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1.  Evaluating adherence to the International Committee of Medical Journal Editors’ policy of mandatory, timely clinical trial registration 
To determine whether two specific criteria in Uniform Requirements for Manuscripts (URM) created by the International Committee of Medical Journal Editors (ICMJE)—namely, including the trial ID registration within manuscripts and timely registration of trials, are being followed.
Materials and methods
Observational study using computerized analysis of publicly available Medline article data and clinical trial registry data. We analyzed a purposive set of five ICMJE founding journals looking at all trial articles published in those journals during 2010–2011, and data from the (CTG) trial registry. We measured adherence to trial ID inclusion policy as the percentage of trial journal articles that contained a valid trial ID within the article (journal-based sample). Adherence to timely registration was measured as the percentage of trials that registered the trial before enrolling the first participant within a 60-day grace period. We also examined timely registration rates by year of all phase II and higher interventional trials in CTG (registry-based sample).
To determine trial ID inclusion, we analyzed 698 clinical trial articles in five journals. A total of 95.8% (661/690) of trial journal articles included the trial ID. In 88.3% the trial-article link is stored within a structured Medline field. To evaluate timely registration, we analyzed trials referenced by 451 articles from the selected five journals. A total of 60% (272/451) of articles were registered in a timely manner with an improving trend for trials initiated in later years (eg, 89% of trials that began in 2008 were registered in a timely manner). In the registry-based sample, the timely registration rates ranged from 56% for trials registered in 2006 to 72% for trials registered in 2011.
Adherence to URM requirements for registration and trial ID inclusion increases the utility of PubMed and links it in an important way to clinical trial repositories. This new integrated knowledge source can facilitate research prioritization, clinical guidelines creation, and precision medicine.
The five selected journals adhere well to the policy of mandatory trial registration and also outperform the registry in adherence to timely registration. ICMJE's URM policy represents a unique international mandate that may be providing a powerful incentive for sponsors and investigators to document clinical trials and trial result publications and thus fulfill important obligations to trial participants and society.
PMCID: PMC3715364  PMID: 23396544
clinical trials as topic/legislation; registries; cross-sectional analysis; Databases; publication policy; trial registration
2.  Guidelines, Editors, Pharma And The Biological Paradigm Shift 
Mens Sana Monographs  2007;5(1):27-30.
Private investment in biomedical research has increased over the last few decades. At most places it has been welcomed as the next best thing to technology itself. Much of the intellectual talent from academic institutions is getting absorbed in lucrative positions in industry. Applied research finds willing collaborators in venture capital funded industry, so a symbiotic growth is ensured for both.
There are significant costs involved too. As academia interacts with industry, major areas of conflict of interest especially applicable to biomedical research have arisen. They are related to disputes over patents and royalty, hostile encounters between academia and industry, as also between public and private enterprise, legal tangles, research misconduct of various types, antagonistic press and patient-advocate lobbies and a general atmosphere in which commercial interest get precedence over patient welfare.
Pharma image stinks because of a number of errors of omission and commission. A recent example is suppression of negative findings about Bayer's Trasylol (Aprotinin) and the marketing maneuvers of Eli Lilly's Xigris (rhAPC). Whenever there is a conflict between patient vulnerability and profit motives, pharma often tends to tilt towards the latter. Moreover there are documents that bring to light how companies frequently cross the line between patient welfare and profit seeking behaviour.
A voluntary moratorium over pharma spending to pamper drug prescribers is necessary. A code of conduct adopted recently by OPPI in India to limit pharma company expenses over junkets and trinkets is a welcome step.
Clinical practice guidelines (CPG) are considered important as they guide the diagnostic/therapeutic regimen of a large number of medical professionals and hospitals and provide recommendations on drugs, their dosages and criteria for selection. Along with clinical trials, they are another area of growing influence by the pharmaceutical industry. For example, in a relatively recent survey of 2002, it was found that about 60% of 192 authors of clinical practice guidelines reported they had financial connections with the companies whose drugs were under consideration. There is a strong case for making CPGs based not just on effectivity but cost effectivity. The various ramifications of this need to be spelt out. Work of bodies like the Appraisal of Guidelines Research and Evaluation (AGREE) Collaboration and Guidelines Advisory Committee (GAC) are also worth a close look.
Even the actions of Foundations that work for disease amelioration have come under scrutiny. The process of setting up ‘Best Practices’ Guidelines for interactions between the pharmaceutical industry and clinicians has already begun and can have important consequences for patient care. Similarly, Good Publication Practice (GPP) for pharmaceutical companies have also been set up aimed at improving the behaviour of drug companies while reporting drug trials
The rapidly increasing trend toward influence and control by industry has become a concern for many. It is of such importance that the Association of American Medical Colleges has issued two relatively new documents - one, in 2001, on how to deal with individual conflicts of interest; and the other, in 2002, on how to deal with institutional conflicts of interest in the conduct of clinical research. Academic Medical Centers (AMCs), as also medical education and research institutions at other places, have to adopt means that minimize their conflicts of interest.
Both medical associations and research journal editors are getting concerned with individual and institutional conflicts of interest in the conduct of clinical research and documents are now available which address these issues. The 2001 ICMJE revision calls for full disclosure of the sponsor's role in research, as well as assurance that the investigators are independent of the sponsor, are fully accountable for the design and conduct of the trial, have independent access to all trial data and control all editorial and publication decisions. However the findings of a 2002 study suggest that academic institutions routinely participate in clinical research that does not adhere to ICMJE standards of accountability, access to data and control of publication.
There is an inevitable slant to produce not necessarily useful but marketable products which ensure the profitability of industry and research grants outflow to academia. Industry supports new, not traditional, therapies, irrespective of what is effective. Whatever traditional therapy is supported is most probably because the company concerned has a product with a big stake there, which has remained a ‘gold standard’ or which that player thinks has still some ‘juice’ left.
Industry sponsorship is mainly for potential medications, not for trying to determine whether there may be non-pharmacological interventions that may be equally good, if not better. In the paradigm shift towards biological psychiatry, the role of industry sponsorship is not overt but probably more pervasive than many have realised, or the right thinking may consider good, for the health of the branch in the long run.
An issue of major concern is protection of the interests of research subjects. Patients agree to become research subjects not only for personal medical benefit but, as an extension, to benefit the rest of the patient population and also advance medical research.
We all accept that industry profits have to be made, and investment in research and development by the pharma industry is massive. However, we must also accept there is a fundamental difference between marketing strategies for other entities and those for drugs.
The ultimate barometer is patient welfare and no drug that compromises it can stand the test of time. So, how does it make even commercial sense in the long term to market substandard products? The greatest mistake long-term players in industry may make is try to adopt the shady techniques of the upstart new entrant. Secrecy of marketing/sales tactics, of the process of manufacture, of other strategies and plans of business expansion, of strategies to tackle competition are fine business tactics. But it is critical that secrecy as a tactic not extend to reporting of research findings, especially those contrary to one's product.
Pharma has no option but to make a quality product, do comprehensive adverse reaction profiles, and market it only if it passes both tests.
Why does pharma adopt questionable tactics? The reasons are essentially two:
What with all the constraints, a drug comes to the pharmacy after huge investments. There are crippling overheads and infrastructure costs to be recovered. And there are massive profit margins to be maintained. If these were to be dependent only on genuine drug discoveries, that would be taking too great a risk.Industry players have to strike the right balance between profit making and credibility. In profit making, the marketing champions play their role. In credibility ratings, researchers and paid spokes-persons play their role. All is hunky dory till marketing is based on credibility. When there is nothing available to make for credibility, something is projected as one and marketing carried out, in the calculated hope that profits can accrue, since profit making must continue endlessly. That is what makes pharma adopt even questionable means to make profits.
Essentially, there are four types of drugs. First, drugs that work and have minimal side-effects; second, drugs which work but have serious side-effects; third, drugs that do not work and have minimal side-effects; and fourth, drugs which work minimally but have serious side-effects. It is the second and fourth types that create major hassles for industry. Often, industry may try to project the fourth type as the second to escape censure.
The major cat and mouse game being played by conscientious researchers is in exposing the third and fourth for what they are and not allowing industry to palm them off as the first and second type respectively. The other major game is in preventing the second type from being projected as the first. The third type are essentially harmless, so they attract censure all right and some merriment at the antics to market them. But they escape anything more than a light rap on the knuckles, except when they are projected as the first type.
What is necessary for industry captains and long-term players is to realise:
Their major propelling force can only be producing the first type. 2. They accept the second type only till they can lay their hands on the first. 3. The third type can be occasionally played around with to shore up profits, but never by projecting them as the first type. 4. The fourth type are the laggards, real threat to credibility and therefore do not deserve any market hype or promotion.
In finding out why most pharma indulges in questionable tactics, we are lead to some interesting solutions to prevent such tactics with the least amount of hassles for all concerned, even as both profits and credibility are kept intact.
PMCID: PMC3192391  PMID: 22058616
Academia; Pharmaceutical Industry; Clinical Practice Guidelines; Best Practice Guidelines; Academic Medical Centers; Medical Associations; Research Journals; Clinical Research; Public Welfare; Pharma Image; Corporate Welfare; Biological Psychiatry; Law Suits Against Industry
3.  The publication of ethically uncertain research: attitudes and practices of journal editors 
BMC Medical Ethics  2012;13:4.
Publication of ethically uncertain research occurs despite well-published guidelines set forth in documents such as the Declaration of Helsinki. Such guidelines exist to aide editorial staff in making decisions regarding ethical acceptability of manuscripts submitted for publication, yet examples of ethically suspect and uncertain publication exist. Our objective was to survey journal editors regarding practices and attitudes surrounding such dilemmas.
The Editor-in-chief of each of the 103 English-language journals from the 2005 Abridged Index Medicus list publishing original research were asked to complete a survey sent to them by email between September-December 2007.
A response rate of 33% (n = 34) was obtained from the survey. 18% (n = 6) of respondents had published ethically uncertain or suspect research within the last 10 years. 85% (n = 29) of respondents stated they would always reject ethically uncertain articles submitted for publication on ethical grounds alone. 12% (n = 4) of respondents stated they would approach each submission on a case-by-case basis. 3% (n = 1) stated they would be likely to publish such research, but only with accompanying editorial. Only 38% (n = 13) give reviewers explicit instruction to reject submissions on ethical grounds if found wanting.
Editorial compliance with the Declaration of Helsinki in rejecting research that is conducted unethically was difficult to ascertain because of a poor response rate despite multiple attempts using different modalities. Of those who did respond, the majority do reject ethically suspect research but few explicitly advise reviewers to do so. In this study editors did not take advantage of the opportunity to describe their support for the rejection of the publication of unethical research.
PMCID: PMC3378458  PMID: 22494972
Editors; Ethics; Publication ethics
4.  What do letters to the editor publish about randomized controlled trials? A cross-sectional study 
BMC Research Notes  2013;6:414.
To identify published letters to the editor (LTE) written in response to randomized controlled trials (RCTs), determine the topics addressed in the letters, and to examine if these topics were affected by the characteristics and results of the RCTs.
Comparative cross-sectional study of a representative sample of RCTs from a set of high-impact medical journals (BMJ, Lancet, NEJM, JAMA, and Annals of Internal Medicine). RCTs and their published LTE were searched from these 5 journals in 2007. Data were collected on RCTs and their characteristics (author affiliation, funding source, intervention, and effect on the primary outcome) and the topics addressed in published LTE related to these RCTs. Analysis included chi-square and regression analysis (RCT characteristics) and thematic analysis (LTE topics).
Of 334 identified RCTs, 175 trials had at least one LTE. Of these, 381 published LTE were identified. Most RCTs, tested drug interventions (68%), were funded by government (54%) or industry (33%), and described an intervention that had a positive impact on the primary outcome (62%). RCT authors were primarily affiliated with an academic centre (78%). Ninety percent of the 623 LTE topics concerned methodological issues regarding the analysis, intervention, and population in the RCT. There was a significant association between funding source and impact on outcomes (p = 0.002) or type of intervention tested (p = 0.001) in these trials. Clinical and “Other” LTE topics were more likely to be published in response to a government funded RCT (p = 0.005 and p = 0.033, respectively); no other comparisons were significant.
This study showed that most LTE are about methodological topics, but found little evidence to support that these topics are affected by the characteristics or results of the RCTs. The lack of association may be explained by editorial censorship as a small proportion of LTE that are submitted are actually published.
PMCID: PMC3852599  PMID: 24124753
Letters to the editor; Randomized controlled trials; Journalogy
5.  Personalized Medicine Across Disciplines and without Borders. Vural Özdemir speaks to Hannah Wilson, Commissioning Editor 
Personalized medicine  2014;11(7):687-691.
Vural Özdemir began his career as a medical doctor in Turkey in 1990, as a scientist at the Faculty of Medicine, University of Toronto (ON, Canada), where he obtained his MSc and PhD in clinical pharmacology (1998), and subsequently completed a 4-year postdoctoral fellowship in personalized medicine with the late Werner Kalow, a founding pioneer in the field of pharmacogenetics. Özdemir contributed to the conception and development of the repeated drug administration (RDA) method as a novel way of measuring pharmacological heritability, pharmacogenetics of psychiatric drugs and studying the clinical role of CYP2D6 genetic variations for endogenous neurotransmitter metabolism in the human brain. Recognizing that scientific knowledge is a product of both technology and social systems that often remain unaccounted for (e.g., human values, distribution of power and human agency, immigration, racial disparities, socioeconomic class and equity), Özdemir discovered the literature in the field of science and technology studies, a rich scholarly enquiry that asks fundamental questions and challenges assumptions regarding the backstage of technoscience, situates technology within its political context and makes hitherto unseen connections that frame science in ways that enable robust, responsible and sustainable innovation. From 2008 to 2012, Özdemir was awarded a mid-career “science and society” fellowship in order to retool as independent faculty and senior scientist in science and technology studies (STS), conducting research on research and examining his own trade – pharmacogenetics science – as an insider on the outside. Recently, Özdemir was awarded senior career support from the Scientific and Tehnological Research Council of Turkey, is an Associate Professor of both Communications and Human Genetics at the Faculty of Communications and serves as an advisor to the Rector for International Technology and Innovation Policy, Gaziantep University in Turkey. He is also a Visiting Professor (Global Health & Technology Foresight) at Amrita University in Kerala, India, and cofounder of the Data-Enabled Life Sciences Alliance (DELSA Global), an open innovation and knowledge translation platform in Seattle (WA, USA). Özdemir was named as coinventor of 12 World Intellectual Property Organization (WIPO) indexed patents in personalized medicine and has authored more than 130 peer reviewed articles and chapters on the translation of omics technologies into public health action, global technology governance, diagnostics innovation strategy, history of bioethics and the ethics-of-bioethics. ‘Science Peace Corps’ and ‘Microgrants for Big Data’ are two new knowledge translation and science communication concepts developed by Özdemir for the global governance of biotechnology. He is Editor-in-Chief of OMICS: A Journal of Integrative Biology, published by Mary Ann Liebert, Inc. (NY, USA).
PMCID: PMC4481090  PMID: 26120345 CAMSID: cams4734
6.  Kinetic Proofreading at Single Molecular Level: Aminoacylation of tRNAIle and the Role of Water as an Editor 
PLoS ONE  2013;8(6):e66112.
Proofreading/editing in protein synthesis is essential for accurate translation of information from the genetic code. In this article we present a theoretical investigation of efficiency of a kinetic proofreading mechanism that employs hydrolysis of the wrong substrate as the discriminatory step in enzyme catalytic reactions. We consider aminoacylation of tRNAIle which is a crucial step in protein synthesis and for which experimental results are now available. We present an augmented kinetic scheme and then employ methods of stochastic simulation algorithm to obtain time dependent concentrations of different substances involved in the reaction and their rates of formation. We obtain the rates of product formation and ATP hydrolysis for both correct and wrong substrates (isoleucine and valine in our case, respectively), in single molecular enzyme as well as ensemble enzyme kinetics. The present theoretical scheme correctly reproduces (i) the amplitude of the discrimination factor in the overall rates between isoleucine and valine which is obtained as (1.8×102).(4.33×102) = 7.8×104, (ii) the rates of ATP hydrolysis for both Ile and Val at different substrate concentrations in the aminoacylation of tRNAIle. The present study shows a non-michaelis type dependence of rate of reaction on tRNAIle concentration in case of valine. The overall editing in steady state is found to be independent of amino acid concentration. Interestingly, the computed ATP hydrolysis rate for valine at high substrate concentration is same as the rate of formation of Ile-tRNAIle whereas at intermediate substrate concentration the ATP hydrolysis rate is relatively low. We find that the presence of additional editing domain in class I editing enzyme makes the kinetic proofreading more efficient through enhanced hydrolysis of wrong product at the editing CP1 domain.
PMCID: PMC3688713  PMID: 23840412
7.  Vision Science and Schizophrenia Research: Toward a Re-view of the Disorder Editors’ Introduction to Special Section 
Schizophrenia Bulletin  2011;37(4):681-689.
This theme section on vision science and schizophrenia research demonstrates that our understanding of the disorder could be significantly accelerated by a greater adoption of the methods of vision science. In this introduction, we briefly describe what vision science is, how it has advanced our understanding of schizophrenia, and what challenges and opportunities lay ahead regarding schizophrenia research. We then summarize the articles that follow. These include reviews of abnormal form perception (perceptual organization and backward masking) and motion processing, and an article on reduced size contrast illusions experienced by hearing but not deaf persons with schizophrenia. These articles reveal that the methods of basic vision research can provide insights into a number of aspects of the disorder, including pathophysiology, development, cognition, social cognition, and phenomenology. Importantly, studies of visual processing in schizophrenia make it clear that there are impairments in the functioning of basic neural mechanisms (eg, center-surround modulation, contextual modulation of feedforward processing, reentrant processing) that are found throughout the cortex and that are operative in multiple forms of cognitive dysfunction in the illness. Such evidence allows for an updated view of schizophrenia as a condition involving generalized failures in neural network formation and maintenance, as opposed to a primary failure in a higher level factor (eg, cognitive control) that accounts for all other types of perceptual and cognitive dysfunction. Finally, studies of vision in schizophrenia can identify sensitive probes of neural functioning that can be used as biomarkers of treatment response.
PMCID: PMC3122283  PMID: 21700588
schizophrenia; perception; vision; cognition; CNTRICS; RDoC
8.  Photoletter to the editor: Hyperkeratosis lenticularis perstans (Flegel's disease) with unusual clinical presentation. Response to isotretinoin therapy. 
Hyperkeratosis lenticularis perstans also known as Flegel's disease is a keratinisation disorder characterized by small keratotic papules with horny scales. Most cases have been reported in Europe with age of presentation between 35 and 60 years. We report a case of a 25-year-old man, who presented with 1-5 mm multiple asymptomatic hyperkeratotic papules of 15 years duration on both legs and hand along with lichenified plaques with Koebner phenomenon in the axillary folds, anticubital and popliteal fossae. Similar lesions were present in the eyelids also. There was no involvement elsewhere. Similar illness was found in the younger brother aged 13 years with the duration of illness for the past 5 years. Histopathology confirmed the clinical diagnosis. Patient was treated with oral isotretinoin in a daily dose of 20 mg per day to which he responded immediately with clearing of the lesions in two weeks.
PMCID: PMC3470798  PMID: 23091588
Flegel's disease; hyperkeratosis lenticularis perstans; Koebner phenomenon; isotretinoin
9.  Science and policy on endocrine disrupters must not be mixed: a reply to a “common sense” intervention by toxicology journal editors 
Environmental Health  2013;12:69.
The “common sense” intervention by toxicology journal editors regarding proposed European Union endocrine disrupter regulations ignores scientific evidence and well-established principles of chemical risk assessment. In this commentary, endocrine disrupter experts express their concerns about a recently published, and is in our considered opinion inaccurate and factually incorrect, editorial that has appeared in several journals in toxicology. Some of the shortcomings of the editorial are discussed in detail. We call for a better founded scientific debate which may help to overcome a polarisation of views detrimental to reaching a consensus about scientific foundations for endocrine disrupter regulation in the EU.
PMCID: PMC3765603  PMID: 23981490
Endocrine disrupting chemicals; Environment; Health; Precautionary principle; Regulatory toxicology
10.  Photoletter to the editor: Diffuse cocaine-related purpura 
Diffuse purpura is an uncommon skin manifestation found in platelet and coagulation disorders, meningococcemia, vasculitides and cocaine use. Reports of cocaine-related purpura predominantly involve adulteration with the anti-helminthic, levamisole. Levamisole enhances the effects of cocaine and is known to cause vasculitis. Recently, the CDC also released an advisory of oxymorphone being used intravenously causing thrombogenic thrombocytopenic purpura (TTP). We report the case of a patient with diffuse purpura ultimately diagnosed with cocaine-related thrombogenic vasculopathy. In the current environment of adulterated cocaine usage and increased prescription narcotic abuse, it is crucial to investigate substance abuse as a cause of diffuse purpura.
PMCID: PMC3888784  PMID: 24421868
cocaine; levamisole; oxymorphone; purpura
11.  A survey of the awareness, knowledge, policies and views of veterinary journal Editors-in-Chief on reporting guidelines for publication of research 
Wider adoption of reporting guidelines by veterinary journals could improve the quality of published veterinary research. The aims of this study were to assess the knowledge and views of veterinary Editors-in-Chief on reporting guidelines, identify the policies of their journals, and determine their information needs. Editors-in-Chief of 185 journals on the contact list for the International Association of Veterinary Editors (IAVE) were surveyed in April 2012 using an online questionnaire which contained both closed and open questions.
The response rate was 36.8% (68/185). Thirty-six of 68 editors (52.9%) stated they knew what a reporting guideline was before receiving the questionnaire. Editors said they had found out about reporting guidelines primarily through articles in other journals, via the Internet and through their own journal. Twenty of 57 respondents (35.1%) said their journal referred to reporting guidelines in its instructions to authors. CONSORT, REFLECT, and ARRIVE were the most frequently cited. Forty-four of 68 respondents (68.2%) believed that reporting guidelines should be adopted by all refereed veterinary journals. Qualitative analysis of the open questions revealed that lack of knowledge, fear, resistance to change, and difficulty in implementation were perceived as barriers to the adoption of reporting guidelines by journals. Editors suggested that reporting guidelines be promoted through communication and education of the veterinary community, with roles for the IAVE and universities. Many respondents believed a consensus policy on guideline implementation was needed for veterinary journals.
Further communication and education about reporting guidelines for editors, authors and reviewers has the potential to increase their adoption by veterinary journals in the future.
PMCID: PMC3922819  PMID: 24410882
Veterinary journals; Veterinary research; Reporting guidelines; Reporting quality; Editors; Editorial policies; Views; Barriers
12.  The CROWN initiative: journal editors invite researchers to develop core outcomes in women’s health 
Clinical trials, systematic reviews and guidelines compare beneficial and non-beneficial outcomes following interventions. Often, however, various studies on a particular topic do not address the same outcomes, making it difficult to draw clinically useful conclusions when a group of studies is looked at as a whole. This problem was recently thrown into sharp focus by a systematic review of interventions for preterm birth prevention, which found that among 103 randomised trials, no fewer than 72 different outcomes were reported. There is a growing recognition among clinical researchers that this variability undermines consistent synthesis of the evidence, and that what is needed is an agreed standardised collection of outcomes - a “core outcomes set” - for all trials in a specific clinical area. Recognising that the current inconsistency is a serious hindrance to progress in our specialty, the editors of over 50 journals related to women’s health have come together to support The CROWN (CoRe Outcomes in WomeN’s health) Initiative.
PMCID: PMC4066690  PMID: 24957208
Research design/standards; Treatment outcome; Endpoint determination/standards; Clinical trials; Systematic reviews; Guidelines; Bias (Epidemiology); Evidence-based medicine; Consensus
13.  The CROWN Initiative: journal editors invite researchers to develop core outcomes in women’s health 
BMC Women's Health  2014;14:75.
Clinical trials, systematic reviews and guidelines compare beneficial and non-beneficial outcomes following interventions. Often, however, various studies on a particular topic do not address the same outcomes, making it difficult to draw clinically useful conclusions when a group of studies is looked at as a whole. This problem was recently thrown into sharp focus by a systematic review of interventions for preterm birth prevention, which found that among 103 randomised trials, no fewer than 72 different outcomes were reported. There is a growing recognition among clinical researchers that this variability undermines consistent synthesis of the evidence, and that what is needed is an agreed standardised collection of outcomes - a “core outcomes set” - for all trials in a specific clinical area. Recognising that the current inconsistency is a serious hindrance to progress in our specialty, the editors of over 50 journals related to women’s health have come together to support The CROWN (CoRe Outcomes in WomeN’s health) Initiative.
PMCID: PMC4080758  PMID: 24993666
Research design/standards; Treatment outcome; Endpoint determination/standards; Clinical trials; Systematic reviews; Guidelines; Bias (Epidemiology); Evidence-based medicine; Consensus
14.  Photoletter to the editor: A neurocutaneous rarity: phacomatosis pigmentokeratotica 
Phacomatosis pigmentokeratotica is characterized by the coexistence of nevus sebaceus, papular nevus spilus and associated neurologic abnormalities. We report a case of phacomatosis pigmentokeratotica in a 28-year-old male who presented with palmar-plantar dysesthesia and ipsilateral brain hemiatrophy. As a characteristic neuroimaging finding of the disorder, we found multiple hypointense lesions involving the ipsilateral hemisphere.
PMCID: PMC4094740  PMID: 25024780
atrophy; bones; congenital abnormalities; dysesthesia; nevus sebaceous; neuropathy; nevus spilus; unilateral
15.  The CROWN Initiative: journal editors invite researchers to develop core outcomes in women’s health 
Clinical trials, systematic reviews and guidelines compare beneficial and non-beneficial outcomes following interventions. Often, however, various studies on a particular topic do not address the same outcomes, making it difficult to draw clinically useful conclusions when a group of studies is looked at as a whole. This problem was recently thrown into sharp focus by a systematic review of interventions for preterm birth prevention, which found that among 103 randomised trials, no fewer than 72 different outcomes were reported. There is a growing recognition among clinical researchers that this variability undermines consistent synthesis of the evidence, and that what is needed is an agreed standardised collection of outcomes - a "core outcomes set" - for all trials in a specific clinical area. Recognising that the current inconsistency is a serious hindrance to progress in our specialty, the editors of over 50 journals related to women's health have come together to support The CROWN (CoRe Outcomes in WomeN's health) Initiative.
PMCID: PMC4104682  PMID: 25050130
Research design/standards; Treatment outcome; Endpoint determination/standards; Clinical trials; Systematic reviews; Guidelines; Bias (Epidemiology); Evidence-based medicine; Consensus
16.  The CROWN initiative: journal editors invite researchers to develop core outcomes in women’s health 
Reproductive Health  2014;11:42.
Clinical trials, systematic reviews and guidelines compare beneficial and non-beneficial outcomes following interventions. Often, however, various studies on a particular topic do not address the same outcomes, making it difficult to draw clinically useful conclusions when a group of studies is looked at as a whole. This problem was recently thrown into sharp focus by a systematic review of interventions for preterm birth prevention, which found that among 103 randomised trials, no fewer than 72 different outcomes were reported. There is a growing recognition among clinical researchers that this variability undermines consistent synthesis of the evidence, and that what is needed is an agreed standardised collection of outcomes - a "core outcomes set" - for all trials in a specific clinical area. Recognising that the current inconsistency is a serious hindrance to progress in our specialty, the editors of over 50 journals related to women's health have come together to support The CROWN (CoRe Outcomes in WomeN's health) Initiative.
PMCID: PMC4104729  PMID: 25048583
Research design/standards; Treatment outcome; Endpoint determination/standards; Clinical trials; Systematic reviews; Guidelines; Bias (Epidemiology); Evidence-based medicine; Consensus
17.  Light chain editors of anti-DNA receptors in human B cells 
Human L chain repertoire includes editor L chains that appear to regulate anti-DNA B cells and shape the B cell repertoire.
Receptor editing is a mechanism of self-tolerance used in newly generated B cells. The expressed heavy (H) or light (L) chain of an autoreactive receptor is replaced by upstream V genes which eliminate or modify autoreactivity. Editing of anti-DNA receptors has been characterized in anti-DNA transgenic mouse models including 3H9, 3H9/56R, and their revertant 3H9GL. Certain L chains, termed editors, rescue anti-DNA B cells by neutralizing or modifying DNA binding of the H chain. This editing mechanism acts on the natural H chain repertoire; endogenous H chains with anti-DNA features are expressed primarily in combination with editor L chains. We ask whether a similar set of L chains exists in the human repertoire, and if so, do they edit H chains with anti-DNA signatures? We compared the protein sequences of mouse editors to all human L chains and found several human L chains similar to mouse editors. These L chains diminish or veto anti-DNA binding when expressed with anti-DNA H chains. The human H chains expressed with these L chains also have relatively high arginine (Arg) content in the H chain complementarity determining region (H3), suggesting that receptor editing plays a role in establishing tolerance to DNA in humans.
PMCID: PMC3920568  PMID: 24470445
18.  Multistate Model Builder (MSMB): a flexible editor for compact biochemical models 
BMC Systems Biology  2014;8:42.
Building models of molecular regulatory networks is challenging not just because of the intrinsic difficulty of describing complex biological processes. Writing a model is a creative effort that calls for more flexibility and interactive support than offered by many of today’s biochemical model editors. Our model editor MSMB — Multistate Model Builder — supports multistate models created using different modeling styles.
MSMB provides two separate advances on existing network model editors. (1) A simple but powerful syntax is used to describe multistate species. This reduces the number of reactions needed to represent certain molecular systems, thereby reducing the complexity of model creation. (2) Extensive feedback is given during all stages of the model creation process on the existing state of the model. Users may activate error notifications of varying stringency on the fly, and use these messages as a guide toward a consistent, syntactically correct model. MSMB default values and behavior during model manipulation (e.g., when renaming or deleting an element) can be adapted to suit the modeler, thus supporting creativity rather than interfering with it. MSMB’s internal model representation allows saving a model with errors and inconsistencies (e.g., an undefined function argument; a syntactically malformed reaction). A consistent model can be exported to SBML or COPASI formats. We show the effectiveness of MSMB’s multistate syntax through models of the cell cycle and mRNA transcription.
Using multistate reactions reduces the number of reactions need to encode many biochemical network models. This reduces the cognitive load for a given model, thereby making it easier for modelers to build more complex models. The many interactive editing support features provided by MSMB make it easier for modelers to create syntactically valid models, thus speeding model creation. Complete information and the installation package can be found at MSMB is based on Java and the COPASI API.
PMCID: PMC4234935  PMID: 24708852
Systems biology; Biological networks; Mathematical modeling; Chemical reaction systems; COPASI; SBML; Software; Model editor; Multistate
19.  Editors and Researchers Beware: Calculating Response Rates in Random Digit Dial Health Surveys 
Health Services Research  2012;48(2 Pt 1):665-676.
To demonstrate that different approaches to handling cases of unknown eligibility in random digit dial health surveys can contribute to significant differences in response rates.
Data Source
Primary survey data of individuals with chronic disease.
Study Design
We computed response rates using various approaches, each of which make different assumptions about the disposition of cases of unknown eligibility.
Data Collection
Data were collected via telephone interviews as part of the Aligning Forces for Quality (AF4Q) consumer survey, a representative survey of adults with chronic illnesses in 17 communities and nationally.
Principal Findings
We found that various approaches to estimating eligibility rates can lead to substantially different response rates.
Health services researchers must consider strategies to standardize response rate reporting, enter into a dialog related to why response rate reporting is important, and begin to utilize alternate methods for demonstrating that survey data are valid and reliable.
PMCID: PMC3626345  PMID: 22998192
Survey research; random digit dial; response rate calculation; survey methodology
20.  An RNA Editor, Adenosine Deaminase Acting on Double-Stranded RNA (ADAR1) 
Adenosine deaminase acting on RNA1 (ADAR1) catalyzes the C6 deamination of adenosine (A) to produce inosine (I) in regions of RNA with double-stranded (ds) character. This process is known as A-to-I RNA editing. Alternative promoters drive the expression of the Adar1 gene and alternative splicing gives rise to transcripts that encode 2 ADAR1 protein size isoforms. ADAR1 p150 is an interferon (IFN)-inducible dsRNA adenosine deaminase found in the cytoplasm and nucleus, whereas ADAR1 p110 is constitutively expressed and nuclear in localization. Dependent on the duplex structure of the dsRNA substrate, deamination of adenosine by ADAR can be either highly site-selective or nonspecific. A-to-I editing can alter the stability of RNA structures and the coding of RNA as I is read as G instead of A by ribosomes during mRNA translation and by polymerases during RNA replication. A-to-I editing is of broad physiologic significance. Both the production and the action of IFNs, and hence the subsequent interaction of viruses with their hosts, are among the processes affected by A-to-I editing.
PMCID: PMC4046350  PMID: 24905200
21.  Photoletter to the editor: Lamellar ichthyosis and arthrogryposis in a premature neonate 
Lamellar ichthyosis is a rare congenital disorder characterized by collodion membrane at birth and facial anomalies (eclabium and ectropion). The major underlying genetic defect is in TGM1, with mutations of this gene found in 50% of patients. An early diagnosis is fundamental in view of establishing a specific treatment due to the severity of the disease. We report a case of severe lamellar ichthyosis and arthrogryposis, without the typical facial presentation, negative for TGM1 mutations. The clinical improvement was achieved only after treatment with oral retinoids, highlighting the importance of early diagnosis and prompt administration of a specific therapy.
PMCID: PMC4517804
autosomal recessive congenital ichthyoses; congenital ichthyoses; lamellar ichthyosis; oral acitretin; transglutaminase-1 gene mutations
22.  An editor for pathway drawing and data visualization in the Biopathways Workbench 
BMC Systems Biology  2009;3:99.
Pathway models serve as the basis for much of systems biology. They are often built using programs designed for the purpose. Constructing new models generally requires simultaneous access to experimental data of diverse types, to databases of well-characterized biological compounds and molecular intermediates, and to reference model pathways. However, few if any software applications provide all such capabilities within a single user interface.
The Pathway Editor is a program written in the Java programming language that allows de-novo pathway creation and downloading of LIPID MAPS (Lipid Metabolites and Pathways Strategy) and KEGG lipid metabolic pathways, and of measured time-dependent changes to lipid components of metabolism. Accessed through Java Web Start, the program downloads pathways from the LIPID MAPS Pathway database (Pathway) as well as from the LIPID MAPS web server . Data arises from metabolomic (lipidomic), microarray, and protein array experiments performed by the LIPID MAPS consortium of laboratories and is arranged by experiment. Facility is provided to create, connect, and annotate nodes and processes on a drawing panel with reference to database objects and time course data. Node and interaction layout as well as data display may be configured in pathway diagrams as desired. Users may extend diagrams, and may also read and write data and non-lipidomic KEGG pathways to and from files. Pathway diagrams in XML format, containing database identifiers referencing specific compounds and experiments, can be saved to a local file for subsequent use. The program is built upon a library of classes, referred to as the Biopathways Workbench, that convert between different file formats and database objects. An example of this feature is provided in the form of read/construct/write access to models in SBML (Systems Biology Markup Language) contained in the local file system.
Inclusion of access to multiple experimental data types and of pathway diagrams within a single interface, automatic updating through connectivity to an online database, and a focus on annotation, including reference to standardized lipid nomenclature as well as common lipid names, supports the view that the Pathway Editor represents a significant, practicable contribution to current pathway modeling tools.
PMCID: PMC2763869  PMID: 19799790
23.  Skyline: an open source document editor for creating and analyzing targeted proteomics experiments 
Bioinformatics  2010;26(7):966-968.
Summary: Skyline is a Windows client application for targeted proteomics method creation and quantitative data analysis. It is open source and freely available for academic and commercial use. The Skyline user interface simplifies the development of mass spectrometer methods and the analysis of data from targeted proteomics experiments performed using selected reaction monitoring (SRM). Skyline supports using and creating MS/MS spectral libraries from a wide variety of sources to choose SRM filters and verify results based on previously observed ion trap data. Skyline exports transition lists to and imports the native output files from Agilent, Applied Biosystems, Thermo Fisher Scientific and Waters triple quadrupole instruments, seamlessly connecting mass spectrometer output back to the experimental design document. The fast and compact Skyline file format is easily shared, even for experiments requiring many sample injections. A rich array of graphs displays results and provides powerful tools for inspecting data integrity as data are acquired, helping instrument operators to identify problems early. The Skyline dynamic report designer exports tabular data from the Skyline document model for in-depth analysis with common statistical tools.
Availability: Single-click, self-updating web installation is available at This web site also provides access to instructional videos, a support board, an issues list and a link to the source code project.
Supplementary information: Supplementary data are available at Bioinformatics online.
PMCID: PMC2844992  PMID: 20147306
24.  A Diagram Editor for Efficient Biomedical Knowledge Capture and Integration 
Understanding the molecular mechanisms underlying complex disorders requires the integration of data and knowledge from different sources including free text literature and various biomedical databases. To facilitate this process, we created the Biomedical Concept Diagram Editor (BCDE) to help researchers distill knowledge from data and literature and aid the process of hypothesis development. A key feature of BCDE is the ability to capture information with a simple drag-and-drop. This is a vast improvement over manual methods of knowledge and data recording and greatly increases the efficiency of the biomedical researcher. BCDE also provides a unique concept matching function to enforce consistent terminology, which enables conceptual relationships deposited by different researchers in the BCDE database to be mined and integrated for intelligible and useful results. We hope BCDE will promote the sharing and integration of knowledge from different researchers for effective hypothesis development.
PMCID: PMC3041526  PMID: 21347131
25.  Authors, editors, and the signs, symptoms and causes of plagiarism 
Saudi Journal of Anaesthesia  2011;5(3):303-307.
Plagiarism and inadequate citing appear to have reached epidemic proportions in research publication. This article discusses how plagiarism is defined and suggests some possible causes for the increase in the plagiarism disease. Most editors do not have much tolerance for text re-use with inadequate citation regardless of reasons why words are copied from other sources without correct attribution. However, there is now some awareness that re-use of words in research articles to improve the writing or “the English” (which has become a common practice) should be distinguished from intentional deceit for the purpose of stealing other authors’ ideas (which appears to remain a very rare practice). Although it has become almost as easy for editors to detect duplicate text as it is for authors to re-use text from other sources, editors often fail to consider the reasons why researchers resort to this strategy, and tend to consider any text duplication as a symptom of serious misconduct. As a result, some authors may be stigmatized unfairly by being labeled as plagiarists. The article concludes with practical advice for researchers on how to improve their writing and citing skills and thus avoid accusations of plagiarism.
PMCID: PMC3168350  PMID: 21957412
Plagiarism; editors; authors

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