Advancing prehospital care of stroke patients in Berlin: a new study to see the impact of STEMO on functional outcome

There are strange ambulances driving around in Berlin. They are the so-called STEMO cars, or Stroke Einsatz Mobile, basically driving stroke units. They have the possibility to make a CT scan to rule out bleeds and subsequently start thrombolysis before getting to the hospital. A previous study showed that this descreases time to treatment by ~25 minutes. The question now is whether the patients are indeed better of in terms of functional outcome. For that we are currently running the B_PROUD study of which we recently published the design here.

Pregnancy loss and risk of ischaemic stroke and myocardial infarction

2016-04-08 13_36_29-Posteingang - - Outlook

Together with colleagues I worked on a paper on relationship between pregnancy, its complications and stroke and myocardial infarction in young women, which just appeared online on the BJH website.

The article, which analyses data from the RATIO study, concludes that only if you have multiple pregnancy losses, your risk of stroke is increased (OR 2.4) compared to those who never experienced a pregnancy loss. The work was mainly done by AM, and is a good example of international collaborations where we benefitted from the expertise of all team members.

The article, with the full title “Pregnancy loss and risk of ischaemic stroke and myocardial infarction” can be found via PubMed, or via my personal Mendeley page.

Causal Inference in Law: An Epidemiological Perspective


Finally, it is here. The article I wrote together with WdH, MZ and RM was published in the European Journal of Risk and Regulation last week. And boy, did it take time! This whole project, an interdisciplinary project where epidemiological thinking was applied to questions of causal inference in tort law, took > 3 years – with only a couple of months writing… the rest was waiting and waiting and waiting and some peer review. but more on this later.

First some content. in the article we discuss the idea of proportional liability that adheres to the epidemiological concept of multi-causality. But the article is more: as this is a journal for non epidemiologist, we also provide a short and condensed overview of study design, bias and other epidemiological concepts such as counterfactual thinking. You might have recognised the theme from my visits to the Leiden Law school for some workshops. The EJRR editorial describes it asas: “(…) discuss the problem of causal inference in law, by providing an epidemiological viewpoint. More specifically, by scrutinizing the concept of the so-called “proportional liability”, which embraces the epidemiological notion of multi-causality, they demonstrate how the former can be made more proportional to a defendant’s relative contribution in the known causal mechanism underlying a particular damage.”

Getting this thing published was tough: the quality of the peer review was low (dare I say zero?),communication was difficult, submission system flawed etc. But most of all the editorial office was slow – first submission was June 2013! This could be a non-medical journal thing, i do not know, but still almost three years. And this all for an invited article that was planned to be part of a special edition on the link between epi and law, which never came. Due several delays (surprise!) of the other articles for this edition, it was decided that our article is not waiting for this special edition anymore. Therefore, our cool little insight into epidemiology now seems to be lost between all those legal and risk regulation articles. A shame if you ask me, but I am glad that we are not waiting any longer!

Although i do love interdisciplinary projects, and I think the result is a nice one, I do not want to go through this process again. No more EJRR for me.

Ow, one more thing… the article is behind a pay wall and i do not have access through my university, nor did the editorial office provide me with a link to a pdf of the final version. So, to be honest, I don’t have the final article myself! Feels weird. I hope EJRR will provide me with a pdf quite soon. In the meantime, anybody with access to this article, please feel free to send me a copy!

First results from the RATIO follow up study

Another article got published today in the JAMA Int Med, this time the results from the first analyses of the RATIO follow-up data. For these data, we linked the RATIO study to the dutch national bureau of statistics (CBS), to obtain 20 years of follow-up on cardiovascular morbidity and mortality. We first submitted a full paper, but later we downsized to a research letter with only 600 words. This means that only the main message (i.e. cardiovascular recurrence is high, persistent over time and disease specific) is left.

It is a “Leiden publication”, where I worked together with AM and FP from Milano. Most of the credit of course goes to AM, who is the first author of this piece. The cool thing about this publication is that the team worked very hard on it for a long time (data linking and analyses where not an easy thing to do, as well as changing from 3000 words to 600 in just a week or so), and that in the end all the hard work paid off. But next to the hard work, it is also nice to see results being picked up by the media. The JAMA Int Med put out an international press release, whereas the LUMC is going to publish its own Dutch version. In the days before the ‘online first’ publication I already answered some emails from writers for medical news sites, some with up to 5.000K views per month. I do not know if you think that’s a lot, but for me it is. The websites that cover this story can be found here (, / / / / and perhaps more to come. Why not just take a look at the Altmetric of this article).

– edit 26.11.2015: a dutch press release from the LUMC can be found here) – edit: oops, has a published great report/interview, but used a wrong title…”Repeat MI and Stroke Risks Defined in ‘Younger’ Women on Oral Contraceptives”. not all women were on OC of course.

Of course, @JAMAInternalMed tweeted about it


The article, with the full title Recurrence and Mortality in Young Women With Myocardial Infarction or Ischemic Stroke: Long-term Follow-up of the Risk of Arterial Thrombosis in Relation to Oral Contraceptives (RATIO) Study can be found via JAMA Internal Medicine or via my personal Mendeley page.

As I reported earlier, this project is supported by a grant from the LUF den Dulk-Moermans foundation, for which we are grateful.

Spectrum of cerebral spinal fluid findings in patients with posterior reversible encephalopathy syndrome


This is one of the first projects that I was involved with from start to finish since my start in Berlin to be published, so I’m quite content with it. A cool landmark after a year in Berlin.

Together with TL and LN I supervised a student from the Netherlands (JH). This publication is the result of all the work JH did, together with the great medical knowledge from the rest of the team. About the research: Posterior reversible encephalopathy syndrome, or PRES, is a syndrome that can have stroke like symptoms, but in fact has got nothing to do with it. The syndrome was recognised as a separate entity only a couple of years ago, and this group of patients that we collected from the Charite is one of the largest collections in the world.

It is a syndrome characterised by edema (being either vasogenic or cytotoxic), suggesting there is something wrong with the fluid balance in the brain. A good way to learn more about the fluids in the brain is to take a look at the different things you can measure in the cerebrospinal fluid. The aim of this paper was therefore to see to what extend the edema, but also other patients characteristics, was associated with CSF parameters.

Our main conclusion is indeed the total amount of protein in the CSF is elevated in most PRES patients, and that severe edema grade was associated with more CSF. Remind yourself that this is basically a case series (with some follow up) but CSF is therefore measured during diagnosis and only in a selection of the patients. Selection bias is therefore likely to be affecting our results as well as the possibility of reverse causation. Next to that, research into “syndromes” is always complicated as they are a man-made concept. This problem we also encountered in the RATIO analyses about the antiphospholipid syndrome (Urbanus, Lancet Neurol 2009): a real syndrome diagnosis could not be given, as that requires two blood draws with 3 months time in between which is not possible in this case-control study. But still, there is a whole lot of stuff to learn about the syndromes in our clinical research projects.

I think this is also true for the PRES study: I think that our results show that it is justified to do a prospective and rigorous and standardised analyses of these patients with the dangerous syndrome. More knowledge on the causes and consequences is needed!

The paper can be cited as:

Neeb L, Hoekstra J, Endres M, Siegerink B, Siebert E, Liman TG. Spectrum of cerebral spinal fluid findings in patients with posterior reversible encephalopathy syndrome. J Neurol; 2015; (e-pub) and can be found on pubmed or on my mendeley profile

New article published: the relationship between ADAMTS13 and MI

2015-06-16 14_26_12-Plasma ADAMTS13 levels and the risk of myocardial infarction_ an individual pati

this article is a collaboration with a lot of guys. initiated from the Milan group, we ended up with a quite diverse group of researchers to answers this question because of the methods that we used: the individual patient data meta-analysis. The best thing about this approach: you can pool the data from different studies, even while you can adjusted for potential sources of confounding in a similar manner (given that the data are available, that is). On themselves, these studies showed some mixed results. But in the end, we were able to use the combined data to show that there was an increase MI risk but only for those with very low levels of ADAMTS13. So, here you see the power of IPD meta-analysis!

The credits for this work go primarily to AM who did a great job of getting all PI’s on board, analysing the data and writing a god manuscript. The final version is not online, but you find the pre-publication on pubmed



New article: the intrinsic coagulation proteins and the risk of arterial thrombosis

I got good news today! A manuscript on the role of the intrinsic coagulation factors in the causal mechanisms leading to myocardial infarction and ischaemic stroke has been accepted for publication by the JTH. It took sometime, but in the end I’m very glad that this paper was published in the JTH because its readership is both clinical as well as biomedical: just the place where I feel most at home.

The basic message? These factors do contribute to ischaemic risk, but not to the risk of myocardial infarction. This is mostly the case for coagulation factor XI, which is a nice finding, because it could be a new target for anti-thrombotic therapies.

The article is now in print and will be made available soon. In the mean time, you can refer to my thesis, in which this research was also described.

New article published: review on obesity and venous thrombosis

Together with colleagues I worked on a review on the role of obesity as a risk factor for venous thrombosis. I’m second author on the article, which come online last week, and most work has been done by SKB from Norway, who is visiting our department for a full year.

The article is written from an epidemiological point of view and discusses several points that are worth mentioning here. First of all, obesity is an ill-defined concept: are we only talking BMI, or do also other measures of obesity need to be taken into account? Second, even when defined, the results are not always easy to interpret. In causal research there are a couple of things that need to be fulfilled before one can answer the question whether something is risk factor of disease. For example, BMI can be reduced by means of exercise   diet or disease, which all three have completely different effects on thrombosis risk. We discuss all these epidemiological problems, together with the existing body of evidence in the new article in seminars of thrombosis and hemostasis. These question are not only important for our understanding of thrombotic disease, but also to grasp the causal role of obesity in (cardiovascular) disease. This research question has in ast couple of years been put on the research agenda of the NEO study, on which perhaps more in the future.

The article, with the full title “Role of Obesity in the Etiology of Deep Vein Thrombosis and Pulmonary Embolism: Current Epidemiological Insights” can be found via PubMed, or via my personal Mendeley page.

Is science self-cleansing? An article in the “Academische Boekengids” discussing report cie. Schuyt

Earlier I wrote about the “Adviescommissie onderzoeksgegevens in de wetenschap van de KNAW” and their report “Zorgvuldig en integer omgaan met wetenschappelijke onderzoeksgegevens”. This report induced a discussion in the March 2013 edition of the Academische Boekengids .

Three scientist give their vision: Miedema (dean of Medicine at the UMCU) Vandenbroucke (KNAW professor and professor of epidemiology at the LUMC, member of committee Schuyt) and Paul (professor of secularization studies in Groningen). Important to note is that the contradiction between the authors was known beforehand.

Miedema identifies a change in science, especially medical and social science, in which economic and social forces influence science and scientists. These forces have led to a ‘system failure’ of science, leading to shoddy science or in his words ‘post academic science’. Miedema argues that these changes cannot be undone and certain measures need to be taken to correct this system failure. What measures? Miedema points toward Quality Assurance and Quality Control (QA/QC) making a comparison with so called pharmaceutical research embedded within Good Clinical Practice (GCP). This should be done by governments, universities and funding bodies. Interestingly, he leaves scientist out of this list. And what does Miedema think of the report of the committee? He believes the vision of the report is based on the old idea of science where all scientist are directly held accountable by peer pressure, a vision that according to Miedema is not valid in this day and age.

Vandenbroucke points out an error in the argumentation: Miedema targets post academic science. Vandenbroucke agrees that this is a problem, but not the problem discussed by the committee. Their task was to see how data during and after research should be treated in order to keep science workable without to many hiccups and problems. The committee provides some answers but one of the main themes is that scientist should self-regulate, for they are the only experts in this area. This is in contrast to who Miedema who abhors the idea of self-regulation: science is not science anymore, so how can scientist self-regulate with all these strong forces that are incomprehensible to grasp for a simple scientist. Vandenbroucke counteracts Miedema by explaining that his vision of science (science is the search for truth) is not at odds with the problems that arise with post academic science (science is a complex social construct in which forces other than the truth have a big influence). Even more: these two notions can coexist, a concept first noted by Stephen Jay Gould.

Paul tries to reconcile the two previous writers: he agrees with Miedema that in earlier times the scientist was appreciated for his behavior as a person, whereas this view seems to be outdated in this day and age. But Paul also approaches the problem from the other side: the solution of the problems that come with post academic science calls for strong personalities that can counter unwanted forces that trouble science. Paul mentions the work of the science historian which he – ought enough in this context- announces as an ‘honored scientist’ (Dutch: gelauwerde wetenschapper) who published his ‘handsome study’ (Dutch: fraaie studie).

So what are the suggested solutions? Because the authors disagree on the origins of the problem, their solution also differ. Especially Vandenbroucke and Miedema find themselves on first glance diametrically opposed to one other. Vandenbroucke wants to start a discussion bottom up on what it is to be a good scientist, whereas Miedema wants top down QA and QC. These ideas are not new. For example, Jacobus Lubsen also brought this concept in an article in the NRC of December of 2011. Quality control and forensic statistics should increase the detection rate of wrongdoing and should therefore be instituted. I responded to this article with a small letter to the NRC in which I state that complete control is difficult and expensive and often only identifies shoddy and fraudulent science with hindsight. Additionally it will have a preventive effect on bad science, but will it have such an effect on fraud? After all, other fields that have huge governance structures such as banking and accountancy also have their fraud scandals. Even more, the frequency of sloppy science is hardly affected by these measures. A better way to prevent both sloppy and fraudulent science is, I believe, a better training of young scientist. By introducing young scientist to the key concepts of scientific conduct, creating a critical but non-repressive atmosphere, perhaps even in several research groups to prevent tunnel vision of individuals, will lead to an increased informal control and a decrease in sloppy and shoddy science. The committee also mentions this concept and calls this “increasing peer pressure” and puts scientist at the helm of this operation.

It will not surprise you that I agree with Vandenbroucke for the most part. But I also see merit in the argumentation of Miedema. Perhaps I agree with both to some extent because they address two different concepts: science is the quest for knowledge and based on epistemic virtues. Self-regulation by education of young aspiring scientist in a positive but critical atmosphere will increase the quality of research over time. But science is also a social construct and scientist need, besides guidance by peers, governance and regulations for certain scenarios: the cases Stapel and Poldermans as well as the previously discussed book ‘Bad Pharma’ by Ben Goldacre are examples why this might be true. Besides informal peer review and guidance, an extended system of checks and balances, GCP or not, might help to keep colleagues accountable for their work. Science in itself is a system of checks and balances, but this system might be expanded with some form of regulation and standardization with efficacy and efficiency kept in mind. But most of all, now is the time train the young.

– update on 25/3/2013: an interview with both JvdB and FM was published in the NTVG. Together with the editor-in-chief they discuss performing research, obtaining a PhD and publishing your results. click here for the pdf (NTVG website, in Dutch)


Hora Est – thesis is topic of a Cicero article

cicero maart 2013The Cicero, the monthly magazine of the LUMC, wrote an article on my thesis. During the interview, I was able to bring fort the nuances of the work in the thesis. That is, my thesis does not fully provide all the answers in details for allr esearch questions but it does provide a simple overview: an increased clotting potential is a risk factor for ischaemic stroke but not for moycardial infarction. Unfortunately, space limitations dictated that some remarks had to be left out. Fortunately, the last remarks is about the relevance of teaching experience as a PhD: a great link to one of my propositions.

The picture above was placed in the Cicero to accompany the interview. I like it very much because it has a certain epidemiological feel to it: a group (a cohort?) of women all different, but with certain patterns.

The text of the interview can be downloaded from the media page, directly directly clicking here (pdf). The text can also be read online if you… Continue reading “Hora Est – thesis is topic of a Cicero article”