 359:185–192. doi: 10.1016/j.jns.2015.10.046

5.de Jong MC, Moll AC, Göricke S, et al (2016) From a Suspicious Cystic Pineal Gland to Pineoblastoma in a Patient with Familial Unilateral Retinoblastoma. Ophthalmic Genet 37:116–8. doi: 10.3109/13816810.2014.929717

6.Duncan JL, Scott IU, Murray TG, et al (2001) Routine neuroimaging in retinoblastoma for the detection of intracranial tumors. Arch Ophthalmol 119:450–2. 7.Dunst J, Fellner E, Erhardt J (1990) Trilaterales Retinoblastom mit spinalen Metastasen. Rofo 153:343–4. doi: 10.1055/s-2008-1033391

8.Gururangan S, McLaughlin C, Quinn J, et al (2003) High-dose chemotherapy with autologous stem-cell rescue in children and adults with newly diagnosed pineoblastomas. J Clin Oncol 21:2187–91. doi: 10.1200/JCO.2003.10.096

9.Jin J, Tang H-F, Zhou Y-B (2006) Trilateral retinoblastoma: a case report. World J Pediatr 2:151–153.

10.Lim FPM, Soh SY, Iyer JV, et al (2013) Clinical profile, management, and outcome of retinoblastoma in Singapore. J Pediatr Ophthalmol Strabismus 50:106–12.

11.Mauger TF, Makley TA, Davidorf FH, Rogers GL (1992) Retinoblastoma, microphthalmia, coloboma, and neuroepithelioma of the pineal body. Ann Ophthalmol 24:290–4.

12.Onadim Z, Woolford AJ, Kingston JE, Hungerford JL (1997) The RB1 gene mutation in a child with ectopic intracranial retinoblastoma. Br J Cancer 76:1405–9.

13.Popovic MB, Balmer A, Maeder P, et al (2006) Benign pineal cysts in children with bilateral retinoblastoma: a new variant of trilateral retinoblastoma? Pediatr Blood Cancer 46:755–61.

14.White L, Johnston H, Jones R, et al (1993) Postoperative chemotherapy without radiation in young children with malignant non-astrocytic brain tumours. A report from the Australia and New Zealand Childhood Cancer Study Group (ANZCCSG). Cancer Chemother Pharmacol 32:403–6.

15.Zimmerman L (1985) Trilateral retinoblastoma. In: Blodi F (ed) Retinoblastoma. Churchill Livingstone, New York, pp 185–210

16.Yamanaka R, Hayano A, Takashima Y (2017) Trilateral retinoblastoma: A systematic review of 211 cases. Neurosurg Rev. doi: 10.1007/s10143-017-0890-4

Also posted here: https://pubpeer.com/publications/50D5D3EFEA81DCD2421841D84FDA8D#

On 2018 Feb 04, Sin Hang Lee commented:

The medical profession, including medical schools and hospitals, is now a part of the health care industry, and implementation of editorial policies of medical journals is commonly biased in favor of business interests. PubMed Commons has offered the only, albeit constrained, open forum to air dissenting research and opinions in science-based language. Discontinuation of PubMed Commons will silence any questioning of the industry-sponsored promotional publications indexed in PubMed.

On 2017 Aug 20, Sin Hang Lee commented:

Since the lead author and several co-authors of this report are officers of the Centers of Disease Control and Prevention (CDC), the CDC should clarify if this metabolomics-driven technology is now officially recommended for clinical laboratory tests for the diagnosis of emerging infectious diseases in general, or it is created in competition against the well-established 16S rRNA sequence analysis in bacterial infections [1,2] which should be used for molecular diagnosis of Lyme borreliosis. To rely on finding metabolic biosignature consisting of molecular features in patient body fluids to diagnose or to distinguish between emerging infectious diseases is an unproven technology and may have untoward consequences. Would these authors propose using metabolic biosignature in the blood of patients to diagnose Ebola or to distinguish between Ebola and malaria? Of course not!

The authors cited two articles published by other investigators [3,4] to support their novel approach. However, in one of these articles [3] metabolomics were reported to be used as a tool in precision medicine for disease risk assessment and customized drug therapy in clinics. In the other [4], metabolomics were used as a tool to identify the chemical differences that contribute to health and disease, such as chronic fatigue syndrome. Neither concerned diagnosis of or distinguishing between infectious diseases.

The authors claimed to have “previously demonstrated that metabolic profiling of sera provided a high level of accuracy in differentiating early Lyme disease patients from healthy individuals …” [5]. However, in the latter cited article the same lead author [5] stated that it was only a study of “proof-of-concept for a novel diagnostic approach” and that “the early LD biosignature correctly diagnosed 77%–95% of 2-tier negative early LD patients”. That means there was an up to 23% failure in detecting early Lyme disease. Even this statistical model is highly questionable since the very case definition of early Lyme disease is still open to question. According to the CDC's answer to the question: “Is PCR useful for the diagnosis of Lyme disease? In general, the answer is no.” [6].

The claim to have discovered an objective, diagnostically useful “metabolic biosignature” of Lyme disease or STARI which are both emerging infectious diseases, by analysis of a set of metabolites in tissue fluids of the patients must be supported by undisputed evidence with proven scientific principles. The authors’ novel approach in fact has deviated from the classic teachings of diagnostic microbiology. The findings of metabolic differences between patients with Lyme disease and patients with STARI do not automatically yield a test that can be used to diagnose or to distinguish between Lyme disease and STARI.

Conflicts of Interest: Sin Hang Lee, MD is the director of Milford Molecular Diagnostics Laboratory specialized in developing DNA sequencing-based diagnostic tests. References: [1] https://www.cdc.gov/labtraining/docs/588-100_103-17_16S_rRNA_Sequence_Based_Bacterial_Identification.pdf [2] https://www.cdc.gov/microbenet/about.html [3] Guo L, Milburn MV, Ryals JA, et al. Plasma metabolomic profiles enhance precision medicine for volunteers of normal health. Proc Natl Acad Sci U S A. 2015 Sep 1;112(35):E4901-10. [4] Naviaux RK, Naviaux JC, Li K, et al. Metabolic features of chronic fatigue syndrome. Proc Natl Acad Sci U S A. 2016 Sep 13;113(37):E5472-80. [5] Molins CR, Ashton LV, Wormser GP, et al. Development of a metabolic biosignature for detection of early Lyme disease. Clin Infect Dis. 2015 Jun 15;60(12):1767-75. [6] Christina A. Nelson, MD, MPH, Medical Officer in the Bacterial Diseases Branch of CDC's Division of Vector-Borne Disease. http://www.medscape.com/viewarticle/764501?src=par_cdc_stm_mscpedt&faf=1 Last accessed August 19, 2017.

On 2017 Sep 10, Susanne Bejerot commented:

Intriguingly we published a parallel study with the same methodology using the equipment provided by the company Sensodetect Inc, but we found that the method had a very low ability to identify patients with psychotic disorders, adhd and autism, as well as identifying the healthy controls in a blinded study, see Manouilenko I, Humble MB, Georgieva J, Bejerot S. Brainstem Auditory Evoked Potentials for diagnosing Autism Spectrum Disorder, ADHD and Schizophrenia Spectrum Disorders in adults. A blinded study. Psychiatry Res. 2017 Jul 6;257:21-26. Manouilenko I, 2017. Consequently, I contacted the first author of the Acta Neuropsychiatrica paper, Eva Juselius Baghdassarian, to discuss our conflicting findings. Her explanation was their use of an old stationary auditory brainstem response apparatus, whereas we used the company’s mobile modern machine. Our machine was transported back and fourth between Stockholm and the south of Sweden in a large cabin bag. This is of course highly problematic, as the company currently markets the method that we used. I suggest that the interested reader carefully reads the method section of both papers.

On 2018 Jan 22, Nicholas Lawson commented:

Authors' claims are not supported by their results. Authors do not acknowledge some of the most common criticisms of the studies in their review:

(1) Physician health program (PHP) data may be suspect because PHPs benefit from presenting a rosy picture of their effectiveness.

(2) Self-reports from those being evaluated by PHPs, who have much to lose from responding to surveys in ways that criticize these programs, may not be reliable.

(3) There are considerable reasons to doubt that "programme completion," "return to practice," and "no relapse/recurrence" reflect treatment efficacy. Unwarranted referrals may also result in coerced treatment for physicians who do not have a substance use disorder or problematic performance.

(4) There are no comparisons to those who were not referred for PHP treatment.

Other concerns related to PHP treatment are addressed in "Do state physician health programs encourage referrals that violate the Americans with Disabilities Act?"

https://authors.elsevier.com/a/1WL2XaR~~IVy0

On 2017 Aug 26, Giorgio Cattoretti commented:

The method published is based on blocking the detection of previously deposited antibodies by a second staining round via an undisclosed amount of monomeric Fab fragments of secondary antibodies. “No cross-reactivity was observed between secondary Abs targeting primary Abs from the same species or with the same isotype. The absence of cross-reactivity was dependent on incubation with a blocking buffer before each restaining step (fig. S1) “ [quoted from the paper]. But on page 4, quoted again, ”tissue section was repeatedly stained, destained, and restained with the same anti-CD3 Ab" (legend to Fig. S5), in order to demonstrate "the absence of steric hindrance ….. upon successful consecutive cycles of staining/bleaching using the same marker (fig. S5)." If the block was applied after each staining round in both cases, no staining at all should be the expected result, as the Authors have shown in Fig. S1. If instead no block was applied, resulting in crossreactions between previous staining layers and the successive, any claim regarding steric hindrance has a weak scientific basis at best. In either scenario, the contradiction question the validity of the method, unless explained. In addition, a “dehydration” step in xylene (Fig. 1) most likely entails a reduction of tissue antigenicity, thus reproducibility, as we published (PMID: 26487185) six months before this paper was submitted and afterwards (PMID: 28692376 ): this topic is not sufficiently addressed.

On 2017 Dec 07, HIRENDRA BANERJEE commented:

None

On 2017 Dec 04, Raphael Levy commented:

This article was referenced (and his first author interviewed) in support of the SmartFlare technology (Merck) in a Chemistry World piece entitled Scrutiny of SmartFlares raises questions over RNA probes. It is therefore ironic that ~40% of its introduction is identical text to this blog post (which is highly critical of the SmartFlares).

On 2017 Aug 14, Heinrich Janzing commented:

Unfortunately there are some errors in this abstract. The p-values belong to the evaluation of heterogeneity: so correct is: "This number was significantly lower in patients who received daily subcutaneous injections of LMWH during immobilization, with event rates ranging from 0% to 37% (odds ratio (OR) 0.45, 95% confidence interval (CI) 0.33 to 0.61; with minimal evidence of heterogeneity, I² = 26%; P = 0.23; seven studies; 1676 participants, moderate-quality evidence)" and similar for the following data. It is corrected in the Cochrane publication but not yet in pubmed.

On 2017 Oct 26, Patrick Stokes commented:

Our arXiv response can now be found here: http://arxiv.org/abs/1709.10248

On 2017 Sep 29, Patrick Stokes commented:

Dear Dr. Marinazzo,

Thank you for the comments posted here as well as those on arXiv.

The main points of our work were to 1) characterize statistical properties of the traditional computation of conditional Granger-Geweke (GG) causality, and 2) to analyze how the dynamics of the system are represented in the GG-causality measure.

We acknowledge that you, as well as Drs. Barnett, Barrett, and Seth, are correct that a state-space approach using a single model fit addresses the problems with bias and variance in conditional GG-causality estimates, employing either the spectral factorization in the frequency-domain or the DARE solution in the time-domain. Your simulation study posted on arXiv illustrates this clearly. Unfortunately, as you suggest in your arXiv article, many investigators are still using separate model fits. We hope our article raises awareness of the problems with doing so, particularly in frequency-domain analyses, which again can be avoided by using appropriate state-space methods under a single model fit.

However, our second point about how dynamics are represented in GG-causality seems far more problematic, and is not resolved by the single-model computation, as it is an intrinsic property of GG-causality In most neuroscience studies, the objective is to identify and/or characterize the mechanism of some observed effect. As we have shown, the dynamics of the effect nodes are absent in GG-causality. Oscillations play an important role in systems neuroscience, and interpretation of causality measures appears particularly problematic in systems with strong frequency-dependent structure. Studies of oscillatory phenomena are invariably geared towards understanding the factors that contribute to oscillations observed at specific frequencies. Ignoring these observed dynamics is simply not compatible with the goal of understanding them.

We focused our paper on analyzing GG-causality. Although we also expressed concerns about other related methods, we did not intend to dismiss efforts to develop improved methods for analyzing directed dynamical influences. To the contrary, we believe that such methods will be essential for gaining meaningful insights from modern neuroscience data. As we try to emphasize in our paper, a crucial priority will be to ensure that the models and derived quantities correspond appropriately to the scientific questions being considered. Developing such methods will require a closer partnership between neuroscientists and quantitative scientists going forward. In the meantime, as we suggest in our paper, a good starting point would be for analysts to pay more attention to the underlying models, the dynamics they represent, and the overall modeling process, all of which form the foundations for subsequent inferences on directed influences.

We have submitted to arXiv a more detailed response to the arXiv posts from your group, and from Drs. Barnett, Barrett, and Seth. It will post in the next few days.

We thank you again for your commentary and the insightful dialogue.

Sincerely,

Patrick A. Stokes and Patrick L. Purdon

On 2017 Sep 12, Daniele Marinazzo commented:

Dear authors

thanks a lot for this paper, that has collected quite some attention.

I agree that interpretation issues of Granger Causality in Neuroscience exist (partially due to the historical unfortunate use of the name “causality”, as nicely described in previous literature).

On the other hand I think that the paper uses a formulation of Granger causality which is outdated (albeit still used), and in doing so it dismisses the measure based on a suboptimal use of it.

In order to provide a more balanced view, we replicated their simulations used the updated State Space implementation, proposed already some years ago, in which the pitfalls are mitigated or directly solved.

You can find the report here https://arxiv.org/abs/1708.06990

Another reply has been also posted, addressing more fundamental issues https://arxiv.org/abs/1708.08001

Best regards

On 2017 Nov 24, James Friel commented:

This research demonstrates that infants suffering from gastrointestinal distress when fed bovine fortifier benefit from human milk based fortifier. Our research found in similar infants that systemic oxidative stress increased with increasing amounts of bovine fortifier. (Friel JK, Diehl-Jones B, Cockell KA, Chiu A, Rabanni R, Davies SS, Roberts LJ2nd. Evidence of oxidative stress in relation to feeding type during early life in premature infants. Pediatr Res. 2011 Feb;69(2):160-4).Using more subtle indicators than feeding intolerance supports the current findings. It may be that most premature infants would benefit from the human milk based fortifiers. Hopefully as their use increases they will become more affordable and thus more available.

On 2017 Aug 26, Christopher Southan commented:

The chemical structures and protein targets for this exellent review have been resolved in this blog post https://cdsouthan.blogspot.se/2017/08/name-to-struc-resolution-for-yet.html

On 2017 Sep 02, Randi Pechacek commented:

Marcus Leung, first author of this article, wrote a blog post on microBEnet. It discusses his personal thoughts on the air microbiome of zero carbon buildings.

On 2017 Aug 09, Jacob H. Hanna commented:

This is the third paper from Smith group describing deriving human transgene free naïve "pluripotent" reset cells. However, in all three papers, the authors have failed to describe whether they are able to generate teratomas from any of the described cell lines. It should be noted that mouse naive pluripotent cells have the intrinsic "self organizing capacity" to enter a formative/primed state after in vivo sub-cutaneous injection into immunodeficient mice and robustly make teratomas within 4-8 weeks. In our opinion, without evidence for teratoma formation competence of such transgene free naive cells they do not qualify to be annotated as pluripotent cells at all (neither naive nor primed). We raise the possibility that the cells being propagated in this study may be more akin to a non-pluripotent pre-iPSC/pre-ESC state. I hope the authors can clearly point out and directly address this critical caveat in their future publications.

On 2017 Sep 11, NephJC - Nephrology Journal Club commented:

This randomised controlled trial of oral methylprednisolone on clinical outcomes in patients With IgA nephropathy was discussed on August 29th and September 6th 2017 on #NephJC, the open online nephrology journal club. Introductory comments written by Amit Langote are available at the NephJC website here.

As one of the commoner conditions we Nephrologists face, there was lots of interest in the controversial results of this trial.

The highlights of the tweetchat were:

• There remains some uncertainty regarding the pathogenesis of IgA Nephropathy and the disease may actually comprise a spectrum of conditions. As such treatment should likely be stratified and this limits our ability to interpret RCTs of all-comers.

• It would have been useful to see renal biopsy findings determine or influence randomization procedures.

• The fact that the population were mostly Chinese may limit the generalizability of the results to western populations.

• The GFR decline was much faster than expected or previously reported but this can be the case with certain Asian populations.

• There is a general reluctance to use steroids in the absence of crescents or rapid GFR decline among Nephrologists currently and this trial further re-enforces this sentiment. We keenly await the results from the low-TESTING trial.

Transcripts of the tweetchats, and curated versions as storify will be shortly available from the NephJC website.

Interested individuals can track and join in the conversation by following @NephJC or #NephJC on twitter, liking @NephJC on facebook, signing up for the mailing list, or just visit the webpage at NephJC.com.

On 2017 Sep 15, Robin Kok commented:

Regarding bias, this 'review' is an exercise in confirmation bias.

The rationale and execution of this systematic review are confusing at best, and misleading at worst. The authors invoke some metric of 'strength of evidence', which consists of tallying up positive conclusions from meta-analyses. For example, they conclude: "Protocols improve anxiety in adults: 8/9 meta-analyses", which we are to believe is strong evidence for cognitive bias modification (CBM).

However:

a) many of these meta-analyses draw from the same pool of primary studies, resulting in a great deal of overlap. Yet the authors treat these as if they are independent data points - demonstrably, they are not. If one would perform 10 meta-analyses on 40 studies, then it should come as no surprise that these meta-analyses report comparable outcomes. This greatly exaggerates positive effects by counting single studies multiple times. It is disconcerting that the peer reviewers did not spot this serious and elementary flaw. Then again, given that the entire process of submission, reviews and editorial acceptance took just over a month, reviewers and/or editor(s) must have been particularly pleased with this manuscript to favour it with an expedient review process.

b) many of these meta-analyses - and the primary outcomes from which they draw data - fail even the most basic quality criteria for rigorously conducted meta-analyses and randomised controlled trials.

c) many of these meta-analyses and primary studies reported therein were conducted by investigators with an investigator allegiance or other conflicts of interest. Studies performed by independent researchers often fail to find effects.

d) there is evidence for extreme publication bias in the field of CBM, as apparent by both statistical indicators (which the authors mostly ignore), as well as by the great number of trials in official trial registries which are still awaiting publication - some for almost 10 years. The reader can easily find an abundance of file-drawered CBM studies in the WHO, ISRCTN, ANZCTR, and Clinicaltrials.gov trial registries.

In short, this review is strongly biased in favour of cognitive bias modification and serves only to promote CBM as a 'promising therapy'. It adds to an already overwhelming number of positively biased reviews and analyses which essentially draw from the same pool of biased literature, strengthening the echo-chamber effect that seriously diminishes the scientific credibility of the CBM field. Reviews such as these are no more than opinion/promotion pieces in disguise, and should be interpreted with extreme caution as a reader unwary of these issues might easily conclude that there is overwhelming evidence for the efficacy of CBM - which there is not.

If there is any value in CBM, it deserves fair testing - which means pre-registered, transparent replication efforts by disinterested, independent researchers. The disturbing phenomenon where biased CBM trials are recycled in reviews and meta-analyses in quick succession by biased investigators is the academic equivalent of an echo-chamber. And if CBM is to be seen as a serious alternative to psychotherapy, it is to be held to the same standards of methodology and transparency and step away from the cargo cult science we have seen so far.

DECLARATION OF INTEREST: I have co-authored two (mostly critical) meta-analyses included in this review.

On 2017 Aug 07, DAVID ALLISON commented:

A letter to the editor (and response) have been published indicating erroneous statistical inferences in the article such that the conclusions regarding differential effectiveness by pubertal status are unsubstantiated.

See: http://pediatrics.aappublications.org/content/early/2017/06/08/peds.2016-4285.comments

On 2017 Oct 10, Shaun Khoo commented:

Green Open Access: The accepted manuscript is available from the UNSW Institutional Repository.

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

On 2017 Oct 13, Martine Crasnier-Mednansky commented:

The authors really should not write in legend of figure 7, "Our results indicate that for robust growth on chitin, the transporters responsible for uptake of [ABC-transported] chitobiose and [PTS-transported] GlcNAc play the largest role". In fact, data in figure 6A indicate lack of either one of these two transporters does not impair growth on chitin at all. Also, the 'chitosan' PTS (PTS^Chs, VC1282 in the figure), cannot possibly be a major player considering there is little glucosamine in chitin. Moreover, PTS^Chs transport is most likely inhibited by Enzyme IIA^Glc-dependent PTS transports (including PTS^Nag), as it was reported chs expression is positively regulated by cAMP (Berg T, 2007).

A proper question is whether or not the two transporters can be used simultaneously, as depicted in figure 7. Upon in vitro characterization of the periplasmic chitodextrinase activity (VCA0700 in Vibrio cholerae), Keyhani NO, 1996 proposed the ABC transport at first predominates up to a threshold concentration of (GlcNAc)n, n≥3, above which the PTS transport predominates. The two transport systems are not physiologically redundant.

On 2017 Aug 14, David Mage commented:

Hauck et al., prepared an interesting report on Sudden Unexpected Infant Death (SUID) and priorities for research to explain it. They state in the very first sentences of their introduction that 25 years ago, research into SIDS led to a ‘breakthrough’ which identified that “infants who slept on their stomachs were significantly more likely to die of SIDS than infants who slept on their backs [1].” Breakthrough? Schmakethrough!

Almost 75 years ago, Harald Abramson [2] published a proscription against the daytime practice of placing the infant in the prone position for sleep – unless constantly guarded. “The practice should, furthermore, be entirely done away with at night.” Fortunately, my thesis professor taught me the importance of reading the references of references to prevent such oversights when a blind eye is turned to the past literature. Reference 20 [Gilbert et al.] of their first reference [1] [Horne et al.] cites the Abramson 1944 paper.

1. Horne RSC, Hauck FR, Moon RY. Sudden infant death syndrome and advice for safe sleeping. BMJ 2015;350:h1989 doi: 10.1136/bmj.h1989

2. Abramson H. Accidental mechanical suffocation in infants. The Journal of Pediatrics 1944;25:404-413.

On 2017 Oct 19, Polina Vishnyakova commented:

Dear colleagues, in order to maintain a healthy scientific debate we need to clarify the statement, which you provided in Discussion of this paper. You wrote: «These findings are inconsistent with the findings of Vishnyakova et al. who reported that OPA1 was upregulated in PE placentas. […] The findings of Vishnyakova et al. were mainly based on gene expression. Levels of DNA or RNA may be unable to predict protein levels accurately, as they do not account for post-transcriptional/translational modifications». It is important to note than in our work we observed changes both on mRNA and protein content level of OPA1 and these findings surely disagree with your data. But we think that this could be explained by the difference in patients characteristic: we divided patients with preeclampsia basing on gestational age while you included women only with severe preeclampsia. Plus in current paper you analyzed only OPA1-L form, but not both forms (full OPA1-L and cleaved OPA1-S). So obtained difference in our findings could be explained with these points. Best regards.

On 2018 Jan 01, DAVID ALLISON commented:

A letter to the editor has been published indicating unsubstantiated conclusions in this article due to the use of difference in nominal significance (DINS) analyses.

See: http://onlinelibrary.wiley.com/doi/10.1111/1753-6405.12755/full

A response from the authors has also been published: http://onlinelibrary.wiley.com/doi/10.1111/1753-6405.12767/abstract

On 2017 Aug 05, Pedro Moreno commented:

Regarding the authors: No (A Moreno P). It is Moreno PA. Please correct this.

On 2018 Jan 27, Viktor Müller commented:

While it is true that there is considerable overlap in the recognition of self and (possibly pathogenic) non-self epitopes (Calis et al [1] estimated an overlap of around one third for HLA class I alleles), this is likely to make the job of the immune system harder, rather than easier. The overlapping peptides tend to be non-immunogenic, indicating tolerance, and the immune system needs to be able to target epitopes that are distinguishable from self peptides even with the degenerate recognition of T cell receptors [1]. Furthermore, even if the recognition task was indeed reduced to self and similar peptides, this would still vastly exceed the capacity of a fixed germline-encoded receptor repertoire. The number of distinct potential epitopes (for HLA class I) is of the order of magnitude 10⁷ in humans [2] and in mice [3]; this exceeds the maximum number of germline immune receptors found in any species by several orders of magnitude.

We still maintain that "Distinguishing tumours from normal self is likely to be the most challenging task for Darwinian immunity that could only be added at advanced stages of its evolution" [4], but have never claimed the same for positive selection. Amphioxus has proto-MHC, and positive selection might indeed be an ancient characteristic of (vertebrate) Darwinian immunity. It will be instructive to elucidate whether and how the divergent adaptive system of jawless fish handles positive selection, or anything analogous to MHC restriction in general.

Finally, we note that the origin of vertebrate adaptive immunity is a notoriously difficult problem. We certainly do not know the whole truth about the complex events that took place more than half a billion years ago -- but we hope that, by surveying the most recent evidence, we have taken a small step in the right direction.

[1] Calis JJA, de Boer RJ, Keşmir C (2012) Degenerate T-cell Recognition of Peptides on MHC Molecules Creates Large Holes in the T-cell Repertoire. PLoS Comput Biol 8(3): e1002412. https://doi.org/10.1371/journal.pcbi.1002412

[2] Burroughs, N.J., de Boer, R.J. & Keşmir, C. Immunogenetics (2004) 56: 311. https://doi.org/10.1007/s00251-004-0691-0

[3] Müller, V. & Bonhoeffer, S. (2003). Quantitative constraints on the scope of negative selection. Trends Immunol 24, 132-5. https://doi.org/10.1016/S1471-4906(03)00028-0

[4] Müller V, Boer RJ de, Bonhoeffer S, Szathmáry E (2018) Biol Rev 93:505-528. https://doi.org/10.1111/brv.12355

On 2018 Jan 20, Donald Forsdyke commented:

PATHOGEN COEVOLUTION AND THE ANTIGENIC UNIVERSE

The distinction between selective and instructive (Lamarckian) systems of immunity (1) – originating with Paul Ehrlich – was clearly set out in 1957 by Talmage (2) who, with Burnet, can be considered a "father of clonal selection theory" (3, 4). Its historical omissions aside, this bold attempt to place the evolution of immune systems in a broad context raises other concerns.

Although mentioning "the complex adaptation of the immune repertoire to the antigenic environment," and the need "continuously to acquire and store open-ended information about the antigenic environment," the coevolution of that antigenic environment (e.g. the coevolution of pathogens) does not seem to have been considered.

While the authors agree with Burnet that "distinguishing tumours from normal self is likely to be the most challenging task for Darwinian immunity," it is not recognized that the most successful pathogens are those that, through mutation, can come close to self. Whereas tumours represent mutations away from self, successful pathogens represent mutations towards self (by means of which they seek to exploit 'holes' in immune repertoires; 5). In both circumstances, this greatly simplifies the evolutionary task of a host. It does not have to depend on "the open-ended nature of the receptor repertoire." It does not have to "constitute a system of 'unlimited heredity' within the immune system." It does not have to "be broad enough to recognize the 'potential universe of antigens'." The scope of its task is greatly reduced.

As long ago proposed (6), and increasingly recognized (7, 8), it would be evolutionarily advantageous for organisms to focus their immune cell receptors on 'near self' antigenic specificities, rather than to attempt to anticipate the entire universe of antigens. Organisms achieve this, not through negative, but through positive selection of their immune repertoires. From the outset, organisms and their pathogens have coevolved and it would seem incorrect to suppose for the immune system that positive selection "could only be added at advanced stages of its evolution" (9). It is fundamental to immune system evolution.

1.Muller V, Boer RJ de, Bonhoeffer S, Szathmary E (2018) Biol Rev 93:505-528. Müller V, 2018

2.Talmage DW (1957) Allergy and immunology. Ann Rev Med 8:239-256 TALMAGE DW, 1957

3.Forsdyke DR (1996) The origins of the clonal selection theory of immunity. FASEB J 9:164-166.Forsdyke DR, 1995

4.Lederberg J (2002) Instructive selection and immunological theory. Immunol Rev 185:50-53.Lederberg J, 2002

5.Calis JJA, de Boer RJ, Kesmir C (2012) Degenerate T-cell recognition of peptides on MHC molecules creates large holes in the T-cell repertoire. PLoS Comput Biol 8:e1002412.Calis JJ, 2012

6.Forsdyke DR (1975) Further implications of a theory of immunity. J Theoret Biol 52:l87-l98.Forsdyke DR, 1975

7.Vrisekoop N, Monteiro JP, Mandl JN, Germain RN (2014) Revisiting thymic positive selection and the mature T cell repertoire for antigen. Immunity 41:181-190.Vrisekoop N, 2014

8.Marrack P. et al. (2017) The somatically generated portion of T cell receptor CDR3alpha contributes to the MHC allele specificity of the T cell receptor. eLife 6:e30918.Marrack P, 2017

9.Forsdyke DR (2016) Evolutionary Bioinformatics. 3rd Edition. Springer, New York.

On 2017 Aug 25, Jason R Richardson commented:

Drs. Blakely and Melikian, thank you both for your insightful comments. In working with these cells over a number of years, we have found that while the cell line expresses all of the necessary components to be identified as dopaminergic, it neither synthesizes a significant amount of dopamine nor has functional dopamine uptake. This is likely because of the diffuse nature of the protein expression identified by Dr. Melikian, which may be because it was generated by immortalizing cells from embryonic day 12 rat. I believe when I was a postdoc, I did some co-labeling and observed that the DAT was primarily present in the ER and golgi in these cells, suggesting that the intracellular machinery may not be mature enough to fully generate a functional and fully glycosylated DAT. I should note that the original group that made the N27 line recently re-cloned it and purified cells from this new clone had higher expression levels of both TH and DAT (Gao et al., 2016). Although, there were no functional studies for DAT-mediated uptake with the re-cloned line, they did show a modest increase in susceptibility to 6-OHDA and MPP+. Our primary goal for this paper was to better characterize the role of histone acetylation and transcription factor binding in the epigenetic regulation of DAT expression based on our previous studies in SK-N-AS cells (Green et al., 2015) in a rat cell line that we could then translate to in vivo studies. I certainly agree that additional studies in cells that display a more mature phenotype that allow for determination of function are warranted. I think both comments bring out a very important point regarding the study of transporter regulation. That is, cell context and system are critical to the interpretation and translation of mechanisms regulating the DAT to in vivo systems.

On 2017 Aug 19, Randy Blakely commented:

Thanks Haley for your note. The field studying dopamine transporter regulation would greatly benefit from a a cell line expressing endogenous transporter protein, validated through RNA, western blotting and critically transport activity measurements demonstrating pharmacological sensitivities appropriate to brain DAT. Some cell lines are said to be "dopaminergic", e.g. SH-SY5Y, but these express NET activity not DAT activity, like PC-12 cells.

On 2017 Aug 19, Haley Melikian commented:

We have also used the cell line in this study (N27), but have neither detected DAT protein by immunoblot, nor measured specific DA uptake using a standard radiotracer flux assay. While low DAT mRNA levels may be expressed, the evidence presented does not strongly support endogenous DAT protein expression. The immunofluorescence signal shown appears primarily diffuse and intercellular, and not in agreement with the typical plasma membrane DAT localization. Indeed, these cells have been used by transporter biologists, but only in the context of heterologous DAT expression. I would be curious to know whether the authors have measured specific DA uptake in these cells.

On 2017 Dec 05, Karen Woolley commented:

Congratulations to Dr Pushparajah on this editorial and congratulations again to her and her colleagues at UCB for generating evidence on the value of making the results of clinical research more accessible to the public via plain-language summaries. http://journals.sagepub.com/doi/abs/10.1177/2168479017738723. Ironically, when clinical research results go public (eg, through a peer-reviewed PUBLIC-ation), the public is rarely involved. This needs to change. Publications should be "of the people, BY the people, FOR the people". We need patients to be engaged - ethically and meaningfully - in the publication ecosystem. We know patients are diverse, but some patients are accessing the peer-reviewed literature for information. We need to work with patients, journal editors, sponsors, and publication professionals to help make the "patient-to-peer-reviewed publication" journey better, easier, and more reliable than their journey to Dr Google.Disclosures: Financial: I am a paid employee of Envision Pharma Group, which provides medical communication services and technology solutions. I have shares in Johnson & Johnson and have been a government-appointed director on the board of 5 hospitals. Nonfinancial: I am an active member and past director of associations that advocate for ethical publication practices. I am a research partner with international patient leaders and advocacy organisations

On 2017 Oct 11, Harri Hemila commented:

Zinc lozenges and vitamin C are promising approaches for the common cold

Papadopoulos NG, 2017 reviewed promising approaches for the treatment and prevention of viral respiratory tract infections, but did not include any meta-analyses or trial reports on zinc lozenges and vitamin C.

Three randomized trials using zinc acetate lozenges found that common cold duration was shortened by 2.7 days (95% CI: 1.8-3.3 days), Hemilä H, 2016, and that the rate of recovery from colds was increased 3.1-fold (2.1-4.7), Hemilä H, 2017. Although zinc lozenges are dissolved in the oro-pharyngeal region, they also shortened the duration of symptoms in the nasal region: nasal discharge by 34% (17-51%) and nasal congestion by 37% (15-58%), Hemilä H, 2015.

The binding of zinc to acetate is weaker than to gluconate and there have been suggestions that zinc acetate might therefore be a better salt for lozenges. Nevertheless, it is not evident that differences at the chemical level between these salts are translated into substantial differences at the clinical level. A meta-analysis found no evidence that lozenges formulated from either of these 2 salts differed in their effects on common cold duration, Hemilä H, 2017. In addition, 2 zinc gluconate trials found that the rate of recovery from colds was influenced to a similar extent as that for the 3 zinc acetate trials, Hemilä H, 2017.

In the trials that reported benefits of zinc lozenges, the total daily dose of elemental zinc was over 75 mg/day. This dose is higher than the recommended intake of 11 mg/day for men and 8 mg/day for women in the USA. However, 100-150 mg/day of zinc has been administered to certain patient groups for months with few adverse effects, and 150 mg/day of zinc is currently one standard treatment for Wilson’s disease, Hemilä H, 2017. Thus, it seems unlikely that 80-100 mg/day of zinc for about a week for treating a cold might lead to long-term adverse effects. There are therefore good reasons for classifying zinc lozenges as a promising approach to treat colds.

A Cochrane review showed with a narrow confidence interval that vitamin C does not prevent colds in the general community, Hemilä H, 2013. However, a meta-analysis of 5 randomized trials with participants under heavy short-term physical stress showed that vitamin C decreased the incidence of colds by 52% (36-65%). Thus, vitamin C seems to have prophylactic effects albeit only in special conditions.

A meta-analysis of more than 2 dozen placebo-controlled trials calculated that ≥1 g/day of vitamin C shortens the duration of colds in children by 18% (9-27%) and in adults by 8% (4-12%), Hemilä H, 2013. Furthermore, 2 trials found a linear dose-response association in the effects on common cold duration by up to 6- and 8-g/day of vitamin C, with colds being shortened by about 20% with the higher dose, Hemilä H, 2017. Still higher therapeutic dosages might lead to greater benefits but such dosages have not been investigated yet. More research also on vitamin C is evidently warranted.

On 2017 Oct 11, Clive Bates commented:

The most misleading thing about this paper is not merely the paper itself, but the way authors chose to present the findings to the media. As so often happens in academic work in this field, association became causation, uncertainty became confidence and very weak methods became the foundations of an assertive press release.

The press notice headline is:

Vaping doubles risk of smoking cigarettes for teens.

Of course, that is a made-for-media headline but deeply misleading about causation and grossly over-confident, given the study's limitations.

Much more likely is that the characteristics (personality, social and family context) that cause people to smoke also cause them to vape and the effects measured are the result of uncorrected confounding or reverse causation. It is quite possible that vaping acts to prevent smoking in people who would otherwise be susceptible to taking up smoking - an obvious possibility given the decline in teenage smoking in the US that coincided with the rise of vaping (albeit mostly experimentation and mostly without nicotine) - trends charts here.

My more detailed review of this study is here: Review of controversial Canadian ‘gateway effect’ study

On 2017 Sep 18, Neil McKeganey commented:

This paper will be interpreted by some as proof that using e-cigarettes acts as a gateway to smoking. That misleading impression is actually encouraged by one of the lead authors of the paper who in an interview for the Business New under the headline "E-cigarettes may double risk of tobacco smoking in teenagers" comments that the study provides a "yes" answer to the question of whether vaping lead to smoking. That statement is however in direct conflict with the stated limitations included within the published paper to the effect that "..the current study makes no claim of cause and effect". In fact this study is not even about the relationship between e-cig use and actual smoking but about e-cig use and a constructed variable for individual's susceptibility to smoke with the latter defined in terms of adolescents indication that they had not taken a firm decision not to smoke. So not having decided not to smoke is interpreted here as an indication that the individual is susceptible to future smoking. The authors rightly acknowledge that not all of those who are judged to be susceptible to smoking will actually go on to smoke in the future. Clearly that definition is problematic since it may well have been that many of the younger pupils had not found themselves in a situation where they felt they felt compelled to establish a clear view for themselves on the possibility of their future smoking. What the researchers have found here is that those pupils who in their definition were susceptible to smoking were more likely to have used e-cigarettes. As with other similar studies there is an entirely different possible explanation for that finding which has to do with the possibility that those pupils who reported past e-cig use were indeed more likely to smoke in the future because of the influence of a different variable e.g. willingness to experiment with different substances with that variable influencing both the likelihood of smoking and the likelihood of e-cig use rather than the latter influencing the former. As the authors acknowledge they have no measure here of intensity of e-cig use; rather they used a measure of any past use (of whatever actual frequency) and any use over the last 30 days (again of whatever actual frequency). As a result the e-cig using group could contain individuals who had used e-cigs on a single occasion in the past or a single occasion in the last 30 days. The only real conclusion which the authors can draw from this study is as they say that "use of e cigarettes among never smokers may increase the risk of future cigarette use.." It could equally be pointed out, though the authors choose not to say this, that "e-cigarette use amongst non-smokers may not increase future cigarette use."

On 2017 Aug 16, Deepa Bhartiya commented:

Authors report primitive, rare Oct-4 positive neural stem cells (pNSCs) in adult mouse brain that form spheres in vitro and also participate in endogenous regeneration. The pNSCs are activated in response to a stress produced by treatment with an antimitotic agent. Authors claim credit for pNSC to be the only adult stem cell to express OCT-4. But this is not true.

We have similarly reported that rare, small sized, pluripotent OCT-4 positive stem cells exist in adult testis, survive chemotherapy (https://www.ncbi.nlm.nih.gov/pubmed/27663915) and rather get activated in response to stress produced by busulphan treatment. Similarly OCT-4 expressing stem cells in adult bone marrow survive and are activated after radiotherapy (https://www.ncbi.nlm.nih.gov/pubmed/21034791) and chemotherapy (https://www.ncbi.nlm.nih.gov/pubmed/27095238). OCT-4 positive stem cells exist in all adult organs and are not limited to only the adult brain as claimed by the authors of this study. This needs to be corrected and a bigger picture of existence of pluripotent OCT-4 positive stem cells in various adult tissues needs to emerge.

On 2017 Oct 31, ANTHONY BAUGHN commented:

My coauthors and I stand firmly behind the design of our study, methods for data collection, presentation and interpretation, and the major conclusions that were drawn in our manuscript. We look forward to continued dialogue and the objective responses of others in the tuberculosis and antimicrobial drug communities regarding this matter.

On 2017 Oct 19, Wanliang Shi commented:

Please see the response: https://www.nature.com/articles/s41598-017-06415-5

On 2017 Dec 05, Joseph M Barnby commented:

This letter to the editor was originally submitted to JMIR uHealth and mHealth. The letter was later withdrawn as we became aware it was eligible to have an APC applied to it; in spite of what we understood the JMIR APC policy to be regarding letters to the editor. Neither of our institutions at the time of publication were able to cover the relevant fees. We have posted our reviewed letter here and invited Clare Killikelly to post her submitted response.

Authors:

Mr J M Barnby - Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, SE5 8AF. (Corresponding Author; joe.barnby@kcl.ac.uk)

Dr S A J Fonseca - Division of Psychiatry, University College London, WC1E 6BT.

The Editor JMIR mHealth and uHealth

On 20th July 2017, your journal published a useful and wide-ranging systematic review of mobile and web-based technologies for people with psychosis [1] – a field of mental health which has huge potential to shape the way service users are able to take control of their treatment. Authors found service user aid in design, length of intervention, and social support were all important factors in whether a participant would stop using a digital intervention.

Part of the authors’ summary was that, a) symptom severity may not have a significant effect on drop-out, and b) continuing to develop these interventions alongside users is vital. However, we believe that point a) is not clearly supported by the evidence presented in the article, and point b) misses out (or doesn’t plainly state) a crucial aspect of the technology.

We believe concluding that symptom severity doesn’t have a significant effect on drop-out is premature. The authors reviewed 20 studies that used web-based or mobile technologies and found 6 that measured the impact of symptom severity, chronicity, and duration on drop-out [2, 3, 4, 5, 6, 7]. However, the review only presents the results of those who stayed in the trials, and we believe it’s safe to assume that participants did not drop out randomly. As there were several individuals who declined to take part or dropped out of the study, and since we have no data for this group, we cannot assume that symptom severity does not affect drop-out. In fact, we would argue that it is likely this group were more symptomatic than those who took part. We believe the authors should have stated this more clearly and commented on it in their conclusions about drop-out, including suggesting ways to test this.

The authors only mention that intensity, frequency, and duration of interventions are all vital to adherence, but don’t specifically discuss the role of User Experience/User Interface (UXUI) – a role in software design which tries to make interaction with content as smooth and intuitive as possible. This is a separate but related concept to ‘co-production’ – the involvement of service users in intervention design. Commercial mobile-phone and web-based software is continuously developing more sophisticated and visually pleasing versions. It’s reasonable to hypothesise that better UXUI may result in less drop-out of interventions. Testing this hypothesis may give insight into how a more pleasing user experience may affect drop-out, and how extra investment into UXUI with user input may improve symptom control through better engagement. Indeed, research has suggested this approach might be useful in other areas of healthcare [9] and proposed it might be an important aspect to health intervention design [10]. UXUI focus is increasingly more relevant as mainstream software designers find more ways to keep users engaged, and we believe this highlights that digital interventions may have to compete for attention to meet the expectations of the users they wish to benefit.

In future research aimed at improving user adherence we suggest testing, a) whether simple, text-based designs are as effective as visually pleasing well-designed interfaces when the content is constant (for example, computerised cognitive behavioural therapy), and b) if gamification of therapeutic content improves engagement.

We would like to thank the authors for their current review in this important and emerging area of mental health research, and hope that these comments serve to constructively build upon the discussion.

Yours sincerely, Joseph M Barnby & Dr J Andres S Fonseca

References:

[1] Killikelly C, He Z, Reeder C, Wykes T. Improving Adherence to Web-Based and Mobile Technologies for People With Psychosis: Systematic Review of New Potential Predictors of Adherence. JMIR Mhealth Uhealth 2017; 5(7):e94

[2] van der Krieke L, Emerencia A, Boonstra N, Wunderink L, de JP, Sytema S. A web-based tool to support shared decision making for people with a psychotic disorder: randomized controlled trial and process evaluation. J Med Internet Res 2013 Oct 07;15(10):e216

[3] Ben-Zeev D, Brenner C, Begale M, Duffecy J, Mohr D, Mueser K. Feasibility, acceptability, and preliminary efficacy of a smartphone intervention for schizophrenia. Schizophr Bull 2014 Nov;40(6):1244-1253

[4] Palmier-Claus J, Ainsworth J, Machin M, Dunn G, Barkus E, Barrowclough C, et al. Affective instability prior to and after thoughts about self-injury in individuals with and at-risk of psychosis: a mobile phone based study. Arch Suicide Res 2013;17(3):275-287.

[5] Schlosser D, Campellone T, Kim D, Truong B, Vergani S, Ward C, et al. Feasibility of PRIME: a cognitive neuroscience-informed mobile app intervention to enhance motivated behavior and improve quality of life in recent onset schizophrenia. JMIR Res Protoc 2016 Apr 28;5(2):e77

[6] Kimhy D, Vakhrusheva J, Khan S, Chang RW, Hansen MC, Ballon JS, et al. Emotional granularity and social functioning in individuals with schizophrenia: an experience sampling study. J Psychiatr Res 2014 Jun; 53: 141-148

[7] Hartley S, Haddock G, Vasconcelos ES, Emsley R, Barrowclough C. An experience sampling study of worry and rumination in psychosis. Psychol Med 2014 Jun;44(8):1605-1614.

[8] Gleeson J, Lederman R, Wadley G, Bendall S, McGorry P, Alvarez-Jimenez M. Safety and privacy outcomes from a moderated online social therapy for young people with first-episode psychosis. Psychiatr Serv 2014 Apr 01;65(4):546-550

[9] Boulos MN, Gammon S, Dixon MC, MacRury SM, Fergusson MJ, Rodrigues FM, Baptista TM, Yang SP. Digital games for type 1 and type 2 diabetes: underpinning theory with three illustrative examples. JMIR Serious Games. 2015 Jan;3(1).

[10] Wilhide III CC, Peeples MM, Kouyaté RC. Evidence-based mHealth chronic disease mobile app intervention design: development of a framework. JMIR research protocols. 2016 Jan;5(1).

On 2017 Aug 28, Daniel Corcos commented:

Haymart et al. recommend active surveillance by mammography for ductal carcinoma in situ (DCIS) of the breast, on the basis that it is a low-risk cancer. Actually, DCIS is at low-risk because it is removed soon after diagnosis, so there is no direct evidence for an intrinsic low malignant potential of this form of early breast cancer. The idea that breast cancer is overdiagnosed rests on the observation of an excess of breast cancers concomitant to mammography screening implementation, which is persistent over years. However, mammography-induced cancers better explain this excess, as they occur with a delay and in older women, like the excess cancers that are observed. Delayed surgery has a dramatic effect on breast cancer survival (1). Active surveillance of DCIS would worsen the prognosis of this otherwise low-risk cancer.

1) Bleicher RJ, Ruth K, Sigurdson ER, et al. Time to Surgery and Breast Cancer Survival in the United States. JAMA Oncol 2016;2:330-9.

On 2017 Oct 04, Gurpreet K. Rana commented:

The MEDLINE search strategies are available upon request from the authors as they were not included in article as intended. - G.K. Rana

On 2017 Jul 30, Zvi Herzig commented:

The RCTs instructing controls to avoid artificial sweeteners (Peters et al and Blackburn et al) show significantly reduced BMI in the treatment group. It shouldn't be surprising that the other trials, merely assigning controls to water or placebo, fail to show reduced BMI in the treatment group. Artificial sweeteners can only reduce BMI if they're positioned to displace sugar intake. This isn't the case where the controls are given water or placebo instead of the artificial sweetener.

On 2017 Sep 05, William Davies commented:

CCN3 has recently been associated with vulnerability to Obstructive Sleep Apnea (Weingarten JA, Bellner L, Peterson SJ, Zaw M, Chadha P, Singh SP, Abraham NG. The association of NOV/CCN3 with obstructive sleep apnea (OSA): preliminary evidence of a novel biomarker in OSA. Horm Mol Biol Clin Investig. 2017 doi:10.1515/hmbci-2017-0029); this is interesting in light of the fact that sleep disruption may precipitate postpartum psychosis (Lewis KJ, Foster RG, Jones IR. Is sleep disruption a trigger for postpartum psychosis? Br J Psychiatry. 2016 May;208(5):409-11)

On 2017 Jul 31, Tom Kindlon commented:

Overall averages for Table 2, "Mean change (95% CI) in patient-reported measures between assessment and 1-year follow-up across CFS/ME specialist services":

Frustratingly, the overall weighted averages for the measures included in Table 2 were not included in the paper.

Two people have independently calculated them. Here they are: n = 432

Chalder Fatigue Scale (range 0–33) -6.05

SF36 Physical Function Subscale (range 0–100) 4.19

Work & Social Adjustment Scale (range 0–40) -3.40

Visual analogue pain rating scale (range 0–100) -4.42

HADS Anxiety Score (range 0–21) -0.56

HADS Depression Score (range 0–21) -1.35

Epworth Sleepiness Scale (range 0–24) -1.07

Jenkins Sleep Jenkins (range 0–20) -1.37

CIS20R Fatigue Subscale (range 8–56) -4.73

CIS20R Concentration Subscale (range 5–35) -2.67

CIS20R Motivation Subscale (range 4–28) -2.42

CIS20R Activity Subscale (range 3–21) -1.95

On 2017 Sep 07, Pranay Jindal commented:

Thank you for your comments and feedback.

The purpose of the article was to critically analyze the Flesch Reading Ease (FRE) and Flesch-Kincaid Reading Grade Level (FKRGL) and their use in assessing the reading level/perceived difficulty of a written text. We agree with you that grade level as assessed by readability formulas do not equate with readers understanding. In the article, we mention “in their assessments, FRE and FKRGL do not take into account (1) document factors (layout, pictures and charts, color, font, spacing, legibility, and grammar), (2) person factors (education level, comprehension, health literacy, motivation, prior knowledge, information needs, anxiety levels), and (3) style of writing (cultural sensitivity, comprehensiveness, and appropriateness), and thus, inadequately assess reading level”.

We do not explicitly support the use of readability formulas to assess the reading level/perceived difficulty of a written text, and in our article recommended that “future research needs to develop generic and disease-specific readability measures to evaluate comprehension of a written document based on individuals' literacy levels, cultural background, and knowledge of disease”. We encourage researchers and clinicians to move towards assessment of comprehension of written documents. However, in the absence of a reliable and valid measure to measure comprehension and the ease of using Flesch Reading Ease (FRE) and Flesch-Kincaid Reading Grade Level (FKRGL) via Microsoft office makes them a popular and easy choice.

On 2017 Jul 24, Donna Berryman commented:

While the authors do a pretty good job of pulling together the basic information about some popular readability formulas, they tend to support the idea that these formulas are somehow worthwhile. It is time to focus on the idea that grade level or readability formula results do not equate to reader understanding. As Leroy, Kauchak and Hogue (2016) write: "The lack of strong evidence for increased comprehension after using readability formulas may indicate that it is perceived difficulty that is being manipulated: The text looks easier but may not necessarily be easier to understand." (PMID 27043754) Wan et al (2013) do a good job of showing how different readability formulas vary in their calculations (see PMID 22835706). They conclude that "the SMOG formula appears to be more ideally suited for use in a health care context, as it has been validated against 100% comprehension..." But, beyond that, I would heartily encourage that we start thinking beyond written materials. I'd recommend the work of Donald L. Rubin on listenability (see PMID 23030569 for one example). Most health information is dispensed orally.

On 2017 Sep 01, Seán Turner commented:

Alou et al. (2016) [PMID 27330818] write that strain Marseille-P2366 (= CSUR P2366 = DSM 102091) is the type strain of Bacillus mediterraneensis. Contradictorily, Cadoret et al. (2017) [PMID 28706723] write that the type strain of Bacillus mediterraneensis is Marseille-P2384 (= CSUR P2384 = DSM 102091), and that strain Marseille-P2366 (= CSUR P2366 = DSM 102112) is the type strain of Bacillus massilinigeriensis.

On 2017 Oct 02, Serge Ahmed commented:

This article reports an interesting set of experiments showing that ravens repeatedly choose among a set of different objects, an object that will prove several minutes or hours later to be useful to obtain food. The authors interpret this preference as evidence that ravens would be able to plan for the future. However, since the preferred object was repeatedly and selectively paired with food reward during initial training, one cannot definitively rule out the involvement of non-planning processes. For instance, ravens could prefer the would-be useful object, not because they anticipate its future utility, as hypothesized by the authors, but merely because they attach more affective and/or motivational value to the object due to its past selective association with food reward. To rule out this associative mechanism, it is important to add a control condition where, all else being equal, choice of the previously food-paired object is not followed by an opportunity to use it to obtain food (for a similar criticism and a specific example of a control condition, see: Redshaw et al. https://www.ncbi.nlm.nih.gov/pubmed/28927634).

On 2017 Sep 05, MARK VRABEL commented:

Good to see the "Librarian AS" author has been corrected.

On 2017 Aug 16, MARK VRABEL commented:

Thanks for commenting after seeing my MEDLIB-L post and #medlibs tweet about this "Librarian AS" error.

On 2017 Aug 14, Melissa Rethlefsen commented:

Sam Johnson is the Academic Support Librarian, and he is named as an author. Let's hope this gets updated, though!

On 2017 Aug 14, Donna Berryman commented:

It's quite jarring to see that "Academic Support Librarian" - a position, not a person - is listed as an author on this paper. Assuming that an academic support librarian actually did participate, then the person (not the position) should be named. I'm hoping this will be corrected by the time the article is in print (rather than the epub ahead of print status).

On 2017 Jul 31, George McNamara commented:

Please note that supporting materials.zip (Word document inside) is available online at http://onlinelibrary.wiley.com/doi/10.1002/cphg.42/full#hg0404-sec-0023

On 2017 Jul 28, Morten Oksvold commented:

“Dunoyer has been a long-time colleague and collaborator of Olivier Voinnert, and recently a number of their studies, three with Dunoyer as first author, have been retracted while a number more have had formal corrections published to address problems with presented data."

Please note that Olivier VOINNET is his correct name and Dunoyer's master has so far eight retractions and twenty corrections(only 12 of them are directly searchable in PubMed):

https://www.ncbi.nlm.nih.gov/pubmed?term=(voinnet o[Author]) AND "retracted publication"[Publication Type]

https://www.ncbi.nlm.nih.gov/pubmed?term=(Voinnet o[Author]) AND "published erratum"[Publication Type]

(Link to full report here: https://www.ethz.ch/content/dam/ethz/news/medienmitteilungen/2015/PDF/untersuchungsbericht/Report_of_ETH_Commission_Voinnet.pdf )

Please also note that in reference 7 in the mentioned article (Incarbone, M et al., Nature Plants, June 2017) they cite Deleris A et al., Science 2006, which represents one of the articles that supposed to be retracted (see quote from the report below).

From the investigation report: "Although it is obviously the journal's prerogative, the former (category 2) papers, particularly those containing well documented intentional manipulations (PLoS Pathogens 2013 9:e1003435; Plant Cell 2004 16: 1235; Science 2006 313: 68; PNAS 2006 103: 19593 and EMBO J 2010 29: 1699), should be retracted through OV's requests as being non-factual, irrespectively of whether the reported observations have been reproduced by others."

I find it problematic that Nature Plants accept this kind of practice, by apparently legitimating well documented intentional manipulations as facts.

On 2017 Aug 20, Daniel Weiss commented:

This review of Tickborne diseases other than Lyme by Drs. Eickhoff and Blaylock paints a frightening picture of diverse illnesses increasing in prevalence in the United States.

A recent survey found over 20% of U.S residents reporting a tick attached to themselves or a family member within the previous year(1). Yet, as Eickhoff and Blaylock point out, the absence of a known tick bite “never precludes the diagnosis of a tick-borne infection” and “co-infections with multiple pathogens may occur”. Throughout their review, the authors emphasize that insensitive laboratory testing methods increase the complexity of diagnosis, and result in an unknown risk to the blood supply. All health care practitioners require a high index of suspicion and sound clinical judgment to identify individual tick-borne infections. Simultaneous co-infections increase the diagnostic and therapeutic challenge.

As examples of the challenges faced, Borrelia miyamoti infection may not demonstrate the erythema migrans rash occurring with B. burgdorferi—the agent of Lyme disease. But up to 70% of patients with Lyme disease have no history of this rash(2). Similarly, there is no proven clinical difference between the rash seen with B. lonestari and B. burgdorferi. Lonestar ticks can transmit both spirochetes(3).

Because no gold standard exists to prove the absence of any of these infections, practitioners must avoid declaring with certitude that no infection is present—especially if an acute infection has gone untreated or undertreated. In his accompanying editorial, Dr. Mandell reiterated the difficulty of identifying acute tick-borne infection. Therefore, we were confused by his concluding paragraph. Given the diagnostic uncertainties, one must not dismiss dogmatically the possibility of an infection, either acute or chronic. A call for improved diagnostics and more effective therapeutics is the more logical response to the issues raised by this important review.

1. Hook SA, Nelson CA, Mead PS. U.S. public's experience with ticks and tick-borne diseases: Results from national HealthStyles surveys. Ticks Tick Borne Dis. 2015;6(4):483-8. doi: 10.1016/j.ttbdis.2015.03.017. PubMed PMID: 25887156.
2. Aucott JN, Seifter A, Rebman AW. Probable late lyme disease: a variant manifestation of untreated Borrelia burgdorferi infection. BMC Infect Dis. 2012;12:173. Epub 2012/08/03. doi: 10.1186/1471-2334-12-173. PubMed PMID: 22853630; PMCID: PMC3449205.
3. Clark KL, Leydet B, Hartman S. Lyme borreliosis in human patients in Florida and Georgia, USA. Int J Med Sci. 2013;10(7):915-31. doi: 10.7150/ijms.6273. PubMed PMID: 23781138; PMCID: PMC3675506.

On 2017 Aug 09, David Keller commented:

Two Large Epidemiological Studies Reach Opposite Conclusions Regarding Dementia Risk From PPI Use

A recent German study [1] found a significant 44% increased incidence of dementia with regular proton-pump inhibitor (PPI) antacid use, in a cohort of 73,679 baseline non-demented persons over age 75, of whom 29,510 developed dementia over 8 years, and 2950 were regular PPI users. The authors of that study boldly concluded that "avoidance of PPI medication may prevent the development of dementia" and called for a randomized controlled trial of PPIs to better assess this risk.

The current study [2] looked at the 70,718 cases of Alzheimer disease (AD) diagnosed in Finland over a 7-year period and found no difference in risk based on regular PPI use, and a confirmatory lack of association of risk with dose of PPI, or duration of PPI use.

Which of these two large, painstaking studies in similar populations is correct? PPI use either does or does not increase the risk of dementia, and it is crucial to know which is true. Millions take PPI medication daily to control acid reflux, but would be better off taking less effective or tolerable treatments if PPIs increase the risk of dementia.

Taipale and colleagues identified PPI users from medication-purchase data, whereas Gomm and colleagues identified PPI users from prescription data, which did not indicate whether the prescriptions were actually filled. Obviously, persons who purchase a medication are more likely to be taking it than persons who are merely prescribed it. However, the effect of non-compliance with prescribed PPI therapy in the Gomm study is to actually increase the risk of dementia caused by taking PPI medication. The more non-compliance among patients in Gomm's PPI group, the greater the dementia-increasing effect PPIs must have had on compliant patients to explain the observed overall increased dementia in the PPI group. So, the difference in how PPI-takers were identified cannot account for the discrepant results of these studies.

How much credence can we place in epidemiological results if two large studies can report polar opposite conclusions with such apparent certainty? Is it ethical, or even possible, to randomize patients to less-effective medications than PPIs in a controlled trial, to definitively determine whether PPIs truly increase the risk of dementia?

References

1: Gomm W, von Holt K, Thomé F, Broich K, Maier W, Fink A, Doblhammer G, Haenisch B. Association of Proton Pump Inhibitors With Risk of Dementia: A Pharmacoepidemiological Claims Data Analysis. JAMA Neurol. 2016 Apr;73(4):410-6. doi: 10.1001/jamaneurol.2015.4791. PubMed PMID: 26882076.

2: Taipale H, Tolppanen AM, Tiihonen M, Tanskanen A, Tiihonen J, Hartikainen S. No Association Between Proton Pump Inhibitor Use and Risk of Alzheimer's Disease. Am J Gastroenterol. 2017 Jul 11. doi: 10.1038/ajg.2017.196. [Epub ahead of print] PubMed PMID: 28695906.

On 2017 Jul 14, Seán Turner commented:

The authors cite strain CECT 9186 as type, but this is also cited as the type strain of Blastomonas quesadae (PMID 28631592) and is listed as such in the CECT online catalog.

On 2017 Jul 17, Donald Forsdyke commented:

IF G-QUADRUPLEXES, WHY SO MANY ADENINES?

It is good to see the problem of EBV immune evasion focused, not on the translation product of EBNA1 mRNA (1), but on the mRNA itself (2). However, it is puzzling that the sequence encoding the glycine-alanine repeats is enriched not only in guanines (Gs), but also in adenines (As). In such a GC-rich genome (60% GC), there is a scarcity of As, yet they are concentrated in the glycine-alanine repeat-encoding region. In other words, codons have been selected for their general purine-richness, not just for their G-richness (3). While it is conceivable that the As somehow assist consecutive Gs to form G-quadruplexes, consideration might have been given to the hypothesis that the G-quadruplexes may merely be helpful by-products of the fundamental need to purine-load the mRNA.

EBV is not alone in this respect. EBV and HTLV-1 share common characters. Both are deeply latent, GC-rich viruses. They persist in their human hosts for long periods often with no obvious detrimental effects. Most of their proteins are encoded by pyrimidine-rich mRNAs. The HTLV-1 provirus encodes its pyrimidine-rich mRNAs in its "top" sense strand. But there is a "bottom" strand transcript. This is heavily R-loaded and is translated into a basic zipper protein (HBZ) which is poorly immunogenic and is increasingly seen, like EBNA-1, as playing a major role in immune evasion (4-6).

1. 1.Levitskaya, J. et al. (1995) Inhibition of antigen processing by the internal repeat region of the Epstein-Barr virus nuclear antigen-1. Nature 375:685–688. Levitskaya J, 1995
2. 2.Lista MJ et al. (2017) Nucleolin directly mediates Epstein-Barr virus immune evasion through binding to G-quadruplexes of EBNA-1 mRNA. Nature Commun 8:16043. Lista MJ, 2017
3. 3.Cristillo AD et al. (2001) Double-stranded RNA as a not-self alarm signal: to evade, most viruses purine-load their RNAs, but some (HTLV-1, Epstein-Barr) pyrimidine-load. J Theor Biol 208:475–491.Cristillo AD, 2001
4. 4.Cook LB et al. (2013) HTLV-1: Persistence and pathogenesis. Virology 435:131–140. Cook LB, 2013
5. 5.Shiohama et al. (2016) Absolute quantification of HTLV-1 basic leucine zipper factor (HBZ) protein and its plasma antibody in HTLV-1 infected individuals with different clinical status. Retrovirology 13:29 Shiohama Y, 2016
6. 6.Forsdyke DR EBV Webpage

On 2017 Sep 08, Falk Leichsenring commented:

Toward a more Balanced Perspective on Anxiety Treatment

Falk Leichsenring 1, Allan Abbass 2, Patrick Luyten13

1 Department of Psychosomatics and Psychotherapy, Justus-Liebig-University Giessen, Ludwigstr. 76, D-35392 Giessen, Germany 2 Department of Psychiatry, Dalhousie University; Centre for Emotions and Health, Halifax, 8203 5909 Veterans Memorial Lane, Halifax, NS, Canada, B3H 2E2 3 Faculty of Psychology and Educational Sciences, University of Leuven, Klinische Psychologie (OE), Tiensestraat 102 - bus 3722, 3000 Leuven, Belgium, and Research Department of Clinical, Educational and Health Psychology, University College London, Gower Street, London WC1E 6BT, UK

Stein and Craske recently published a viewpoint article entitled "Treating Anxiety in 2017".1 Yet, the treatment section excludes other evidence-based, widely-used non-medical treatment options while exclusively recommending pharmacotherapy and Cognitive Behavioral Therapy (CBT).

The authors state that most empirical support exists for CBT. However, a recent meta-analysis showed that only one sixth of studies are of high quality.2 In more than 80% of the studies CBT was compared to a waiting list, that is to a relatively weak comparator that may even represent a nocebo condition.2 In panic disorder, CBT was not superior to treatment-as-usual, only to waiting list.2 There was also significant evidence of publication bias.2 Based on these and other findings, this meta-analysis concluded that CBT was “at best probably effective” in anxiety disorders, which markedly contrasts with the overly optimistic depiction of the effects of CBT by Stein and Craske.

In exclusively recommending CBT, Craske and Stein completely bypass other forms of psychotherapy such as interpersonal therapy or psychodynamic therapy, even though both are efficacious in anxiety disorders. 3,4 Moreover, comorbidity is the norm in anxiety disorders but there is lack of evidence to support CBT in complex or comorbid anxiety populations, whereas brief psychodynamic therapy has been found to be more effective than other treatments in reducing anxiety in patients with depression. 5 The evidence for the proposed working mechanisms in anxiety disorders is also far less clear than Craske and Stein suggest, and their assertion that working mechanisms of CBT are different from other types of psychotherapy is similarly largely unsupported.

It is also quite perplexing that the authors recommend benzodiazepines for patients for whom SSRIs or CBT failed without consideration of the above mentioned other commonly used, non-medical treatments. Given evidence that long-term effects of pharmacotherapy in anxiety disorders are unknown due to the lack of follow-up studies6, such a suggestion biases patient care in favour of often endless medication treatments.

This unbalanced discussion of treatments for anxiety disorders is the more perplexing since the authors' attention was recently called to the fact that other types of psychotherapy have been found to be equally effective in anxiety disorders7, based on studies of good quality .4

Biased clinical guidance such as the one by Stein and Craske is highly undesirable from a scientific and clinical perspective, and can be easily avoided by including proponents of rival approaches (adversarial collaboration).

References

1. Stein MB, Craske MG. Treating Anxiety in 2017: Optimizing Care to Improve Outcomes. JAMA. Jul 18 2017;318:235-236.
2. Cuijpers P, Cristea IA, Karyotak E, Reijnders M, Huibers MHJ. How effective are cognitive behavior therapies for major depression and anxiety disorders? A meta-analytic update of the evidence World Psychiatry. 2016;15:245-258.
3. Markowitz JC, Petkova E, Neria Y, Van Meter PE, Zhao Y, Hembree E, Lovell K, Biyanova T, Marshall RD. Is Exposure Necessary? A Randomized Clinical Trial of Interpersonal Psychotherapy for PTSD. Am J Psychiatry. May 2015;172:430-440.
4. Keefe JR, McCarthy KS, Dinger U, Zilcha-Mano S, Barber JP. A meta-analytic review of psychodynamic therapies for anxiety disorders. Clin Psychol Rev. Jun 2014;34:309-323.
5. Driessen E, Hegelmaier LM, Abbass AA, Barber JP, Dekker JJ, Van HL, Jansma EP, Cuijpers P. The efficacy of short-term psychodynamic psychotherapy for depression: A meta-analysis update. Clin Psychol Rev. Aug 1 2015;42:1-15.
6. Leichsenring F, Leweke F. Social Anxiety Disorder. N Engl J Med. Jun 08 2017;376:2255-2264.
7. Steinert C, Leichsenring F. No psychotherapy monoculture for anxiety disorders. Lancet. May 13 2017;389:1882-1883.

On 2017 Sep 02, Randi Pechacek commented:

Aaron J. Prussin II, second author of this article, and Amy J. Pruden wrote a blog post on microBEnet. The blog post explores the topic of the exposome of the built environment.

On 2017 Aug 18, NephJC - Nephrology Journal Club commented:

The position paper for the ISPD on the length of time on peritoneal dialysis (PD) and encapsulating peritoneal sclerosis (EPS) was discussed on July 11th and 12th 2017 on #NephJC, the open online nephrology journal club. Introductory comments written by Nikhil Shah are available at the NephJC website here

There was a lot of interest in this updated position paper, with 98 participants in the discussion and nearly 700 tweets. Of note, the PDI editor and the UK authors also joined in to provide further background and context to this paper.

The highlights of the tweetchat were:

• There participants agree with the epidemiological challenges as outlined by the authors – difficulty defining EPS, lack of interventions, conflicting data on effect of time on PD, difficulty applying available evidence into individual risk assessment. As such, they recognise that this is only a position statement as opposed to a set of guidelines.

• Ascertainment bias may affect reported incidence rates. Clearer diagnostic criteria may encourage earlier diagnosis and intervention.

• Applying empiric time-limitations to PD is probably not the solution.

• Aggressive nutrition, switching dialysis modality and referral to a specialist surgical centre were the preferred management strategies of this group. Some advocate tamoxifen or steroids in addition.

Transcripts of the tweetchats, and curated versions as storify are available from the NephJC website.

Interested individuals can track and join in the conversation by following @NephJC or #NephJC on twitter, liking @NephJC on facebook, signing up for the mailing list, or just visit the webpage at NephJC.com.

On 2017 Aug 04, Luis Mauricio T. R. Lima commented:

This is an interesting article showing the pramlintide and zinc interaction, and the role of His18 in zinc interaction such as previously reported for human amylin. https://www.ncbi.nlm.nih.gov/pubmed/20536124 https://doi.org/10.1021/ja1007867

We have also recently reported (2016) the amyloid aggregation of pramlintide, spontaneously and without zinc. https://www.ncbi.nlm.nih.gov/pubmed/27665170 https://doi.org/10.1016/j.bpc.2016.09.007

Murine amylin, another "stable" (compared to human) amylin analogue, also behaves as amyloid in solution. https://www.ncbi.nlm.nih.gov/pubmed/23974296 https://doi.org/10.1016/j.bpc.2013.07.013

Murine amylin can also interact with zinc, and this peptide has no His18, and interaction is mediated by several other contacts, and can result in modulation of the amyloid aggregation process. https://www.ncbi.nlm.nih.gov/pubmed/27693831 http://dx.doi.org/10.1016/j.bpc.2016.09.008

Collectively, these data suggest an universal amyloid behavior of amylin analogues and interaction with zinc, regardless of the presence of proline or His18.

On 2017 Jul 05, Jim Woodgett commented:

Kudos for a super study (and bonus for getting the GSK3 isoforms right).

On 2017 Jul 15, James Tsung commented:

Video of vaginal foreign body on transabdominal ultrasound: https://youtu.be/B22Ae0z7i64

On 2017 Jul 04, Parmit Singh commented:

Very interesting finding that sad-7 is showing localization in cytoplasm, peripheral and in nuclear regions. Understanding the correlation of localization with its function in meiotic silencing might be interesting. Interestingly, its expression is similar to sad-4. Also like sad-4, it produces 50% round spores in a heterozygous cross. Homozygous cross is barren in case of sad-7 whereas it is very less productive in case of sad-4. In case of sad-5 and sad-6 (both sad-5 and sad-6 are nucleus localized suppressors, homozygous crosses are fertile. This suggests that the meiotic function of sad-7 might be related to its perinuclear localization or peripheral part of meiotic silencing similar to sad-4. This is further supported by the fact that recently identified two other suppressors cbp20 and cbp80 (cap - binding proteins) produce 80% round spores (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5386863/pdf/1149.pdf). Proteins of both genes cbp20 and cbp80 are localized in nucleus and homozygous crosses are fertile like sad-4.

On 2017 Oct 22, George Kunos commented:

We read with interest the above article (Varga B, 2017), comparing the pharmacological properties of a series of cannabinoid receptor 1 (CB1R) blockers, including first generation brain-penetrant compounds and more recently introduced peripherally restricted compounds in various tests, including their anti-obesity effects in a mouse diet-induced obesity (DIO) model. The complete lack of effect of the peripheral CB1R inverse agonist JD-5037 in the DIO mouse model was of particular interest to us, as we have earlier documented its high anti-obesity efficacy in DIO mice (Tam J, 2012, Cinar R, 2014) and in a mouse model of Prader-Willi syndrome (Knani I, 2016), as well as its anti-diabetic efficacy in a rat model of type 2 diabetes (Jourdan T, 2013, Jourdan T, 2014). In these as well as in more recent studies (Tam J, 2017, Hinden L, 2018, Udi S, 2017), JD-5037 was dissolved in 4% DMSO/1% Tween-80 in PBS (vehicle #1) for administration by oral gavage (see Jourdan T, 2013), whereas Varga et al. used a 5% Tween-80 solution (vehicle #2). Because in our hands the inclusion of DMSO was critical for keeping this highly lipophilic compound in solution, we compared the oral bioavailability and peripheral target engagement of JD-5037 dissolved in these 2 vehicles. Using vehicle #1, the peak plasma concentration of JD-5037 measured by LC-MS/MS 1 h after oral administration to lean, male C57Bl6/J mice was 1076 ± 208 ng/mL (1840 nM), similar to values we published earlier (Tam J, 2012). In contrast, using vehicle #2, the plasma level of JD-5037 was 0.38 ± 0.02 ng/mL (0.67 nM), more than 1,000-fold lower and barely detectable. JD-5037 is 99.6% protein-bound in plasma (Tam J, 2012), so its calculated free concentration was 7.4 nM using vehicle #1 versus 2.7 pM using vehicle #2, the latter value being 2 orders of magnitude below the binding Kd of JD-5037 for CB1R (0.4 nM), which predicts no significant CB1R occupancy. We further verified this by using the upper GI motility test as a measure of peripheral CB1R occupancy (Tam J, 2012). In vehicle-treated mice, an oral charcoal bolus traveled 54 ± 3% of the length of the small intestine in 30 minutes, whereas In mice treated with a maximally effective dose of the CB1R agonist ACEA, the charcoal bolus traveled only 25 ± 3%, indicating a 54% inhibition. The inhibitory effect of ACEA was completely blocked by pretreatment with a single dose of 3 mg/kg JD-5037 in vehicle #1 (53 ± 3%), in agreement with our published data (Tam J, 2012). In contrast, the same dose of JD-5037 administered in vehicle #2 was completely without effect, the distance traveled by the charcoal bolus (29 ± 2%) being the same as with ACEA alone. Thus, the negative findings of Varga et al. can be attributed to lack of absorption and a consequent lack of peripheral CB1R occupancy by JD-5037, due to the use of an inappropriate vehicle. Such pitfalls are avoidable by verifying bioavailability and target engagement, which is a basic requirement when testing the in vivo efficacy of novel compounds.

George Kunos, Joseph Tam^1, Resat Cinar, Tony Jourdan; National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA

¹ Current address: School of Pharmacy, The Hebrew University, Jerusalem, Israel

On 2017 Sep 15, Cicely Saunders Institute Journal Club commented:

We chose this paper for our monthly Journal Club on 6th September 2017 and some comments from our discussion are below.

This is a useful paper to explore the experiences of clinicians and relatives to determine why hospital deaths predominate in haematological cancers. This paper focused on an important and under-researched topic. We felt that this paper would be improved if the authors could

1) Use Consolidated criteria for reporting qualitative studies (COREQ): 32-item checklist.

2) State what methodological orientation underpinned the study? E.g. grounded theory, ethnography, phenomenology.

3) Explain the reasons for the imbalance of sample (45 clinicians vs. 10 relatives) and why patients’ perspectives were not included.

4) Elaborate the views of ‘co-dependency’ in more detail.

5) Provide more in-depth cross-comparison of perspectives between different groups of participants (healthcare practitioners across different settings and relatives of deceased patients)

The paper generated a lively discussion among clinicians, researchers and academics, and we thank the authors for drawing attention to this important area.

On 2017 Sep 08, Ping Guo commented:

None

On 2017 Jul 12, Felipe Santiago commented:

I don't disagree with their main message, but I think is not addressing the problem at all. I do believe the current environment makes the job look "unattainable" but still is very "desirable". Less than 10% of all the postdocs in my current research-intensive institution actually successfully complete an academic job search, but almost all still try! Most go elsewhere after trying at least 2 cycles. So I disagree with the statement that PIs are discouraging grad students and postdocs to follow this path, they are just been good, realistic mentors, that know the many problems postdocs can face in today's hypercompetitive academic job search.

On 2017 Oct 10, Shaun Khoo commented:

Green Open Access: The accepted manuscript is available from the UNSW Institutional Repository (subject to a 12 month publisher embargo).

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

On 2017 Jul 26, Mohammed AlJasser commented:

I cannot access this article although it is labelled as "Free full text".