Wetenschap in het Albert Schweitzer Ziekenhuis Anno 2007

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Wetenschap in het Albert Schweitzer Ziekenhuis Anno 2007

onder redactie van de Wetenschapscommissie

Albert Schweitzer series, jaargang 3 Dordrecht, 2007

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Inhoud 1. Voorwoord

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2. Programma Wetenschapsdag 19-6-2008

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3. Publicaties geproduceerd in het Albert Schweitzer Ziekenhuis in 2007 blz 10 1. Cleophas T, Zwinderman A, Chaib A. Novel procedures for validating surrogate endpoints in clinical trials. 2. Cleophas T, Van Ouwerkerk B, Weijters B, Kassai B. The Monte Carlo method in cardiovascular research. 3. Van Bommel E, Siemes C, Van der Veer S, Han S, Huiskes A, Hendriksz T. Clinical value of gallium-67 SPECT scintigraphy in diagostic and therapeutic evaluation of retroperitoneal fibrosis: a prospective study. 4. Van Bommel E, Siemes C, Hak L, Van der Veer S, Hendriksz T. Long term renal and patient outcome in idiopathic retroperitoneal fibrosis treated with prednisone. 5. Constantinescu A, Berendes P, Levin M. Disseminated intravascular coagulation and a negative D-dimer test. 6. Muller A, Korten E. Glomus-caroticumtumoren en duplexdiagnostiek. 7. Cleophas T, Zwinderman A. Statistical primer for cardiovascular research, meta-analysis. 8. Van Kemenade Y, Hopstaken L. Het ziekenhuis in 2020. 9. Van Kemenade Y. Gezondheidszorg internationaal vergeleken. 10. Bartels P, Hanff L, Mathot R, Steegers E, Vulto A, Visser W. Nicardipine in pre -eclamptic patients: placental transfer and disposition in breast milk. 11. Kaijser J, Scheerder M, Plaisier P, Kooi G. Een ovarieel gemetastaseerd melanoom en zwangerschap: een moeilijke combinatie. 12. Kaijser J, Roelofs H, Breimer L, Kooi G. Excessive fluid overload with severe hyponatriemie, cardiac failure, and cerebral edema complicating hysteroscopic myomectomy. 13. Korten E. Verslaglegging op het vaatlaboratorium en het elektronisch patientendossier. 14. Tijssen-Humme M, Tijssen G. De onverwachte gevolgen van een pastille.

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15. Jansen R, Niemeijer M, Cleophas T, Zwinderman A, Van der Wall E, Tuna J, Smejkal J, Riha V, Kozak M, on behalf of the IQOLAN investigators. Replacement of multiple-daily with once-daily nitrate therapy and quality of life in 2675 patients with stable angina pectoris. 16. Van der Zwaal P, Van den Berg I, Plaisier P, Tutein Nolthesius R. Mesh fixation using staples in Lichtenstein’s inguinal hernioplasty: less complications and less recurrences. 17. Van Brakel J, Van Ouwerkerk B, Cleophas T. Peritoneal mesothelioma, a case report. 18. Basumaid S, Van Dongen M, Cleophas T. Khat abuse in Yemen, a population-based survey. 18. Okken V, Niemeijer M, Dijkstra A, Otten S, Cleophas T. The effect of physical, social and psychological factors on drug-compliance in patients with mild hypertension. 20. Cleophas T, Zwinderman A, Van Ouwerkerk B, Sobh M. Cardiovascular trials: how to examine interaction, and why so. 21. Cleophas T, Zwinderman A. Clinical trials: how to assess confounding and why so. 22. Cleophas T, Van Ouwerkerk B, Zwinderman A. Clinical trials: log likelihood ratio tests for assessing cardiovascular events. 23. Cleophas T, Van Ouwerkerk B. The sense and nonsense of exponential models in clinical research. 24. Cleophas G, Cleophas M, Cleophas T. Physicians’daily life and the scientific method.

4. Posters geaccepteerd voor de wetenschapsdag 19-6-2008

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1. Atiqi R, Cleophas T, Van Ouwerkerk B, Van Bommel E. Iatrogenic admissions to hospital. 2. Gerestein C, Damhuis R, De Vries M, Reedijk A, Burger C, Kooi G. Causes of postoperative death after surgery for ovarian cancer. 3. Tax G, Droogendijk J, Berendes P, Beukers R, Levin M. PAGAS: Project of Anemia analyses from the General practitioner to the Albert Schweitzer Hospital. 4. Tax G, Droogendijk J, Levin M, Beukers R, Berendes. Hoezo, verhoogd transferrine bij ijzergebreksanemie. 5. Ketharanan N, Lee W, Smit-Kleinlugtenbelt E, De Mol A. Health-related quality of life and behavioral problems in pre-school children born at 32 to 36 weeks of gestational age. 6. Breuls N. Active fixation in proximal and distal coronary sinus pacing for paroxysmal

4 atrial fibrillation. 7. Schilthuizen C, Levin M. Risicofactoren voor trombosevorming bij myeloproliferatieve aandoeningen. 8. Droogendijk J, Berendes P, Beukers R, Levin M. Project of anemia analysis from the General Practitioner to the Albert Schweitzer Hospital (PAGAS): the retrospective study. 9. Elhani S, Cleophas T. Non-pharmaceutical treatment of hypertension. 10. Muller-Rijnaard A, Korten-Van Putten E, Glomus-caroticum tumoren en duplexdiagnostiek. 11. Driessen E, Levin M. Richter’s transformation in three patients with chronic lymphocytic leukemia. 12. Prins J, Fouraux M, Kooijman H, Levin M. Een jaar Jak2-diagnostiek. 13. Van den Berg-De Bakker. Niet-invasieve thermometrie: verhit debat over warmte patient. 14. Gerestein C, Eijkelman M, Dijkgraaf R, De Jong D, Kooi G, Baalbergen A, Van der Burg M, Burger C, Ansink A. Predictors for progression-free and overall survival in patients with advanced epithelial ovarian cancer. 15. De Jong P, Boot H, Van Uffelen R, Van der Meulen J. Chronic fatigue or chronic hypersomnia, a ten year follow up. 16. Van Putte-Katier N, Hendriksz T. Prevalence of mesenteric panniculitis in a large hospital-based population. 17. Oei H. Unexpected side effect of aspirin 80 mg. 18. Oei H. Eyelid dermatitis due to contact alleregy to cocamidopropyl betaine. 19. Karim-Kos H, Janssen-Heijnen M, Van Iersel C, De Vries E, Coebergh J. The beginning of the end of the lung cancer epidemic in Dutch women. 20. Pauw R, Dieleman H, De Vogel E, Eussen M. Een retrospectief onderzoek naar het switchen van ADHD-medicatie. 21. De Jong P, Van Leendert R, De waal M, Van Bommel E. Severe hyponatriemie as clinical presentation of neurosarcoidosis with hypopituitarism. 22. Jansen I, Han S, Hendriksz T, Van Bommel E. Prospective evaluation of 18F-FDG PET in assessing disease activity in retroperitoneal fibrosis: preliminary results. 23. Riedl J, Van de Werken M, IJpma S, Berendes P. pH in pleura: de bloedgasanalyzer als gouden standaard. 24. Dik S. Pneumocystis Jirovecii pneumonia after treatment with R-iCHOP: is the

5 bronchoalveolar lavage still reliable? 25. Dijkstra A, Okken V, Niemeijer M, Cleophas T. Determinants of perceived severity of hypertension and drug-compliance in mildly hypertensive patients. 26. Jansen R, Niemeijer M, Cleophas T. Replacement of multiple daily with once-daily nitrate therapy and quality of life in 2675 patients with stable angina pectoris. 27. Lambeek A, Hellendoorn I, Akerboom B, Den Breejen M, Brouwers E, Duvekot J, Kooi G. Heupdysplasie en stuitligging: de waarde van versie van stuit- naar hoofdligging. 28. Van Ouwerkerk B, Cleophas TJ, Weijters B. The Monte Carlo method in cardiovascular research. 29. Okken V, Niemeijer M, Dijkstra A, Otten S, Cleophjas T. The effect of physical, social and psychological factors on drug-compliance in patients with mild hypertension. 30. Cleophas G, Cleophas M, Cleophas T. Physicians’daily life and the scientific method. 31. Cleophas G, Cleophas M, Cleophas T. Testing equivalence, inferiority and superiority in clinical trials. 32. Droogendijk J, Van Ouwerkerk B, Cleophas T. Validating diagnostic tests: correct and incorrect methods 33. Van Ouwerkerk B, Cleophas T, Zwinderman A. Clinical trials: how to assess confounding and why so. 34. Sobh M, Ccleophas T, Chaib A, Zwinderman A. Clinical trials; odds ratios and multiple regression models, why to assess them and how to do so. 35. Westenend P. Cancer of the stomach in breast cancer patients is often metastatic disease. 36. Den hoed M, De Mol A. Mictiecysto-urogram; emotionele gevolgen voor het kind? 37. Kamalesh M, Cleophas T. Heart failure and mortality in diabetes, pooled analysis of 30,197 subjects. 38. Dunker MS, Somers I, Oostenbroek RJ, Gouma DJ. Is de richtlijn voor preoperatief aftekenen van een stoma breukbaar bij patienten met een opgezette buik.

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5. Overige publicaties geproduceerd door medewerkers 1. Allergologie 2. Beleidsadviseur 3. Cardiologie 4. Chirurgie 5. Farmacie 6. Gynecologie 7. Interne geneeskunde 8. Oncologie 9. Pathologische anatomie 10. Pediatrie 11. Radiologie

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1.Voorwoord Voor u ligt het derde jaarboek “Wetenschap in het Albert Schweitzer Ziekenhuis”. Werden er vorig jaar nog 5 artikelen gepubliceerd over in het ziekenhuis verricht onderzoek, dit jaar is het aantal gestegen naar 24 artikelen. Het aantal posters geaccepteerd voor de postersessie tijdens de wetenschapsdag op 19-6-2008 is gestegen van 32 naar 38. Het ziekenhuis heeft sinds 1 januari 2007, naast een achttal workshops “Zelf opzetten en analyseren van wetenschappelijk onderzoek”, een wekelijks spreekuur voor onderzoekers op woensdag 14.00 – 17.00 uur. Tijdens dit spreekuur waren er in 2007 in totaal 136 contacten met onderzoekers. Dat betekent 3,1 contact per spreekuur. De volgende disciplines kwamen met vragen: Interne 52 maal Chirurgie 15 Apotheek 8 Maagdarm-leverziekten 3 Isotopenafdeling 1 Neurologie 2 KNO 1 Geriatrie 1 Cardiologie 1 Skill lab 1 Personeelszaken 3 Anesthesie 5 Pediatrie 2 Longziekten 1 Klinische fysica 2 --------------Totaal 97 De overige 39 contacten hadden te maken met vragen over de workshops “zelf opzetten wetenschappelijk onderzoek”, de voorbereiding van de wetenschapsdag, werkzaamheden in verband met externe stageairs, en hulpvragen bij de statistische analyses van inmiddels voltooid onderzoek. Er werden 8 workshops gegeven voor onderzoekers op woensdagen 1700- 1900 uur. Niet alle verzoeken om deel te nemen konden worden gehonoreerd. Wel waren er achteraf nogal wat afmeldingen, wat spijtig is voor degenen die op de wachtlijst stonden voor deelname. 1. 14-3 Zelf een onderzoeksprotocol schrijven 2. 18-4 Zelf steekproefgrootte berekenen 3. 09-5 Zelf statistische software gebruiken 4. 13-6 Zelf opzetten van diagnostisch onderzoek 5. 29-8 Zelf een onderzoeksprotocol schrijven 6. 19-9 Zelf steekproefgrootte berekenen 7. 31-10 Zelf statistische software gebruiken 8. 12-12 Zelf opzetten van diagnostisch onderzoek

8 Met ingang van 2008 zal het ziekenhuis een certificaat uitreiken aan de deelnemers die een volledige cyclus van 4 workshops gevolgd hebben. Vanuit het Albert Schweitzer Ziekenhuis als STZ ziekenhuis (STZ = Samenwerkende Topklinische Ziekenhuizen) worden sinds 2008 ook workshops verzorgd in een tiental andere STZ ziekenhuizen in Nederland. Het door de wetenschapscommissie geproduceerde boekje “Zelf opzetten en analyseren van wetenschappelijk onderzoek” is inmiddels ook buiten het ziekenhuis met zoveel enthousiasme onthaald, dat het door de uitgever van het Nederlands Tijdschrift voor Geneeskunde, Bohn Stafleu, in productie genomen is. De royalties komen ten goede aan onderzoek in het Albert Schweitzer Ziekenhuis.

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2. Programma Wetenschapsdag 19-6-2008 MFB Gebouw Dordrecht 16.00 u. Opening Introductie externe spreker door T. Cleophas, internist. Voordracht Professor Dr. J. Akveld, gezondheidshjurist met als titel: Problemen bij afsluiting verzekeringen voor patienten die aan genetisch onderzoek hebben deelgenomen. 16.30 u Introductie externe spreker door P. Plaisier, chirurg. Voordracht Mevrouw Drs. Ing. C Schroten - Loef, onderzoeksmedewerker Integraal Kanker Centrum Rotterdam met als titel: Overleven in het Albert Schweitzer Ziekenhuis. 17.00 u Voordrachten van de auteurs van de beste publicaties van het jaar 2007 17.30 u Five-minutes talks van de auteurs van de beste posters van het jaar 2007 18.00 u Uitreiking prijzen voor de beste publicaties en beste posters van het jaar 2007 18.00 – 20.00 u Posterbezichtiging en lopend buffet.

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3. Publicaties geproduceerd in het Albert Schweitzer Ziekenhuis

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Published in PERFUSION 2007; 20: 224-8

The Monte Carlo method in cardiovascular research

Ton J Cleophas, MD, Bas M van Ouwerkerk, MD, Basile Weijters, MD, Behrouz Kassai, MD, European College of Pharmaceutical Medicine, Lyon France and Albert Schweitzer Hospital Dordrecht, Netherlands Keywords: Monte Carlo method, bootstraps, clinical research, random samples, statistical analysis. Correspondence to: Professor Ton J Cleophas, Box 444, 3300 AK Dordrecht, Netherlands Summary Background: For more than a century statistical tests based on Gaussian curves have been applied in clinical research. Current cardiovascular trials often make use of convenience samples and small samples that do not follow Gaussian curves. This raises the risk of false negative results. Objective: To elucidate the Monte Carlo method as an alternative method for the assessment of such data. Results: The Monte Carlo method derives confidence intervals from the data without prior assumption about the presence of Gaussian curves in the data. For 2-parallel-groups studies with continuous data the basic idea is to produce multiple random samples from your own 2 parallel groups. If in at least 95 % of these random samples the first group scores better than the second, then a statistically significant difference between the two groups will be accepted at p < 0.05. Also for population-based cohort studies with proportional data multiple random samples can be produced from your own observed data. If in at least 95% of these random samples the expected proportion exceeds the observed proportion, then a statistically significant difference between the observed and expected data will be accepted at p < 0.05. Conclusions: Advantages of the Monte Carlo method include: - It does not depend upon Gaussian curves. - It is less time-consuming than many standard methods. A disadvantages is that, although less time-consuming than many standard methods, it is still rather laborious without a computer. We do hope that this paper will strengthen the awareness of the Monte Carlo method as an often more reliable alternative for analysis of cardiovascular research. Introduction For more than a century statistical tests based on Gaussian curves have been applied in clinical research, like t-tests, chi-square tests, analysis of variance and most regression analyses methods. Current cardiovascular trials often make use of convenience samples and small samples that do not follow Gaussian curves. This raises the risk of false negative

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17 (Circulation. 2007;115:2870-2875.) © 2007 American Heart Association, Inc.

Statistical Primer for Cardiovascular Research Meta-Analysis Ton J. Cleophas, MD, PhD; Aeilko H. Zwinderman, DSc, PhD From the European College of Pharmaceutical Medicine, Lyon, France (T.J.C., A.H.Z.), and Academic Medical Center, Amsterdam, the Netherlands (A.H.Z.). Correspondence to Ton J. Cleophas, MD, PhD, Department of Medicine, Albert Schweitzer Hospital, Dordrecht, The Netherlands. E-mail [email protected]

Key Words: population characteristics • meta-analysis • publication bias

Introduction In 1982, thrombolytic therapy for acute coronary syndromes was controversial. In a metaanalysis of 7 trials, Stampfer et al1 found a reduced risk of mortality of 0.80 (95% CI, 0.68 to 0.95). These findings were not accepted by cardiologists until 1986, when a large clinical trial confirmed the conclusions,2 and streptokinase became widely applied. Meta-analyses can be defined as systematic reviews with pooled data. Traditionally, they are post hoc analyses. However, probability statements may be more valid than they usually are with post hoc studies, particularly if performed on outcomes that were primary outcomes in the original trials. Problems with pooling are frequent: Correlations are often nonlinear3; effects are often multifactorial rather than unifactorial4; continuous data frequently have to be transformed into binary data for the purpose of comparability5; poor studies may be included, and coverage may be limited6; and data may not be homogeneous and may fail to relate to hypotheses.7 Despite these problems, the methods of meta-analysis are an invaluable scientific activity: they establish whether scientific findings are consistent8 and can be generalized across populations and treatment variations9 and whether findings vary between subgroups.10 The methods also limit bias, improve reliability and accuracy of conclusions,11 and increase the power and precision of treatment effects and risk exposures.6 The objective of this article is to review statistical procedures for the meta-analysis of cardiovascular research. The Google database system provides 659 000 references on the methods of meta-analysis and refers to hundreds of books of up to 600 pages,12 illustrating the complexity of this subject. The basic statistical analysis of meta-analyses, however, is not complex if the basic scientific methods are met.13 We first will review the scientific methods and then introduce the statistical analysis, including the analysis of potential pitfalls. Finally, we will cover some new developments.

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Geaccepteerd voor publicatie 2-2-2008 door Hernia the Journal of hernias and abdominal wall

Mesh fixation using staples in Lichtenstein’s inguinal hernioplasty: less complications and less recurrences P. van der Zwaal, I.R. van den Berg, P.W. Plaisier, R.P. Tutein Nolthenius Department of Surgery Albert Schweitzer Hospital Dordrecht The Netherlands

Address for correspondence: P.W. Plaisier, MD/PhD, Department of Surgery, Albert Schweitzer Hospital, P.O. Box 444 NL-3300 AK Dordrecht, The Netherlands +31-78-6541111 (phone) +31-78-6542264 (fax) [email protected] Abstract Background Fixation of the mesh in Lichtenstein’s inguinal hernioplasty is traditionally performed by polypropylene sutures. A modification of this technique uses staples for securing of the mesh. Method A retrospective comparative study of 149 elective repairs of a primary inguinal hernia was performed. A control group of 67 patients undergoing mesh fixation using sutures and a study group of 82 patients undergoing staple fixation. Operating time, recurrence, postoperative pain, complications and costs were studied. Results Seven recurrences (11%) occurred in the polypropylene group as compared to 1 recurrence (1%) in the staple group (p < 0.01). There was a trend of fewer complications in the staple group. Operative time and long term postoperative pain did not differ significantly between the two groups. The costs per surgery for mesh fixation and skin closure was € 11.13 for the suture group and € 24.35 in the staple group. Conclusion Staple fixation of the mesh in Lichtenstein’s inguinal hernioplasty can be considered equal to traditional fixation with sutures with regard to operating time and postoperative pain. However, staple fixation seems to show fewer recurrences and fewer complications. Keywords: Inguinal Hernia; Mesh Fixation; Staple; Recurrence Introduction The inguinal hernia is a very common medical condition with considerable morbidity. Its exact incidence and prevalence are not known [1]. In the Netherlands 30.000 inguinal hernia repairs are performed annually, of which 14 to 17% is recurrent [2]. In 1989 Lichtenstein and co-authors introduced a technique for tension-free inguinal hernia repair using a polypropylene mesh for reduction of the hernia and reinforcement of the transversalis fascia. The mesh is secured to the posterior wall of the inguinal canal using polypropylene sutures [3]. In 1996 Egger and co-authors described a variation on Lichtenstein’s technique in which they used staples for fixation of the mesh with good results. The main advantage was a reduction in operating time without increasing recurrence rates [4]. Some authors, however, commented on the potential risk of increased wound infections, postoperative pain, vascular injury and increased cost [5-8]. We performed a comparative study in patients who underwent Lichtenstein’s inguinal hernioplasty with mesh fixation using either polypropylene sutures or staples. Our main goal was to compare operating time, recurrence rate, postoperative pain and costs between these two groups.

27 Letter to the editor Neth J Med 2007; 65: 43-4.

Peritoneal mesothelioma, a case report

J van Brakel, coasssistent, B van Ouwerkerk en TJ Cleophas, internisten, Albert Schweitzer Ziekenhuis, Dordrecht. Summary: Based on a 16 year old article of seven cases the condition may be rare, indeed. However, using the Internet we noticed that peritoneal mesothelioma is the second most frequent primary malignancy associated with asbestos, with 100-500 new cases in the USA each year (approximately 10-20 % of all asbestos associated malignancies).Studies including hundreds of patients have been published.It may be true that diagnosing an abdominal mesothelioma is difficult due to the non specific presentation and mild symptoms of the disease. But lack of familiarity with the condition may further delay the diagnosis as demonstrated in the underneath experience from our own practice. A 69-year-old male patient followed, because of intermittant ascites, for over 3 three years in a multi-specialists practice of internal medicine. The results of endoscopies and computerized tomographies were negative while peritoneal paracentheses gave non-specific results. A provisional diagnosis of Familial Mediterranean Fever was made, because a far ancestor was from the Mediterranean. A few weeks ago, he developed symptoms of intermittant subileus of the ileum. At laparoscopy it was very hard to get access to the peritoneal cavity caused by the extreme hard white fibrotic rectus fascia. The ileum was attached to the peritoneum with a lot of scare tissue. A fibrotic white liver was observed. Biopsies were taken from it and from the rectus fascia. Pathologic specimens were compatible with a diagnosis of malignant mesothelioma. The authors (NJM 2006;64:157) report no history of exposure to asbestos in their patient, a fork-lift truck driver. Asbestos was some 30 years ago, the latency time given by the authors, commonly employed in the floors and walls of store houses for insulation and fire-protection. Lorry drivers were particularly at risk due to the continuous dust their work caused. We should add that both our case and that of the authors underline the importance of a thorough history taken. Particularly, workers at shipyards, mines, and factories were at risk. Our patient was from the first group, albeit only for two years some 30 years ago. As for many future patients the latency time has been completed by now, we need to be alert. This is relevant since the prognosis is dependent on the stage, with over 90% 5 year survival in nonmetastasized cases. In order to enhance diagnosis-making we recommend the algorithm provided by the Mesothelioma Specialty Group, that is laparoscopy with multiple biopsies guided by CT chest, abdomen, and pelvis, rather than scintigraphic methods, like those used by other authors.

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Accepted for publication by Clinical Research & Regulatory Affairs , 28-2-2008

Khat abuse in Yemen, a population -based survey Suhail Basunaid, MD,1 Martien van Dongen, Md, PhD,2 Ton J Cleophas, MD, Ph D, Professor3 1

Department of Internal Medicine, Albert Schweitzer Hospital Dordrecht, 2Academic Medical Center Maastricht, 3Claude Bernard University Lyon Correspondence to Cleophas Ton J, Department of Medicine, Albert Schweitzer Hospital, Dordrecht, Netherlands, PO box 444, 3300 AKJ Dordrecht, Netherlands, tel 0031 184 434222, fax. 0031 184 434340, E-mail [email protected] Summary Background: Khat is a centuries old substance of abuse produced on a large scale in Yemen. Betaketoamphetamine, otherwise called cathinone, is the main contributor to the stimulant effect of khat. A recent unpublished study from Yemen found that the percentage of native users may be as large as 70%. Objective: To evaluate this figure, to study users’ personal characteristics in order to find out whether there are subgroups, particularly, at risk of abuse, and to assess the immediate adverse effects of the compound as well as the main motivations for abuse. Method: The entire population of a randomly selected district of Yemen’s capital city Sana’a was used. Self-administered questionnaires were applied. Results: Of 600 questionnaires distributed only 200 were completed and usable. 159 persons (80%) were users. 86% of the males and 50 % of the females were users ( p < 0.001). The majority of the users were between 15 and 30 years old. The numbers of females and males in different age classes were similarly distributed. Daily adverse effects included tiredness, gastrointestinal and cardiac complaints, and headache occurring between 38 and 85% of the users (95% confidence interval). The main reasons for chewing khat was for accomplishing study and hard work in the males and attending social events in the females ( difference between genders at p < 0.05). Discussion: 1. Our study shows that about 80% of the Yemeni people use khat on a daily base. 2. The proportion of male users is larger than that of females. This may be a consequence of the dominant role of the males in the Yemeni society. 3. Both time and money are lost among users, which must affect their lifes profoundly. This is, particularly, serious because the majority of users are between 13 and 30 years and thus in an active age of life. 4. Khat has a wide range of unpleasant daily side effects, and enhances the risks of infectious diseases. Studying serious adverse effects was not the objective of our survey but many case reports are currently being published.

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Accepted for publication by Netherlands Heart Journal Feb 2008

The effect of physical, social and psychological factors on drug-compliance in patients with mild hypertension Okken VS1, Niemeijer MG2, Dijkstra A1, Otten S1, Cleophas TJ3 Rijksuniversiteit Groningen, Sectie Sociale en Organisatiepsychologie, 2Martini Hospital Groningen, 3Albert Schweitzer Hospital Dordrecht

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Correspondence to Professor Dr. Ton J Cleophas, Department of Medicine, Albert Schweitzer Hospital, PO Box 444, 3300 AK Dordrecht, Tel 0184 434222, Fax 0184 434340, E-mail [email protected] Summary Background:In patients with hypertension non-compliance with drug-treatment is between 15 to 54%, and has been recognized a relevant contributor to the burden of cardiovascular morbidity. Up to 92% of the patients experience unpleasant symptoms of their condition, and, particularly, in them experienced symptoms may enhance compliance. Objective:To simultaneously assess the effects of physical, social and psychological factors on non-compliance. Methods:Mildly hypertensive patients, despite drug treatment, from the cardiology and internal medicine departments were requested to answer a self-administered questionnaire addressing their presence of physical symptoms as well as psychosocial factors. The questionnaire was based on previously used test-batteries and consisted of two lists of physical complaints and 4 lists addressing the 4 domains of planned behaviour regarding medical non-adherence by Baron and Byrne. These domains assess psychosocial factors mainly. Each list consisted of 3 items or more and each item was scored on 5-7 points scales. Mean scores were used for assessment. The lists were also separately assessed for internal consistency and reliability using Crohnbach’s alphas. One-way Analysis of variance and multivariate analysis of variance (MANOVA) with compliance as outcome variable and the physical, social and psychological variables as indicator variables were used for data analysis. MANOVA was adjusted for multiple testing. Results:Many patients experienced physical symptoms due to hypertension, e.g., tiredness 31% , hot flushes 28%, headache 24%, reduced daily life energy 23%, palpitations 22% with 95% confidence intervals between 16 to 38%. Scores of physical symptoms and social factors were not different between self-reported compliants (n = 165) and non-compliants (n = 11). However, the score of psychological factors was significantly larger in the compliants than in the non-compliants, 5.05 versus 3.06, p < 0.018. The MANOVA showed a significant overall difference between the compliants and non-compliants in the data at p<0.012 which was mainly due to the score of psychological factors. Discussion: The effect of physical symptoms on non-compliance in mildly hypertensive patients is negligible. So is the effect of social factors. Psychological factors like lacking sense of grief, regret and shame are major determinants of non-compliance. Physicians may play an educational role in improving their patients’ compliance by addressing these determinants. We should add that the conclusions should be made with reservations given the small number of non-compliants in our sample.

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Published in the Neth Heart J 2007; 15: 61-8

Cardiovascular drug trials: how to examine interaction, and why so

T.J. Cleophas, MD, PhD, Associate-Professor, A.H.Zwinderman, DMath, PhD, Professor From the European College of Pharmaceutical Medicine, Lyon France Reprint request: Dr. Ton J Cleophas, MD, PhD, Associate-Professor, Dept Medicine, Albert Schweitzer Hospital, Box 444, 3300 AK, Dordrecht Netherlands, tel 0031 184 434222, fax 0031 184 434340, e-mail [email protected] Keywords: pharmaceutical research, clinical trials, interaction, regression analyses Summary Background: In practice the benefit of cardiovascular medicines is less consistent than it is in clinical trials. This is due to multiple uncontrolled factors that co-determine the efficacy of the new treatment. In statistical terms, they interact with the new treatment. Interaction effects are rarely assessed in cardiovascular trials. Objective: To review (1) important factors that may interact with the treatment efficacy, (2) how to examine such factors, and (3) why so. Results: Important factors include (a) concomitant medications, (b) comorbidities, (c) heterogeneities of investigators, health centers, individual patients. Such factors can be assessed by comparing subgroups. A common but incorrect approach is the comparison of p-values. Instead, a direct comparison of effect sizes relative to the standard errors is adequate. As an alternative regression modelling is adequate and convenient. Results of interaction assessments are post-hoc, and, therefore, of an exploratory and unconfirmed nature. Why should they be performed even so? In cardiovascular research drug-drug interactions, and effects of comorbidities on drug efficacies are numerous. It is valuable to account at least post-hoc for such mechanisms. Second, current cardiovascular trials involve heterogeneous health centers, investigators, and patient groups. Accounting these heterogeneities can be helpful to better predict individual responses in future patients. Conclusions: Cardiovascular trials enrolling patient groups at risk for heterogeneity should include at least a post-hoc assessment for interaction. Correct and incorrect methods for that purpose are described. Interaction assessments are helpful to better predict the efficacy/safety of new cardiovascular medicines in the future treatment of individual patients.

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Published in Current Clinical Pharmacology 2007; 2; 129-33

Clinical trials: how to assess confounding and why so

Ton J Cleophas, MD, PhD, Associate-professor, Aeilko H Zwinderman, DSc, PhD, Professor European Interuniversity College Pharmaceutical Medicine, Lyon France Key words: clinical trials, confounders, subclassification, regression analysis, propensity scores Correspondence to; Ton J Cleophas, Dept Medicine, Albert Schweitzer Hospital, box 444, 3300 AH, Dordrecht, Netherlands, tel 0031 184 434222, fax 0031 184 434340, [email protected] Abstract Background: In large randomized controlled trials the risk of random imbalance of the covariates is mostly negligible. However, with smaller studies it may be substantial. In the latter situation assessment and adjustment for confounders is a requirement in order to reduce a biased assessment of the treatment comparison. Objective: In the current paper three methods for confounding assessment and adjustment are reviewed for a nonmathematical readership. Methods: First method, subclassification: the study population is divided into subclasses with the same subclass characteristic, then, treatment efficacy is assessed per subclass, and, finally, a weighted average is calculated. Second method, regression modeling: in a multivariable regression model with treatment efficacy as independent and treatment modality as dependent variable, the covariates at risk of confounding are added as additional dependent variables to the model. An analysis adjusted for confounders is obtained by removing the covariates that are not statistically significant. Third method, propensity scores: each patient is assigned several odds ratios (ORs), which are his/her probability, based on his/her covariate value of receiving a particular treatment modality. A propensity score per patient is calculated by multiplying all of the statistically significant ORs. These propensity scores are, then, applied for confounding adjustment using either subclassification or regression analysis. Conclusions: The advantages of the first method include that empty subclasses in the treatment comparison are readily visualized, and that subclassification does not rely on a linear or any other regression model. A disadvantage is, that it can only be applied for a single confounder at a time. The advantage of the second method is, that multiple variables can be included in the model. However, the number of covariates is limited by the sample size of the trial. An advantage of the third method is, that it is generally more reliable and powerful with multiple covariates than regression modeling. However, irrelevant covariates and very large / small ORs reduce power and reliability of the assessment. The above methods can not be used for the assessment of interaction in the data.

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Published in PERFUSION 2007; 2007; 20: 79-82 Clinical trials: log likelihood ratio tests for assessing cardiovascular events

Cleophas TJ, MD, PhD 1,2, Van Ouwerkerk B, MD, PhD2, Zwinderman AH, DMath, PhD 1 1

European College of Pharmaceutical Medicine, Lyon France and 2Dept Medicine Albert Schweitzer Hospital, Dordrecht Netherlands Key words: likelihood ratio statistics, invariance principle, exact tests, cardiovascular events, statistical analysis Summary Background: Traditional statistical tests for the analysis of cardiovascular events have limited sensitivity, particularly with smaller samples. Exact tests, although infrequently used so far, should have better sensitivity, because they do not include standard errors as a measure of uncertainty. The log likelihood ratio test is one of them. Objective: To assess the above question using real and hypothesized data examples. Results: In three studies of cardiovascular events the log likelihood ratio test was consistently more sensitive than traditional tests, including the chi-square and the odds ratio test, producing p-values respectively between <0.05 and <0.002 and between not-significant and <0.05. This was true both with larger and smaller samples. Other advantages of the log likelihood ratio were: exponents can be conveniently handled by the log transformation and an exponential equation is turned into a simpler quadratic equation. A potential disadvantage of numerical problems is avoided by taking in the final analysis the ratios of likelihoods instead of separate likelihoods. Conclusions: Log likelihood ratio tests are consistently more sensitive than traditional statistical tests. We hope that the paper will stimulate cardiovascular researchers to more often apply them. Introduction For Gandhi non-violence was a primary invariance principle, while for his political successor Nehru justice was so. Invariance principles signify that while everything changes in life, some laws of life do not. Consequently, these laws of life do not include a measure of error. For example, Einstein’s invariance principle is expressed in the famous equation E = mc2. Most statistical tests, including t - (and z-) tests, F-tests, chi-square tests, odds ratio tests, do not meet the invariance principle, because they apply estimated likelihoods like averages and proportions that have their standard errors as a measure of uncertainty. However, a few statistical tests use likelihoods without standard error. These tests, called exact tests, should, by their very nature, provide the best precision and sensitivity of testing. They include, among others, the Fisher exact test and the log likelihood ratio test. Particularly, the log likelihood ratio test, avoiding some of the numerical problems of the other exact likelihood tests, is straightforward, and is available through most major software programs1-8, although infrequently used so far. This paper reviews the advantages and problems of the log likelihood ratio test, and gives real and hypothesized data examples supporting its better sensitivity. We do hope that the paper will stimulate cardiovascular researchers to more often apply this test.

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Published in Clinical Research and Regulatory Affairs 2007; 24: 25-37

The sense and nonsense of exponential models in clinical research Van Ouwerkerk B, MD, PhD, Cleophas TJ, MD, PhD, European College Pharmaceutical Medicine Lyon France, and Albert Schweitzer Hospital Dordrecht Netherlands

Correspondence to Ton J Cleophas, Professor, Dept Medicine, Albert Schweitzer Hospital, Box 444, 3300 AK Dordrecht, Netherlands Key words: clinical research, exponential models, logistic regression, Cox proportional hazard regression, Markow models, polynomial regression, Laplace transformed multiexponential models Summary Background: Exponential models are very popular for the assessment of clinical research. Nature is unpredictable and exponential models may be adequate for simple organisms but less so for human beings. Objective: To review the potential advantages and limitations of this approach. Methods: The following models were reviewed: Cox proportional hazard regression, Markow modeling, polynomial regression for Laplace transformed multi-exponential models, and logistic regression. Real and hypothesized data were used as examples. Results and conclusions: Advantages include: 1. The possibility to conveniently study subgroup effects, otherwise called confounders. 2. The possibility to derive pharmacokinetic parameters. 3. The possibility to make long-term predictions from observational data. Limitations include: 1. The exponential models may not fit the data well enough. 2. They may give rise to some serious misinterpretations of the data. 3. Most of the statistical software for exponential models assumes that confounders are homogeneous, while, in reality, this is virtually never true. 4. The exponential models are a major simplification for the description of research data in human beings. We underline that exponential modeling, although a very interesting tool for exploratory research, is not adequately reliable for confirmational research. It is to be hoped that this paper will help investigators to more cautiously interpret the results of their exponential data analysis. 1. Introduction A major goal of clinical research is making predictions about efficacy/safety of new treatments in future patients. For that purpose best-fit linear or curvilinear models of the data are calculated and it is, subsequently, tested how far the individual data are distant from their best-fit model. If the data are closer to their model than could happen by random sampling, the model is assumed to be adequate for making predictions. Particularly, exponential models are very popular for the purpose. This is because trials often use longitudinal data like survival data or concentration-time relationships and/or odds of responding as outcome

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Published in Clinical Research and Regulatory Affairs 2007; 24: 87-93

Physicians’ daily life and the scientific method G.Cleophas, DLaw1 ,M.T.Cleophas, DLaw 2 , T.Cleophas, MD, PhD, Professor 3 1 Ethic committee, Albert Schweitzer Hospital, Dordrecht Netherlands, 2 Netherlands Institute for Arbitration, Rotterdam Netherlands, 3 European Interuniversity College of Pharmaceutical Medicine, Lyon France. Key words: clinical trials, observational studies, chi-square tests, clinical hypotheses, scientific methods, medical statistics Summary Background: So far, few physicians have followed the scientific method for answering practical questions they simply do not know the answer of. The scientific method is, in a nutshell: reformulate your question into a hypothesis and try to test this hypothesis against control observations. Objective: To give simple examples of how the scientific method can be implied in a physician’s daily life. Results and conclusions: Of 9 unanswered daily questions, 4 qualified for simple statistical assessments, that were very clarifying for the physicians involved. Additional advantages of the scientific method include: (1) since the scientific method has been recognized to produce the best evidence you can get from your observations, physicians applying it serve their population in the best possible way; (2) being actively involved in the scientific method is a strong antidote against the hazards of accepting published studies from others with too little of scepticism or rejecting them with too much of it. Limitations of the scientific method include: (1) type I and II errors; (2) misinterpretations due to different frequency distributions, (3) lack of leisure time on the part of the physicians to write a study protocol, (4) the risk of a damaged patient-doctor relationship. Introduction Physicians’ daily life largely consists of routine, with little need for discussion. However, there are questions physicians simply do not know the answer of. Some will look for the opinions of their colleagues or the experts in the field. Others will try and find a way out by guessing what might be the best solution. The benefit of the doubt doctrine1 is often used as a justification for unproven treatment decisions, and, if things went wrong, another justification is the expression: clinical medicine is an error-ridden activity.2 So far, few physicians have followed a different approach, the scientific method. The scientific method is, in a nutshell: reformulate your question into a hypothesis and try to test this hypothesis against control observations. In clinical settings this approach is not impossible, but rarely applied by physicians, despite their lengthy education in evidence based medicine, which is almost entirely based on the scientific method. This paper was written to give simple examples of how the scientific method can be implied in a physician’s daily life, and to explain its advantages and limitations. We do hope that this paper will stimulate physicians to more often apply the scientific method for a better outline of their patients’ best possible treatment options.

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4. Posters geaccepteerd voor de wetenschapsdag 19-6-2008

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Iatrogenic admissions to hospital R.Atiqi, TJ Cleophas, B van Ouwerkerk, E van Bommel Dept Medicine Albert Schweitzer Dordrecht Netherlands Background: According to a prospective analysis in the city of Liverpool published in the BMJ 2004 (Vol 329, 15-9) the prevalence of admissions due to adverse drug reactions is 6.5 %. This percentage was taken from an entire population of patients admitted. In departments of internal medicine the percentage may be different. In the Liverpool study 41.8% % of the iatrogenic admissions were due to diuretics and antihypertensive drugs like ace-inhibitors, AII-blockers and beta-blockers followed by 29.6% caused by NSAIDs. Objective: To assess the burden of iatrogenic admissions in a department of internal medicine of a large teaching hospital in the Netherlands. To assess whether diuretics and the antihypertensive drugs produce a significantly larger risk of iatrogenic admissions than other classes of drugs. Methods: The investigators will be trained in order to better recognize rare adverse effects. Thousand subsequent emergency admissions will be assessed for main diagnoses on admission, co-morbidities, co-medications, adverse drugeffects, and possible drug-drug interactions. Also assessed will be the length of hospital stay, prevalence of fatality, other complications, and diagnoses missed at the emergency department as well as the specific drug classes involved in the iatrogenic admissions. Expected results: In a pilot study of 195 patients we found 46% iatrogenic admissions. In this assessment also iatrogenic complications from non-drug treatments and other medical interventions, like surgery and angioplasty were included. Excluding the latter reduced this percentage to 40%. With a similar frequency distribution of drug classes causing the adverse drug reactions, a population of 1000 will be adequate to find a significant difference between different classes of drugs at a power of 80%. Conclusions: The percentage of iatrogenic admission to a department of internal medicine may be as large as 40%. Over 2/5 of the emergency admissions may be due to diuretics and other antihypertensive drugs. Non-drug treatments for hypertension may be helpful to reduce the burden of iatrogenic admissions.

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Causes of postoperative death after surgery for ovarian cancer Cornelis G. Gerestein1*, Ronald A. Damhuis2, Marjolijn de Vries1, Ardine Reedijk2, Curt W. Burger3, and Geertruida S. Kooi1. 1 Department of Obstetrics and Gynecology, Albert Schweitzer Hospital, Dordrecht, The Netherlands, 2 Comprehensive Cancer Center, Rotterdam, The Netherlands, 3 Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Daniel Den Hoed/Erasmus MC University Medical Center, Rotterdam, The Netherlands. Objective: To determine causes of postoperative death after surgery for epithelial ovarian cancer. Methods: The Rotterdam Cancer Registry records all newly diagnosed cases of cancer in the southwestern part of the Netherlands. All patients who died within 30 days after surgery for cancer of the ovary or fallopian tube were identified and analysed by reviewing medical notes. Results: Between 1989 and 2005, 2434 patients underwent resectional surgery for ovarian cancer with a 30-day mortality of 3.1% (n=76). Operative mortality increased with age from 1.5% (26/1765) for the age-group 20-69 to 6.6 % (32/486) for the agegroup 70-79 and 9.8% (18/183) for patients aged 80 years or older. Review of the medical notes revealed pulmonary failure (18%) and surgical site infection (15%) as the most common causes of death. General complications (n=42) were more frequent than surgical complications (n=37). Optimal cytoreductive surgery (<1cm) had only been achieved in 32% of patients. Associations between cause of death and type of hospital or surgeon specialty were inconclusive. Conclusion: The causes of death after surgery for ovarian cancer are very heterogeneous. Age, comorbidity and the extent of the surgical procedure act as confounding factors. Given the impact of general complications, progress in preoperative risk assessment, preoperative preparation and postoperative care seem essential to reduce the occurrence of fatal complications.

38 PAGAS: Project of Anemia analyses from the General practitioner to the Albert Schweitzer hospital GHM Tax1, J Droogendijk2, P Berendes1, R Beukers3, MD Levin2. Albert Schweitzer ziekenhuis, 1Geïntegreerd Klinisch Chemisch Laboratorium, 2Afdeling Interne geneeskunde, 3Afdeling MDL-ziekten, Dordrecht. Achtergrond & Doel: Het PAGAS-project is opgestart om het diagnostisch proces bij de anemische patiënt (mannen > 18 jaar en vrouwen > 50 jaar) te verbeteren en gastro-enterologische tumoren sneller te diagnosticeren. Het PAGAS-project is een samenwerkingsproject tussen huisarts, laboratoriumspecialist, MDLarts en internist-hematoloog. Methodiek: De huisarts meldt zich via internet aan als deelnemer van het PAGAS-project (www.PAGAS.nl). Bij anemische patiënten van "PAGAS-huisartsen" wordt een uitgebreide laboratoriumanalyse uitgevoerd (o.a. Hb, MCV, RDW, ferritine, transferrine, ijzer, ijzerverzadiging, TIJBC, foliumzuur, vitamine B12, CRP). Aan de hand van de laboratoriumuitslagen wordt door de laboratoriumspecialist de differentiaal diagnose van de anemie en bijbehorend advies gegeven. De MDL-arts biedt de mogelijkheid om iedere patiënt met een nieuw ontdekte ijzergebreksanemie binnen 4 weken te scopiëren (gastro- en colonscopie). De internist-hematoloog geeft advies en beheert het project. Resultaat: Het PAGAS-project is gestart op 01 januari 2007. Drieënzestig huisartsen zijn inmiddels als PAGAS-deelnemer aangemeld. Tot nu toe werden bloedmonsters van 728 patiënten ingestuurd. IJzergebreksanemie werd bij 63 mannen (ferritine < 25 ug/L) en 80 vrouwen (ferritine < 20 ug/L) gevonden. In de eerste 11 maanden zijn 19 gastro- en colonoscopiëen uitgevoerd via deze route (een substantieel deel van de ijzergebrekspatienten wordt nog steeds via klinische opname of poliklinisch gescopiëerd. Hierbij werd gevonden: coecumcarcinoom (2), oesofagitis (1), angiodysplasie (2), maagpoliep (1) en status na B2 maagresectie (1). Conclusies: Met de resultaten van het PAGAS-project wordt het inzicht in de diagnostiek en behandeling van een patiënt met anemie in de huisartspraktijk vergroot (zie abstract transferrine). Wij hopen de verschillende oorzaken van ijzergebrek eerder te achterhalen om m.n. de prognose van gastro-intestinale tumoren (oorzaak van ca 15% van de ijzergebreksanemie bij ouderen) te verbeteren.

39 Hoezo, verhoogd transferrine bij ijzergebreksanemie? G.H.M. Tax1, J. Droogendijk2, M-D. Levin2, R. Beukers3, P. Berendes1. Albert Schweitzer ziekenhuis, 1Geïntegreerd Klinisch Chemisch Laboratorium, 2 Afdeling Interne geneeskunde, 3Afdeling MDL-ziekten, Dordrecht. Achtergrond & Doel: Volgens de NHG-standaard ‘anemie’ en het alternatief stroomschema voor het laboratoriumonderzoek bij anemie (NTvG 2007) wordt de diagnose ‘ijzergebreksanemie’ gesteld op basis van: a) het ferritine en/of b) de combinatie van een laag serumijzer en een verhoogd transferrine. Een absoluut afkappunt van de laatste parameters wordt niet opgegeven. Methodiek: In het kader van het transmurale PAGAS project is bij 728 anemische patiënten oa het Hb, MCV, RDW, ferritine, transferrine, serumijzer, vitamine B12 en foliumzuur bepaald. De patiënten zijn onderverdeeld in anemie met ijzergebrek (ferritine <20 ug/l vrouwen en <25 ug/l mannen) en anemie zonder ijzergebrek en vergeleken v.w.b. transferrine (g/l) (WHO-criteria). ROC-curves zijn gemaakt, waarbij ijzergebrek zeer strikt is gedefinieerd als ferritine <15 ug/l (NHG-standaard). IJzergebrek is uitgesloten bij ferritine >100 ug/l. Resultaat: Bij ijzergebrek is de gemiddelde transferrinewaarde 3.22 g/l (2.24-4.20 -/+2SD) en 2.22 g/l (1.31-3.12 -/+2SD) zonder ijzergebrek. Beide Gausse-curves overlappen bij transferrinewaarden tussen 2.0 g/l en 3.5 g/l. Een transferrine van 4.1 g/l - het afkappunt in de NHG-standaard (diagnostisch kompas) - heeft een specificiteit van 100%; de sensitiviteit is met 6.7% laag. Een hogere sensitiviteit (24.8%) wordt - met behoud van de maximale specificiteit - gevonden bij 3.6 g/l. Het afkappunt met de hoogst mogelijke specificiteit (94%) en sensitiviteit (95.2%) ligt bij 2.6 g/l De "Area Under the Curve (AUC)" is bij de verschillende ROC-curves (hoog naar laag): transferrine 0.98, TIJBC 0.98, ijzerverzadiging 0.91, MCV 0.87, RDW 0.79 en serumijzer 0.78. Conclusies: Uit deze studie blijkt dat men bij een anemische patiënt ijzergebrek moet overwegen bij transferrinewaarden vanaf 2.6 g/l. Het serumijzer heeft slechts een diagnostisch toegevoegde waarde, wanneer deze als TIJBC en/of ijzerverzadiging in de anemie analyse wordt betrokken. 1. Wijk MAM van, et al. NHG-standaard ‘anemie’. Huisarts Wet 2003;46:21. 2. Oosterhuis WP, et al. Ned Tijdschr Geneeskd 2007;151:2326. 3. Diagnostisch kompas. Diemen: College voor zorgverzekeringen;2003.

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Health-related quality of life and behavioral problems in pre-school children born at 32 to 36 weeks of gestational age N Ketharanan, WL Lee, EA Smit-Kleinlugtenbelt, AC de Mol, Afdeling kindergeneeskunde-neonatologie, Albert Schweitzer Ziekenhuis, Dordrecht. Introduction The rise of neonatal (intensive) care has resulted in increased survival rates in neonates born prematurely. There seems to be a lacuna of information on the group of moderate to mild premature neonates (32-33 and 34-36 weeks of gestational age respectively), the majority of premature births. Next to this it is known that even near term infants have significantly more clinical problems in comparison to full-term healthy newborns. Objective: Aim of this study is to determine health related quality of life (HR-QoL) and the occurrence of behavioural and emotional problems at the age of 2 to 5 years in children born between 32 and 36 weeks of gestational age and cared for in non-NICU surroundings. Methods: All neonates born at 32 weeks and 0 days up to 35 weeks and 6 days of gestational age and who were between 2 up to 5 years of age at the time of our study were selected to enter in a single centre descriptive cohort study (n=381). As 17 patients were excluded because of congenital abnormalities, history of NICU admission or incomplete data, 6 were lost to follow up and 7 refused to participate, 351 children were elegible for the study. The parents were contacted by phone twice (240 successfully). Subsequently, three questionnaire forms were sent to the parents, who were requested to respond within 4 weeks. To investigate the HR-QoL as experienced by proxies we employed the TNO-AZL Preschool Quality of Life (TAPQOL) questionnaire. Data will be compared to validated data of the common Dutch population. To study behavioural and emotional problems we employed the Childhood Behavioral Checklist (CBCL). Reference data of this are based on validation studies the common population. Socio-demographic data were collected by a self-designed questionnaire, based on those used in literature, and items were subdivided into factors concerning the study subject, parental factors and social-economic status. Patient characteristics were extensively described for the children who’s parents responded as well as for those who did not return the questionnaires. Items concerned the perinatal medical history, clinically important medical disorders and subsequent treatment during admission. Data were retrieved from a retrospective medical chart review. Expected Results: We expect to be able to present these results at the upcoming research meeting of the Albert Schweitzer Hospital in 2008. Conclusion: We expect to be able to conclude whether there is a difference in outcome concerning HR-QoL and emotional and behavioural problems in moderate and mild premature newborns at pre-school age. A second consecutive study will analyse factors within this group of premature children which might be predictors of either HR-QoL or emotional and behavioural problems. Even if the whole group does not show any statistically significant difference with the common population, this might be of interest.

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Active fixation in proximal and distal coronary sinus pacing for paroxysmal atrial fibrillation Nico Breuls, Hans Schmidt, and Jan CJ Res, Dept of Cardiology, Albert Schweitzer Ziekenhuis, Dordrecht, and Dept of Electrophysiology, Erasmus MC, Rotterdam Purpose:Biatrial pacing (BAP) is effective in suppressing PAF. This study reports on the safe use of 4Fr Active Fixation (4FAF) (Medtronic 3830) in the PCS and DCS. Methods: Left atrial pacing (LAP)was done in 17 patients (Pts) for the treatment of PAF. Before implant, PAF was symptomatic despite medication. Sick sinus (SSS) was present in 8 Pts. In 4 Pts BAP was an upgrade from single right atrial pacing (SRAP). SRAP in combination with right ventricular stimulation (RVS) was performed in 3 Pts. BAP was present in 14 Pts. LA dimensions were 43,0 ± 4,5 mm, all Pts had normal left ventricular function with normal enddiastolic dimensions (50,8 ± 4,6 mm). Quality of Life score (QOLS) on a Visual Analog Score was used on a scale of 1 to 10 Statistical analysis: The data are presented as mean ± SD. Paired t-Test were used. Results: Fluoroscopy times were 13 ± 6.8 min and procedure times were 85.3 ± 26 min. Stimalation Thresholds (ST) in the RA (n=14) vs LA (n=17) were 0,6 ±0,2 V and 1,3±0,7V, P<0,05 vs RA. Sensing RA vs LA was 3,7± 1,9 mV and 2,8 ± 1,7 mV resp. ( NS). After 6 months ST remained unchanged in the LA, but sensing declined significantly: 1,3 ± 0,5 mV, P<0,05. In 5 Pts, the LA electrode was positioned in the DCS. Their electrical results did not differ significantly from the proximal positioned leads. QOLS before implant was 4±1,7 and after 7,7 ±1,1, P< 0,0001. No complications were observed. Conclusion: 4FAF can be safely used in the proximal and distal part of the coronary sinus for LAP. LAP improves QOL in Pts with PAF.

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Risicofactoren voor trombosevorming bij myeloproliferatieve aandoeningen Celine Schilthuizen, Mark-David Levin, Interne Geneeskunde Albert Schweitzer Ziekenhuis Achtergrond: De chronische myelopoliferatieve aandoeningen worden ingedeeld in verschillende subgroepen. Deze vier ziekten zijn: polycythemia vera (PV), chronisch myeloïde leukemie (CML), idiopathische myelofibrose (IMF) en essentiële trombocytose (ET). De belangrijkste complicaties van deze aandoeningen zijn het ontwikkelen van arteriële en/of veneuze trombosen. Een mutatie in het JAK2-transcriptie-eiwit (JAK2V617) komt bij een groot deel van de patiënten met een myeloproliferatieve aandoeningen voor. Er is op dit moment onvoldoende bewijs over een verband tussen deze mutatie en een verhoogd risico op trombosen. Recente onderzoeken tonen echter een associatie tussen leukocytose en een verhoogd risico op trombosen bij patiënten met PV en ET. Bij myeloproliferatieve aandoeningen kunnen geactiveerde neutrofielen zich binden aan trombocyten, dit leidt tot endotheelactivatie en –schade met als gevolg een verhoogd risico op veneuze trombosen. Deze resultaten impliceren een belangrijke rol voor leukocytose als prognostische marker voor myeloproliferatieve aandoeningen. Nader onderzoek naar de etiologie van trombosevorming en de rol van leukocytose bij myeloproliferatieve aandoeningen is daarom geïndiceerd. Studieprotocol: Objective: Het doel van deze studie is om meer inzicht te krijgen in risicofactoren die zijn betrokken bij het ontwikkelen van trombose bij patiënten met myeloproliferatieve aandoenigen. Study design: Retrospectief cohortonderzoek. Patiënten: Patiënten uit drie verschillende ziekenhuizen met een myeloproliferatieve aandoening (n=350). Methoden: Verschillende klinische parameters zullen door middel van status onderzoek worden vastgelegd in een database. Vervolgens wordt gekeken naar associaties tussen deze klinische parameters (bijv. aanwezigheid van de JAK2mutatie en leukocytose) en het risico op trombose. Van alle patiënten wordt de JAK2-mutatie aangetoond door middel van de PCR-techniek. Verder wordt van elke patiënt een aantal buisjes bloed afgenomen waaruit RNA en DNA wordt geïsoleerd. Vervolgens wordt met behulp van een Single Nucleotide Polymorphisms(SNP)-array gekeken naar SNP’s die mogelijk betrokken zijn bij de pathogenese van trombosen bij myeloproliferatieve aandoeningen.

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Project of Anemia analysis from the General Practitioner to the Albert Schweitzer hospital (PAGAS): the retrospective study Droogendijk J, Berendes P, Beukers R, Levin MD, Albert Schweitzer Hospital, Dordrecht Introduction: The prevalence of iron deficiency anemia (IDA) is 2 to 5 percent in men and postmenopausal women in the developed world. IDA is commonly caused by chronic gastrointestinal blood loss, and a thorough examination of the gastrointestinal tract must be standard practice. Objective: To retrospectively study endoscopic evaluations of patients with IDA in order to determine the cause of IDA and the number of gastrointestinal malignancies. Material and methods: We retrospectively evaluated all patients with IDA diagnosed by the general practitioner in the region of our hospital from January 1st 2004 until 31 December 2005. We included women older than 50 and men older than 18 years without a history of IDA in the two years previously. Iron deficiency anemia was defined as a hemoglobin level <8.5 mmol/L and a serum ferritin level <25 µg/L for men and a hemoglobin <7.5 mmol/L and serum ferritin level <20 µg/L for women. Results: In two years time 291 patients were newly diagnosed with IDA; 130 men and 161 women. Only 93 (32%) patients were endoscopically evaluated within 4 months; 43 (15%) patients underwent complete screening of the gastrointestinal tract (gastroduodenoscopy and colonoscopy), 33 (11%) patients underwent gastroduodenoscopy and 17 (6%) patients colonoscopy. Gastrointestinal endoscopy revealed at least one lesion potentially responsible for blood loss in 47 of 93 (51%) patients. A potential upper gastrointestinal tract lesion was found in 23 (25%) patients. A lower gastrointestinal lesion was found in 20 (22%) patients. Four (4%) patients had lesions in both the upper and lower gastrointestinal tracts. The most common lesions identified by gastroduodenoscopy were erosive esophagitis, gastritis and duodenitis. Cancer was the most common lesion in the colon, accounting for 18 of the 24 colonic lesions (75%). In the literature one study identified colon cancer in 11 percent of patients with IDA . Conclusion: In our retrospective study of patients with IDA only 32% received any form of endoscopic evaluation. After excluding premenopausal women we found colon cancer in 22 percent of screened patients with IDA. In order to improve endoscopic evaluation in patients with IDA we started a prospective study (PAGAS).

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Non-pharmaceutical treatment of hypertension S.Elhani, TJ Cleophas, Albert Schweitzer Hospital, Dordrecht Summary Background: Non-pharmaceutical treatment was beneficial in clinical trials and is devoid of the common side effects of drug treatment. In spite of these benefits it is only briefly mentioned in consensus-reports. Objective: To assess the different non-pharmaceutical treatments as applied by general practitioners in the Netherlands. Methods: The entire population of general practitioners in the areas of Dordrecht and Gorinchem, with 350,000 inhabitants, 50 % practicing in the city, 50% in the country, was included. Self-administered questionnaires included general questions (5 items), specific questions about non-pharmaceutical treatments (12 items), questions about blood pressure increasing factors including blood pressure increasing medicines (10 items), life style questions (3 items) were used. Mostly binary questions were used. Both summary statistics and regression analyses for subgroup-assessments were performed. Prior to study the questionnaire was tested and approved by three experienced general practitioners and three internists and hypertension specialists. Results: Of the 176 physicians mailed 105 replied adequately. Body weight reducing measures, stop smoking, and physical exercise advise were given by 95, 93, and 93% of the physicians. Life style and reduction of intake of licorice advise were given by only 20 and 30 % of the physicians. Physicians practicing in city practices tended to use less non-pharmaceutical treatments than their counterparts from the country. The older physicians tended to use more often non-pharmaceutical treatments then did the younger ones. Blood pressure increasing drugs were virtually never taken into account as a possible cause of hypertension and consequently were never replaced with less hazardous compounds. Conclusions: 1. Non-pharmaceutical treatments are far from routinely applied by general practitioners. 2. In the country they are used more often. 3. They are also used more often by older physicians. 4. Blood pressure increasing drugs are virtually never taken into account as a possible contributing factor in patients not adequately regulated.

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Richter’s transformation in three patients with chronic lymphocytic leukemia Emma Driessen, Mark-David Levin, Afdeling Interne, Albert Schweitzer Ziekenhuis Cases: Patient A, a 69-year old male with a history of chronic lymphocytic leukemia (CLL), RAI stage I and Binet B presented with signs of a vena cava superior syndrome. After emergency irradiation of the neck and mediastinum, a lymph node biopsy from the right axilla was performed, which revealed a transformation from CLL to a diffuse large B-cell lymphoma. He was subsequently treated with RCHOP. Patient B, a 72-year old male with a history of CLL presented with a fever, lethargy and several jugular swollen lymph nodes. CT examination showed enlarged lymphomas in neck, mediastinum, mesenterium, para-aortic region and inguinal region and an enlarged spleen. A lymph node biopsy was performed and demonstrated a transformation from CLL to a nodular sclerosing Hodgkin’s lymphoma. He is now treated with eight times ABVD. Patient C, a 55-year old male, with a history of CLL for which Chloorambucil previously led to a partial remission. He presented by the dermatologist with a lesion on his cheek. After excision it turned out to be diffuse large B-cell lymphoma. It appeared a transformation from CLL to non-Hodgkin lymphoma had occurred. The patient was now treated with six times R-i-CHOP, which led to a complete remission. Comments: Richter’s transformation denotes the development of high-grade non-Hodgkin lymphoma, prolymphocytic leukemia, Hodgkin disease, or acute leukemia in patients with chronic lymphocytic leukemia/ small lymphocytic lymphoma. The incidence of Richter’s transformation from CLL/ SLL to diffuse B cell lymphoma or Hodgkin lymphoma has been variously estimated at 2-8% versus 0.4%. The transformation is associated by Epstein-Barr virus, trisomy 12, chromosome 11 abnormalities and multiple genetic defects, such as mutations of tumor suppressor gene p53. The clinical presentation shows rapid clinical deterioration with fever, weight loss, drenching night sweats, rapidly progressive lymphadenopathy or elevated levels of serum lactate dehydrogenase. Therapeutic options are intensive chemotherapy, monoclonal antibodies and allogeneic stem cell transplantation, with a response rates range from 5-43%. Nevertheless is Richter’s transformation associated with a poor prognosis, it is rapidly progressive and has a median survival of 5 to 8 months. Conclusion: Richter's transformation should be suspected in patients with CLL, who develop rapidly progressive lymphadenopathy, systemic symptoms, or elevated levels of serum lactate dehydrogenase. Furthermore because of the poor prognosis, in spite of the aggressive therapy, there is a need of curative therapeutic options.

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Glomus-caroticum tumoren en duplexdiagnostiek Annemiek Muller-Rijnaard, Eunice Korten-van Putten, afdeling Radiologie Albert Schweitzer Ziekenhuis, Dordrecht Doel: Kennis vergroten op het gebied van een bij toeval ontdekte glomuscaroticum tumor om met gerichte duplexdiagnostiek een pre-operatieve diagnose in een meerderheid van de gevallen mogelijk te maken. Samenvatting: Tijdens duplexonderzoek naar aanleiding van de vraagstelling:”Verdenking TIA of minor stroke, hemodynamische afwijkingen carotiden?”, werd er tussen de arteria carotis interna (ACI) en de arteria carotis externa (ACE) een gevasculariseerde massa gevonden. Uit vervolgonderzoek door middel van Computer Tomografische Angiografie (CTA) bleek het om een ”sterk aankleurend proces ter plaatse van de carotisbifurcatie te gaan: een glomustumor”. De literatuur beschrijft een benigne laesie die klinisch moeilijk kan worden onderscheiden van bijvoorbeeld een vergrote lymfklier of een vergrote speekselklier, een cyste of indien de zwelling ook pulsatiel is, een vasculair aneurysma, carotis kinking of een prominente carotis bifurcatie. Digitale Subtractie Angiografie (DSA) staat bij deze tumoren ter discussie indien geen pre-operatieve embolisatie noodzakelijk is. Voordelen van duplexdiagnostiek: non-invasief, geen Röntgenstralenbelasting, reproduceerbaar en relatief goedkoop. Beperkingen van duplexdiagnostiek: geen goede weergave achter de mandibula en hoog in de hals, hier zijn Computer Tomografie (CT) en Magnetic Resonance Imaging (MRI) meer geschikt voor een volledig overzicht van het hoofd-hals gebied. Methode: Literatuurstudie naar aanleiding van een toevalsbevinding en het volgen van het diagnostische- en het behandeltraject. Conclusie: Uit deze casus blijkt dat het zinvol is om deze laesie te onderzoeken met duplex op het vaatlaboratorium op zijn grootte en samenhang met de carotiden, zodat er gericht kan worden geanticipeerd door de behandelend arts.

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Eén jaar Jak2-diagnostiek J. Prins1, M.A.Fouraux1, H. Kooijman1, M.D. Levin2. 1 Geïntegreerd Klinisch Chemisch Laboratorium, 2Interne Geneeskunde, Albert Schweitzer ziekenhuis Achtergrond: De diagnostiek van Polycythemia Vera (PV) en Essentiële Trombocytose (ET) is, ondanks diverse richtlijnen en criteria, lastig. De aanwezigheid van de verworven V617F-mutatie in het JAK2-gen wordt gebruikt als additioneel criterium in deze diagnostiek. Methodiek: In het afgelopen jaar is van patiënten met een klinische verdenking op PV (hemoglobine > 10.6 / 9.9 mmol/L voor m/v) of ET (trombocyten > 600 x 109/L) in perifeer bloed via een allel-specifieke PCR-methode de aan- of afwezigheid van de V617F-mutatie in het JAK2-gen aangetoond. Retrospectief is gekeken of er verschillen bestaan in de hematologische parameters tussen de JAK2-mutatie positieve en negatieve PV of ET verdachte patiënten. Resultaat: Van 51 patiënten met verdenking PV en 37 patiënten met verdenking ET is de JAK2-genstatus bepaald. In de PV-verdachte patiënten werd geen verschil in de hemoglobineconcentratie gevonden tussen de 19 Jak2-positieve patiënten en 32 Jak2-negatieve patiënten (10.5±1.2 mmol/L vs 11.0±0.8 mmol/L). Wel werden significant hogere trombocyten- en leucocyten waarden gevonden in de Jak2positieve patiënten (454±220 / 13.3±6.0 x109/L vs 223±65 / 8.5±3.0 x109/L). Ook de trombocytenwaarden van de ET-verdachte patiënten zijn vergelijkbaar (812 ± 201 x109/L vs 826±337 x109/L) voor respectievelijk de 18 Jak2-positieve patiënten en 19 Jak2-negatieve patiënten. Bij de Jak2-positieve patiënten werden wel hogere hemoglobine- en leucocyten-waarden geconstateerd (8.6±1.1 mmol/L / 13.2±7.8 x109/L vs 7.7±1.5 mmol/L / 11.2±4.3x109/L). Conclusies: Uit de resultaten blijkt dat met name bij hoge hemoglobine-waarden het vaststellen van de Jak2-mutatie-status in de praktijk een prominente plaats inneemt bij de differentiatie van patiënten met PV versus andere oorzaken van hemoglobinemie. Daarbij blijkt, overeenkomstig de literatuur1, de aanwezigheid van de Jak2-V617F mutatie invloed te hebben op meerdere cellijnen in het perifere bloed. Referenties: 1 Koene et al. Ned Tijdschr Geneeskd 2007, 151: 1784-7. C:\Documents and Settings\Hulshof\Mijn documenten\Documenten Janke\ASz\4e wetenschapsdag ASz abstract 2008 Jak2.doc

48 Niet-invasieve thermometrie: verhit debat over warmte patiënt Dr. Ir. B.I. van den Berg – de Bakker, Medische Fysica, Albert Schweitzer Ziekenhuis. Achtergrond: Thermometrie is een veelvuldig gebruikte meetmethode in het ziekenhuis bedoeld om de gezondheidstoestand van de patiënt vast te stellen. Het blijkt dat de nauwkeurigheid van de rectale temperatuurmeting het hoogst is, gevolgd door de orale en tympanische meting. Echter, men moet zich realiseren dat deze drie methoden, in vergelijking met de temperatuur in de longslagader, een spreiding hebben van 0.8°C tot meer dan 1°C. Dus, hoe nauwkeurig het meetinstrument de temperatuur aangeeft (meestal < 0.2°C), de meetmethode is onnauwkeuriger. Concluderend, artsen moeten aangeven welke meetmethode in welke situatie te prefereren is terwijl ze rekening houden met de nauwkeurigheid van elke thermometriemethode, patiëntvriendelijkheid en patiëntveiligheid. Doelstelling: Binnen het ziekenhuis is veel onduidelijkheid over wat de beste methode en meetlocatie in het lichaam is om op niet-invasieve wijze de kerntemperatuur te meten. Deze studie heeft tot doel een onderbouwing te geven wat de beste niet-invasieve meetmethode en meetlocatie is voor het vaststellen van de kerntemperatuur. Methodiek: In deze studie zijn de voor- en nadelen van verschillende thermometrielocaties en -methoden naast elkaar gezet, te weten metingen in de longslagader, slokdarm, blaas, rectum, mond, oor, onder de oksel en op de huid. Daarnaast is een literatuurstudie uitgevoerd van onderzoeken waarbij de meetresultaten op de genoemde niet-invasieve meetlocaties zijn vergeleken met resultaten uit longslagader-metingen. Hierbij is gekozen voor studies waarbij een bepaalde thermometrie-methode vergeleken is ten opzichte van de temperatuur gemeten in de longslagader en bovendien de data is geanalyseerd met behulp van de Bland-Altman methode. Resultaat: Dè kerntemperatuur van het menselijk lichaam bestaat niet en hangt af van vele parameters waaronder de meetlocatie. Een vergelijking tussen een temperatuurmeting met behulp van een Swan-Ganz katheter en temperatuurmetingen in de mond, rectum of oor laten zien dat de spreiding van gemeten temperaturen is: ”(0.3-0.4)“C Rectaal, ”(0.3-0.5)“C Oraal en ”(0.40.6)“C Tympanisch. Verder blijkt dat scholing essentieel is voor het nauwkeurig uitvoeren van een temperatuurmeting. Dit geldt in het bijzonder voor het uitvoeren van IRoorthermometrie. Conclusies: - De keuze voor een niet- invasieve temperatuurmethode hangt af van nauwkeurigheid van de meetmethode, patiëntvriendelijkheid en patiëntveiligheid: volgorde van nauwkeurigheid van meetmethode is: Rectaal, Oraal en Tympanisch. - De grenzen voor koorts moeten gedefinieerd worden per meetlocatie. - Scholing is essentieel in het nauwkeurig uitvoeren van een temperatuurmeting.

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Predictors for progression-free and overall survival in patients with advanced epithelial ovarian cancer CG. Gerestein1, M.J. Eijkemans2, R.H.M. Dykgraaf 1, D. de Jong3, G.S. Kooi4, A. Baalbergen5, M.E.L van der Burg6, C.W. Burger1, A.C. Ansink1. 1 Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Daniel Den Hoed/Erasmus MC University Medical Center, Rotterdam, 2 Department of Public Health, Erasmus MC University Medical Center, Rotterdam, 3 Department of Gynecologic Oncology, Princess Margaret Hospital UHN, Toronto, 4 Department of Obstetrics and Gynecology, Albert Schweitzer Hospital, Dordrecht, 5 Department of Obstetrics and Gynecology, Reinier De Graaf Hospital, Delft, 6 Department of Medical Oncology, Erasmus MC University Medical Center, Rotterdam. Objective. Prognosis in ovarian cancer patients mainly depends on FIGO (International Federation of Gynaecology and Obstetrics) stage and the ability to perform optimal cytoreductive surgery. Since ovarian cancer has a heterogeneous presentation and clinical course, predicting progression-free (PFS) and overall survival (OS) in the individual patient is difficult. The objective of this study is to determine predictors of PFS and OS in patients with advanced stage epithelial ovarian cancer (EOC) after primary cytoreductive surgery and first-line platinum-based chemotherapy. Materials and Methods. All patients who underwent primary cytoreductive surgery for advanced stage EOC followed by first-line platinum-based chemotherapy at our three affiliated centres between January 1998 and October 2004, were identified. Patient data were collected retrospectively from hospital records. Follow-up in patients alive at time of analysis ranged from 1.3-7.8 years with a median follow-up time of 3.3 years. To investigate independent predictors of PFS and OS a Cox proportional hazard model was used. Nomograms were generated with the identified predictive parameters. Results. Hundred-eighteen patients entered the study protocol. Optimal cytoreduction (residual tumor <1 cm) was achieved in 57 (48%) patients. Eighty-eight patients (74%) developed progressive disease disease. During the analysed period sixty-three patients (53%) died. Median PFS and OS was 14 and 32 months, respectively. Multivariate analysis showed that the following parameters were predictive for PFS: platelet count (P=0.007), and residual disease <1 cm (P=0.004). The optimism corrected c-statistic was (0.63). Predictive factors for OS were: hemoglobin level (P=0.012), platelet count (P=0.031) and residual disease <1 cm (P=0.028). The optimism corrected c-statistic was 0.67. Conclusion. The parameters: platelet count, and residual disease <1cm after cytoreductive surgery are significant predictors for PFS in patients with advanced stage EOC after primary cytoreductive surgery and first-line platinum based chemotherapy. Hemoglobin level, platelet count, and residual disease <1 cm significantly predict OS. The constructed nomograms will, after validation, contribute to better counselling and a more individualized treatment plan.

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Chronic fatigue or chronic hypersomnia, a ten year follow up PHP de Jong1, H Boot 2, R van Uffelen3, J van der Meulen1. 1 Department of Medicine, 2 Department of Neurology, 3 Department of Pulmonogy, Albert Schweitzer Hospital, Dordrecht. Introduction: Unrefreshing sleep is one of the clinical symptoms of the chronic fatigue syndrome (CFS). Same symptom is a hallmark of chronic hypersomnia which is characterised by somnolence during normal waking hours that may impair cognitive functioning. It is almost impossible for a patient (pt) or even a semanticist to differentiate between fatigue and somnolence. According to the Webster dictionary, a synonym of fatigue is lassitude i.e. listlessness and that of somnolence is drowsiness i.e. listlessness. With this in mind the question arises whether CFS-pts mentioning unrefreshing sleep should undergo polysomnography (PSG) to differentiate between listlessness as part of CFS or as a sequel of hypersomnia. Objective: To establish the incidence of hypersomnia in CFS-pts. Methods: Prospective study in 34 pts (26 female, mean age at presentation 36 years, standard deviation (SD) 11 years), known with CFS since 1994-1995, who had answered the shortened fatigue questionnaire (SFQ) in 2000. These CFS-pts received in 2005 the SFQ again and the respondents were offered polysomnography (PSG) and treatment if needed. Results are expressed per patient or as mean ± SD. Results: In 2000 7 CFS-pts reported a marked improvement (SFQ-score 8,3 ± 4,1), the other 27 CFS-pts had not improved (SFQ-score 24,2 ± 4,0). In 2005 4 of the 7 improved CFS-pts responded, two patients had a relapse (SFQ-scores 17 and 28) and the other 2 felt well (SFQ-scores 4 and 6). Twenty-one of the 27 non-improved CFS-pts responded, two pts had improved (SFQ-scores 6 and 14) and 19 CFS-pts remained the same (SFQ-score 25,9 ± 2,5). Twenty-one CFS-pts (2 with relapse and 19 non-improved) were offered PSG and 10 of them accepted sleep registration. Eight of them had an abnormal PSG: 6 pts had obstructive sleep apnoea syndrome (OSAS), 1 pt periodic leg movements syndrome (PLMS), 1 pt OSAS+PLMS and 1 pt delayed sleep phase syndrome. These 8 pts were offered appropriate treatment. Two pts refused, 2 pts accepted and felt a marked improvement (SFQ-score 8 and 14) and 4 pts accepted but stopped because they did not notice any improvement (SFQ-score 27,2 ± 1,3). Conclusion: CFS-pts complaining of unrefreshing sleep should have polysomnography to differentiate between CFS and hypersomnia. With polysomnigraphy and consecutive treatment, in at least 2 out of 21 CFS-pts the diagnosis hypersomnia seems more appropriate than chronic fatigue syndrome.

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Prevalence of mesenteric panniculitis in a large hospital-based population N. van Putte-Katier, MD, PhD; T.R. Hendriksz, MD. Albert Schweitzer Ziekenhuis, Afdeling Radiologie, Dordrecht Background: Mesenteric panniculitis is an uncommon idiopathic disorder characterised by chronic inflammation of the intestinal mesentery. The specific etiology is unknown, although various causes have been suggested. Objective: The objective of this study was to assess the prevalence of mesenteric panniculitis as an isolated finding as well as related to other diseases. Material and methods: Between January 2006 and January 2007 consecutive abdominal CT examinations of in total 3822 patients were evaluated for mesenteric panniculitis. CT criteria for the diagnosis of mesenteric panniculitis were a well-defined hyperattenuated fatty mass at the mesenteric root, engulfment of superior mesenteric vessels and displacement of bowel loops without evidence of invasion. Results: CT findings of mesenteric panniculitis were found in 97 patients (2.5%). We found a male predominance (69,1%). In 13 patients (13,4%) mesenteric panniculitis was the only abnormality found despite thorough clinical and imaging investigation and considered to be responsible for the patients’ clinical symptoms. In 47 (48,5%) patients a coexisting malignancy was present. In the remaining 37 (38,1%) patients mesenteric panniculitis coexisted with a benign disorder, which could explain the patients’ clinical symptoms. Conclusion: We found a high prevalence of mesenteric panniculitis in a large hospital-based population undergoing abdominal CT for various reasons. In 13,4% of the patients mesenteric panniculitis was considered to be responsible for the patients’ clinical manifestations.

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Unexpected side effect of aspirin 80 mg H.D. Oei, Dept Allergology, Albert Schweitzer Hospital, Dordrecht. Rationale: Low-dose Aspirin (A) have been widely prescribed to prevent the risk of strokes. There are many reports concerning its side effects, such as: acute urticaria. However, reports of intermittent urticaria (U) and angio-oedema (AO) due to the daily 80 mg intake of A are not common. Methods: We have seen 4 patients (56ym, 64ym, 77yw, 79yw) who used a daily dose of 80 mg A for more than 6 weeks. They complained about multiple episodes of swelling of the tongue, cheeks and U. The frequency varied from once a week until 4 weeks, within a period of 6 to 12 months. Some patients consulted a dermatologist and another physician without any results. Routine screening investigations were negative. Results: The symptoms disappeared in 3-6 weeks after they stop taking A and taking clopidogrel (Plavix® =P) instead. U and AO will reappear within 3-5 weeks, after the patients continue taking the 80mg daily dose of A, instead of the replacement P. Conclusion: We conclude that the intake of low dose A may have caused U and AO in these patients. The reason behind the attack of U and AO that only happened in once a week or once in the 2-4 weeks is still unclear. The intermittent nature of U and AO attacks may also be the reason why many physicians are not aware that the daily 80 mg dose of A may cause of this problem.We suggest replacing the daily 80 mg use of A with P, for those patients with U and AO possibly caused by A.

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Eyelid dermatitis due to contact allergy to cocamidopropyl betaine H.D. Oei, Albert Schweitzer Hospital, Department of Allergology, Dordrecht. Background : Allergic contact dermatitis has been considered the most common of the many dermatologic conditions found with eyelid dermatitis. Important sources of contact sensitivity include cosmetics (fragrance components, preservatives, emulsifiers, artificial nails and nail lacquer) topical medications , metals, rubber, derivatives, resins and plants. artificial nails and nail lacquer. Eyelid dermatitis is a multifaceted clinical problem. Contact allergy to cocamidopropyl betaine is frequently undiagnosed because clinical awareness is low and because of the absence of this screening allergen in the European Standard Series . Methods: We described 5 cases of cosmetic allergy to cocamidopropyl betaine, all were caused by shampoo or shower gels. 23 patients who came to our allergology clinic with eyelids dermatitis were tested with cocamidopropyl betaine in addition to the ESS. Readings were taken on day 4. Cocamidopropyl betaine was supplied by Trolab Hermal. Results: 5 patients showed a positive reaction to cocamidopropyl betaine Conclusions: We concluded that it is important to do patch tests with cocamidopropyl betaine in all patients with eyelid dermatitis. Cocamidopropyl betaine appears to be an important contact allergen in cosmetics, especially in shampoos and bath foam and this is an surfactant used increasingly in cosmetic products. Although rinseoff products generally are not associated with allergic contact dermatitis, a surfactant used increasingly in shampoos, bath gels, and similar products can trigger such a reaction. The major allergen is the impurity dimethylaminopropylamine used in the synthesis of cocamidopropyl betaine.

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The beginning of the end of the lung cancer epidemic in Dutch women Henrike E. Karim-Kos1, Maryska L.G. Janssen-Heijnen2, Carola A. van Iersel3, Esther de Vries1, Jan Willem W. Coebergh1,2 1 Department of Public Health, Erasmus MC University Medical Centre Rotterdam, P.O. Box 2040, 3000 CA Rotterdam; 2 Eindhoven Cancer Registry, Comprehensive Cancer Centre South, Eindhoven; 3 Albert Schweitzer Hospital, Dordrecht, The Netherlands In some European countries, female lung cancer mortality and incidence have started to decrease or flatten out, whereas they are still rising in the Netherlands. We present recent mortality and incidence trends of lung cancer in the Netherlands to show the end of the lung cancer epidemic in Dutch women. Lung cancer mortality and incidence rates by sex were analysed for four age groups (20-44, 45-49, 50-54, 55-59) using joinpoint regression and birth cohort analysis. Data on mortality for the period 1960-2006 were derived from Statistics Netherlands and on incidence from the Netherlands Cancer Registry for the period 1989-2003. Due to decreasing lung cancer mortality and incidence rates among males and dramatically increasing rates among females, male rates were recently surpassed by female rates. However, although in young women (20-49) mortality increased with 4-5% per year, it flattened out (no significant in- or decreases) since 1999. Among older women, mortality rates were still increasing markedly. According to birth cohort analyses, mortality rates tended to decrease in women born after the 1950s. This is the first report that showed the lung cancer epidemic in Dutch women is coming to an end. Although the increase in lung cancer incidence and mortality among Dutch women has been one of the most dramatic in Europe, the recent decrease in young women will undoubtedly be followed by a future decrease in overall female lung cancer rates.

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Een retrospectief, observationeel onderzoek naar het switchen van ADHD-medicatie R.T. Pauw*, H.G. Dieleman**, E.M. de Vogel**, M.L.J.M. Eussen*** * Ziekenhuisapotheker i.o. en ** Ziekenhuisapothekers Albert Schweitzer Ziekenhuis *** Opleider Jeugdpsychiatrie GGZ De Grote Rivieren, Regio Zuid-Holland Zuid-Oost Achtergrond: ADHD (Attention-Defecit Hyperactivity Disorder) is de meest voorkomende psychiatrische aandoening onder kinderen.[1] Momenteel is een kortwerkend methylfenidaatpreparaat (zoals Ritalin®) de eerste keuze in de medicamenteuze ADHD-behandeling. Het is niet bekend hoe vaak patiënten switchen naar een ander preparaat, wat het percentage switchers is en om welke reden(en) wordt geswitched. Doel: Gekeken wordt hoeveel procent van de gestarte ADHD-medicatie wordt gecontinueerd, geswitcht of gestopt en welke (patiënt)factoren hierop van invloed zijn. Methode: Uit de EPD’s van poliklinische ADHD patiënten van De Grote Rivieren (leeftijd 6 t/m 21 jaar) zijn, van de periode januari 2005 t/m december 2006, de volgende gegevens verzameld; leeftijd, geslacht, startmedicatie, wel / geen medicatieswitch /-stop, tijdstip van switch / stop, reden van switch / stop, vervolgmedicatie na switchen, comedicatie, comorbiditeit (psychische en somatische), ernst van de ADHD (gedefinieerd als totale AVL score < en • 20 (max. 30) en voorschrijvend psychiater. Alle patiënten werden minimaal 1 jaar gevolgd. Een multipele logistische regressie analyse uitgevoerd, met als afhankelijke variabele “wel of niet switchen/stoppen”. Resultaten: Van de 169 patiënten continueerde 42% de gestarte medicatie, switchte 50,3% minimaal één maal en 7,7% stopte met de medicatie. 87% van de ADHD-patiënten was gestart met een kortwerkend methylfenidaatpreparaat. De overige 13% startte voornamelijk met een langwerkend methylfenidaatpreparaat en enkelen met een ander ADHD-middel, zoals atomoxetine, risperidon, dipiperon en dexamfetamine. 55% van de switches en stops vond plaats binnen de eerste 6 maanden na medicatiestart. In 80% werd geswitched van een kortwerkend (werkingsduur ca. 4-6 uur) naar een langwerkend methylfenidaatpreparaat (werkingsduur ca. 8-12 uur). Patiënten boven de 12 jaar, met “ernstige”ADHD of met comedicatie switchten / stopten significant vaker (p=0,048 resp. p=0,015 resp. p=0,0015). Daarnaast vertoonde de groep met somatische comorbiditeit ook een trend naar vaker switchen / stoppen (p=0,058). De voornaamste reden voor switchen / stoppen was het optreden van bijwerkingen. Onvoldoende werking, adherence en rebound waren significante voorspellers voor switchen / stoppen (p<0,0001 resp. p=0,002 resp. p=0,004). De voorschrijvend psychiater had geen invloed op het switchen / stoppen. Conclusie: Dit retrospectieve onderzoek laat zien dat 42% van de ADHD-patiënten de gestarte medicatie continueert, 50,3% switcht naar een alternatief ADHD-middel en dat 7,7% stopt met de medicatie. Leeftijd ouder dan 12 jaar, “ernstige” ADHD en gebruik van comedicatie, zijn significante voorspellers voor switchen/ stoppen. Daarnaast lijkt de aanwezigheid van een somatische comorbiditeit van invloed te zijn. Significante redenen voor switchen/stoppen waren: onvoldoende werking, adherence en rebound. Er werd voornamelijk geswitched van een kortwerkend naar een langwerkend methylfenidaatpreparaat. Referenties: 1 Taylor E, Döpfner M, et al. European clinical guidelines for hyperkinetic disorder First upgrade. Eur Child Adolesc Psychiatry 2004; 13 Suppl 1: I 7-30.

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Severe hyponatremia as clinical presentation of neurosarcoidosis with hypopituitarism PHP de Jong1, RJM van Leendert1, M de Waal2, EFH van Bommel1 1 department of internal medicine and 2Department of Neurology Albert Schweitzer hospital, Dordrecht Introduction: Sarcoidosis is an inflammatory multisystem granulomatous disorder of unknown etiology. Although best known for its thoracic involvement, extrapulmonary, ocular, and neurologic manifestations of sarcoidosis may cause significant complications. Central nervous system involvement is rare, occurring in 3-5% of patients with sarcoidosis. We present a patient with severe hyponatremia caused by neurosarcoidosis with hypopituitarism and secondary hypocortisolism. Case report: A 35-year-old man patient presented himself with complaints of progressive fatigue, decreased appetite and weight loss over a period of 6 months. Past medical history was unremarkable. Physical examination revealed no signs of dehydration. investigation showed severe hyponatremia 114 mmol/l (135-145 mmol/l). Urine analysis showed Creatinine 14,2 mmol/l, Natrium 61 mmol/l and osmalaliteit 721 mOsm/kg. Syndrome of inappropriate antiduretic hormone secretion (SIADH) was considered. Because of severe symptomatic hyponatremia, initial treatment with hypertonic saline was considered prudent. To further examine cause of hyponatremia, presence of hypothyroidism or adrenal insufficiency was assessed. Thyroid function was normal (TSH 1,7; range 0,4-4,0 mE/l). Cortisol level (<28 nmol/l, 240-700 nmol/l) and adrenocorticotropic hormone (ACTH) (<5,0 ng/l, range 750ng/l) was not measurable, suggesting secondary adrenal insufficiency as the probable cause of hyponatremia. Levels of several other hypophysic hormones were also low (Luteinizing and Follicle Stimulating Hormones), suggesting hypopituitarism. Chest radiograph was normal but thoracic CT scanning showed mediastinal lymphadenopathy. Cerebral MRI scanning showed broadening of the pituitary stalk and edema of the hypothalamus region. Serum ACE level was normal (17 E/l, range 8-21 E/l). Histologic examination of endo-echographic guided biopsy demonstrated granulomas. A diagnosis of neurosarcoidosis with hypopituarism was made, albeit with normal ACE level, and highdose steroid treatment was started. This led to rapid normalisation of serum sodium level and subsequent normalisation of cerebral MRI findings. However, hormone suppletion with levothyroxine and hydrocortisone remained needed. Conclusion: Neurosarcoidosis is a rare disease with clinical heterogeneity. Careful follow-up and intensive search for systemic sarcoidosis are mandatory in patients with presumed neurosarcoidosis. Treatment consists of high-dose steroids over a longer period of time. Clinical course and prognosis are variable and depend of accompanying symptoms.

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Prospective Evaluation of 18F-FDG PET in Assessing Disease Activity in Retroperitoneal Fibrosis: Preliminary Results I. Jansen1, S.H. Han2, T.R. Hendriksz1, E.F.H. van Bommel3, Dept of radiology1, nuclear medicine2 and internal medicine3, Albert Schweitzer hospital, Dordrecht, The Netherlands Purpose: Accurate determination of disease activity is important when assessing treatment response in retroperitoneal fibrosis (RPF).We evaluated prospectively whether use of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) is a reliable method for evaluating RPF disease activity. Materials and Methods: Twenty-one RPF patients receiving tamoxifen monotherapy underwent repeated FDG-PET (baseline and, if positive, at 3 mo) and CT scanning (baseline, 4 and 8 mo). Maximal RPF mass thickness in 3 different view directions (AP, lateral, transversal [mm]) and craniocaudal length (mm) were measured on each CT scan; 18F-FDG uptake was semi-quantified using a visual 4-points scale. FDGPET (activity and extensiveness) and CT scan follow-up data were correlated with clinical and laboratory follow-up data. Results: Baseline FDG-PET was positive in 81%. Visual PET score correlated with CRP (r = 0.58 [0.18-0.81]; P < 0.01) and CT thickness (r = 0.50 [0.07-0.78]; P = 0.02) at baseline. During follow-up, both visual PET score and PET extensiveness decreased significantly as compared to baseline (P < 0.01). There was also continued decrease in maximal CT thickness (P = 0.03) and ESR and CRP levels (P < 0.001 for both) at repeated follow-up (test for linear trend). Conclusion: FDG-PET scanning may be a reliable imaging modality in assessing RPF disease activity. Upcoming results from this on-going study may further clarify its’ clinical value in predicting treatment response.

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pH in pleura: de bloedgasanalyser als gouden standaard J.A. Riedl1, M. van de Werken2, S.T. IJpma1, P.B. Berendes1,2 1 Albert Schweitzer Ziekenhuis, Geïntegreerd Klinisch Chemisch Laboratorium, Dordrecht, 2Beatrixziekenhuis, Geïntegreerd Klinisch Chemisch Laboratorium, Gorinchem Inleiding: Het is al langer bekend dat het meten van pH in pleuravochten met een pHmeter of indicator strips minder nauwkeurig is dan het meten van de pH in pleuravochten m.b.v. een bloedgasanalyser (1,2). Echter, wegens vrees voor verstopping weigeren veel ziekenhuislaboratoria de pH in pleuravochten met een bloedgasanalyser te meten. Methode: pH metingen op een pH-meter en een bloedgasanalyser werden vergeleken. Daarnaast werd de pH van monsters voor en na filtratie vergeleken op een bloedgasanalyser. Resultaat: Van 26-5-2004 t/m 15-6-2005 (Beatrixziekenhuis, Gorinchem) werd de pH in pleuravochten gemeten met een Hamilton Biotrode. De gemiddelde pH van de 75 monsters bedroeg 8.0 en waarden ver buiten de fysiologisch mogelijke range werden gemeten. Tussen 29-6-2005 t/m 28-12-2006 werd de pH gemeten m.b.v. een NPT-7 bloedgasanalyser. Deze bloedgasanalyser werkt met disposable cartridges. De kliniek levert pleuravocht voor pH metingen af in een - na afname - direct afgedopte bloedgasspuit. De gemiddelde pH van de 79 pleuravochten in de periode met de bloedgasanalyser bedroeg 7.4, een waarde overeenkomend met de literatuur (3). Vanwege de vrees voor verstopping van bloedgasanalysers, die niet met disposable cartridges werken, werd onderzocht of filtratie (Filcons, 70µm) van pleuravochtsamples invloed had op de pH. Twintig pleuravochten werden met en zonder filtratie gemeten op de NPT-7 bloedgasanalyser. Na verwijdering van twee uitbijters, bleek de gemiddelde pH zonder filtratie 7.34 te bedragen en 7.4 met filtratie. Conclusie: Vanwege de te grote verschillen met andere methoden dient de pH in pleuravochten op een bloedgasanalyser gemeten te worden. Filtratie van pleuramonsters, korte tijd na afname, heeft weinig invloed op de gemeten pH en alle pleuravochten worden tegenwoordig gefilterd en direct aan de bloedgasanalyser (ABL-700) in het Albert Schweitzerziekenhuis in Dordrecht aangeboden. Referenties : 1. Cheng et al. Chest 1998, 114: 1368 2. Chandler et al. South Med J 1999, 92: 214 3. Kohn et al. Chest 2000, 118: 1626

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Pneumocystis Jirovecii pneumonia after treatment with R-iCHOP: is the bronchoalveolar lavage still reliable? Stefan Dik, Afdeling interne, Albert Schweitzer Ziekenhuis, Dordrecht A case is reported in whom bilateral infiltrates after treatment with RiCHOP are caused by pneumocystis jirovecii (PJ), which was diagnosed post-mortem in spite of clinical suspicion for pneumocystis jirovecii pneumonia (PCP). The diagnosis of PCP could not be established in spite of two subsequent BAL samples. A lack of sensitivity of the BAL for pneumocystis jirovecii by immunohistochemic stains in non-HIV patients is suspected. This decreased sensitivity of the BAL for PJ in non-HIV patients may be caused by (1) decreased experience of microbiologic examinators for PJ and (2) the lower pathogenic load of pneumocystis jirovecii in the BAL fluid of non-HIV patients compared to HIV patients. A polymerase chain reaction for PJ of the BAL fluid may increase the sensitivity for the diagnosis of PCP. In addition, the interobserver variability of microbiologic examinators is reduced. However, positive PCR results of PJ are found in chronic carriers for PJ too, which may lead to false positive results. Recent studies reveal that a lower limit of a real time PCR for PJ may increase the specificity. In the future a quantative PCR with a fixed lower cutt-off point may increase the sensitivity of the BAL for the diagnosis of PCP without losing specificity.

60 Determinants of perceived severity of hypertension and drugcompliance in mildly hypertensive patients Arie Dijkstra, D Psychol, PhD1 ,Vanessa Okken, D Psychol1 , Menco Niemeijer, MD, PhD1, Ton Cleophas, MD, PhD, Professor2, 1University Hospital, Groningen, Netherlands, 2Claude Bernard University, Lyon, France Background: Severity of illness is not an important determinant of drug-compliance. In this paper we hypothesize that the perceived severity of illness rather than the true severity of illness is a determinant of drug-compliance. If this is true, then it will be worthwhile for physicians to look for factors determining this perceived severity of illness. Objectives: ( I ) To test in a prospective survey whether this hypothesis can be confirmed in mildly hypertensive patients, and ( II ) to identify factors determining their perceived severity of illness. Methods: 450 patients were invited to participate in a prospective survey if their systolic blood pressure had been between 140 and 170 mm Hg and their diastolic blood pressure between 90 and 100 mm Hg despite treatment, for at least three clinic visits. Based on previously published data three factors possibly contributing to the perceived severity of hypertension were identified: (1) objective medical information, (2) expected physical symptoms, and (3) a positive social identification with fellow-patients. These factors were used as independent determinants in a multiple linear regression model with perceived severity of hypertension as outcome variable. Subsequently, this outcome variable together with patient characteristics was used as an independent variable in a multiple logistic regression model with drug-compliance as outcome variable. Results: 176 patients, mean age 62 years, 52% females, completed the study. In the multiple linear regression analysis all of the three identified factors were statistically significant predictors of the perceived severity of hypertension with beta-values from 0.22 to 0.26, and p-values between 0.031 and 0.004. The multiple logistic regression analysis demonstrated that, after adjustment for gender, age, school, and general health status, the perceived severity of hypertension was a significant determinant of drug-compliance at p = 0.040. Discussion: The present study shows what information patients use to conclude on the level of their blood pressure being too high or not. This information can be used to better understand the patients’ ideas about health and possibly to influence these ideas. Patients’ conclusion about the level of their blood pressure predicted their drug-compliance. Our study increased insight into the psychology of the patient and the results may be helpful to physicians in order to further understand and influence patient behaviors, particularly, adherence to antihypertensive medication.

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Replacement of Multiple -Daily with Once -Daily Nitrate Therapy and Quality of Life in 2675 Patients with Stable Angina Pectoris RMG Jansen, MD , MG Niemeyer, MD, PhD, TJ Cleophas, MD, PhD, et al Albert Schweitzer Hospital, Dordrecht, Netherlands

Background: Asymmetric nitrate dosages provided better therapeutic efficacy in patients with stable angina pectoris, than did multiple daily dosages. The effects on quality of life (QOL) have been less established. Also, anginal patients with comorbidities may score better from nitric-oxide- (NO) donor therapy than those without due to an underlying impairment of endothelium-dependent NO-activity. Objectives: 1. To compare QOL and exercise capacity before and after replacement of multiple daily with once-daily nitrate therapy. 2. To investigate the influence of cardiovascular comorbidities on the observed changes. Methods: Out-patients with stable angina pectoris and at least three months pretreatment with 3 times daily 20-40 mg of isosorbide mono-or dinitrate were switched to the equivalent single daily dose of the compound early in the morning. We assessed predefined QOL-indices, painfree walking distances, New York Heart Association (NYHA) anginal class, and the influence of cardiovascular risk factors and comorbidities. Standard multi- and univariate methods were applied. Results: Of 2675 patients included, 2574 (96.2%) completed the study. After three months once-daily nitrate mean QOL-scores improved from 10 to 19% (p<0.0001 for all of the QOL-domains). The percentage of patients in NYHA anginal class I increased by 23.4% (p<0.0001), while exercise capacity increased from a median painfree walking distance of 300 to 500 m (p<0.001). In patients with concomitant hypertension or hypercholesterolemia anginal class improved better (27.4 and 24.6 %, both p<0.001). Young age, advanced NYHA anginal class, hypercholesterolemia and coronary artery disease (CAD) in the family were important independent determinants of the improved QOL. Conclusions: Replacement of multiple-dose with once-daily nitrate treatment was associated with (1) an improved QOL, (2) anginal NYHA class, and (3) exercise capacity. Patients with concomitant hypertension or hypercholesterolemia scored better than did their counterparts without.

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Heupdyplasie en stuitligging: de waarde van versie van stuit- naar hoofdligging A.F. Lambeek, I. Hellendoorn, B.A. Akerboom, E.M.J. Brouwers, M.P den Breejen, J.J. Duvekot, G.S. Kooi, Afdeling Gynecologie, Albert Schweitzer Ziekenhuis, Dordrecht Doel: Het beoordelen van de invloed van versie van stuit- naar hoofdligging op de kans op developmental dysplasia of the hip (DDH, heupdysplasie). Opzet: Prospectieve observationele studie Methoden: Er werden 167 zwangeren met een kind in stuitligging, vanaf een amenorroe van 34 weken, geincludeerd, bij wie een korte vragenlijst werd ingevuld en na informed consent, een versiepoging werd gedaan. Postnataal werd tussen 24 uur en 7 dagen na geboorte onderzoek door een kinderarts verricht en na drie maanden vond echografisch onderzoek van de heupen plaats door de radioloog. Bij afwijkende bevindingen vond verwijzing naar een orthopeed plaats. Resultaten: Bij 75% (n=125) vond een versiepoging plaats, die bij 40% succesvol was. Van de totale groep werden 6 kinderen verwezen en behandeld door de orthopeed. Deze kinderen, 5 meisjes en 1 jongen, lagen bij geboorte in onvolkomen stuitligging. Dit is conform de verwachte incidentie van DDH bij kinderen die in stuitligging geboren worden. Conclusie: Vooralsnog was de belangrijkste motivatie voor een versiepoging reductie van de kans op een sectio caesarea. Uit de voorlopige resultaten lijkt de versie naar hoofdligging wellicht ook de kans op heupdysplasie te verminderen.

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The Monte Carlo method in cardiovascular research Bas M van Ouwerkerk, MD, Ton J Cleophas, MD, Basile Weijters MD, Albert Schweitzer Hospital Dordrecht, Netherlands Background: For more than a century statistical tests based on Gaussian curves have been applied in clinical research. Current cardiovascular trials often make use of convenience samples and small samples that do not follow Gaussian curves. This raises the risk of false negative results. Objective: To elucidate the Monte Carlo method as an alternative method for the assessment of such data. Results: The Monte Carlo method derives confidence intervals from the data without prior assumption about the presence of Gaussian curves in the data. For 2parallel-groups studies with continuous data the basic idea is to produce multiple random samples from your own 2 parallel groups. If in at least 95 % of these random samples the first group scores better than the second, then a statistically significant difference between the two groups will be accepted at p < 0.05. Also for population-based cohort studies with proportional data multiple random samples can be produced from your own observed data. If in at least 95% of these random samples the expected proportion exceeds the observed proportion, then a statistically significant difference between the observed and expected data will be accepted at p < 0.05. Conclusions: Advantages of the Monte Carlo method include: - It does not depend upon Gaussian curves. - It is less time-consuming than many standard methods. A disadvantages is that, although less time-consuming than many standard methods, it is still rather laborious without a computer. We do hope that this paper will strengthen the awareness of the Monte Carlo method as an often more reliable alternative for analysis of cardiovascular research.

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The effect of physical, social and psychological factors on drugcompliance in patients with mild hypertension Okken VS1, Niemeijer MG2, Dijkstra A1, Otten S1, Cleophas TJ3, 1Rijksuniversiteit Groningen, Sectie Sociale en Organisatiepsychologie, 2Martini Hospital Groningen, 3Claude Bernard University Lyon, France Background: In patients with hypertension non-compliance with drug-treatment is between 15 to 54%, and has been recognized a relevant contributor to the burden of cardiovascular morbidity. Up to 92% of the patients experience unpleasant symptoms of their condition, and, particularly, in them experienced symptoms may enhance compliance. Objective: To simultaneously assess the effects of physical, social and psychological factors on non-compliance. Methods: Mildly hypertensive patients, despite drug treatment, from the cardiology and internal medicine departments were requested to answer a self-administered questionnaire addressing their presence of physical symptoms as well as psychosocial factors. The questionnaire was based on previously used testbatteries and consisted of two lists of physical complaints and 4 lists addressing the 4 domains of planned behaviour regarding medical nonadherence by Baron and Byrne. These domains assess psychosocial factors mainly. Each list consisted of 3 items or more and each item was scored on 5-7 points scales. Mean scores were used for assessment. The lists were also separately assessed for internal consistency and reliability using Crohnbach’s alphas. One-way Analysis of variance and multivariate analysis of variance (MANOVA) with compliance as outcome variable and the physical, social and psychological variables as indicator variables were used for data analysis. MANOVA was adjusted for multiple testing. Results: Many patients experienced physical symptoms due to hypertension, e.g., tiredness 31% , hot flushes 28%, headache 24%, reduced daily life energy 23%, palpitations 22% with 95% confidence intervals between 16 to 38%. Scores of physical symptoms and social factors were not different between self-reported compliants (n = 165) and non-compliants (n = 11). However, the score of psychological factors was significantly larger in the compliants than in the non-compliants, 5.05 versus 3.06, p < 0.018. The MANOVA showed a significant overall difference between the compliants and non-compliants in the data at p<0.012 which was mainly due to the score of psychological factors. Discussion: The effect of physical symptoms on non-compliance in mildly hypertensive patients is negligible. So is the effect of social factors. Psychological factors like lacking sense of grief, regret and shame are major determinants of noncompliance. Physicians may play an educational role in improving their patients’ compliance by addressing these determinants. We should add that the conclusions should be made with reservations given the small number of noncompliants in our sample.

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Physicians’ daily life and the scientific method G.Cleophas, DLaw, M.T.Cleophas, DLaw T.Cleophas, MD, PhD, Professor Ethic committee, Albert Schweitzer Hospital, Dordrecht Netherlands, Background: So far, few physicians have followed the scientific method for answering practical questions they simply do not know the answer of. The scientific method is, in a nutshell: reformulate your question into a hypothesis and try to test this hypothesis against control observations. Objective: To give simple examples of how the scientific method can be implied in a physician’s daily life. Results and conclusions: Of 9 unanswered daily questions, 4 qualified for simple statistical assessments, that were very clarifying for the physicians involved. Additional advantages of the scientific method include: (1) since the scientific method has been recognized to produce the best evidence you can get from your observations, physicians applying it serve their population in the best possible way; (2) being actively involved in the scientific method is a strong antidote against the hazards of accepting published studies from others with too little of scepticism or rejecting them with too much of it. Limitations of the scientific method include: (1) type I and II errors; (2) misinterpretations due to different frequency distributions, (3) lack of leisure time on the part of the physicians to write a study protocol, (4) the risk of a damaged patient-doctor relationship.

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Testing equivalence, inferiority and superiority in clinical trials G.C.Cleophas, DLaw, M.T.Cleophas, DLaw, T.J.Cleophas, MD, PhD, Professor Ethics Committee, Albert Schweitzer Hospital, Dordrecht Netherlands, Background: One of the flaws of modern statistics is that it can produce statistically significant results even if treatment effects are very small. Objectives: (1) To give some examples of studies that have been published as unequivocally positive studies, although the treatment effects were substantially smaller than they were expected to be. (2) To introduce superiority-testing as a novel statistical approach avoiding the risk of statistically significant but clinically irrelevant results. Methods and Results: We extracted from recent volumes of the Lancet six original articles of controlled clinical trials that were reported as being positive studies, although they did not meet their expected power. The studies produced only 53 to 83 % of the statistical power expected, while the new treatments produced only 46 to 86 % of the magnitude of response expected. Instead of a p-value of 0.05 as cut-off criterion for demonstrating superiority a stricter criterion seems to be welcome. For that purpose, similar to equivalence-testing and non-inferiority-testing, prior boundaries of superiority have to be defined in the protocol. If the 95% interval of the study turns out to be entirely within these boundaries, then superiority is accepted. Conclusions: Nowadays, too many borderline significant studies are being reported as convincingly positive studies. This is a misleading practice, as it produces overestimated expectations from new treatments. Superiority-testing, as introduced in this paper, is a simple method to avoid this problem.

Validating diagnostic tests: correct and incorrect methods Jolanda Droogendijk, Bas M van Ouwerkerk, Ton J Cleophas Dept Medicine Albert Schweitzer Hospital Dordrecht, Netherlands Background: Clinical trials are impossible without adequate diagnostic tests. Several working parties including the Consolidated Standard Randomized Trials (CONSORT) movement and the Standard for Reporting Diagnostic Accuracy (STARD) group have recently launched quality criteria for diagnostic tests. Particularly, accuracy-, reproducibility- and precision-assessments have been recommended, but methods of assessment have not been clearly defined so far. Objective: To review correct and commonly-used incorrect methods for that purpose. Results: A diagnostic test can be either qualitative, e.g., the presence of an elevated C reactive protein to demonstrate myocardial damage, or quantitative, e.g., the ultrasound flow velocity to estimate the invasive electromagnetic flow velocity. Qualitative diagnostic tests are usually assessed (1) for accuracy using sensitivity / specificity / overall accuracy, and receiver operated (ROC) curves, (2) for reproducibility using Cohen’s kappas, and (3) for precision using confidence intervals of sensitivity / specificity / overall accuracy. Quantitative diagnostics tests are usually assessed (1) for accuracy using a linear regression line ( y = a + b x ) and testing a = 0.00 / b = 1.00, (2) for reproducibility using duplicate standard errors, repeatability coefficients or intraclass correlations, and (3) for precision by calculating confidence intervals. Commonly-used incorrect methods include testing a significant linear correlation between the diagnostic test and the golden standard, calculating the mean difference between repeated measures or assessing their linear correlation. Discussion: Validity assessments of diagnostic tests are rarely communicated in research papers and this may contribute to the low reproducibility of clinical trials. We expected validation would, at least, be a standard procedure in clinical chemistry studies where a close to 100% accuracy / reproducibility requirement is not unusual. However, even in a journal like the 2006 volume of the Journal of the International Federation of Clinical Chemistry and Laboratory Medicine out of 17 original papers communicating novel chemistry methods none communicated validity assessments except for one study. Ironically, this very study reported two incorrect methods. A more general explanation for the underreporting of validation procedures for diagnostic tests in research communications is that the scientific community although devoted to the study of disease management, is little motivated to devote its energies to assessing the validity of the diagnostic procedures required for the very study of disease management. Clinical investigators favor the latter to the former. Also the former gives no clear-cut career path, while the latter more often does so. And there is the injections from the pharmaceutical industry. To counterbalance this is a challenge for governments and university staffs.

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Clinical trials: how to assess confounding and why so Bas van Ouwerkerk, MD, PhD, Ton J Cleophas, MD, PhD, Professor, Aeilko H Zwinderman, DSc, PhD, Professor European Interuniversity College Pharmaceutical Medicine, Lyon France Background: In large randomized controlled trials the risk of random imbalance of the covariates is mostly negligible. However, with smaller studies it may be substantial. In the latter situation assessment and adjustment for confounders is a requirement in order to reduce a biased assessment of the treatment comparison. Objective: In the current paper three methods for confounding assessment and adjustment are reviewed for a nonmathematical readership. Methods: First method, subclassification: the study population is divided into subclasses with the same subclass characteristic, then, treatment efficacy is assessed per subclass, and, finally, a weighted average is calculated. Second method, regression modeling: in a multivariable regression model with treatment efficacy as independent and treatment modality as dependent variable, the covariates at risk of confounding are added as additional dependent variables to the model. An analysis adjusted for confounders is obtained by removing the covariates that are not statistically significant. Third method, propensity scores: each patient is assigned several odds ratios (ORs), which are his/her probability, based on his/her covariate value of receiving a particular treatment modality. A propensity score per patient is calculated by multiplying all of the statistically significant ORs. These propensity scores are, then, applied for confounding adjustment using either subclassification or regression analysis. Conclusions: The advantages of the first method include that empty subclasses in the treatment comparison are readily visualized, and that subclassification does not rely on a linear or any other regression model. A disadvantage is, that it can only be applied for a single confounder at a time. The advantage of the second method is, that multiple variables can be included in the model. However, the number of covariates is limited by the sample size of the trial. An advantage of the third method is, that it is generally more reliable and powerful with multiple covariates than regression modeling. However, irrelevant covariates and very large / small ORs reduce power and reliability of the assessment. The above methods can not be used for the assessment of interaction in the data. It is to be hoped that this paper will affect the assessment of confounding variables in future clinical trials.

69 Clinical trials: odds ratios and multiple regression models, why to assess them and how to do so Mohamad Sobh, Ton J. Cleophas, Amel Hadj-Chaib, Aeilko H. Zwinderman European College of Pharmaceutical Medicine, Lyon France Background: Odds ratios (ORs) unlike Ȥ2 – tests provide a direct insight in the strength of the relationship between treatment modalities and treatment effects. Multiple regression models can reduce the data spread due to certain patient characteristics, and thus, improve the precision of the treatment comparison. Despite these advantages the use of these methods in clinical trials is relatively uncommon. Objective: 1. To emphasize the great potential of odds ratios and multiple regression models as a basis of modern methods. 2. To illustrate their ease of use. 3. To familiarize the non-mathematical readership of the journal with these important methods. Results and conclusions: Advantages of the ORs are multiple: 1. They describe the probability that people with a certain treatment will have an event compared to people without the treatment, and are, therefore, a welcome alternative to the widely used Ȥ2 – tests for analyzing binary data in clinical trials. 2. Statistical software of ORs is widely available. 3. Computations using risk ratios (RRs) are less sensitive than those using ORs. 4. ORs are the basis for modern methods like meta-analyses, propensity scores, logistic regression, Cox regression etc. For analysis logarithms of the ORs have to be used, results are obtained by calculating antilogarithms. A limitation of the ORs is that they present relative benefits but not absolute benefits. ORs, despite a fairly complex mathematical background, are easy to use, even for non-mathematicians. Both linear and logistic regression models can be adequately applied for the purpose of improving precision of parameter estimates like treatment effects. We caution that, although application of these models is very easy with computer programs widely available, the fit of the regression models should always be carefully checked, and the covariate selection should be carefully considered and sparse. We do hope that this paper will stimulate clinical investigators to use odds ratios and multiple regression models more often.

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Cancer of the stomach in breast cancer patients is often metastatic disease P.Westenend, Pathologisch Anatomisch Laboratorium, Dordrecht In patients with breast cancer, the differential diagnosis between metastatic disease or primary cancer of the stomach can be challenging in a gastric biopsy and these diagnoses have completely different clinical implications. Since the incidence of primary gastric cancer in western countries is low compared to the incidence of breast cancer, we hypothesized that cancer of the stomach in a breast cancer patient is often metastatic disease. Patients with breast cancer and cancer of the stomach in the years 1988 until 2005 were retrieved from our files. In our laboratory approximately 300 new patients with breast cancer are diagnosed each year. Patients with gastric cancer preceding the diagnosis of breast cancer were excluded. Age at the time of the breast cancer diagnosis and interval-time until the diagnosis of cancer of the stomach were recorded. Slides of the stomach and breast were reviewed to determine the type of tumour and histological similarity. Cancer of the stomach was classified according to Lauren. All cases were stained with antibodies for cytokeratin 7, cytokeratin 20, E-cadherin, estrogen receptor and progesteron receptor and slides were stained in a Benchmark XT automatic stainer (Ventana). A total of 26 patients were retrieved from our files and in 18 slides of the breast and stomach could be reviewed and sufficient material was available for additional staining. Median age was 67 years (37-79). In 7 patients (37-71 years) the cancer of the stomach was shown to be metastatic disease. In 6 patients the gastric metastasis had a diffuse growth pattern and in 5 patients the breast cancer was of the invasive lobular type. Median time between diagnosis of breast cancer and gastric metastasis was 32 months (1-167 months). In 2 patients a diagnosis of gastric metastasis was made only after resection of the stomach. All gastric metastases were positive for hormone receptors. Cancer of the stomach can be metastatic disease in breast cancer patients, even in those with a remote history of breast cancer. Proper clinical information and staining of the gastric biopsy are most helpful in avoiding misclassification.

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Mictiecysto-urogram; emotionele gevolgen voor het kind? Mieke den Hoed Nurse Practitioner i.o., Amerik de Mol, Kinderarts en Neonatoloog, Claudi Oude Nijhuis, Kinderarts en Leermeester (medeauteur) Inleiding: Het MCUG (mictiecystogram), waarbij via een blaaskatheter contrast in de blaas wordt gebracht en gedurende mictie een serie doorlichtingopnames wordt gemaakt, vindt in het Albert Schweitzer ziekenhuis plaats in dagopname. Gezien de aard van de procedure kan dit potentieel als beangstigend of stressvol worden ervaren door het kind. Doel: Doel van dit onderzoek is om in het de mogelijke emotionele gevolgen van het verrichten van het MCUG bij het kind te evalueren en zo mogelijk die aspecten te achterhalen, welke hiervoor bepalend zijn. Methode: De studie betreft een cohort studie in minimaal 20 kinderen van 1 tot en met 12 jaar, die na doorgemaakte urineweginfecties in aanmerking komen voor aanvullende diagnostiek middels een MCUG. Resultaten: Momenteel vindt de inclusie van patiënten plaats, deze zal tot eind maart lopen. Gezien het verzoek ook lopende studies aan te melden voor de wetenschapsdag van het Albert Schweitzer ziekenhuis wilden wij echter toch dit abstract aanbieden ter presentatie. Naar verwachting zal in mei 2008 een begin worden gemaakt met de analyse van de verzamelde data. Mogelijk kunnen wij de eerste analyses laten zien ten tijde van de wetenschapsdag in juni. Conclusie: Na analyse verwachten wij te kunnen beschrijven of het verrichten van een MCUG leidt tot angst en of spanning bij het kind op korte en/of langere termijn. Indien dit zo is hopen wij dat het mogelijk is om binnen de gehele procedure aspecten aan te wijzen, die in het bijzonder verantwoordelijk zijn hiervoor. Mogelijk kunnen deze factoren in de toekomst gunstig beïnvloed worden. Literatuur: Merritt, K. et al.1993. ‘Children's Memory for a Salient Medical Procedure: Implications for Testimony’. Pediatrics. 94(1):17-23 Robson,W. et al.2006. ‘Catheterization of the Bladder in Infants and Children’. Clinical Pediatrics. 45(9):795-800 Stashinko, E.& J. Goldberger.1998. ‘Test or trauma? The voiding cystourethrogram experience of young children’. Issues Comprehensive Pediatric Nursing. 21(2):85-96.

72 Heart Failure and Mortality in Diabetes, Pooled Analysis of 30,197 Subjects Masoor Kamalesh MD, FACC and Ton J Cleophas MD, Ph D Krannert Institute of Cardiology, Indiana University, Indianapolis, IN 46202 and European College of Pharmaceutical Medicine, Lyon, France Background: Diabetes prevalence is rising worldwide and heart failure (CHF) remains the leading admitting diagnosis in United States. Despite recent successes in improving mortality from CHF with drugs and devices, several reports suggest increased mortality among CHF subjects with diabetes. Our objective was to conduct a meta-analysis to determine aggregate risk of mortality and hospitalization in CHF and diabetes. Methods: Observational and randomized trials reporting on CHF and mortality in diabetes since 2001 were identified through MEDLINE and Cochrane database searches and hand searching of cross references. Major outcome measure of mortality and secondary outcome measure of CHF hospitalization were extracted from published results. Analysis was done for composite mortality and hospitalization risk, heterogeneity, robustness and publication bias. Results: A total of 15 trials (n=30,197 subjects) were eligible. There were a total of 8260 deaths with 2351 among diabetics, from available data. The relative risk (RR) was significantly higher for diabetics by 28% (95% confidence interval CI 1.22-1.34 -p<0.0001). Similarly pooled RR for hospitalization was significantly higher for diabetics by 36% (95% CI 1.26-1.48p<0.0001). Heterogeneity was present (p<0.01) and accounted for by observational studies. There was no significant publication bias and lack of robustness was not obvious. Conclusions: Risk for mortality and recurrent hospitalization for diabetic subjects with CHF remains substantially higher than for non-diabetic subjects. Since, in the foreseeable future, physicians will have to deal with increasing numbers of subjects with diabetes and heart failure, future trials should specifically focus on improving survival in these subjects.

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Is de richtlijn voor preoperatief aftekenen van een stoma bruikbaar bij patiënten met een opgezette buik? MS Dunker, I Somers, RJ Oostenbroek, DJ Gouma, Albert Scheitzer Ziekenhuis Dordrecht, Academisch Medisch Centrum Amsterdam. Het adequaat functioneren van een stoma is onder andere afhankelijk van de lokalisatie. Idealiter wordt de lokalisatie van het stoma preoperatief afgetekend door een stoma-verpleegkundige. Als richtlijn wordt het stoma afgetekend op 1/3 van de denkbeeldige lijn tussen de navel en de spina iliaca anterior superior rekening houdend met de habitus van de patiënt. Er bestaan geen richtlijnen voor de “juiste lokalisatie” van een stoma positie bij patiënten met een ileus beeld die acuut geopereerd moeten worden. Het doel van de studie is om te onderzoeken of er een verschil is in de lokalisatie van de positie van het stoma bij een opgezette buik versus een niet opgezette (vlakke) buik op de denkbeeldige lijn 1/3 van de navel naar de spina iliaca anterior superior. Beide posities van de stippen werden vergeleken met de positie die de stomaverpleegkundige het beste achtte. Bij patiënten waarbij een pneumoperitoneum werd aangelegd voor een electieve laparoscopische procedure, werd een stoma afgetekend. Postoperatief werd bij dezelfde patiënt een stoma afgetekend op de vlakke buik. Tevens werd door de stomaverpleegkundige een stoma afgetekend. Een afstand van 1,5 cm of kleiner tussen de stoma stippen werd als klinisch acceptabel gedefiniëerd. Er werden 50 opeenvolgende patiënten (14 mannen en 36 vrouwen) geȧncludeerd die een laparoscopische cholecystectomie of een diagnostische laparoscopie ondergingen. De gemiddelde leeftijd was 52 jaar met een BMI van 26 kg/m2 (sd 3.9). De gemiddelde intra-abdominale druk was 14 mmHg (sd 1.3). De afstand tussen navel en spina iliaca was 19 cm (sd 2.5) bij een opgezette buik versus 17 cm (sd 2.5) bij een vlakke buik (p < 0.05). In 80% van de patiënten was de afstand tussen de stoma stippen ”1,5 cm bij een opgezette versus niet vlakke buik. Bij een opgezette buik en vlakke buik was in 48.7% respectievelijk 45% de afstand tussen de positie van het stoma en de ideale positie van de stoma verpleegkundige ” 1,5 cm. Uit deze studie mogen wij concluderen dat de mate van uitzetting van de buik de positie van de stoma stip niet significant beïnvloed. Aftekenen van het stoma volgens de richtlijn om het stoma op 1/3 tussen navel en spina af te tekenen, komt slecht overeen met de positie die de stomaverpleegkundige verkiest.

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5. Overige publicaties waaraan medewerkers hebben meegewerkt

75 1. Allergologie: 1. Eyelid dermatitis due to contact allergy to cocamidopropyl betaine Abstract Book AAAAI 63nd Annual Meeting February 23-27, 2007 San Diego. USA. H.D. Oei. Dept of Allergology, Albert Schweitzer Hospital, Dordrecht 2. Eyelid dermatitis due to contact allergy to cocamidopropyl betaine The Journal of Allergy and Clinical Immunology, January 2007; 119: s1: 797. 2. Beleidsadviseur: 1. Van Kemenade Y, Hopstaken L. Het ziekenhuis in 2020. Zorgvisie 2007; 5: 37-40. 2. Van Kemenade Y. Gezondheidszorg internationaal vergeleken. ZN MAGAZINE 2007: 1 - 5. 3. Cardiologie : 1. Dirkali A, van der Ploeg T, Nangrahary M, Cornel JH, Umans VA. The impact of admission plasma glucose on long-term mortality after STEMI and NSTEMI myocardial infarction. Int J Cardiol 2007;121:215-7. 2. Jansen WPJ, de Ruiter GS, Dirkali A, Wever EFD. Deteriorating consciousness and pathognomonic ECG: risk of sudden death? Neth Heart J 2007;15:313 3. Kurvers MJM, Braam RL, Verzijlbergen JF, Heestermans AACM, ten Berg JM. Myocardial salvage in STEMI patients treated with primary coronary angioplasty as demonstrated by myocardial SPECT. Neth Heart J 2007; 15:422-423. 4. Breuls N, Schmidt H, Res JCJ. The feasibility of 4 Fractive fixation in the proximal and distal coronary sinus in patients with paroxysmal atrial fibrillation. Abstract book World Congress on Cardiac Pacing & EP, Dec 3th 2007 5. Kofflard MJM, van der Straaten F. Een 80-jarige dame met kortademigheid door myxoma cordis. Ned Tijdschr Geneeskd 2007;151:649-652. 6. Michels M, Hoedemaekers YM, Kofflard MJ, Frohn-Mulder I, Dooijes D, MajoorKrakauer D, Ten Cate FJ. Familial screening and genetic counseling in hypertrophic cardiomyopathy: the Rotterdam experience. Neth Heart J 2007;15:184-189. 7. Kofflard MJ, Michels M, Krams R, Kliffen M, geleijnse ML, Ten Cate FJ, Serruys PW. Coronary flow reserve in hypertrophic cardiomyopathy: relation with microvascular dysfunction and pathophysiological characteristics. Neth Heart J 2007;15:209-15. 8. Liu T, de Heer HJ, Kofflard M. Significance of increased serum troponin I in patients with atrial fibrillation. Neth Heart J 2007 (suppl I). 9. Michels M, Hoedemaekers Y, Kofflard M, Soliman O, Dooijes D, Majoor-Krakauer D, Ten Cate F. The yield of cardiac screening and risk stratification for sudden cardiac death in asymptomatic hypertrophic cardiomyopathy mutation carries. Eur Heart J 2007; 28(Suppl): 473.

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10. Van Mieghem CAG, Weustink AC, Kofflard M, Schreve-Steensma A, Matheijssen NA, Den Boer A, De Feyter PJ. Radiation exposure, procedure time and contrast load in patients referred for coronary angiography: head-to-head comparison of Dual Source CT with conventional coronary angiography. Circulation 2007;116 (Suppl II): 575. 11. Michels CM, Kofflard MJ, Soliman OO, Dooijes D, Majoor-Krakauer D, Ten Cate FJ. Tissue Doppler imaging in a genotyped hypertrophic cardiomyopathy population with Dutch founder mutations in myosin binding protein C. Abstract book Eur Congress Echocardiography Lissabon 2007. 12. Weustink AC, Van Mieghem CAG, M. Kofflard, Matheijssen NAA, Den Boer A, Mollet NR, De Feijter PJ, Krestin GP. Radiation exposure, procedure time and contrast load in patients referred for coronary angiography: head-to-head comparison of Dual Source CT with conventional coronary angiography. Abstract book American Congress of Radiology Chicago 2007. 4. Chirurgie: 1. Van der Zwaal P, Van den Berg IR, Plaisier PW, Tutein Nolthesius RP. Mesh fixation using staples in Lichtenstein’s inguinal hernioplasty: less complications and less recurrences. Hernia, the Journal of hernias and abdominal wall; 2008: accepted for publication. 5. Farmacie: 1. M. Tijssen-Humme, G. Tijssen. Sterk spul he. De onverwachte gevolgen van een pastille. Cordiaal: 2007 (28) 10-12 2. Bartels PA, Hanff LM, Mathot RA, Steegers EA, Vulto AG, Visser W. Nicardipine in preeclamptic patients: a placental transfer and disposition in breast milk. 2007 in: www.blackwellpublishing.com/bjog 6. Gynecologie: 1. Klaassens AHA, Wijk H van, Hanifi-Moghaddam P, Sijmons B, Ewing P, Ten Kate-Booij M, Kooi S, Kloosterboer H, Blok L, Burger C. Histological and immunohistochemical evaluation of post menopausal endometrium after 3 weeks of treatment with tibolone, estrogen-only, or estrogen plus progestagen. Fertility and Sterility 2006 July 6. 2. Lie Fong S, Eijkemans MJ, De Jong D, Gerestein CG, Kooi GS, Baalbergen A, Van der Burg ME, Burger CW, Ansink AC. Oral poster presentation at the international Gynaecological Cancer Society Meeting October 2006 in Santa Monica USA, Abstract book. 3. Kaijser J, Scheerder MJ, Plaisier PW, Kooi GS. Een ovarieel gemetastaseerd melanoom en zwangerschap: een moeilijke combinatie. Ned Tijdschr Obstet Gyn 2007; 120: 5-8. 4. Bandell ML, Schnater JM, Mouthaan PJ, Kooi GS. Thecoma of the Ovaries With Sclerosing Peritonitis. Is There an Association With Systemic Lupus Erythematosus? J Pelvic Med Surg 2007; 13: 203–5.

77 5. Kaijser J, Roelofs HJM, Breimer LTM, Kooi GS. Excessive Fluid Overload With Severe Hyponatremia, Cardiac Failure, and Cerebral Edema Complicating Hysteroscopic Myomectomy. A Case Report and Review of the Literature. J Pelvic Med Surg 2007; 13: 36773. 6. Van Doorn HC, Opmeer BC, Burger CW, Duk MJ, Kooi GS, Mol BWJ. Inadequate office endometrial sample requires further evaluation in women with postmenopausal bleeding and abnormal ultrasound results. Int. J. Gynaecol Obstet 2007, Sep 21. 7. Kaijser J, Toolenaar AAM, Kooi GS. Een zwangere met acute kaakkramp. Ned Tijdschr Obstet Gyn 2007; 120: 64. 8. Gerestein CG, Eijkemans MJ, Dykgraaf RHM , De Jong D, Kooi GS, Baalbergen A, Van der Burg MEL, Burger CW, Ansink AC. Preoperative predictors for achieving a clinical complete response in patients with the preoperative differential diagnosis of advanced stage epithelial ovarian cancer. Poster presentation at the BGCS Spring meeting, Abstract book, May 2007. 9. Gerestein CG, Eijkemans MJ, Dykgraaf RHM , De Jong D, Kooi GS, Baalbergen A, Van der Burg MEL, Burger CW, Ansink AC. Predictors for overall survival in patients with a preoperative diagnosis of epithelial ovarian cancer. Poster presentation at 15th International meeting of the European Society of gynaecological Oncology , October 2007, Abstract book p 32. 10. De Jong D, Eijkemans MJ, Lie Fong S, Gerestein CG, Kooi GS, Baalbergen A, Van der Berg MEL, Burger CW, Ansink AC. Preoperative Predictors for Residual Tumor after Surgery in Patients with Ovarian Carcinoma. Oncology 2007; 72: 293-301. 11. De Ruiter A, Koman-Ouwerkerk M, Hofman LN, Kooi GS. Het optimaliseren van de zorg rond de oncologische patiënt is in ieders belang. Ned Tijdschr Obstet Gyn, geaccepteerd voor publicatie. 12. Van Doorn HC, Timmermans A, Opmeer BC, Kruitwagen RFMP, Dijkhuizen FPHLJ, Kooi GS, Van de Weijer PHM, Mol BWJ . What is the recurrence rate of postmenopausal bleeding in women who have a thin endometrium during a first episode of postmenopausal bleeding? Acta Obstetricia et Gynecologica Scandinavica 2007; 87: 89 – 93. 13. Bandell ML, Basalan H, Lambers MDA. Major life events after IVF treatment: motherhood and divorce. Posterpresentatie Ned Ver Obstet Gyn – Congres, 2007, Abstract book. 14. Verkleij-Hagoort AC, Verlinde M, Ursem NTC, Lindemans J, et al. Maternal hyperhomocysteinaemie is a risk factor for congenital heart disease. Br J Obstet and Gyn 2006; 12: 1412-8. 15. Van Heesch PNAC, De Weerd S, Kotey S, Steegers EAP. Dutch community midwives views on preconception care. Midwifery 2006; 22: 120-4. 16. Vennemans P, Kiger KT, Lindken R, Groenendijk BC, Stekelenburg-de Vos S, Hagen TL et al. In vivo micro particle image velocimetry measurements of blood-plasma in the embryonic avia heart. J Biomech 2006; 39: 1191-200.

78 17. De Jong D, Eijkemans MJ, Lie Fong S, Gerestein CG, Kooi GS, Baalbergen A, Berg MEL van der, Burger CW, Ansink AC. Preoperative Predictors for Residual Tumor after Surgery in Patients with Ovarian Carcinoma. Oncology 2007; 72: 293-301. 18. Gok M, Coupe VM, Berkhof J, Verheijen RH, Helmerhorst TJ, Hogewoning CJ, Snijders PJ, Meijer CJ. HPV16 and increased risk of recurrence after treatment for CIN. Gynecol Oncol 2007; 104: 273-5. 19. Hogewoning CJ, Ottevanger HP, Adriaanse AH, Trum JW. The practice guideline ‘ vaginal discharge’ from the Dutch college of general practitioners; a response of the perspective of gynecology. Ned Tijdschr Geneeskd.2007; 151: 1330-2. 21. Verhulsdonk, Hassell, Oei. Septic shock as a result of group A Beta hemolytic streptococcal meningitis with empyema in the last trimester of pregnancy, a case report. Int J Gynecol Obstet 2007; 13: 197-8. 22. Verhulsdonk, Papatsonis, Heydanus. Uitkomsten van zwangerschapsafbreking wegens foetale congenitale of chromosomale afwijkingen en bij intra uteriene vruchtdood door middel van mefepriston oraal en/of misoprostol vaginaal+ resultaten van een retrospectieve studie. Ned Tijdschr Geneeskd 2007; 151: 815-20. 23. Verkleij-Hagoort AC, Van Driel LMJW, Lindemans J, Isaacs A, Steegers EAP, Helbing WA, Uitterlinden AG, Steegers-Theunissen RPM. Polymorphisms in the transcobalamin-2 and methionine synthase reductase genes, maternal vitamin B12 intake and the association with congenital heart defects. Annual Scientific Meeting of the Society for Gynecologic Investigation, 14-17 maart 2007, Reno, USA. J Soc Gynecol Investig 2007; 14: (Supplement 2): p. 699. 24. Verkleij-Hagoort AC, Bliek JB, Sayed-Tabatabaei FA, Ursem NTC, Steegers EAP, Steegers-Theunissen RPM. Hyperhomocysteinemia and MTHFR polymorphisms in association with orofacial clefts and congenital heart defects. A meta-analysis. Annual Scientific Meeting of the Society for Gynecologic Investigation, 14-17 maart 2007, Reno, USA. J Soc Gynecol Investig 2007; 14: (Supplement 2): p 700. 25. Verkleij-Hagoort AC, Ursem NT, Hop WC, Geurts-Moespot A, Steegers EA, Sweep FC, Steegers-Theunissen RP. Complex congenital malformations and the impact of the plasminogen activator system and beta-hCG in amniotic fluid. Eur J Obstet Gynecol Reprod Biol 2007; 135: 47-52. 26. Verkleij-Hagoort AC, de Vries JH, Stegers MP, Lindemans J, Ursem NT, SteegersTheunissen RP. Validation of the assessment of folate and vitamin B12 intake in women of reproductive age: the method of triads. Eur J Clin Nutr 2007; 61: 610-5. 27. Verkleij-Hagoort A, Bliek J, Sayed-Tabatabaei F, Ursem N, Steegers E, SteegersTheunissen R. Hyperhomocysteinemia and MTHFR polymorphisms in association with orofacial clefts and congenital heart defects. A meta-analysis. Am J Med Genet Part A 2007; 143A: 952-60. 28. Groenendijk BC, Stekelenburg-de Vos S, Venneman P, Wladimiroff JW, Nieuwstadt FT, Lindken R, westerweel J, Hierck BP, Ursem NT, Poelmann RE. The endothelin-1 pathway

79 and the development of cardiovascular defects in the haemodynamically challenged chicken embryo. J Vasc Res 2008; 45: 54-68. 29. Stekelenburg-de Vos S, Steendijk P, Ursem NT, Wladimiroff JW, Poelmann RE. Systolic and diastolic ventricular function in the normal and extra-embryonic venous clipped chicken embryo of stage 24: a pressure-volume loop assessment. Ultrasound Obstet Gynecol 2007; 30: 325-31. 30. CLR Jansen CLR, Hogewoning CJA, Schram JHN, Droogendijk J, Vierhout ME. Posterior slingplasty with pelvicol graft for vaginal vault prolapse and/or concurrent recto / enterocele - a prospective study. Abstract book, Ned Ver Obstet Gyn Symposium Maastricht 2007. 31. Gerestein CG, Eijkemans MJ, Dijkgraaf RHM, De Jong D, Kooi GS, Baalbergen A, Van der Burg MEL, Burger CW, Ansink AC. Preoperative predictors for achieving a clinical complete response in patients with the preoperative differential diagnosis of advanced stage epithelial ovarian cancer. ESGO Berlijn 2007, Abstract book. 32. Bandell ML, Basalan H, Lambers MDA. Spontaneous pregnancy and live birth after IVF treatment. NVOG symposium Maastricht 2007, Abstract book. 7. Interne geneeskunde: 1. Van Bommel EF, Siemes C, Van der Veer SJ, Han SH, Huiskes AW, Hendriksz TR. Clinical value of gallium-67 SPECT scintigraphy in the diagnosis and therapeutic evaluation of retroperitoneal fibrosis: a prospective study. J Intern Med 2007; 262: 224-34. 2. Van Bommel EF, Siemes C, Hak LE, Van der Veer SJ, Hendriksz TR. Long-term renal and patient outcome in idiopathic retroperitoneal fibrosis treated with prednisone. Am J Kidney Dis 2007; 49: 615-25. 3. Van Os E, Van den Broek WW, Mulder PG, Ter Borg PC, Bruijn JA, Van Buuren HR. Depression in patients with primary biliary cirrhosis and primary sclerosing cholangitis. J Hepatol. 2007; 46: 1099-103. 4. Verhaag S, Van Vliet ACM. Vitamine B12-tekort: een vergeten oorzaak van bloedarmoede. Kraamsupport 2007; 10 : 14-6. 5. Ceelie H, Harteveld CL, Van Vliet ACM, Giordana PC. Compound heterozygosity Į+ - thalassemia (ĮTĮ / ĮĮT) in a Dutch Hindustani patient induced by two rare point mutations, Hb Bleuland (a2108 ThrĺAsn) and aI IVS-I-117 (GĺA). In: BJ Biemond editor, Abstract book 19e Internistendagen. Alphen aan den Rijn: Van Zuiden, 2007 : 68-9. 6. Ter Borg PCJ, Levin MD, Van Vliet ACM. High risk chronic myelomonocytic leukemia in a patient with Crohn’s disease treated with azathioprine. In: BJ Biemond editor, Abstract book 19e Internistendagen. Alphen aan den Rijn: Van Zuiden, 2007 : 93-4.

7. Darbas A, Frenay HME, Van Vliet ACM. Zoonosis as a clue to infectious disease in humans. In: BJ Biemond editor, Abstract book 19e Internistendagen. Alphen aan den Rijn: Van Zuiden, 2007 : 1

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8. Jansen RG, Cleophas TJ, Niemeijer MG, Zwinderman AH, et al. Replacement of multiple with once-daily nitrate therapy: quality of life assessment in 2675 patients with stable angina pectoris. Perfusion 2007; 20: 116-21. 9. Cleophas TJ, Van Ouwerkerk B, Zwinderman AH, Sobb M. Interaction effects in cardiovascular trials. Neth Heart J 2007; 15: 61-8. 10. Cleophas TJ, Zwinderman AH. Primer in Statistics: Meta-analysis. Circulation 2007; 115: 2870-5. 11. Cleophas TJ, Zwinderman AH, Van Ouwerkerk B. Novel procedures to validate surrogate endpoints. Cur Clin Pharmacol 2007; 2: 123-8. 12. Cleophas TJ, Zwinderman AH, Van Ouwerkerk B. Confounding, why so and how so including propensity scores. Cur Clin Pharmacol 2007; 2: 129-33. 13. Jansen RG, Niemeijer MG, Cleophas TJ, Zwinderman AH. Chapter 3, Factors influencing efficacy of nitrate therapy for stabl angina pectoris. In: Quality of life in patients with angina pectoris. Book edited by Gildeprint bv Enschede, 2007; pp 39-48. 14. Jansen RG, Niemeijer MG, Cleophas TJ, Zwinderman AH et al. Chapter 4, Once daily versus multiple daliy dose nitrate treatment. In: Quality of life in patients with angina pectoris. Book edited by Gildeprint bv Enschede, 2007; pp 53-64. 15. Jansen RG, Cleophas TJ, Zwinderman AH, Niemeijer MG. Chapter 5, Chronic nitrate therapy in patients with angina pectoris with comorbidity. In: Quality of life in patients with angina pectoris. Book edited by Gildeprint bv Enschede, 2007; pp 69-77. 16. Jansen RG, Niemeijer MG, Cleophas TJ, Zwinderman AH, et al. Chapter 6, Replacement of multiple daily with once-daily nitrate therapy. In: Quality of life in patients with angina pectoris. Book edited by Gildeprint bv Enschede, 2007; pp 81-95. 17. Jansen RG, Vos SD, Cleophas TJ, Niemeijer MG et al. Chapter 7, Quality of life with heart failure. In: Quality of life in patients with angina pectoris. Book edited by Gildeprint bv Enschede, 2007; pp 99-107. 18. Cleophas TJ, Van Ouwerkerk B, Weijters B, Kassai B. Monte Carlo methods in cardiovascular research. Perfusion 2007; 20: 224-7. 19. Cleophas TJ, Zwinderman AH, Van Ouwerkerk B. Log likelihood ratio tests for the assessment of cardiovascular events. Perfusion 2007; 20: 79-82. 20. Cleophas TJ, Zwinderman AH, Van Ouwerkerk B.Sense and nonsense of exponential models in clinical research. Clin Res Reg Aff 2007; 24: 25-37. 21. Van Brakel J, Cleophas TJ, Van Ouwerkerk B. Mesothelioma. Neth J Med 2007; 65: 43-4. 22. Cleophas G, Cleophas M-T, Cleophas TJ. Physicians’daily life practice and the scientific method. Clin Res Reg Aff 2007; 24: 87-93.

81 23. Cleophas G, Cleophas M-Th, Cleophas TJ. The scientific method. Webgsite 2007: iOpen Access Service. http://cats.tfinforma.com/pts/in?t=rl&0=aa&m=268211. 24. Basunaid S, Van Dongen M, Cleophas TJ. Khat abuse in Yemen, a population-based survey. Clin Res Reg Aff 2008: accepted for publication. 8. Oncologie: 1. Van Iersel CA, De Koning HJ, Draisma G, Mali WP, Scholten ET, Nackaerts K, Prokop M, Habbema JD, Oudkerk M, Van Klaveren RJ. Risk-based selection from the general population in a screening trial: selection criteria, recruitment and power for the Dutch-Belgian randomized lung cancer multi-slice CT screening trial ( NELSON). Int J Cancer 2007; 120: 868-74. 9. Pathologische anatomie: 1. Gilissen F, Oostenbroek R, Storm R, et al. Prevention of futile sentinel node procedures in breast cancer: Ultrasonography of the axilla and fine-needle aspiration cytology are obligatory. Eur J Surg Oncol. 2007. 2. Herfkens HF, Westenend PJ, Oostenbroek RJ. Mammazorg in goede banen. Medisch Contact 2007; 1820 - 3. 3. Maaijwee KJ, Van Meurs JC, Kirchhof B, et al. Histological evidence for revascularisation of an autologous retinal pigment epithelium - choroid graft in the pig. Br J Ophthalmol 2007; 91: 546 - 50. 4. Rub U, Brunt ER, Seidel K, et al. Spinocerebellar ataxia type 7 (SCA7): widespread brain damage in an adult-onset patient with progressive visual impairments in comparison with an adult-onset patient without visual impairments. Neuropathol Appl Neurobiol. 2007. 5. Schoneveld JM, Hesp WL, Teune TM. Parotid metastasis from a gastroesophageal carcinoma:report of a case. Dig Surg 2007; 24: 68 - 9. 6. Schonhuth CP, Bosman HG, Van de Ven, et al. Open biopsy: the ultimate test for pulmonary embolism. Neth J Med. 2007; 65: 267 - 9. 7. Van Hest NA, Smit F, Baars HW, et al. Completeness of notification of tuberculosis in The Netherlands: how reliable is record-linkage and capture-recapture analysis? Epidemiol Infect 2007; 135: 1021 - 9. 8. Westenend PJ, Storm R, Oostenbroek RJ. Gynecomastia. N Engl J Med 2007; 357: 2636-7. 9. Westenend PJ, Reedijk AMJ, Damhuis RA. Laboratorium verschillen voor de Her2 receptorbepaling in mammacarcinoom in de IKR regio. Abstract boek NVVP 2007. 10. Westerman BA, Breuer RH, Poutsma A, et al. Basic helix-loop-helix transcription factorprofiling of lung tumors shows aberrant expression of the proneural gene atonal homolog 1 (ATOH1, HATH1, MATH1) in neuroendocrine tumors. Int J Biol Markers 2007; 22: 114 - 23.

82 10. Pediatrie: 1. Boogaard R, Smit F, Schornagel R et al. Recombinant human deoxyribonuclease for the treatment of acute asthma in children. Thorax 2008; 63: 141 - 6. 11. Plastische chirurgie: 1. De Groot H, Gosens P, Van Leeuwen N. Wear-induced osteolysis and synovial swelling in a patient with a metal-polyethylene wrist prosthesis. Am J Hand Surg 2006; 31A: 1615-8. 12. Radiologie: 1. Den Heijer T, Ruitenberg A, Bakker J, Hertzberger L, Kerkhoff H. Bilateral caudate nucleus infarction associated with variant in circle of Willis. J Neurol Neurosurg Psychiatry 2007; 78; 1175. 2. Herfkens HF, Westenend PJ, Oostenbroek RJ. Mammazorg in goede banen. Met radioloog als poortspecialist krijgen patiënten sneller zekerheid. Medisch Contact 2007; 62: nr 44, 1820 - 3. 3. Westenend PJ, Storm R, Oostenbroek RJ. Letter to the Editor, Gynecomastia, N Engl J Med 2007; 357: 2636-7. 4. Peters N, Borel Rinkes I, Storm R, Plaisier P, Peeters P. Breast MRI in nonpalpable breast lesions: a randomize trial with diagnostic and therapeutic outcome-MONET-Study. Trials 2007; 8: 40. 5. Gilissen F, Oostenbroek RJ, Storm R, Westenend P, Plaisier P. Prevention of futile sentinel node procedures in breast cancer: Ultrasonography of the axilla and fine-needle aspiration cytology are obligatory. Eur J Oncol 2007; Sep 8. 6. Kofflard MJM, Van der Straaten F. Een 80-jarige vrouw met kortademigheid door myxoma cordis. Ned. Tijdschr. Geneeskd. 2007; 151(11). 7. Hilling DE, Van den Berg PM, Makkus ACF, Van der Straaten F, Plaisier PW. Recurrent Pneumothorax In A Patient With Rheumatoid Arthritis On Leflunomide Treatment: Case Report And Overview Of The Literature. The Internet Journal of Rheumatology 2007; 3: 1. 8. Schönhuth CP, Bosman HG, Van der Valk PHM, Krijnen JL, Plaisier PW. Open biopsy: the ultimate test for pulmonary embolism. Neth J Med 2007; 65: 267 - 9. 9. Van Woensel M, Van der Valk PHM, Te Velde L. Effecten van de ziekenhuisranglijsten. ZM Magazine 2007; september: p 2-4. 10. Elgersma OEH, Korteweg M, Van der Valk PHM, Avontuur JAM, Tutein Nolthenius RP, Hoedt MTC. Cryoplasty van het femoropopliteaal traject bij patiënten met claudicatio intermittens. Abstract book Radiologendagen 2007.

83 11. Van Vliet EPM, Hermans JJ, De Wever W, Eijkemans MJC, Steyerberg EW, Faasse C, Van Helmond EPM, De Leeuw AM, Sikkenk AC, De Vries AR, De Vries EH, Kuipers EJ, Siersema PD. Radiologist Experience and CT Scan Quality Determine Metastasis Detection in Patients with Esophageal or Gastric Cardia Cancer. Am J Gastroenterol 2007. 12. Van Bommel EF, Siemes C, Van der Veer SJ, Han SH, Huiskes AW, Hendriksz TR. Clinical value of gallium-67 SPECT scintigraphy in the diagnosis and therapeutic evaluation of retroperitoneal fibrosis: a prospective study. J Intern Med 2007; 262: 224-34. 13. Van Bommel EF, Siemes C, Hak LE, Van der Veer SJ, Hendriksz TR. Long-term renal and patient outcome in idiopathic retroperitoneal fibrosis treated with prednisone. Am J Kidney Dis 2007; 49: 615-25. 14. Elgersma OEH, Korteweg M, Van der Valk PHM, Avontuur JAM, Tutein Nolthenius RP, Hoedt MTC. Cryoplasty van het femoropopliteaal traject bij patiënten met claudicatio intermittens. Abstract book Radiologendagen 2007

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1 Appendix Wetenschap in het Albert Schweitzer Ziekenhuis anno 2007

Optimal blood management for elective orthopaedic surgery: the Transfusie Op Maat (Tailor made) Study C.So-Osman#, R. Nelissen*, A. Koopman-van Gemert^, E. Kluiver**, R. Poll##, R. Onstenk^^, R. Brand$ and A. Brand#. #Sanquin Blood Bank SWR, *Dept Orthopaedics LUMC, ^Dept Anesthesiology, Albert Schweitzer Hospital, Dordrecht,**Dept Anesthesiology and ## Dept Orthopaedics, Slotervaart Hospital Amsterdam, ^^Dept Orthopaedics, Groene Hart Hospital, Gouda, $ Dept Med Statistics LUMC, Leiden, The Netherlands Study design and methods: A prospective, double randomized, open, multicenter study in which patients are stratified according to their preoperative haemoglobin (Hb) level 1) Stratum I: Hb between 6.1 and 8.2 mmol/L (LOW). These patients are first randomized for erythropoietin (rHuEpo) or no rHuEpo. 2) Stratum II: Hb of 8.2 mmol/L and higher (HIGH), are not eligible for rHuEpo and thus not randomized. Patients in both strata will be randomized for three modalities: a cell saver (to wash, filter and reinfuse autologous shed blood) which is used intra- and postoperatively or a postoperative autologous wounddrainage system (to filter and reinfuse autologous shed blood) or a restrictive transfusion trigger only (controls). Inclusion criteria: All orthopaedic patients of 18 years and older being considered for a THR or TKR. Outcome measures: Primary outcome: number of allogeneic RBC transfusions. Secondary outcome: transfusion reactions, rehabilitation time, length of hospital stay (days), peri- and postoperative complications during hospitalization, quality of life, cost analysis. Power/data analysis: In order to be able to detect a 75% reduction of allogeneic RBC transfusions by rHuEpo and a reduction of 30% by autologous (shed blood) transfusions (cell saver or wounddrain) with a power of 0.9 and an alpha of 0.05, inclusion of 2250 surgery patients (in a worst case scenario of high standard deviations) are required for intentionto-treat analysis. With an estimated loss of 10%, 2500 patients will be included. Aim of the study: To investigate whether the use of several transfusion alternatives in patients undergoing elective total hip replacement (THR) or knee replacement (TKR) surgery can lead to allogeneic red blood cell (RBC) saving if a restrictive transfusion policy is used. Time schedule: In 2004 the study started as a feasibility study. With the funding of the Dutch health Organization (ZonMW) and Sanquin Bloodbank, the study could be continued (ISRCTN number 96327523). Four Dutch hospitals are participating with a mean inclusion rate of 80 per month (Figure 2: patient inclusions). After collecting 1000 complete patient records, an interim analysis was performed (December 2007). The Data Safety Monitoring Board advised continuation of the study without adjustments. Up to now (March 31th 2008), 2101 patients have been included. The study will close in 2009.

Na deadline ontvangen posters die door de wetenschapscommissie alsnog geaccepteerd werden.

Assessment of cardiac biomarker release in hypertrophic cardiomyopathy at rest and after exercise G.E. Cramer, T. Baks, M. Kurvers, J. Bakker, T. Hendriksz, M.H.M. Kofflard, Albert Schweitzer Hospital, Dordrecht Background: Hypertrofische cardiomyopathie(HCM) is een erfelijke hartspier ziekte gekenmerkt door een asymmetrische verdikking van de hartspier. Het klinisch beloop is zeer heterogeen varierend van de asymptomatische patient tot het optreden van plotse dood op jonge leeftijd door ventriculaire ritmestoornissen. Het pathofysiologisch substraat voor het optreden van fatale gebeurtenissen bestaat uit myocardiale fibrose, myocard ischemie en myocardiale "disarray". De rol van troponine als teken van ischemie is tot op heden onduidelijk. Objective: (1) Onderzoek naar de incidentie van troponine lekkage uit de hartspier voor en na fietsergometrisch onderzoek bij patienten met HCM (2) De relatie tussen troponine lekkage en (a) diverse patienten karakteristieken (b) de verschillende mutaties verantwoordelijk voor deze aandoening. (c) MRI metingen, zoals de massa van de linker ventrikel en delayed enhancement (DE), een parameter die de mate van fibrose meet. (d) het optreden van cardiale gebeurtenissen. Methods: Prospectieve single-centre studie. De populatie bestaat uit 120 patiënten welke worden vervolgd op de polikliniek cardiologie van het Albert Schweitzer ziekenhuis. Het protocol bestaat uit 1) fietsergometrisch onderzoek 2) Bepaling van de troponine I en T voor fietsergometrisch onderzoek en respectievelijk 6 en 24 uur na het onderzoek. 3) MRI onderzoek voor de bepaling van de LV massa en het bepalen van DE middels toedienen van Gadolinium. Follow-up van de patiënten vindt plaats na 1 en 5 jaar voor controle van het optreden van cardiale gebeurtenissen. Conclusion: Het verband tussen genotype en fenotypische karakteristieken is op velerlei vlak onderzocht echter troponine ontbreekt in deze discussie, terwijl troponine als marker van ischemie mogelijk een link vormt tussen genotype, fenotypische

2 Anaphylactoid Reaction to Diclofenac R.Veugelers, L te Velde, Albert Schweitzer Hospital, Dordrecht Diclofenac is a commonly prescribed drug, with many known adverse effects, including severe anaphylactic reactions. Although prevalence of severe anaphylaxis by NSAIDs is not known is can be estimated at roughly 1-10 per million people, with a disproportionally large risk for diclofenac due to it’s wide use as a primary analgesic in the emergency department in Europe. Despite it’s wide use in Emergency Medicine, consideration of the possibility of diclofenac as a cause of anaphylaxis is often overlooked. We present a 72 year old female with short term use of diclofenac 50 mg. She presented at the emergency department after developing severe symptoms at home. She was hypotensive, tachycardiac and tachypnoeic and she had a markedly red face. Initially she was considered to be septic, after a series of diagnostic tests no focus was found and a arrhythmia was considered. A challenge with diclofenac on the intensive care unit revealed the anaphylactic reaction to diclofenac. A systematic literature review was done using Pubmed MeSH terms “anaphylaxis” and “Diclofenac”. Although prevalence of severe anaphylaxis by NSAID’s is not known is can be estimated in the range of roughly 1-10 per million people, with a disproportionally large risk for Diclofenac. Drug anaphylaxis is characterized by a high frequency of cardiovascular collapse with rapid onset (within minutes), especially in older patients. Substance release of mast cells and basophil degranulation mediates an increase vascular permeability, tachycardia, bronchospasm, pruritus, rhinorrhea, vasodilation, hypotension, flushing, and headache. It remains unclear whether anaphylactic or anaphylactoid reactions predominates in Diclofenac anaphylaxis. NSAID’s have wide use in the Emergency Department for non-narcotic analgesia, thus we do not advocate a ban on the use of these agents. The wide variety of preparations available over the counter and the potential risks involved in wide-spread NSAID use could, however, be debated. It is important to point out the possibility of an unsuspected anaphylactic reaction to a NSAID when confronted with cardiovascular collapse in the Emergency Department setting if clues for other causes are lacking. A formal provocation test in a controlled setting during the initial hospital admission should be considered. In our opinion not performing such a test but assuming the diagnosis per exclusion will lead to the potential risk of a missed diagnosis and therewith reoccurrence due to the wide use of these drugs and multiple preparations available.

Mortality analysis, Albert Schweitzer data from the nationwide Move Your Dot Project So R, Ponssen H, Van Genderen P, Heijkoop R, Taks M, Department of Intensive Care, Albert Schweitzer Hospital Introduction: The incidence of adverse events experienced by hospital patients in the Netherlands is 5.7 percent. Of these, more than 40 percent are potentially preventable. Our aim was to analyze in our hospital which system-wide interventions should be started in order to avoid (serious) adverse events and possible deaths. Therefore, we participated in a nationwide project Move Your Dot [may 2006-june 2007] in which 9 Dutch hospitals evaluated and analyzed their hospital mortality rates in order to initiate system-wide improvement projects based on the implications of the mortality data. This abstract reports the results and the implications of our hospital mortality analysis. Methods: The Albert Schweitzer Hospital is a large 1000-beds teaching hospital located in Dordrecht, the Netherlands. First, a dedicated team of medical specialists and nurses was trained and then reviewed 50 charts of either internal medicine or general surgery patient deaths using the IHI Hospital Mortality Review Tool.2; thus we formed a 2x2 matrix. Second, special attention was paid to charts of patients who on admission were admitted to a general ward for active treatment but who died. Finally, by using the .IHI Global Trigger Tool.3, we performed an incidence analysis both quantitatively and qualitatively on the latter charts. Results: ICU admission general ward admission. comfort care only Yes 0 % (0/50), 12 % (6/50), only No 20 % (10/50, 68 % (34/50). Type of incident total: failure to communicate 44; remaining complications 28 decubitus 12; failure to rescue 12; delay in diagnosis 12; adverse events with the use of medication 11; infection 5; failure to plan 4; sepsis 3; unresponsive to a question 1. Conclusion: 1. A total of 132 incidents was found in 34 charts i.e. almost 4 incidents per chart. 2. Miscommunication was the major contributor of all types of incidents. 3. Implementation of a rapid response system could be a system-wide intervention to prevent severe adverse events. References: (1) Bruijne MC de, Zegers M, Hoonhout LHF, Wagner C. Onbedoelde schade in Nederlandse ziekenhuizen: dossieronderzoek van ziekenhuisopnames in 2004. Utrecht/ Amsterdam: NIVEL/EMGO, Instituut VUmc, 2007. (2) Move Your Dot.: Measuring, Evaluating, and Reducing Hospital Mortality Rates (Part 1). IHI Innovation Series white paper. Boston: Institute for Healthcare Improvement; 2003 (3) Griffin FA, Resar RK. IHI Global Trigger Tool for Measuring Adverse Events. IHI Innovation Series white paper. Cambridge, MA: Institute for Healthcare Improvement; 2007

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