Diane-35: Geen Reden tot Paniek!

12 03 2013

Dear english-speaking readers of this blog.

This post is about the anti-acne drug Diane-35 that (with other 3rd and 4th generation combined oral contraceptives (COCs)) has been linked to the deaths of several women in Canada, France and the Netherlands. Since there is a lot of media attention (and panic) in the Netherlands, the remainder of this post is in Dutch. Please write in the comments (or tweet) if you would like me to summarize the health concerns of these COCs in a separate English post.

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Mediaophef 

Er is de laatste tijd nogal veel media-aandacht voor Diane-35. Het begon allemaal in Frankrijk, waar de Franse toezichthouder op geneesmiddelen ANSM Diane-35* eind januari van de markt wilde halen omdat in de afgelopen 25 jaar 4 vrouwen na het gebruik ervan waren overleden. In beroep werd dit afgewezen, waarna de ANSM de EMA (European Medicines Agency) verzocht om de veiligheid van Diane en 3e/4e generatie orale combinatie anticonceptiepillen (OAC) nog eens te onderzoeken.

In januari overleed ook een 21-jarige gebruikster van Diane-35 in Nederland. Met terugwerkende kracht ontving het Nederlandse Bijwerkingscentrum Lareb 97 meldingen van bijwerkingen van Diane-35. Hieronder waren 9 sterfgevallen uit 2011 en eerder.** Overigens werden ook sterfgevallen gemeld van vrouwen die vergelijkbare (3e en 4e generatie) orale anticonceptiemiddelen hadden gebruikt, zoals Yasmin.

Alle vrouwen zijn overleden aan bloedproppen in bloedvaten (trombose dan wel longembolie).  Totaal waren er  89 meldingen van bloedstolsels, wat altijd (ook zonder dodelijke afloop) een ernstige bijwerking is.

Aanleiding voor Canada en België, om ook in de statistieken te duiken. In Canada bleken sinds 2000 11 vrouwen die Diane-35 slikten te zijn overleden en in België zijn er sinds 2008 29 meldingen van trombose door het gebruik van de 3e/4e generatiepil (5 door Diane-35, geen doden)

Dit nieuws sloeg in als een bom. Veel mensen raakten in paniek. Of zijn boos op Bayer*, het CBG (College ter Beoordeling van Geneesmiddelen) en/of minister Schippers die het naar hun idee laten afweten. Op Twitter zie ik aan de lopende band tweets voorbijkomen als:

Diane-35 pil: heet deze zo omdat je er niet altijd de 35 jaar mee haalt?“.

Tonnen #rundvlees halen we uit de handel om wat #paardenvlees. Maar doden door de Diane 35 #pil doet de regering niks mee.

Oud Nieuws

Dergelijke reacties zijn sterk overdreven. Er is absoluut geen reden tot paniek.

Echter waar rook is, is vuur. Ook al gaat het hier om een klein brandje.

Maar wat betreft Diane-35 is die rook er al jaren…. Waarom roept men nu ineens: “Brand!”?

De meeste sterfgevallen zijn van vòòr dit jaar. Dat de Fransen authoriteiten nu zoveel daadkracht tonen komt waarschijnlijk omdat hen laksheid verweten werd bij recente schandalen met PIP-borstimplantaten en Mediator, dat meer dan 500 sterfgevallen veroorzaakt heeft. [Reuterszie ook het blog van Henk Jan Out]

Verder was allang bekend dat Diane-35 de kans op bloedstolsels verhoogde.

Niet alleen Diane-35

Men kan de risico’s van Diane-35 niet los zien van de risico’s van orale anticonceptiemiddelen (OAC’s) in het algemeen.

Diane-35 lijkt qua samenstelling erg op de 3e generatie OAC.  Het is echter uniek omdat het in plaats van een 3e generatie progestogeen cyproteronacetaat bevat. ‘De pil’ bevat levonorgestrel, dit is een 2e generatie progestogeen. Al de OAC combinatiepillen bevatten daarnaast (tegenwoordig) een lage dosering ethinylestradiol.

Zoals gezegd, is al jaren bekend dat alle OAC’s, dus ook ‘de pil’, de kans op bloedstolsels in bloedvaten licht verhogen[1,2,3]. Op zijn hoogst verhogen 2e generatie OAC’s (met levonorgestrel) die kans met een factor 4. Derde generatie pillen lijken die kans verder te verhogen. Met hoeveel precies, daarover verschillen de meningen. Voor wat beteft Diane-35, ziet de een géén tot nauwelijks effect [4], de ander een 1,5 [5]  tot 2 x [3] sterker effect.  Het totaalplaatje ziet er ongeveer als volgt uit:

7-3-2013 15-48-49 risico's pil

Absolute en relatieve kans op VTE (Veneuze trombo-embolie).
Uit: http://www.anticonceptie-online.nl/pil.htm

Risico’s in Perspectief

Een 1,5-2 x groter risico vergeleken met de “gewone pil”, lijkt een enorm groot risico. Dit zou ook een groot effect zijn als trombo-embolie vaak voorkwam. Stel dat 1 op de 100 mensen trombose krijgt per jaar, dan zouden op jaarbasis 2-4 op de 100 mensen trombose krijgen na de ‘pil’ en 3-8 mensen na Diane-35 of een 3e of 4e generatiepil. Dit is een groot absoluut risico. Dat risico zou je normaal niet nemen.

Maar trombo-embolie is zeldzaam. Het komt voor bij 5-10 op de 100.000 vrouwen per jaar. En totaal zal 1 op miljoen vrouwen daaraan overlijden. Dat is een heel minieme kans.Vier tot zes keer een kans van iets meer dan 0 blijft een kans van bijna 0. Dus in absolute zin, brengen Diane-35 en OAC’s weinig risico met zich mee.

Daarbij komt dat trombose niet direct door de pil veroorzaakt hoeft te zijn. Roken, leeftijd, (over)gewicht, erfelijke aanleg voor stollingsproblemen kunnen ook een (grote) rol spelen. Verder kunnen deze factoren samenspelen. Om deze reden worden OAC’s (ook de pil) afgeraden aan risicogroepen (oudere vrouwen die veel roken, aanleg voor trombose e.d.)

Het aantal bijwerkingendat mogelijk samenhangt met het gebruik van Diane-35, geeft eigenlijk aan dat dit een relatief veilig middel is.

Aanvaardbaar risico?

Om het nog meer in perspectief te plaatsen: zwangerschap geeft een 2x hoger risico op trombose dan Diane-35, en in de 12 weken na de bevalling is de kans nog weer 4-8 keer hoger dan in de zwangerschap (FDA). Toch zullen vrouwen het daarvoor niet laten om zwanger te worden. Het krijgen van een kind weegt meestal (impliciet) op tegen(kleine) risico’s (waarvan trombose er één is).

Men kan de (kans op) risico’s dus niet los zien van de voordelen. Als het voordeel hoog is zal men zelfs een zeker risico op de koop toe willen nemen (afhankelijk van de ernst van de aandoening en eht nut). Aan de andere kant wil je zelfs een heel klein risico niet lopen, als je geen baat hebt bij een middel of als er even goede, maar veiliger middelen zijn.

Maar mag de patiënte die overweging niet zelf met haar arts maken?

Geen plaats voor Diane-35  als anticonceptiemiddel

Diane-35 heeft een anticonceptiewerking, maar het is hiervoor niet (langer) geregistreerd. De laatste anticonceptie-richtlijn van de nederlandse huisartsen (NHG) uit 2010 [6] zegt expliciet dat er geen plaats meer is voor de pil met cyproteronacetaat. Dit omdat de gewone ‘pil’ even goed zwangerschap voorkomt én (iets) minder kans geeft op trombose als bijwerking. Dus waarom zou je een een potentieel hoger risico lopen, als dat niet nodig is? Helaas is de NHG-standaard minder expliciet over 2e en 3e generatie OAC’s.

In andere landen denkt men vaak net zo (In de VS is Diane-35 echter niet geregistreerd).

Dit zegt bijv de RCOG (Royal College of Obstetricians and Gynaecologist, UK) in hun evidence-based richtlijn die specifiek gaat over OAC’s en kans op trombose [1]

10-3-2013 17-27-40 RCOG CPA

Diane-35 als middel tegen ernstige acne en overbeharing.

Omdat het cyproteron acetaat in Diane-35 een sterk anti-androgene werking heeft kan het worden ingezet  bij ernstige acné en overbeharing (dat laatste met name bij vrouwen met PCOS, een gynecologische aandoening). Desgewenst kan het dan tevens dienst doen als anticonceptiemiddel: 2 vliegen in één klap.

Clinical Evidence, dat een heel mooie evidence based bron is die voor-en nadelen van behandelingen tegen elkaar afzet, concludeert dat middelen met cyproteron acetaat ondanks hun prima werking, bij ernstige overbeharing (bij PCOS) niet de voorkeur verdienen boven middelen als metformine. Het risico op trombose is in deze overweging meegenomen.[7]

3-3-2013 14-54-14 CLINical Evidence PCOS cyproterone acetate

Volgens een Cochrane Systematisch Review hielpen alle OAC’s wel bij acné, maar OAC’s met cyproteron leken wat effectiever dan pillen met 2e of 3e generatie progestogeen. De resultaten waren echter tegenstrijdig en de studies niet zo erg sterk.[8]

Sommigen concluderen op basis van dit Cochrane Review dat alle OAC’s even goed helpen en dat de gewone pil dus voorkeur verdient (zie bijv. dit recente artikel van Helmerhorst in de BMJ [2], en de NHG standaard acne [9]

Maar in de meest recente Richtlijn Acneïforme Dermatosen [10] van de Nederlandse Vereniging voor Dermatologie en Venereologie (NVDV) wordt er op basis van dezelfde evidence iets anders geconcludeerd: 10-3-2013 22-43-02 ned vereniging voor dermatologie

De Nederlandse dermatologen komen dus met een positieve aanbeveling van Diane-35 ten opzichte van andere anticonceptiemiddelen bij vrouwen die ook anticonceptie wensen. Nergens in deze richtlijn wordt expliciet gerefereerd aan trombose als mogelijke bijwerking.

Het voorschrijfbeleid in de praktijk.

Als Diane-35 niet als anticonceptiemiddel voorgeschreven wordt, en het wordt slechts bij ernstige vormen van acne of overbeharing gebruikt, hoe kan dit middel met een zo’n laag risico dan zo’n omvangrijk probleem worden? De doelgroep èn de kans op bijwerkingen is immers heel klein. En hoe zit het met 3e en 4e generatie OAC’s die niet eens bij acné voorgeschreven zullen worden? Daar zou de doelgroep nog kleiner moeten zijn.

De realiteit is dat de omvang van het probleem niet zozeer door het on-label gebruik komt maar, zoals Janine Budding al aangaf op haar blog Medical Facts door off-label voorschrijfgedrag, dus voor een  andere indicatie dan waarvoor het geneesmiddel is geregistreerd. In Frankrijk gebruikt de helft van de vrouwen die OAC’s gebruiken, de 3e en 4e generatie OAC: dat is ronduit buitensporig, en niet volgens de richtlijnen.

In Nederland slikkten ruim 161.000 vrouwen Diane-35 of een generieke variant met exact dezelfde werking. Ook veel Nederlandse en Canadese gebruiken Diane-35 en andere 3e en 4e generatie OAC’s puur anticonceptiemiddel. Voor een deel, omdat sommige huisartsen het ‘in de pen’ hebben of denken dat een meisje dan gelijk van haar puistjes afgeholpen is. Voor een deel omdat, in  Nederland en  Frankrijk, Diane-35 vergoed wordt en de gewone pil niet. Er is, zeker in Frankrijk, een run op een ‘gratis’ pil.

Online bedrijven spelen mogelijk ook een rol. Deze lichten vaak niet goed voor. Eén zo’n bedrijf (met gebrekkige info over Diane op hun website) gaat zelfs zover het twitter account @diane35nieuws te creeeren als dekmantel voor online pillenverkoop.

Wat nu?

Hoewel de risico’s van Diane-35 allang bekend waren en gering lijken te zijn, en bovendien vergelijkbaar met die van de 3e en 4e generatie  OAC’s, is er een massaal verzet tegen Diane-35 op gang gekomen, die niet meer te stuiten lijkt. Niet de experts, maar de media en de politiek lijken de discussie te voeren.Erg verwarrend en soms misleidend voor de patiënt.

Mijn inziens is het besluit van de Nederlandse huisartsen, gynecologen en recent ook de dermatologen om Diane-35 voorlopig niet voor te schrijven aan nieuwe patiënten tot de autoriteiten een uitspraak hebben gedaan over de veiligheid***, gezien de huidige onrust, een verstandige.

Wat niet verstandig is om zomaar met de Diane-35 pil te stoppen. Overleg altijd eerst met uw arts wat voor u de beste optie is.

In 1995 heeft een vergelijkbare reactie op waarschuwingen over de tromboserisico’s van bepaalde OAC’s geleid tot een ware “pil scare”: vrouwen gingen massaal over op een andere pil of stopten er in het geheel mee. Gevolg: een piek aan ongewenste zwangerschappen (met overigens een veel hogere kans op trombose) en abortussen. Conclusie destijds [10]:

“The level of risk should, in future, be more carefully assessed and advice more carefully presented in the interests of public health.”

Kennelijk is deze les aan Nederland en Frankrijk voorbijgegaan.

Hoewel ik denk dat Diane-35 maar voor een beperkte groep echt zinvol is boven de bestaande middelen, is het te betreuren dat op basis van ongefundeerde reacties, patiënten straks mogelijk zelf geen keuzevrijheid meer hebben. Mogen zij zelf de balans tussen voor-en nadelen bepalen?

Het is begrijpelijk (maar misschien niet zo heel professioneel), dat dermatologen nogal gefrustreerd reageren, nu een bepaalde groep patienten tussen wal en schip raakt. Tevens moet men niet op basis van evidence en argumenten, maar onder druk van media en politiek, tot een ander beleid overgaan.

11-3-2013 23-27-37 reactie dermatologen 2

Want laten we wel wezen, sommige dermatologische en gynecologische patiënten hebben wel baat bij Diane-35.

en

En tot slot een prachtige reactie van een acne-patiënte op een  blog post van Ivan Wolfers. Zij vat de essentie in enkele zinnen samen. Net als bovenstaande dames, een patient die zeer weloverwogen met haar arts beslissingen neemt op basis van de bestaande info.

Zoals het zou moeten…

12-3-2013 0-57-27 reactie patient

Noten

* Diane-35 wordt geproduceerd door Bayer. Het staat ook bekend als Minerva, Elisa en in buitenland bijvoorbeels als Dianette. Er zijn verder ook veel merkloze preparaten met dezelfde samenstelling.

**Inmiddels heeft zijn er nog 4 dodelijke gevallen na gebruik van Diane-35 in Nederland bijgekomen (Artsennet, 2013-03-11)

***Hopelijk wordt de gewone pil dan ook in de vergelijking meegenomen. Dit is wel zo eerlijk: het gaat immers om een vergelijking.

Referenties 

  • Venous Thromboembolism and Hormone Replacement Therapy – Green-top Guide line 40 (2010) Royal College of Obstetricians and Gynaecologists, 

    2011

  • Helmerhorst F.M. & Rosendaal F.R. (2013). Is an EMA review on hormonal contraception and thrombosis needed?, BMJ (Clinical research ed.), PMID:
  • van Hylckama Vlieg A., Helmerhorst F.M., Vandenbroucke J.P., Doggen C.J.M. & Rosendaal F.R. (2009). The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progestogen type: results of the MEGA case-control study., BMJ (Clinical research ed.), PMID:
  • Spitzer W.O. (2003) Cyproterone acetate with ethinylestradiol as a risk factor for venous thromboembolism: an epidemiological evaluation., Journal of obstetrics and gynaecology Canada : JOGC = Journal d’obstétrique et gynécologie du Canada : JOGC, PMID:
  • Martínez F., Ramírez I., Pérez-Campos E., Latorre K. & Lete I. (2012) Venous and pulmonary thromboembolism and combined hormonal contraceptives. Systematic review and meta-analysis., The European journal of contraception & reproductive health care : the official journal of the European Society of Contraception, PMID:
  • NHG-Standaard Anticonceptie 2010 Anke Brand, Anita Bruinsma, Kitty van Groeningen, Sandra Kalmijn, Ineke Kardolus, Monique Peerden, Rob Smeenk, Suzy de Swart, Miranda Kurver, Lex Goudswaard.

  • Cahill D. (2009). PCOS., Clinical evidence, PMID:
  • Arowojolu A.O., Gallo M.F., Lopez L.M. & Grimes D.A. (2012). Combined oral contraceptive pills for treatment of acne., Cochrane database of systematic reviews (Online), PMID:
  • Kertzman M.G.M., Smeets J.G.E., Boukes F.S. & Goudswaard A.N. [Summary of the practice guideline ‘Acne’ (second revision) from the Dutch College of General Practitioners]., Nederlands tijdschrift voor geneeskunde, PMID:
  • Richtlijn Acneïforme Dermatosen, © 2010, Nederlandse Vereniging voor Dermatologie en Venereologie (NVDV)
  • Furedi A. The public health implications of the 1995 ‘pill scare’., Human reproduction update, PMID:




Of Mice and Men Again: New Genomic Study Helps Explain why Mouse Models of Acute Inflammation do not Work in Men

25 02 2013

ResearchBlogging.org

This post is update after a discussion at Twitter with @animalevidence who pointed me at a great blog post at Speaking of Research ([19], a repost of [20], highlighting the shortcomings of the current study using just one single inbred strain of mice (C57Bl6)  [2013-02-26]. Main changes are in blue

A recent paper published in PNAS [1] caused quite a stir both inside and outside the scientific community. The study challenges the validity of using mouse models to test what works as a treatment in humans. At least this is what many online news sources seem to conclude: “drug testing may be a waste of time”[2], “we are not mice” [3, 4], or a bit more to the point: mouse models of inflammation are worthless [5, 6, 7].

But basically the current study looks only at one specific area, the area of inflammatory responses that occur in critically ill patients after severe trauma and burns (SIRS, Systemic Inflammatory Response Syndrome). In these patients a storm of events may eventually lead to organ failure and death. It is similar to what may occur after sepsis (but here the cause is a systemic infection).

Furthermore the study only uses one single approach: it compares the gene response patterns in serious human injuries (burns, trauma) and a human model partially mimicking these inflammatory diseases (human healthy volunteers receiving  a low dose endotoxin) with the corresponding three animal models (burns, trauma, endotoxin).

And, as highlighted by Bill Barrington of “Understand Nutrition” [8], the researchers have only tested the gene profiles in one single strain of mice: C57Bl6 (B6 for short). If B6 was the only model used in practice this would be less of a problem. But according to Mark Wanner of the Jackson Laboratory [19, 20]:

 It is now well known that some inbred mouse strains, such as the C57BL/6J (B6 for short) strain used, are resistant to septic shock. Other strains, such as BALB and A/J, are much more susceptible, however. So use of a single strain will not provide representative results.

The results in itself are very clear. The figures show at a glance that there is no correlation whatsoever between the human and B6 mouse expression data.

Seok and 36 other researchers from across the USA  looked at approximately 5500 human genes and their mouse analogs. In humans, burns and traumatic injuries (and to a certain extent the human endotoxin model) triggered the activation of a vast number of genes, that were not triggered in the present C57Bl6 mouse models. In addition the genomic response is longer lasting in human injuries. Furthermore, the top 5 most activated and most suppressed pathways in human burns and trauma had no correlates in mice. Finally, analysis of existing data in the Gene Expression (GEO) Database showed that the lack of correlation between mouse and human studies was also true for other acute inflammatory responses, like sepsis and acute infection.

This is a high quality study with interesting results. However, the results are not as groundbreaking as some media suggest.

As discussed by the authors [1], mice are known to be far more resilient to inflammatory challenge than humans*: a million fold higher dose of endotoxin than the dose causing shock in humans is lethal to mice.* This, and the fact that “none of the 150  candidate agents that progressed to human trials has proved successful in critically ill patients” already indicates that the current approach fails.

[This is not entirely correct the endotoxin/LPS dose in mice is 1000–10,000 times the dose required to induce severe disease with shock in humans [20] and mice that are resilient to endotoxin may still be susceptible to infection. It may well be that the endotoxin response is not a good model for the late effects of  sepsis]

The disappointing trial results have forced many researchers to question not only the usefulness of the current mouse models for acute inflammation [9,10; refs from 11], but also to rethink the key aspects of the human response itself and the way these clinical trials are performed [12, 13, 14]. For instance, emphasis has always been on the exuberant inflammatory reaction, but the subsequent immunosuppression may also be a major contributor to the disease. There is also substantial heterogeneity among patients [13-14] that may explain why some patients have a good prognosis and others haven’t. And some of the initially positive results in human trials have not been reproduced in later studies either (benefit of intense glucose control and corticosteroid treatment) [12]. Thus is it fair to blame only the mouse studies?

dick mouse

dick mouse (Photo credit: Wikipedia)

The coverage by some media is grist to the mill of people who think animal studies are worthless anyway. But one cannot extrapolate these findings to other diseases. Furthermore, as referred to above, the researchers have only tested the gene profiles in one single strain of mice: C57Bl6, meaning that “The findings of Seok et al. are solely applicable to the B6 strain of mice in the three models of inflammation they tested. They unduly generalize these findings to mouse models of inflammation in general. [8]”

It is true that animal studies, including rodent studies, have their limitations. But what are the alternatives? In vitro studies are often even more artificial, and direct clinical testing of new compounds in humans is not ethical.

Obviously, the final proof of effectiveness and safety of new treatments can only be established in human trials. No one will question that.

A lot can be said about why animal studies often fail to directly translate to the clinic [15]. Clinical disparities between the animal models and the clinical trials testing the treatment (like in sepsis) are one reason. Other important reasons may be methodological flaws in animal studies (i.e. no randomization, wrong statistics) and publication bias: non-publication of “negative” results appears to be prevalent in laboratory animal research.[15-16]. Despite their shortcomings, animal studies and in vitro studies offer a way to examine certain aspects of a process, disease or treatment.

In summary, this study confirms that the existing (C57Bl6) mouse model doesn’t resemble the human situation in the systemic response following acute traumatic injury or sepsis: the genomic response is entirely different, in magnitude, duration and types of changes in expression.

The findings are not new: the shortcomings of the mouse model(s) were long known. It remains enigmatic why the researchers chose only one inbred strain of mice, and of all mice only the B6-strain, which is less sensitive to endotoxin, and only develop acute kidney injury (part of organ failure) at old age (young mice were used) [21]. In this paper from 2009 (!) various reasons are given why the animal models didn’t properly mimic the human disease and how this can be improved. The authors stress that:

the genetically heterogeneous human population should be more accurately represented by outbred mice, reducing the bias found in inbred strains that might contain or lack recessive disease susceptibility loci, depending on selective pressures.” 

Both Bill Barrington [8] and Mark Wanner [18,19] propose the use of “diversity outbred cross or collaborative cross mice that  provide additional diversity.” Indeed, “replicating genetic heterogeneity and critical clinical risk factors such as advanced age and comorbid conditions (..) led to improved models of sepsis and sepsis-induced AKI (acute kidney injury). 

The authors of the PNAS paper suggest that genomic analysis can aid further in revealing which genes play a role in the perturbed immune response in acute inflammation, but it remains to be seen whether this will ultimately lead to effective treatments of sepsis and other forms of acute inflammation.

It also remains to be seen whether comprehensive genomic characterization will be useful in other disease models. The authors suggest for instance,  that genetic profiling may serve as a guide to develop animal models. A shotgun analyses of gene expression of thousands of genes was useful in the present situation, because “the severe inflammatory stress produced a genomic storm affecting all major cellular functions and pathways in humans which led to sufficient perturbations to allow comparisons between the genes in the human conditions and their analogs in the murine models”. But rough analysis of overall expression profiles may give little insight in the usefulness of other animal models, where genetic responses are more subtle.

And predicting what will happen is far less easy that to confirm what is already known….

NOTE: as said the coverage in news and blogs is again quite biased. The conclusion of a generally good Dutch science  news site (the headline and lead suggested that animal models of immune diseases are crap [6]) was adapted after a critical discussion at Twitter (see here and here), and a link was added to this blog post). I wished this occurred more often….
In my opinion the most balanced summaries can be found at the science-based blogs: ScienceBased Medicine [11] and NIH’s Director’s Blog [17], whereas “Understand Nutrition” [8] has an original point of view, which is further elaborated by Mark Wanner at Speaking of Research [19] and Genetics and your health Blog [20]

References

  1. Seok, J., Warren, H., Cuenca, A., Mindrinos, M., Baker, H., Xu, W., Richards, D., McDonald-Smith, G., Gao, H., Hennessy, L., Finnerty, C., Lopez, C., Honari, S., Moore, E., Minei, J., Cuschieri, J., Bankey, P., Johnson, J., Sperry, J., Nathens, A., Billiar, T., West, M., Jeschke, M., Klein, M., Gamelli, R., Gibran, N., Brownstein, B., Miller-Graziano, C., Calvano, S., Mason, P., Cobb, J., Rahme, L., Lowry, S., Maier, R., Moldawer, L., Herndon, D., Davis, R., Xiao, W., Tompkins, R., , ., Abouhamze, A., Balis, U., Camp, D., De, A., Harbrecht, B., Hayden, D., Kaushal, A., O’Keefe, G., Kotz, K., Qian, W., Schoenfeld, D., Shapiro, M., Silver, G., Smith, R., Storey, J., Tibshirani, R., Toner, M., Wilhelmy, J., Wispelwey, B., & Wong, W. (2013). Genomic responses in mouse models poorly mimic human inflammatory diseases Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.1222878110
  2. Drug Testing In Mice May Be a Waste of Time, Researchers Warn 2013-02-12 (science.slashdot.org)
  3. Susan M Love We are not mice 2013-02-14 (Huffingtonpost.com)
  4. Elbert Chu  This Is Why It’s A Mistake To Cure Mice Instead Of Humans 2012-12-20(richarddawkins.net)
  5. Derek Low. Mouse Models of Inflammation Are Basically Worthless. Now We Know. 2013-02-12 (pipeline.corante.com)
  6. Elmar Veerman. Waardeloos onderzoek. Proeven met muizen zeggen vrijwel niets over ontstekingen bij mensen. 2013-02-12 (wetenschap24.nl)
  7. Gina Kolata. Mice Fall Short as Test Subjects for Humans’ Deadly Ills. 2013-02-12 (nytimes.com)

  8. Bill Barrington. Are Mice Reliable Models for Human Disease Studies? 2013-02-14 (understandnutrition.com)
  9. Raven, K. (2012). Rodent models of sepsis found shockingly lacking Nature Medicine, 18 (7), 998-998 DOI: 10.1038/nm0712-998a
  10. Nemzek JA, Hugunin KM, & Opp MR (2008). Modeling sepsis in the laboratory: merging sound science with animal well-being. Comparative medicine, 58 (2), 120-8 PMID: 18524169
  11. Steven Novella. Mouse Model of Sepsis Challenged 2013-02-13 (http://www.sciencebasedmedicine.org/index.php/mouse-model-of-sepsis-challenged/)
  12. Wiersinga WJ (2011). Current insights in sepsis: from pathogenesis to new treatment targets. Current opinion in critical care, 17 (5), 480-6 PMID: 21900767
  13. Khamsi R (2012). Execution of sepsis trials needs an overhaul, experts say. Nature medicine, 18 (7), 998-9 PMID: 22772540
  14. Hotchkiss RS, Coopersmith CM, McDunn JE, & Ferguson TA (2009). The sepsis seesaw: tilting toward immunosuppression. Nature medicine, 15 (5), 496-7 PMID: 19424209
  15. van der Worp, H., Howells, D., Sena, E., Porritt, M., Rewell, S., O’Collins, V., & Macleod, M. (2010). Can Animal Models of Disease Reliably Inform Human Studies? PLoS Medicine, 7 (3) DOI: 10.1371/journal.pmed.1000245
  16. ter Riet, G., Korevaar, D., Leenaars, M., Sterk, P., Van Noorden, C., Bouter, L., Lutter, R., Elferink, R., & Hooft, L. (2012). Publication Bias in Laboratory Animal Research: A Survey on Magnitude, Drivers, Consequences and Potential Solutions PLoS ONE, 7 (9) DOI: 10.1371/journal.pone.0043404
  17. Dr. Francis Collins. Of Mice, Men and Medicine 2013-02-19 (directorsblog.nih.gov)
  18. Tom/ Mark Wanner Why mice may succeed in research when a single mouse falls short (2013-02-15) (speakingofresearch.com) [repost, with introduction]
  19. Mark Wanner Why mice may succeed in research when a single mouse falls short (2013-02-13/) (http://community.jax.org) %5Boriginal post]
  20. Warren, H. (2009). Editorial: Mouse models to study sepsis syndrome in humans Journal of Leukocyte Biology, 86 (2), 199-201 DOI: 10.1189/jlb.0309210
  21. Doi, K., Leelahavanichkul, A., Yuen, P., & Star, R. (2009). Animal models of sepsis and sepsis-induced kidney injury Journal of Clinical Investigation, 119 (10), 2868-2878 DOI: 10.1172/JCI39421




Health Experts & Patient Advocates Beware: 10 Reasons Why you Shouldn’t be a Curator at Organized Wisdom!! #OrganizedWisdom

11 05 2011

Last year I aired my concern about Organized Wisdom in a post called Expert Curators, WisdomCards & The True Wisdom of @organizedwisdom.

Organized Wisdom shares health links of health experts or advocates, who (according to OW’s FAQ), either requested a profile or were recommended by OW’s Medical Review Board. I was one of those so called Expert Curators. However, I had never requested a profile and I seriously doubt whether someone from the a medical board had actually read any of my tweets or my blog posts.

This was one of the many issues with Organized Wisdom. But the main issue was its lack of credibility and transparency. I vented my complaints, I removed my profile from OW, stopped following updates at Twitter and informed some fellow curators.

I almost forgot about it, till Simon Sikorski, MD, commented at my blog, informing me that my complaints hadn’t been fully addressed and convincing me things were even worse than I thought.

He has started a campaign to do something about this Unethical Health Information Content Farming by Organized Wisdom (OW).

While discussing this affair with a few health experts and patient advocates I was disappointed by the reluctant reactions of a few people: “Well, our profiles are everywhere”, “Thanks I will keep an eye open”, “cannot say much yet”. How much evidence does one need?

Of course there were also people – well known MD’s and researchers – who immediately removed their profile and compared OW’s approach with that of Wellsphere, that scammed the Health Blogosphere. Yes, OW also scrapes and steals your intellectual property (blog and/or tweet content), but the difference is: OW doesn’t ask you to join, it just puts up your profile and shares it with the world.

As a medical librarian and e-patient I find the quality, reliability and objectivity of health information of utmost importance. I believe in the emancipation of patients (“Patient is not a third person word”, e-patient Dave), but it can only work if patients are truly well informed. This is difficult enough, because of the information overload and the conflicting data. We don’t need any further misinformation and non-transparency.

I belief that Organized Wisdom puts the reputation of  its “curators” at stake and that it is not a trustworthy nor useful resource for health information. For the following reasons (x see also Simon’s blog post and slides, his emphasis is more on content theft)

1. Profiles of Expert Curators are set up without their knowledge and consent
Most curators I asked didn’t know they were expert curators. Simon has spoken with 151 of the 5700 expert curators and not one of those persons knew he/she was listed on OW. (x)

2. The name Expert Curator suggests that you (can) curate information, but you cannot.
The information is automatically produced and is shown unfiltered (and often shown in duplicate, because many different people can link to the same source). It is not possible to edit the cards.
Ideally, curating should even be more than filtering (see this nice post about 
Social Media Content Curators, where curation is defined as the act of synthesizing and interpreting in order to present a complete record of a concept.)

3. OW calls your profile address: “A vanity URL¹”.

Is that how they see you? Well it must be said they try to win you by pure flattery. And they often succeed….

¹Quote OW: “We credit, honor, and promote our Health Experts, including offering: A vanity URL to promote so visitors can easily share your Health Profile with others, e.g. my.organizedwisdom.com/ePatientDave.
Note: this too is quite similar to the Wellsphere’s approach (read more at E-patients-net)

4. Bots tap into your tweets and/or scrape the content off their website
(x: see healthcare content farms monetizing scheme)

5. Scraping your content can affect your search rankings (x)
This probably affects starting/small blogs the most. I checked two posts of well known blogs and their websites still came up first.

6.  The site is funded/sponsored by pharmaceutical companies.
 “Tailored” ads show up next to the so called Wisdom Cards dealing with the same topic. If no pharmaceutical business has responded Google ads show up instead.
See the form where they actually invite pharma companies to select a target condition for advertizing. Note that the target conditions fit the OW topics.

7. The Wisdom Cards are no more than links to your tweets or posts. They have no added value. 

8. Worse, tweets and links are shown out of context.
I provided various examples in my previous post (mainly in the comment section)

A Cancer and Homeopathy WisdomCard™ shows Expert Curator Liz Ditz who is sharing a link about Cancer and Homeopathy. The link she shares is a dangerous article by a Dr. who is working in an Homeopathic General Hospital, in India “reporting” several cases of miraculous cures by Conium 1M, Thuja 50M and other watery-dilutions. I’m sure that Liz Ditz, didn’t say anything positive about the “article”. Still it seems she “backs it up”. Perhaps she tweeted: “Look what a dangerous crap.”
When I informed her, Liz said:“AIEEEE…. didn’t sign up with Organized Wisdom that I know of”. She felt she was used for credulous support for homeopathy & naturopathy.

Note: Liz card has disappeared (because she opted out), but I was was surprised to find that the link (http://organizedwisdom.com/Cancer-and-Homeopathy/wt/medstill works and links to other “evidence” on the same topic.


9. There is no quality control. Not of the wisdom cards and not of the expert curators.
Many curators are not what I would call true experts and I’m not alone: @holly comments at a Techcrunch postI am glad you brought up the “written by people who do not have a clue, let alone ANY medical training [of any kind] at all.” I have no experience with any kind of medical education, knowledge or even the slightest clue of a tenth of the topics covered on OW, yet for some reason they tried to recruit me to review cards there!?! )

The emphasis is also on alternative treatments: prevention of cancer, asthma, ADHD by herbs etc. In addition to “Health Centers”, there also Wellness Centers (AgingDietFitness etc) and Living Centers (BeautyCookingEnvironment). A single card can share information of 2 or 3 centers (diabetes and multivitamins for example).

And as said, all links of expert curators are placed unfiltered, even when you make a joke or mention you’re on vacation. Whether you’re a  Top health expert or advocate (there is a regular shout-out) just depends on the number of links you share, thus NOT on quality. For this reason the real experts are often at lower positions.

Some cards are just link baits.

 

10.  Organized Wisdom is heavily promoting its site.
Last year it launched activitydigest, automatic digests meant to stimulate “engagement” of expert curators. It tries to connect with top health experts, pharma -people and patient advocates. Hoping they will support OW. This leads to uncritical interviews such as at Pixels and Pills, at Health Interview (
Reader’s Digest + Organized Wisdom = Wiser Patients), Xconomy.com organizedwisdom recruits experts to filter health information on the web.

What can you do?

  • Check whether you have a profile at Organized Wisdom here.
  • Take a good look at Organized Wisdom and what it offers. It isn’t difficult and it doesn’t take much time to see through the facade.
  • If you don’t agree with what it represents, please consider to opt out.
  • You can email info@organizedwisdom.com to let your profile as expert curator removed.
  • If you agree that what OW does is no good practice, you could do the following (most are suggestions of Simon):
  • spread the word and inform others
  • join the conversation on Twitter #EndToFarms
  • join the tweetup on what you can do about this scandal and how to protect yourself from being liable. (more details will be offered by Simon at his regularly updated blogpost)
  • If you don’t agree this Content Farm deserves HONcode certification, notify HON at  https://www.healthonnet.org/HONcode/Conduct.html?HONConduct444558
Please don’t sit back and think that being a wisdom curator does not matter. Don’t show off  with an Organized Wisdom badget, widget or link at your blog or website.  Resist the flattery of being called an expert curator, because it doesn’t mean anything in this context. And by being part of Organized Wisdom, you indirectly support their practice. This may seriously affect your own reputation and indirectly you may contribute to misinformation.

Or as Heidi’s commented to my previous post:

I am flabbergasted that people’s reputation are being used to endorse content without their say so.
Even more so that they cannot delete their profile and withdraw their support.*

For me those two things on their own signal big red flags:

The damage to a health professional’s reputation as a result could be great.
Misleading the general public with poor (yes dangerous) information another

Altogether unethical.

*This was difficult at that time.

Update May 10, 2011: News from Simon: 165 individuals & 5 hospitals have now spoken up about unfolding scandal and are doing something about it (Tuesday )

Update May 12, 2011: If I failed to convince you, please read the post of Ramona Bates MD (@rlbates at Twitter, plastic surgeon, blogger at Suture for a Living), called “More Organized Wisdom Un-Fair Play. Ramona asked her profile to be removed from OW half a year ago).  Recommended pages at her blog seem to be written by other people.
She concludes:

“Once again, I encourage my fellow healthcare bloggers (doctors, nurses, patient advocates, etc) to remove yourself from any association with Organized Wisdom and other sites like them”

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FDA to Regulate Genetic Testing by DTC-Companies Like 23andMe

14 06 2010

Direct-to-consumer (DTC) genetic testing refers to genetic tests that are marketed directly to consumers via television, print advertisements, or the Internet. This form of testing, which is also known as at-home genetic testing, provides access to a person’s genetic information without necessarily involving a doctor or insurance company in the process. [definition from NLM’s Genetic Home Reference Handbook]

Almost two years ago I wrote about 23andMe (23andMe: 23notMe, not yet),  a well known DTC company, that offers a genetics scan (SNP-genotyping) to the public ‘for research’, ‘for education’ and ‘for fun’:

“Formally 23andMe denies there is a diagnostic purpose (in part, surely, because the company doesn’t want to antagonize the FDA, which strictly regulates diagnostic testing for disease). However, 23andme does give information on your risk profile for certain diseases, including Parkinson”

In another post Personalized Genetics: Too Soon, Too Little? I summarized an editorial by Ioannides on the topic. His (and my) conclusion was that “the promise of personalized genetic prediction may be exaggerated and premature”. The most important issue is that predictive power to individualize risks is relatively weak. Ioannidis emphasized that despite the poor evidence, direct to consumer genetic testing has already begun and is here to stay. He proposed several safeguards, including transparent and thorough reporting, unbiased continuous synthesis and grading of the evidence and alerting the public that most genetic tests have not yet been shown to be clinically useful.

And now these “precautionary measures” actually seem to happen.
Last week the FDA sent 5 DTC-companies, including 23andMe a letter saying “their tests are medical devices that must receive regulatory approval before they can be marketed.” (ie. see NY-times article).

Alberto Gutierrez, who leads diagnostic test regulation at the FDA, wrote in the letters:

“Premarket review allows for an independent and unbiased assessment of a diagnostic test’s ability to generate test results that can reliably be used to support good health care decisions,”

These letters are part of an initiative to better explain the FDA’s actions by providing information that supports clinical medicine, biomedical innovation, and public health,” (May 19 New England Journal of Medicine commentary, source: see AMED-news)

Although it doesn’t look like the tests will be taken from the market, 23andMe does take a quite a rebellious attitude: one of its directors called the FDA “appallingly paternalistic.”

Many support this view: “people have the right to know their own genetic make-up”, so to say. Furthermore as discussed above, 23andMe denies that their genetic scans are meant for diagnosis.

In my view the latter is largely untrue. At least 23andMe suggests that knowing a scan does tell you something about your risks for certain diseases.
However, the risks are often not that straightforward. You just can’t “measure” the risk of a multifactorial disease like diabetes by “scanning” a few weakly predisposing  genes. Often the results are given in relative risk, which is highly confusing. In her TED-talk the 23andMe director Anne Wojcicki said her husband Sergey Brin (Google), had a 50% chance of getting Parkinson, but his relative risk (RR, based on the LRRK2-mutation, which isn’t the most crucial gene for getting Parkinson) varies from 20% to 80% , which means that this mutation increases his absolute risk of getting Parkinson from 2-5% (normal chance) to 4-10% at the most. (see this post).

Furthermore, as reported by Venture in Nature (October 8, 2009): For seven diseases, 50% or less of the predictions of two companies agreed across five individuals (i.e. for one disease: 23andMe : RR 4.02, and Navigenics RR: 1.25). On the other hand *fun* diagnoses could lead to serious concern in, or wrong/unnecessary decisions (removal of ovaries, changing drug doses) by patients.

There are also concerns with regard to their good-practice standards, as 23andMe just flipped a 96-wells plate of costumer DNA (see Genetic Future for a balanced post), which upset a mother noticing that her son didn’t have compatible genes. But lets assume that proper precautions will prevent this to happen again.

There are also positive aspects: results of a preliminary study showed that people who find out they have high genetic risk for cardiovascular disease are more likely to change their diet and exercise patterns than are those who learn they have a high risk from family history. (Technology ReviewGenetic Testing Can Change Behavior).

Furthermore, people buy those tests themselves and, indeed, there genes are their own.

However, I agree with Dr. Gutierrez of the FDA saying: “We really don’t have any issues with denying people information. We just want to make sure the information they are given is correct. (NY-Times). The FDA is putting the consumers first.

However, it will be very difficult to be consistent. What about total body scans in normal healthy people, detecting innocent incidentilomas? Or what about the controversial XMRV-tests offered by the Whittemore Peterson Institute (WPI) directly to CFS- patients? (see these posts) And one step further (although not in the diagnostic field): the ineffective CAM/homeopathic products sold over the counter?

I wouldn’t mind if these tests/products would be held up to the light. Consumers should not be misled by the results of unproven or invalid tests, and where needed should be offered the guidance of a healthcare provider.

But if tests are valid and risk predictions correct, it is up to the “consumer” if he/she wants to purchase such a test.

—————–

What Five FDA Letters Mean for the Future of DTC Genetic Testingat Genomics law Report is highly recommendable, but couldn’t be accessed while writing the post.

[Added: 2010-06-14 13.10]

  • Problem assessing Genomics Law Report is resolved.
  • Also recommendable: the post “FDA to regulate genetic tests as “devices”” at PHG Foundation. This post highlights that simply trying to classify the complete genomic testing service as “a device” is inadequate and will not address the difficult issues at hand. One of the biggest issues is that, while classifying DTC genetics tests as devices is certainly appropriate for assessing their analytical validity and direct safety, it does not and cannot provide an assessment of the service, thus of the predictions and interpretations resulting from the genome scans.  Although standard medical testing has traditionally been overseen by professional medical bodies, the current genomic risk profiling tests are simply not good enough to be used by health care services. (see post)
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Kaleidoscope 2009 wk 47

19 11 2009

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Kaleidoscope is a new series, with a “kaleidoscope” of facts, findings, views and news gathered over the last 1-2 weeks.

Most items originate from Twitter, my Google Reader (RSS) and sometimes real articles (yeah!).

I read a lot, I bookmark a lot, but only some of those things end op in a post. Since tweets have a half-life of less than a week, I thought it would be nice to safeguard some of the tweets in a post. For me to keep, for you to read.

I don’t have the time and the discipline to post daily about health news and social media as Ves Dimov does. It looks more like the compilation at blogs of dr Shock’s (see example),  dr Bates shout-outs, Health Highlights of Highlight HEALTH and Rachel Walden’s Womens health News Round-ups, but less on one subject and less structured. It will just be a mix of old and new, Social Media and science, just a kaleidoscope. Or a potpourri  if you like.

I don’t know if this kaleidoscope will live a long live. I already wrote 2 3 4 5 6 editions, but didn’t have the time to finish them. Well, we will see, just enjoy this one.

Ooh and the beautiful kaleidoscope is made by RevBean and is called: Eyeballs divide like cells. Looks very much like the eyeball-bubblewrap of a previous post but that is thus coincidence. Here is the link (Flickr, CC)

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Medical Grand Rounds

Louise Norris at Colorado Health Insurance Insider is this week’s host of Grand Rounds.(see here). There are many interesting posts again. As a mother of two teens I especially liked the insight Nancy Brown of Teen Health 411 brings us into what teens want when it comes to their relationships with their parents and the “would you rather…?” story that Amy Tenderich of Diabetes Mine shares with us. The punch line is great. Her 9 year old melts my heart.

At InsureBlog’s Hank Stern brings us an article about a British hospital that will no longer admit expectant mothers with a BMI of more than 34, because the hospital’s labor and delivery unit is not equipped to handle complicated births. Hank concludes: “Fear not, though, portly preggies have to travel but 20 miles to the next closest facility. Assuming, of course, that they can make it that far when contractions are minutes apart.”

Dr Charles of the The Examining Room wrote an in depth article about a cheerleader who was supposedly stricken with dystonia following a seasonal flu vaccine in August. Dr Charles not only highlights why (specialists) think it is not dystonia, but gives also background information about the efficacy of vaccins.

Recent editions of the Grand Rounds were at CREGRL, flight nurse (link), NonClinicalJobs (link) and Codeblog, tales of a nurse (link). You can always find previous and upcoming hosts at the Grand Rounds Archive at Blogborygmi.

3621322354_4bc3bb115e Breast cancer screening

The update of the 2002 USPSTF recommendation statement on screening for breast cancer in the general population, published in the November issue of The Annals of Internal Medicine has led to heated discussions in the mainstream media (i.e. New York Times and MedPage Today). Based on current evidence, partly based on 2 other articles in the same journal (comparison screening schedules and an systematic review) the guidelines advise scaling back of the screening. The USPSTF recommends:

  • against routine screening mammography in women aged 40 to 49 years
  • against routine screening mammography of women 75 years or older.
  • biennial (instead of annual) screening mammography for women between the ages of 50 and 74 years.
  • against teaching breast self-examination (BSE).
  • against either digital mammography or magnetic resonance imaging (MRI) instead of film mammography as screening modalities.

The two articles published in Ann Intern Med add to the evidence that the propagation of breast cancer self exam doesn’t save lives (see Cochrane review discussed in a previous post) and that the benefits of routine mammography in the young (<50) or old (>75) do not outweigh the harm (also covered by a  Cochrane review before). Indeed, as put forward by Gary Schwitzer at Schwitzer health news blog this is NOT a new debate. He refers to Slate who republishes a five-year old piece of Amanda Schaffer that does a good job of explaining the potential harms of screening. However it is difficult for women (and some doctors) to understand that “When it comes to cancer screening, more isn’t always better.” Indeed -as Kevin Pho at Kevin MD states, the question is whether “patients will accept the new, evidence-based, breast cancer screening guidelines”.

In the Netherlands it is already practice to start biannual routine mammography at the age of 50. The official breast cancer screening site of the RIVM even states that the US is now going to follow the Dutch guidelines ;) (one of assessed guidelines in one the Ann Intern Med papers is Dutch). But people still find the  long established guidelines difficult to accept: coincidentally I saw tweets today asking to sign a petition to advance the age of screening ‘because breast cancer is more and more frequently observed at young age…(??)’ Young, well educated, women are very willing to sign…

No time to read the full articles, but interested to know more, then listen to the podcast of this Ann Intern Med edition:

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Systematic Reviews, pharma sponsored trials and other publishing news

Cochrane reviews are regarded as scientifically rigorous, yet a review’s time to publication can be affected by factors such as the statistical significance of the findings. A study published in Open Medicine examined the factors associated with the time to publication of Cochrane reviews. A change in authors and updated reviews were predictive factors, but the favorability of the results was not.

Roy Poses of the Health Care Renewal Blog starts this blogpost as follows: “Woe to those of us who have been advocates for evidence-based medicine”. He mainly refers to a study published in the NEJM, that identified selective outcome reporting for trials of off-label use of gabapentin: for 8 of the 12 published trials, there was a disagreement between the definition of the primary outcome in the protocol and that in the published report. This seriously threatens the validity of evidence for the effectiveness of off-label interventions. Roy was surprised that the article didn’t generate much media attention. The reason may be that we have been overwhelmed by manipulation of data, ghostwriting and by the fact that pharma-sponsored trials rarely produce results that are unfavorable to the companies’ product (see previous posts about Ghostwriting (Merck/Elsevier, Conflict of Interest in Cancer Studies and David Tovey about Cochrane Reviews). At least two authors of the NEJM review (Bero and Dickersin) have repeatedly this to be the case [e.g. see here for an overview, and papers of Lisa Bero]. It is some relief that at least 3 of the 4 NEJM authors are also members of the Cochrane Collaboration. Indirectly better control of reporting, i.e. by clinical trials registries, can improve the reliability of pharma sponsored trials and thus systematic reviews summarizing them. As a matter of fact Cochrane authors always have to check these registries.

At Highlight Health Walter Jessen writes about Medical Journal Conflict of Interest Disclosure and Other Issues, which also discusses how money can taint objectivity in scientific publishing. Half of the post discusses the book The Trouble with Medical Journals, written in 2007 by Richard Smith, the former editor of the BMJ.
By the way, Walter just hosted MedLibs Round with the theme “Finding Credible Health Information Online”.

Good news in the Netherlands: right after international Open Access week and the launching of the Dutch Open Access website (www.openaccess.nl), the Netherlands Organization for Scientific Research (NWO) has announced that it is in favor of Open Access. (via PLOS-facebook).

The open access nature of PLOS itself gets out of hand: they even peer-review T-shirts (according to Bora Zivkovic of a Blog around the Clock, see here)

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Other Health & Science News:

Medline Plus summarizes an article in the Journal of Nutrition, that states that Selenium supplements, may pose a heart risk.

Even Folic Acid and vitamin B12, when taken in large doses, have been reported to Increase Cancer Risk (WebMD)

Luckily WebMD also reports that dark chocolate seems to help against stress, that is it reduced stress hormones in the blood. However @evidencematters and @NHSChoices cast doubt on that“Chocolate cuts stress, says newspaper. Does the study really say that? And who paid for the study?…”

Scientists made the unexpected discovery (published in Molecular Cell) that BRAF, which is linked to around 70 per cent of melanomas and seven per cent of all cancers, is in fact controlled by a gene from the same RAF family called CRAF – which has also been linked to the disease. For the first time it is shown “how two genes from the same ‘family’ can interact with each other to stop cancer in its tracks” (Source: Info Cancer Research UK)

For the first time, scientists have successfully used exome sequencing to quickly discover a previously unknown gene responsible for Miller syndrome, a rare disorder. The finding demonstrates the usefulness of exome sequencing in studying rare genetic disorders. The exome is enriched for coding (thus functional) DNA, it is only 1% of the total DNA, but contains 85% of the mutations (Published in , source: PhysOrg.com)

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Web 2.0
For information regarding the FDA hearings on internet and social media see #FDASM: http://www.fdasm.com.

Read Write Web summarizes the new numbers released by analytics firm Postrank that indicate that reader engagement with blogs has changed dramatically over the last three years, primarily because of the rise of online social networks.

Twitter has began to relaunch the new retweet feature, although not without controversy. What do you think about the newest feature?

The Next Web gives an overview of which Twitter application is hot and which is not.

And Finally: Top 100 tools for learning, compiled by Jane Hart from the contributions of 278 learning professionals worldwide. You can see the lists here (HT: http://blogs.netedu.info/?p=1005)

The web 2.0 part is relatively short, but it is time to conclude this edition. Till next time!

  • MEDLIB’s ROUND 1.6 (laikaspoetnik.wordpress.com)
  • Tool Talk: quick links re Facebook, GReader and GWave (socialfish.org)
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    NLM’s PillBox, a new pill identification system

    3 10 2009

    2-10-2009 8-42-20 pillbox beta logoThe National Library of Medicine (NLM) not only launched a redesigned PubMed interface, but also another service (though still in beta): Pillbox beta for “rapid identification and reliable information.
    The web address is http://pillbox.nlm.nih.gov/

    Pillbox was developed to aid in the identification of unknown solid dosage pharmaceuticals. The system combines high-resolution images of tablets and capsules with FDA-approved appearance information (imprint, shape, color, size and scoring) to enable users to visually search for and identify an unknown solid dosage pharmaceutical. (see About-section).

    This system is designed for use by emergency physicians, first responders, other health care providers, Poison Control Center staff, and concerned citizens.
    David Hale from the National Library of Medicine (NLM), argued in his short presentation at the Medicine 2.0 congress that better medication identification can potentially prevent 6000 to 8000 deaths each year due to adverse events. David explained that while FDA data might be available in the public domain, there is a need to make the information more usable.

    The interface is very clear and intuitive. You can choose the visual identification/exploration or the HTML screen reader compatible option to search.

    2-10-2009 8-50-40 Pillbox identify an unknown pillBelow I did a quick search with the latter option. (To show you the search options) I searched for 9mm white pills with the imprint West-ward 254, that can be broken in two and I get one result: a hydrocortisone pill (HC). That is neat. Only the imprint would have done, I guess, but without imprint there remain a lot of white pills to choose from.

    2-10-2009 23-25-00 HC west-ward tot

    The visual identification option is even easier to use.

    As of September 2009 only 779 of the  5,693 records have images, but as the project of the NLM and FDA proceeds in making large-scale photos of prescription medications, verified by manufacturers, more images will be available.

    Once a solid dosage form has been identified, additional information is provided, including brand/generic name, ingredients, and the National Drug File identification number. Links are provided to NLM drug information resources, such as FDA-approved label information (DailyMed) and the Drug Information Portal, which searches all NLM drug information resources (About).

    2-10-2009 23-19-52 HC pillsThe pills are sometimes difficult to discern. Perhaps because of my screen, and/or because white pills (on a black background) all look alike. The Figure left is 50% of the original (enlarged) picture: it is barely recognizable. So, at least in case of white pills, you do depend on correctly identified imprints.

    Furthermore pillbox will not be suitable to identify “illicit drugs”, foreign drugs and pharmacy compounded dosage forms which are not in FDA databases.” For this an “open source” Pillbox where everyone can collaborate (globally) to develop a rapid data rich pill identification system would be the solution (David Hale).

    It should be stresses that the PillBox is still in beta-phase. Feedback is welcomed at pillbox@mail.nih.gov.

    Finally a presentation of David Hale at the US Pharmacopeia’s Annual Scientific Meeting.

    and an interview with him during the Medicine 2.0 congress.

    Hattip: @eagledawg and @rachel_w :see Tweet) and NLM_SIS (see Tweet)

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    One Third of the Clinical Cancer Studies Report Conflict of Interest

    16 05 2009

    While many of us just recovered from the news that Elsevier was paid to produce fake Journals to promote pharmaceutical products, another news item has appeared about “conflicts of interests in scientific publications”

    This news is based on a new journal article from researchers from the University of Michigan’s Comprehensive Cancer Center in Ann Arbor, published in an early online edition of Cancer [1]

    As mentioned in my previous post about the Elsevier “Fake Journals”, pharma-sponsored trials rarely produce results that are unfavorable to the companies’ products [e.g. see 3 for an overview, and many papers of Lisa Bero]. Concerned by these findings, the main medical journals now require researchers to disclose their potential conflicts of interest (COI).

    The present study [1] analyzes the frequency of self-reported conflicts of interest (COI), source of study funding, and (their relationship with) other characteristics in original clinical cancer research (thus no reviews or basic research) published in 8 medical Journals in 2006. The 8 journals are high-impact clinical journals, 5 are oncology journals (Journal of Clinical Oncology, the Journal of the National Cancer Institute, Lancet Oncology,Clinical Cancer Research, Cancer) and 3 are core general medical journals (New England Journal of Medicine,JAMA, the Journal of the American Medical Association, Lancet).

    In these medical journals 1534 original oncology studies were found. Twenty-nine percent of the oncology articles reported COI: 17% declared industrial funding and the remaining 12% of the studies had authors who were an employee of industry at the time of publication, or were funded by industry.

    The study was thoroughly done: 2 students independently coded the articles and 2 other coders, blinded for the initial coding, assessed all randomized trials (within those 1543 papers) for the outcomes. They graded the authors’ subjective interpretations as positive (in favor of the intervention), neutral, or negative (in favor of the control arm). Overall survival was assessed quantitatively.

    The main results:

    • Conflicts of interest varied by discipline (P<.001). Studies that had a corresponding author from a medical oncology department or division were most likely to have conflicts (45%), and studies from diagnostic radiology were least likely to have conflicts (4%)
    • Likewise the cancer type mattered, especially with regard to likelihood of industrial funding (P = .001). Studies on the male reproductive system and lung cancers scored highest and studies on neurological cancers scored lowest as to the likelihood of funding. (however there is some contradiction because gynecologic departments have a high score and gynecologic cancers have a relatively low score, conf. figures 1 and 2)
    • Continental origin was also an important variable (P<.001). COI were observed in 33% of the North American studies, 27% of the European studies, 5% of the Asian studies, and 40% of the studies from other locations.
    • COI was most likely in articles with male first and senior authors (P<.001).
    • Industry funded studies were more likely to focus on treatment (P<.001), and less on epidemiology, prevention, risk factors for incidence, screening, or diagnostic methods.
    • The randomized trials (n=124) that assessed survival were more likely to report positive survival outcomes when a COI was present (P=.04). (see below)

    The paper has received a lot of media attention, initiated by the press release of the University of Michigan Health System itself. The data however are less shocking then they may seem. The main finding is that “conflicts of interest characterize a substantial minority of the clinically oriented cancer research published in high-impact medical journals”. This and the characteristics of the papers with COI (see above) add to earlier papers that report on the occurrence of COI in published articles, including papers in the field of clinical oncology.”

    Some outcomes are not very surprising, such as that pharmaceutical industries and funding will be most involved in intervention studies in medical oncology studies (not so much in radiology or diagnostics).

    In itself, COI does not mean that the results cannot be trusted or that they are plain wrong. Credibility could be questioned if only positive results are published or if the results are represented more positive then they really are.

    Indeed, Jagsi et al show that “randomized trials with a COI were more likely to report positive survival outcomes (P=.04)”. However, the likelihood that the author interpretation was positive or more positive than the objective effect on overall survival wasn’t influenced by COI. And differences in industrial funding didn’t influence any of the blinded outcomes assessed. Also in this study, the non-neutral findings are emphasized. ;)

    On the other hand, authors had to rely on the information given, i.e. not all conflicts of interests may have been reported. Another issue is that not all known COIs are disclosed to the public (i.e. medicalnewstoday)

    The following conclusion of the lead author Reshma Jagsi seems most relevant:[2]

    “Given the frequency we observed for conflicts of interest and the fact that conflicts were associated with study outcomes, I would suggest that merely disclosing conflicts is probably not enough. It’s becoming increasingly clear that we need to look more at how we can disentangle cancer research from industries”

    References
    ResearchBlogging.org

    1. Jagsi, R., Sheets, N., Jankovic, A., Motomura, A., Amarnath, S., & Ubel, P. (2009). Frequency, nature, effects, and correlates of conflicts of interest in published clinical cancer research Cancer DOI: 10.1002/cncr.24315
    2. University of Michigan Health System (2009, May 13). 29 Percent Of Cancer Studies Report Conflict Of Interest. ScienceDaily. Retrieved May 14, 2009, from http://www.sciencedaily.com­ /releases/2009/05/090511090846.htm
    3. Smith R. Medical Journals Are an Extension of the Marketing Arm of Pharmaceutical Companies. PLoS Med. 2005 May; 2(5): e138. Published online 2005 May 17. doi: 10.1371/journal.pmed.0020138.

    You may also want to read:

    Hattip: @sciencebase, Reinout Rietveld (via NRC-next)








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