2015 Amphia Ziekenhuis

Transcription

1 Amphia Wetenschapsboek 2014

2 Amphia Wetenschapsboek 2014

3 2015 Amphia Ziekenhuis Alle rechten voorbehouden. Niets uit deze uitgave mag worden verveelvoudigd, opgeslagen in een geautomatiseerd gegevensbestand, of openbaar gemaakt, in enige vorm of op enige wijze, hetzij elektronisch, mechanisch, door fotokopieën, opnamen, of enige andere manier, zonder voorafgaande toestemming van de uitgever. Voor zover het maken van kopieën uit deze uitgave is toegestaan op grond van artikel 16B Auteurswet 1912 j het Besluit van 20 juni 1974, St.b. 351, zoals gewijzigd bij Besluit van 23 augustus 1985, St.b. 471 en artikel 17 Auteurswet 1912, dient men de daarvoor wettelijk verschuldigde vergoedingen te voldoen aan de Stichting Reprorecht. Voor het overnemen van gedeelte(n) uit deze uitgave in bloem lezingen, readers en andere compilatie- of andere werken (artikel 16 Auteurswet 1912), in welke vorm dan ook, dient men zich tot de samenstellers/vormgever te wenden. De inzichten in de geneeskunde en wetenschap zijn voortdurend aan verandering onderhevig als gevolg van onderzoek en ervaring. De auteurs en uitgever zijn uiterst zorgvuldig te werk gegaan, om ervoor te zorgen dat de in dit boek verstrekte informatie, in overeenstemming is met de huidige kennis van zaken. Dit ontslaat de gebruiker van het boek echter niet van de verplichting om aan de hand van bestaande richtlijnen, protocollen en wetenschappelijke informatie te controleren of de daar verstrekte informatie afwijkt van de gegevens in dit boek en daarmee vast te stellen of de inhoud nog in overeenstemming is met de huidige stand van zaken ten aanzien van kennis en handelen. Ondanks alle aan de samenstelling van deze uitgave bestede zorg, zullen noch de samenstellers, noch de vormgever aansprakelijkheid aanvaarden voor eventuele schade die zou kunnen voortvloeien uit enige fout die in deze uitgave zou kunnen voorkomen. 2

4 Voorwoord Sinds vele jaren publiceert het Amphia Ziekenhuis een overzicht van alle wetenschappelijke publicaties van het afgelopen jaar. Zo ook dit jaar. Eerder was er alleen aandacht voor publicaties in het medisch domein, maar de recente ontwikkelingen maken duidelijk dat de wetenschappelijke ontwikkeling van de ziekenhuiszorg meer omvat dan de geneeskunde. Om die reden is in het nu voorliggende wetenschapsboek een brede variatie van onderzoeksresultaten te vinden. Verheugend is dat velen inmiddels de weg naar een promotietraject hebben gevonden. Amphia stimuleert dit nadrukkelijk. Dit past bij het zijn van een Top Klinisch Opleidingsziekenhuis en houdt de hele Amphiagemeenschap bij de les en gericht op het verrijken van kennis. Los van de wetenschappelijke productie in de vorm van publicaties, zoals in deze bundel weergegeven, werd in 2014 ook de eerste klinische Amphia-leerstoel gevestigd. Collega Joachim Aerts, longarts, werd benoemd tot hoogleraar Longoncologie (in het bijzonder mesothelioom) aan de Erasmus Universiteit te Rotterdam. Professor Aerts is een nationaal en internationaal erkend deskundige op dit bijzondere deel van de longgeneeskunde. Op 24 april 2015 heeft hij zijn oratie gehouden. Namens het Directiecomité wens ik u veel leesplezier bij dit zevende wetenschapsboek. Dr. J.J. (Hans) Meij MBA, lid Directiecomité 3

5 Inhoud Publicaties Medische Staf 6 Anesthesiologie 6 Cardiologie 14 Cardiothoracale Chirurgie 43 Chirurgie 46 Dermatologie 64 Gynaecologie / Verloskunde 65 Interne Geneeskunde en Maag-, Darm-, Levergeneeskunde 81 Keel-, Neus- en Oorheelkunde 102 Kindergeneeskunde 104 Klinisch Chemisch Hematologisch Laboratorium 108 Klinische Farmacie 112 Klinische Geriatrie 115 Laboratorium voor Microbiologie en Infectiepreventie 116 Longgeneeskunde 134 Mondziekten, Kaak- en Aangezichtschirurgie 144 Neurologie / Neurochirurgie 148 Oogheelkunde 150 Orthopedie 152 Pathologisch Anatomisch Laboratorium 168 Radiologie 169 Urologie 174 4

6 Publicaties arts-assistenten 176 Anesthesiologie 176 Chirurgie 176 Interne Geneeskunde en Maag-, Darm-, Levergeneeskunde 186 Klinisch Chemisch Hematologisch Laboratorium 187 Laboratorium voor Microbiologie en Infectiepreventie 188 Longgeneeskunde 194 Orthopedie 196 Publicaties medewerkers zorg- en kenniskernen en Directiecomité 198 Klinisch Chemisch Hematologisch Laboratorium 198 Laboratorium voor Microbiologie en Infectiepreventie 199 Amphia Academy Infectious Disease Foundation 208 Orthopedie 212 Directiecomité 213 Register Medische Staf 214 Register arts-assistenten 247 Register medewerkers zorg- en kenniskernen en Directiecomité 251 5

7 Publicaties Medische Staf Anesthesiologie Kerngegevens 29 anesthesiologen: A. (Anna) Besselink-Lobanova, S.F. (Sjoerd) de Boer, H.P. (Henk) van Driel, M.J.P.G. (Maarten) van Eerd, F.E.A. (Ferd) Geisler, G. (Gerhard) van Gelder, dr. B.M. (Bas) Gerritse, C. (Carla) van Gompel, P. (Pim) van der Heiden, dr. V.L.H. (Vincent) Hoffmann, L.H. (Lode) Jacobs, G.M.J. (Greg) Jansen, A. (Aad) van Keeken, J.D.L. (Johan) Konings, F. (Frank) de Loos, P.P.M. (Paul) Maas, dr. B.J.M. (Nardo) van der Meer, R.J. (Robert) Meulemans, F.X. (Frank) O Connor, P.M.J. (Peter) Rosseel, T.A. (Tom) Rijpstra, D.B. (David) Schockman, T.V. (Thierry) Scohy, G.C.H. (Gilbert) Tjiang, M.W.A. (Miriam) van der Velden, W.A. (Anton) Visser, M.A.J. (Michael) Voets, E. (Erik) Winters, S.I.M. (Simone) van Zijll Langhout-Kokke 1 SPIDMA: I. (Iris) Witsch Chef de clinique: S. (Sylvia) Kilwinger, S. (Stefan) Boeckx, H. (Hester) Boesjes Internist-intensivist: R.A.L. (Ruud) de Waal, F.J. (Frits) Schuitemaker Longarts-intensivist: K.M. (Merijn) Kant 1 CDC pijnanesthesioloog: P.A.V. (Peter) Frietman 8 arts-assistenten niet in opleiding op de ICU (5,5 fte) 6

8 Samenvattingen gepubliceerde artikelen Tolsma M, Bentala M, Rosseel P, Gerritse BM, Dijkstra H, Mulder P, van der Meer N. The value of routine chest radiographs after minimally invasive cardiac surgery: an observational cohort study. J Cardiothorac Surg Nov 11;9(1):174. [Epub ahead of print]. BACKGROUND: Chest radiographs (CXRs) are obtained frequently in postoperative cardiac surgery patients. The diagnostic and therapeutic efficacy of routine CXRs is known to be low and the discussion regarding the safety of abandoning these CXRs after cardiac surgery is still ongoing. We investigated the value of routine CXRs directly after minimally invasive cardiac surgery. METHODS: We prospectively included all patients who underwent minimally invasive cardiac surgery by port access, ministernotomy or bilateral video-assisted thoracoscopy (VATS) in the year A direct postoperative CXR was performed on all patients at ICU arrival. All CXR findings were noted, including whether they led to an intervention or not. RESULTS: The results were compared to the postoperative CXR results in patients who underwent conventional cardiac surgery by full median sternotomy over the same period.main resultsa total of 249 consecutive patients were included. Most of these patients underwent valve surgery, rhythm surgery or a combination of both. The diagnostic efficacy for minor findings was highest in the port access and bilateral VATS groups (56% and 63% versus 28% and 45%) (p < 0.005). The diagnostic efficacy for major findings was also higher in these groups (8.9% and 11% versus 4.3% and 3.8%) (p = 0.010). The need for an intervention was most common after minimally invasive surgery by port access, although this difference was not statistically significant (p = 0.056). CONCLUSION: The diagnostic efficacy of routine CXRs performed after minimally invasive cardiac surgery by port access or bilateral VATS is higher than the efficacy of CXRs performed after conventional cardiac surgery. A routine CXR after these procedures should still be considered. PMID: PMCID: PMC Derikx HJ, Gerritse BM, Gans R, van der Meer NJ. A randomized trial comparing two intraosseous access devices in intrahospital healthcare providers with a focus on retention of knowledge, skill, and self-efficacy. Eur J Trauma Emerg Surg. 2014;40: INTRODUCTION: Intraosseous access is recommended in vitally compromised patients if an intravenous access cannot be easily obtained. Intraosseous infusion can be initiated by various healthcare providers. Currently, there are two mechanical intraosseous devices approved by the U.S. Food and Drug Administration (FDA) for use in adults and children. A comparison is made in this study of the theoretical and practical performance by anesthesiologists and registered nurses of anesthesia (RNAs) in the use of the battery-powered device (device A) versus the Anesthesiologie 7

9 spring-loaded needle device (device B). This study entailed a 12-month follow-up of knowledge, skill retention, and self-efficacy measured by standardized testing. METHODS: A prospective randomized trial was performed, initially comparing 15 anesthesiologists and 15 RNAs, both on using the two types of intraosseous devices. A structured lecture and skill station was given with the educational aids provided by the respective manufacturers. Individual knowledge and practical skills were tested at 0, 3, and 12 months after the initial course. RESULTS: There was no statistical significant difference in the retention of theoretical knowledge between RNAs and anesthesiologists on all testing occasions. However, the self-efficacy of the anesthesiologists is significantly higher (p < 0.01) than the self-efficacy of the RNAs for both devices, on any testing occasion. Insufficient skills were local disinfection (both groups, both devices) and attachment of the needle to the intravenous line (RNAs with both devices). In 33% of all device B handlings, unsafe practice occurred. CONCLUSION: The use of device A is safer in handling in comparison to device B at 12 months follow-up. The hypothesis that doctors are more qualified in obtaining intraosseous access has been disproven, as anesthesiologists were as successful as RNAs. However, the low self-efficacy of RNAs in the use of intraosseous devices could diminish the chance of them actually using one. Hogervorst E, Rosseel P, van der Bom J, Bentala M, Brand A, van der Meer N, van de Watering L. Tolerance of intraoperative hemoglobin decrease during cardiac surgery. Transfusion Oct;54(10 Pt 2): Epub 2014 Apr 14. BACKGROUND: It has been suggested that a decrease of at least 50% from the preoperative hemoglobin (Hb) level during cardiac surgery is associated with adverse outcomes even if the absolute Hb level remains above the commonly used transfusion threshold of 7.0 g/dl. In this study the relation between intraoperative Hb decline of at least 50% and a composite endpoint was analyzed. STUDY DESIGN AND METHODS: This single-center study comprised 11,508 patients who underwent cardiac surgery and had normal preoperative Hb levels ( g/dl in women, g/dl in men) between January 2001 and December Logistic regression modeling was used. The composite endpoint comprised in-hospital mortality, stroke, myocardial infarction, and renal failure. 8 Publicaties Medische Staf

10 RESULTS: Patients whose Hb did not decrease at least 50% and remained above 7 g/dl were used as reference (n = 9672). A total of 363 (3.2%) patients had an intraoperative Hb of less than 7 g/dl during surgery but a Hb decrease of less than 50%; 876 patients (7.4%) showed both a nadir Hb less than 7 g/dl and a Hb decrease of at least 50%, while 597 (5.2%) had a Hb decrease of at least 50% and a nadir Hb of at least 7 g/dl. In this last group the incidence of the composite endpoint was higher than in patients in the reference group (adjusted odds ratio, 1.27; 95% confidence interval, ).CONCLUSIONS: Our findings show that a decrease of at least 50% from baseline Hb during cardiac surgery is associated with adverse outcomes, even if the absolute Hb level remains higher than the commonly used transfusion threshold of 7.0 g/dl. PMID: Joosen AM, Boonen K, Hulsman N, Schuitemaker FJ, Thelen MH. Hypernatraemia in disguise. Clin Chem Lab Med Nov;52(11):e No abstract available. PMID: Bunge JJ, van Osch D, Dieleman JM, Jacob KA, Kluin J, van Dijk D, Nathoe HM; Dexamethasone for Cardiac Surgery (DECS) Study Group* [Van der Meer NJ, Rosseel PM et al...]. Dexamethasone for the prevention of postpericardiotomy syndrome: A DExamethasone for Cardiac Surgery substudy. Am Heart J Jul;168(1): e1. Epub 2014 Apr 5. BACKGROUND: The postpericardiotomy syndrome (PPS) is a common complication following cardiac surgery. The pathophysiology remains unclear, although evidence exists that surgical trauma and the use of cardiopulmonary bypass provoke an immune response leading to PPS. We hypothesized that an intraoperative dose of dexamethasone decreases the risk of PPS, by reducing this inflammatory response. METHODS: We performed a subanalysis of the DECS study, which is a multicenter, double-blind, placebo-controlled, randomized trial of 4,494 patients undergoing cardiac surgery with use of cardiopulmonary bypass. The aim of the DECS study was to investigate whether a single intraoperative dose of 1 mg/kg dexamethasone reduced the incidence of a composite of death, myocardial infarction, stroke, renal failure, or respiratory failure, within 30 days of randomization. In this substudy, we retrospectively analyzed the occurrence of PPS in 822 patients who were included in the DECS trial and underwent valvular surgery. Postpericardiotomy syndrome was diagnosed if 2 of 5 listed symptoms were present: unexplained fever, pleuritic chest pain, pericardial or pleural rub, new or worsening pericardial or pleural effusion. All medical charts, x-rays, and echocardiograms were reviewed. Secondary end point was the occurrence of complicated PPS, defined as PPS with need for evacuation of pleural effusion, pericardiocentesis, and tamponade requiring intervention or hospital readmission for PPS. This is a blinded, singlecenter, post hoc analysis. Anesthesiologie 9

11 RESULTS: Postpericardiotomy syndrome occurred in 119 patients (14.5%). The incidence of PPS after dexamethasone compared with placebo was 13.5% vs 15.5% (relative risk 0.88, 95% CI ). For complicated PPS, the incidence was 3.8% versus 3.2% (relative risk 1.17, 95% CI , P =.66), respectively. CONCLUSION: In patients undergoing valvular cardiac surgery, high-dose dexamethasone treatment had no protective effect on the occurrence of PPS or complicated PPS. Collaborators: Bredée JJ, Buhre WF, Dieleman JM, van Dijk D, van Herwerden LA, Kalkman CJ, van Klarenbosch J, Moons KG, Nathoe HM, Numan SC, Ottens TH, Roes KC, Sauer AM, Slooter AJ, Nierich AP, Ennema JJ, Rosseel PM, van der Meer NJ, van der Maaten JM, Cernak V, Hofland J, van Thiel RJ, Diephuis JC, Schepp RM, Haenen J, de Lange F, Boer C, de Jong JR, Tijssen JG. PMID: Van Eerd M, Patijn J, Sieben JM, Sommer M, Van Zundert J, van Kleef M, Lataster A. Ultrasonography of the cervical spine: an in vitro anatomical validation model. Anesthesiology Jan;120(1): BACKGROUND: Anatomical validation studies of cervical ultrasound images are sparse. Validation is crucial to ensure accurate interpretation of cervical ultrasound images and to develop standardized reliable ultrasound procedures to identify cervical anatomical structures. The aim of this study was to acquire validated ultrasound images of cervical bony structures and to develop a reliable method to detect and count the cervical segmental levels. METHODS: An anatomical model of a cervical spine, embedded in gelatin, was inserted in a specially developed measurement device. This provided ultrasound images of cervical bony structures. Anatomical validation was achieved by laser light beams projecting the center of the ultrasound image on the cervical bony structures through a transparent gelatin. RESULTS: Anatomically validated ultrasound images of different cervical bony structures were taken from dorsal, ventral, and lateral perspectives. Potentially relevant anatomical landmarks were defined and validated. Test/retest analysis for positioning showed a reproducibility with an intraclass correlation coefficient for single measures of Besides providing validated ultrasound images of bony structures, this model helped to develop a method to detect and count the cervical segmental levels in vivo at long-axis position, in a dorsolateral (paramedian) view at the level of the laminae, starting from the base of the skull and sliding the ultrasound probe caudally. 10 Publicaties Medische Staf

12 CONCLUSIONS: Ultrasound bony images of the cervical vertebrae were validated with an in vitro model. Anatomical bony landmarks are the mastoid process, the transverse process of C1, the tubercles of C6 and C7, and the cervical laminae. Especially, the cervical dorsal laminae serve best as anatomical bony landmarks to reliably detect the cervical segmental levels in vivo. Comment in: On the fabric of the human body and modern ultrasound imaging. [Anesthesiology. 2014] PMID: Spoelstra-de Man AM, van der Heiden P, Spijkstra JJ, Verheijen AT, Kooter AJ. Treatment of hyperglycaemia in diabetic ketoacidosis: natura non facit saltus. Neth J Med Jan;72(1):54-8. In the treatment of severe diabetic ketoacidosis the gradual correction of glucose, electrolyte and fluid derangements is of utmost importance. In this paper the authors provide practical recommendations for these corrections based on novel pathophysiological insights. PMID: Hulsman N, Hiddema PA, Veen EJ, van der Meer NJ. Traumatic cardiac injury by gun nails. Int J Crit Illn Inj Sci Apr;4(2): No abstract available. Ottens TH, Dieleman JM, Sauër AM, Peelen LM, Nierich AP, de Groot WJ, Nathoe HM, Buijsrogge MP, Kalkman CJ, van Dijk D; Dexamethasone for Cardiac Surgery (DECS) Study Group [Van der Meer NJ et al...]. Effects of dexamethasone on cognitive decline after cardiac surgery: a randomized clinical trial. Anesthesiology Sep;121(3): BACKGROUND: Cardiac surgery can be complicated by postoperative cognitive decline (POCD), which is characterized by impaired memory function and intellectual ability. The systemic inflammatory response that is induced by major surgery and cardiopulmonary bypass may play an important role in the etiology of POCD. Prophylactic corticosteroids to attenuate the inflammatory response may therefore reduce the risk of POCD. The authors investigated the effect of intraoperative high-dose dexamethasone on the incidence of POCD at 1 month and 12 months after cardiac surgery. Anesthesiologie 11

13 METHODS: This multicenter, randomized, double-blind, placebo-controlled trial is a preplanned substudy of the DExamethasone for Cardiac Surgery trial. A total of 291 adult patients undergoing cardiac surgery with cardiopulmonary bypass were recruited in three hospitals and randomized to receive dexamethasone 1 mg/kg (n = 145) or placebo (n = 146). The main outcome measures were incidence of POCD at 1- and 12-month follow-up, defined as a decline in neuropsychological test performance beyond natural variability, as measured in a control group. RESULTS: At 1-month follow-up, 19 of 140 patients in the dexamethasone group (13.6%) and 10 of 138 patients in the placebo group (7.2%) fulfilled the diagnostic criteria for POCD (relative risk, 1.87; 95% CI, 0.90 to 3.88; P = 0.09). At 12-month follow-up, 8 of 115 patients in the dexamethasone group (7.0%) and 4 of 114 patients (3.5%) in the placebo group had POCD (relative risk, 1.98; 95% CI, 0.61 to 6.40; P = 0.24). CONCLUSION: Intraoperative high-dose dexamethasone did not reduce the risk of POCD after cardiac surgery. PMID: Tolsma M, Rijpstra TA, Schultz MJ, Mulder PG, van der Meer NJ. Significant changes in the practice of chest radiography in Dutch intensive care units: a web-based survey. Ann Intensive Care Apr 4;4(1):10. BACKGROUND: ICU patients frequently undergo chest radiographs (CXRs). The diagnostic and therapeutic efficacy of routine CXRs are now known to be low, but the discussion regarding specific indications for CXRs in critically ill patients and the safety of abandoning routine CXRs is still ongoing. We performed a survey of Dutch intensivists on the current practice of chest radiography in their departments. METHODS: Web-based questionnaires, containing questions regarding ICU characteristics, ICU patients, daily CXR strategies, indications for routine CXRs and the practice of radiologic evaluation, were sent to the medical directors of all adult ICUs in the Netherlands. CXR strategies were compared between all academic and non-academic hospitals and between ICUs of different sizes. A comparison was made between the survey results obtained in 2006 and RESULTS: Of the 83 ICUs that were contacted, 69 (83%) responded to the survey. Only 7% of responding ICUs were currently performing daily routine CXRs for all patients, and 61% of the responding ICUs were said never to perform CXRs on a routine basis. A daily meeting with a radiologist is an established practice in 72% of the responding ICUs and is judged to be important or even essential by those ICUs. 12 Publicaties Medische Staf

14 The therapeutic efficacy of routine CXRs was assumed by intensivists to be lower than 10% or to be between 10 and 20%. The efficacy of on-demand CXRs was assumed to be between 10 and 60%. There is a consensus between intensivists to perform a routine CXR after endotracheal intubation, chest tube placement or central venous catheterization. CONCLUSION: The strategy of daily routine CXRs for critically ill and mechanically ventilated patients has turned from being a common practice in 2006 to a rare current practice. Other routine strategies and an on-demand only strategy have become more popular. Intensivists still assume the value of CXRs to be higher than the efficacy that is reported in the literature. PMID: PMCID: PMC Dietrich W, Faraoni D, von Heymann C, Bolliger D, Ranucci M, Sander M, Rosseel P. ESA guidelines on the management of severe perioperative bleeding: comments on behalf of the Subcommittee on Transfusion and Haemostasis of the European Association of Cardiothoracic Anaesthesiologists. Eur J Anaesthesiol Apr;31(4): Comment in: Reply to: ESA guidelines on the management of severe perioperative bleeding. [Eur J Anaesthesiol. 2014] Comment on: Management of severe perioperative bleeding: guidelines from the European Society of Anaesthesiology. [Eur J Anaesthesiol. 2013] PMID: Anesthesiologie 13

15 Cardiologie Kerngegevens 15 cardiologen: dr. A.M.W. (Marco) Alings, dr. B.J.L. (Ben) van den Branden, W.A.J. (Wim) Bruggeling, dr. P.H.J.M. (Peter) Dunselman, H.P.J. (Henry) de Haan, dr. P. (Peter) den Heijer, dr. B. (Bart) Hooft van Huysduynen, dr. M. (Martijn) Meuwissen, S.G (Sander) Molhoek, dr. J. (Jeroen) Schaap, dr. B. (Bas) Schölzel, dr. S. (Sipke) Strikwerda, dr. J. (Jeroen) Vos, dr. R.P. (Rob) Wielenga, dr. W.J.M. Dewilde Chef de clinique: dr. D.P.W. (Driek) Beelen 3 assistenten in opleiding (gemiddeld 1,16 fte) 10 assistenten niet in opleiding (11 fte) 4 verpleegkundig specialisten (3,35 fte) Subspecialismen: algemene cardiologie (hart- en vaatziekten in brede zin), beeldvorming (echocardiografie, cardiale CT en MRI), interventiecardiologie (stent- en dotterbehandelingen, vervanging hartklep), elektrofysiologie (behandeling van hartritmestoornissen) 14 Publicaties Medische Staf

16 Samenvattingen gepubliceerde artikelen Held C, Hylek EM, Alexander JH, Hanna M, Lopes RD, Wojdyla DM, Thomas L, Al-Khalidi H, Alings M, Xavier D, Ansell J, Goto S, Ruzyllo W, Rosenqvist M, Verheugt FW, Zhu J, Granger CB, Wallentin L. Clinical outcomes and management associated with major bleeding in patients with atrial fibrillation treated with apixaban or warfarin: insights from the ARISTOTLE trial. Eur Heart J Dec 12. [Epub ahead of print]. AIM: In the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial, apixaban compared with warfarin reduced the risk of stroke, major bleed, and death in patients with atrial fibrillation. In this ancillary study, we evaluated clinical consequences of major bleeds, as well as management and treatment effects of warfarin vs. apixaban. METHODS AND RESULTS: Major International Society on Thrombosis and Haemostasis bleeding was defined as overt bleeding accompanied by a decrease in haemoglobin (Hb) of 2 g/dl or transfusion of 2 units of packed red cells, occurring at a critical site or resulting in death. Time to event [death, ischaemic stroke, or myocardial infarction (MI)] was evaluated by Cox regression models. The excess risk associated with bleeding was evaluated by separate time-dependent indicators for intracranial (ICH) and non-intracranial haemorrhage. Major bleeding occurred in 848 individuals (4.7%), of whom 126 (14.9%) died within 30 days. Of 176 patients with an ICH, 76 (43.2%) died, and of the 695 patients with major non-ich, 64 (9.2%) died within 30 days of the bleeding. The risk of death, ischaemic stroke, or MI was increased roughly 12-fold after a major non-ich bleeding event within 30 days. Corresponding risk of death following an ICH was markedly increased, with HR (95% CI ) as was stroke or MI with HR (95% CI ), respectively. Among patients with major bleeds, 20.8% received vitamin K and/or related medications (fresh frozen plasma, coagulation factors, factor VIIa) to stop bleeding within 3 days, and 37% received blood transfusion. There was no interaction between apixaban and warfarin and major bleeding on the risk of death, stroke, or MI. CONCLUSION: Major bleeding was associated with substantially increased risk of death, ischaemic stroke, or MI, especially following ICH, and this risk was similarly elevated regardless of treatment with apixaban or warfarin. These results underscore the importance of preventing bleeding in anti-coagulated patients. CLINICAL TRIALSGOV IDENTIFIER: NCT PMID: Cardiologie 15

17 Habibovi M, Denollet J, Cuijpers P, Spek VR, van den Broek KC, Warmerdam L, van der Voort PH, Herrman JP, Bouwels L, Valk SS, Alings M, Theuns DA, Pedersen SS. E-health to manage distress in patients with an implantable cardioverter-defibrillator: primary results of the WEBCARE trial. Psychosom Med Oct;76(8): The Web-based distress management program for patients with an implantable cardioverterdefibrillator (ICD; WEBCARE) was developed to mitigate distress and enhance health-related quality of life in ICD patients. This study investigated the treatment effectiveness at 3-month follow-up for generic and disease-specific outcome measures. METHODS: Consecutive patients implanted with a first-time ICD from six hospitals in the Netherlands were randomized to either the WEBCARE or the usual care group. Patients in the WEBCARE group received a 12-week fixed, six-lesson behavioral treatment based on the problemsolving principles of cognitive behavioral therapy. RESULTS: Two hundred eighty-nine patients (85% response rate) were randomized. The prevalence of anxiety and depression ranged between 11% and 30% and 13% and 21%, respectively. No significant intervention effects were observed for anxiety (ß = 0.35; p =.32), depression (ß = -0.01; p =.98) or health-related quality of life (Mental Component Scale: ß = 0.19; p =.86; Physical Component Scale: ß = 0.58; p =.60) at 3 months, with effect sizes (Cohen d) being small (range, ). There were also no significant group differences as measured with the disease-specific measures device acceptance (ß = -0.37; p =.82), shock anxiety (ß = 0.21; p =.70), and ICD-related concerns (ß = -0.08; p =.90). No differences between treatment completers and noncompleters were observed on any of the measures. CONCLUSIONS: In this Web-based intervention trial, no significant intervention effects on anxiety, depression, health-related quality of life, device acceptance, shock anxiety, or ICD-related concerns were observed. A more patient tailored approach targeting the needs of different subsets of ICD patients may be warranted. TRIAL REGISTRATION: clinicaltrials.gov. Identifier: NCT Comment in: Distance therapy to improve symptoms and quality of life: complementing office-based care with telehealth. [Psychosom Med. 2014] PMID: Vanassche T, Lauw MN, Eikelboom JW, Healey JS, Hart RG, Alings M, Avezum A, Díaz R, Hohnloser SH, Lewis BS, Shestakovska O, Wang J, Connolly SJ. Risk of ischaemic stroke according to pattern of atrial fibrillation: analysis of 6563 aspirin-treated patients in ACTIVE-A and AVERROES. Eur Heart J Feb 1;36(5): Epub 2014 Sep Publicaties Medische Staf

18 AIMS: The pattern of atrial fibrillation (AF) occurrence-paroxysmal, persistent, or permanentis associated with progressive stages of atrial dysfunction and structural changes and may therefore be associated with progressively higher stroke risk. However, previous studies have not consistently shown AF pattern to predict stroke but have been hampered by methodological shortcomings of low power, variable event ascertainment, and variable anticoagulant use. METHODS AND RESULTS: We analysed the rates of stroke and systemic embolism in 6563 aspirin-treated patients with AF from the ACTIVE-A/AVERROES databases. There was thorough searching for events and adjudication. Multivariable analyses were performed with the adjustment for known risk factors for stroke. Mean age of patients with paroxysmal, persistent, and permanent AF was 69.0 ± 9.9, 68.6 ± 10.2, and 71.9 ± 9.8 years (P < 0.001). The CHA2DS2-VASc score was similar in patients with paroxysmal and persistent AF (3.1 ± 1.4), but was higher in patients with permanent AF (3.6 ± 1.5, P < 0.001). Yearly ischaemic stroke rates were 2.1, 3.0, and 4.2% for paroxysmal, persistent, and permanent AF, respectively, with adjusted hazard ratio of 1.83 (P < 0.001) for permanent vs. paroxysmal and 1.44 (P = 0.02) for persistent vs. paroxysmal. Multivariable analysis identified age 75 year, sex, history of stroke or TIA, and AF pattern as independent predictors of stroke, with AF pattern being the second strongest predictor after prior stroke or TIA. CONCLUSION: In a large population of non-anticoagulated AF patients, pattern of AF was a strong independent predictor of stroke risk and may be helpful to assess the risk/benefit for anticoagulant therapy, especially in lower risk patients. Published on behalf of the European Society of Cardiology. All rights reserved. The Author For permissions please [email protected]. PMID: Mulder BA, Van Veldhuisen DJ, Crijns HJ, Tijssen JG, Hillege HL, Alings M, Rienstra M, Van den Berg MP, Van Gelder IC; RACE II Investigators. Digoxin in patients with permanent atrial fibrillation: data from the RACE II study. Heart Rhythm Sep;11(9): Epub 2014 Jun 9. BACKGROUND: The Atrial Fibrillation Follow-up Investigation of Rhythm Management trial showed that digoxin was associated with increased mortality in patients with atrial fibrillation. OBJECTIVES: To assess the association of digoxin with cardiovascular (CV) morbidity and mortality in patients with permanent atrial fibrillation enrolled in the Dutch Rate Control Efficacy in Permanent AF: A Comparison Between Lenient Versus Strict Rate Control II trial as well as to assess the role of digoxin to achieve heart rate targets. METHODS: The primary outcome was a composite of CV morbidity and mortality. Secondary outcomes included CV hospitalization and all-cause mortality or heart failure (HF) hospitalization. Of the 614 patients, 608 (99%) completed the dose-adjustment phase. Outcome events were analyzed from the end of the dose-adjustment phase until the end of follow-up. The median follow-up period was 2.9 years (interquartile range years). Cardiologie 17

19 RESULTS: In total, 284 patients (46.7%) used digoxin after the dose-adjustment phase (median dosage mg; interquartile range mg). These patients were more often women, previously admitted for HF, had an increased left ventricular end-systolic diameter, and more often randomized to strict rate control. By using Cox proportional hazards regression analysis, the use of digoxin was not associated with an increased risk for the primary and secondary outcomes. For the primary outcome, the 3-year estimated cumulative incidence was 12.9% vs 13.4% in the digoxin group vs the no-digoxin group (unadjusted hazard ratio [HR] 0.97; 95% confidence interval [CI] ). Incidence was 19.4% vs. 19.5% for CV hospitalization (unadjusted HR 1.00; 95% CI ) and 6.6% vs. 9.9% for all-cause mortality or HF hospitalization (unadjusted HR 0.62; 95% CI ) in the digoxin group vs the no-digoxin group. CONCLUSION: The use of digoxin was not associated with increased morbidity and mortality. PMID: Blankestijn PJ, Alings M, Voskuil M, Grobbee DE. The complexity after simplicity: How to proceed with renal denervation in hypertension? Eur J Prev Cardiol Jun 9. pii: [Epub ahead of print] PubMed PMID: No abstract available. PMID: Habibovi M, Cuijpers P, Alings M, van der Voort P, Theuns D, Bouwels L, Herrman JP, Valk S, Pedersen S. Attrition and adherence in a WEB-Based Distress Management Program for Implantable Cardioverter defibrillator Patients (WEBCARE): randomized controlled trial. J Med Internet Res Feb 28;16(2):e52. BACKGROUND: WEB-Based Distress Management Program for Implantable CARdioverter defibrillator Patients (WEBCARE) is a Web-based randomized controlled trial, designed to improve psychological well-being in patients with an implantable cardioverter defibrillator (ICD). As in other Web-based trials, we encountered problems with attrition and adherence. OBJECTIVE: In the current study, we focus on the patient characteristics, reasons, and motivation of (1) completers, (2) those who quit the intervention, and (3) those who quit the intervention and the study in the treatment arm of WEBCARE. METHODS: Consecutive first-time ICD patients from six Dutch referral hospitals were approached for participation. After signing consent and filling in baseline measures, patients were randomized to either the WEBCARE group or the Usual Care group. 18 Publicaties Medische Staf

20 RESULTS: The treatment arm of WEBCARE contained 146 patients. Of these 146, 34 (23.3%) completed the treatment, 88 (60.3%) dropped out of treatment but completed follow-up, and 24 (16.4%) dropped out of treatment and study. Results show no systematic differences in baseline demographic, clinical, or psychological characteristics between groups. A gradual increase in dropout was observed with 83.5% (122/146) completing the first lesson, while only 23.3% (34/146) eventually completed the whole treatment. Reasons most often given by patients for dropout were technical problems with the computer, time constraints, feeling fine, and not needing additional support. CONCLUSIONS: Current findings underline the importance of focusing on adherence and dropout, as this remains a significant problem in behavioral Web-based trials. Examining possibilities to address barriers indicated by patients might enhance treatment engagement and improve patient outcomes. TRIAL REGISTRATION: Clinicaltrials.gov: NCT ; NCT (Archived by WebCite at PMID: PMCID: PMC Wallentin L, Lopes RD, Hanna M, Thomas L, Hellkamp A, Nepal S, Hylek EM, Al-Khatib SM, Alexander JH, Alings M, Amerena J, Ansell J, Aylward P, Bartunek J, Commerford P, De Caterina R, Erol C, Harjola VP, Held C, Horowitz J, Huber K, Husted S, Keltai M, Lanas F, Lisheng L, McMurray JJ, Oh BH, Rosenqvist M, Ruzyllo W, Steg PG, Vinereanu D, Xavier D, Granger CB. Response to letter regarding article, Efficacy and safety of apixaban compared with warfarin at different levels of predicted international normalized ratio control for stroke prevention in atrial fibrillation. Circulation Jan 14;129(2):e21-2. Letter by Replogle and Moore regarding article, Efficacy and safety of apixaban compared with warfarin at different levels of predicted international normalized ratio control for stroke prevention in atrial fibrillation. [Circulation. 2013]. Dello SA, Alings M. Reply to letter from J. Finsterer and S. Zarrouk-Mahjoub. Neth Heart J Jun;22(6):306. No abstract available. PMID: PMC Cardiologie 19

21 Heidbuchel H; all the authors of the EHRA Practical Guide:, Verhamme P, Alings M, Antz M, Hacke W, Oldgren J, Sinnaeve P, John Camm A, Kirchhof P. Author reply on: European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace Jan;16(1): Comment on: European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. [Europace. 2013] Should catheter atrial fibrillation ablation be considered as a high bleeding risk intervention? Bun SS, Latcu DG, Saoudi N. Europace Jan; 16(1): PMID: Alexander JH, Lopes RD, Thomas L, Alings M, Atar D, Aylward P, Goto S, Hanna M, Huber K, Husted S, Lewis BS, McMurray JJ, Pais P, Pouleur H, Steg PG, Verheugt FW, Wojdyla DM, Granger CB, Wallentin L. Apixaban vs. warfarin with concomitant aspirin in patients with atrial fibrillation: insights from the ARISTOTLE trial. Eur Heart J Jan;35(4): Epub 2013 Oct 20. AIMS: We assessed the effect of concomitant aspirin use on the efficacy and safety of apixaban compared with warfarin in patients with atrial fibrillation (AF). METHODS AND RESULTS: In ARISTOTLE, patients were randomized to apixaban 5 mg twice daily or warfarin. Concomitant aspirin use was left to the discretion of the treating physician. In this predefined analysis, simple and marginal structured models were used to adjust for baseline and time-dependent confounders associated with aspirin use. Outcome measures included stroke or systemic embolism, ischaemic stroke, myocardial infarction, mortality, major bleeding, haemorrhagic stroke, major or clinically relevant non-major bleeding, and any bleeding. On Day 1, 4434 (24%) patients were taking aspirin. Irrespective of concomitant aspirin use, apixaban reduced stroke or systemic embolism [with aspirin: apixaban 1.12% vs. warfarin 1.91%, hazard ratio (HR) 0.58, 95% confidence interval (CI) vs. without aspirin: apixaban 1.11% vs. warfarin 1.32%, HR 0.84, 95% CI ; P interaction = 0.10] and caused less major bleeding than warfarin (with aspirin: apixaban 3.10% vs. warfarin 3.92%, HR 0.77, 95% CI vs. without aspirin: apixaban 1.82% vs. warfarin 2.78%, HR without aspirin 0.65, 95% CI ; P interaction = 0.29). Similar results were seen in the subgroups of patients with and without arterial vascular disease. CONCLUSION: Apixaban had similar beneficial effects on stroke or systemic embolism and major bleeding compared with warfarin, irrespective of concomitant aspirin use. PMID: Publicaties Medische Staf

22 Heidbuchel H; all authors of the EHRA Practical Guide:, Verhamme P, Alings M, Antz M, Hacke W, Oldgren J, Sinnaeve P, John Camm A, Kirchhof P. Authors response: from monitoring to vigilance about patient adherence to new oral anticoagulants. Europace Jan;16(1): Epub 2013 Sep 26. Comment on: From monitoring to vigilance about patient adherence to new oral anticoagulants. [Europace. 2014] European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. [Europace. 2013] PMID: Van den Broek KC, Kupper N, van der Voort PH, Alings M, Denollet J, Nyklíček I. Trajectories of perceived emotional and physical distress in patients with an implantable cardioverter defibrillator. Int J Behav Med Feb;21(1): BACKGROUND: Little is known about the course of emotional and physical distress in patients with an implantable cardioverter defibrillator (ICD). PURPOSE: We examined (1) trajectories of emotional and physical distress in the first 18 months postimplantation and (2) predictors of these trajectories, including demographical, clinical, and personality factors. METHODS: Dutch patients with an ICD (N = 645) completed measures on anxiety, depression, somatic symptoms, and perceived disability at the time of implantation, and 2, 12, and 18 months postimplantation. Measures on Type D personality (tendency to inhibit the expression of negative emotions) and anxiety sensitivity (tendency to fear anxiety-related sensations) were also completed at baseline. RESULTS: Latent class analysis (LatentGOLD) identified six to seven distinct trajectories, varying largely in overall levels of distress, and remaining relatively stable after a small initial decline. Multinomial regression showed that Type D personality and anxiety sensitivity were the most prominent predictors, particularly of trajectories that reflected higher distress levels. Cardiac resynchronization therapy and coronary artery disease also increased the risk for distress, whereas ICD indication and shocks did not. CONCLUSIONS: The course of emotional and physical distress may be relatively stable after ICD implantation. In clinical practice, identification of patients with high risk of higher levels of emotional and physical distress may be warranted; as such, patients with high levels of anxiety sensitivity or a Type D personality should be identified and offered behavioral support. PMID: Cardiologie 21

23 Vermond RA, Crijns HJ, Tijssen JG, Alings AM, Van den Berg MP, Hillege HL, Van Veldhuisen DJ, Van Gelder IC, Rienstra M; RACE II investigators. Symptom severity is associated with cardiovascular outcome in patients with permanent atrial fibrillation in the RACE II study. Europace Oct;16(10): Epub 2014 Jun 17. AIMS: Symptoms and symptom burden have a central place in diagnosis and management of atrial fibrillation (AF). The aim of the present study is to investigate whether severity of AF symptoms impacts prognosis in permanent AF. METHODS AND RESULTS: We studied the relation between AF symptom severity [quantified with the Toronto AF Severity Scale (AFSS)] and cardiovascular outcome in patients included in the RACE II study. The primary endpoint was a composite of cardiovascular morbidity and mortality. Secondary outcome was cardiovascular hospitalizations. Of 614 permanent AF patients in RACE II, AFSS questionnaires were available in 558 patients (91%). Mean age was 68 ± 8 years. One hundred and seventy-four patients (31%) reported a low score (score 0-3; lowest tertile), 190 patients (34%) reported a moderate score (score 4-9; middle tertile), and 194 (35%) reported a high score (score 10-35; highest tertile). Patients with the most severe symptoms were more often women, had higher N-terminal prohormone of brain natriuretic peptide concentrations, and had more previous heart failure hospitalizations. Median follow-up was 3.0 (interquartile range ) years. The primary endpoint occurred most frequently in the highest tertile of the AFSS [16 (9%), 19 (10%), 36 (19%), respectively, P = 0.01], being mainly driven by heart failure hospitalizations [4 (2%), 1 (1%), 16 (8%), respectively, P < 0.001]. After multivariable adjustment, higher AFSS scores were associated with the primary endpoint [hazard ratio 1.38 ( ), P = 0.001], as well as with cardiovascular hospitalizations [hazard ratio 1.33 ( ), P < 0.001]. CONCLUSION: In permanent AF, after multivariable adjustment, symptom severity is associated with cardiovascular outcome. Published on behalf of the European Society of Cardiology. All rights reserved. The Author For permissions please [email protected]. PMID: De Bree LC, Alings AM, van Wijngaarden P. Heparin-induced thrombocytopenia after ICD-lead flushing. Acta Cardiol Apr;69(2): Heparin-induced thrombocytopenia (HIT) is a potentially life-threatening prothrombotic complication following heparin administration. We describe a patient, known with idiopathic dilating cardiomyopathy, presenting nine days after a biventricular ICD implantation with dyspnoea and thrombocytopenia. Thirteen days after administration of a single heparin flush during ICD implantation, the patient developed venous thrombosis in two extremities and pulmonary embolism caused by HIT. HIT is the development of thrombocytopenia, caused by IgG antibodies against complexes of platelet factor 4 and heparin, leading to platelet aggregation. HIT may be accompanied by thrombosis in 20-50% of patients and untreated mortality rates are high. Once HIT is suspected, heparin should be replaced by an alternative anti-factor Xa or 22 Publicaties Medische Staf

24 anti-factor II therapy. Regardless of the low incidence of HIT, because of the widespread use of heparin and the potentially life-threatening course of HIT, all physicians should be aware of it. PMID: Teeuwen K, Van den Branden BJ, Koolen JJ, van der Schaaf RJ, Henriques JP, Tijssen JG, Kelder JC, Vermeersch PH, Rensing BJ, Suttorp MJ. Three-year clinical outcome in the Primary Stenting of Totally Occluded Native Coronary Arteries III (PRISON III) trial: a randomised comparison between sirolimus-eluting stent implantation and zotarolimus-eluting stent implantation for the treatment of total coronary occlusions. EuroIntervention Aug 20. pii: [Epub ahead of print]. AIMS: Sirolimus-eluting stents (SES) have been shown to be superior to Endeavor zotarolimus-eluting stents (ZES) and comparable to Resolute ZES at eight-month angiography in patients treated for total coronary occlusions (TCO). This study investigated clinical outcome at three-year follow-up. METHODS AND RESULTS: The PRISON III trial investigated the efficacy and safety of SES against ZES (Endeavor and Resolute) in two study phases. In the first phase, 51 patients were randomised to receive SES and 46 to Endeavor ZES. In the second phase, 103 and 104 patients were randomised to SES or Resolute ZES, respectively. Between one and three years there were only a few additional clinical events in all groups. As a result, the rates of target lesion revascularisation 12.2% vs. 19.6%, p=0.49, target vessel failure 14.3% vs. 19.6%, p=0.68, and definite or probable stent thrombosis 4.1% vs. 2.2% were comparable between SES and Endeavor ZES at three years. In the second study phase, the rates of target lesion revascularisation 10% vs. 5.9%, p=0.42, target vessel failure 10% vs. 7.9%, p=0.79 and definite or probable stent thrombosis 1.0% vs. 0% were similar between SES and Resolute ZES. CONSLUSIONS: The present study demonstrated a low incidence of clinical events between oneand three-year follow-up with either SES compared to Endeavor ZES or SES versus Resolute ZES in patients treated for total coronary occlusions. PMID: Snijder RJ, Post MC, Mulder TB, Van den Branden BJ, Ten Berg JM, Suttorp MJ. Persistent high residual shunt rate 2 years after patent foramen ovale closure using a bioabsorbable device. JACC Cardiovasc Interv Jan;7(1): No abstract available. Cardiologie 23

25 Dewilde WJ, Janssen PW, Kelder JC, Verheugt FW, De Smet BJ, Adriaenssens T, Vrolix M, Brueren GB, Vandendriessche T, Van Mieghem C, Cornelis K, Vos J, Breet NJ, Ten Berg JM. Uninterrupted oral anticoagulation versus bridging in patients with long-term oral anticoagulation during percutaneous coronary intervention: subgroup analysis from the WOEST trial. EuroIntervention Jun 28. pii: [Epub ahead of print]. AIMS: To investigate the optimal periprocedural antithrombotic strategy in patients on longterm oral anticoagulation (OAC) who require percutaneous coronary intervention with stenting. Methods and results: The WOEST study was a randomised controlled trial which recruited 573 patients on long-term OAC who underwent PCI. The periprocedural treatment strategy was left to the operator s discretion. To assess the safety and feasibility of uninterrupted oral anticoagulation (UAC) and bridging therapy (BT), bleeding complications and MACCE were assessed in patients treated according to UAC (n=241) and BT (n=322) regimen. After 30 days, as well as after one year, there were no significant differences in bleeding complications (HR 0.83, 95% CI: , p=0.46, and HR 1.01, 95% CI: , p=0.95, respectively) and MACCE. MACCE tended to be less frequent in the UAC group (respectively HR 0.48, 95% CI: , p=0.21, and HR 0.72, 95% CI: , p=0.16). Additionally, adjustment with a propensity score revealed no significant differences. Periprocedural INR was not associated with bleeding or MACCE. Conclusions: In the WOEST study, UAC was not associated with an increase of bleeding or MACCE compared to bridging therapy. This is the largest study up to now to support the current guidelines. The WOEST trial is registered with ClinicalTrials.gov, number NCT PMID: Bennaghmouch N, Dewilde WJ, Ten Berg JM. Dual antiplatelet therapy in the anticoagulated patient undergoing percutaneous coronary intervention risks, benefits, and unanswered questions. Curr Cardiol Rep Dec;16(12):548. A commonly encountered scenario is the patient with atrial fibrillation (AF) on oral anticoagulation (OAC) who either develops an acute coronary syndrome or has to undergo percutaneous coronary intervention with stent placement. In such patients, separate indications suggest combining OAC and dual antiplatelet therapy (DAPT). This approach, however, increases the risk of bleeding as well as thromboembolic risk if bleeding does not occur. For optimal clinical results, the risks and benefits of all possible treatment options should be determined based on the best available data. This review provides an overview of the most recent data regarding the optimal treatment of AF patients with an indication for combined treatment with OAC and DAPT. PMID: Publicaties Medische Staf

26 Dewilde WJ, Janssen PW, Verheugt FW, Storey RF, Adriaenssens T, Hansen ML, Lamberts M, Ten Berg JM. Triple therapy for atrial fibrillation and percutaneous coronary intervention: a contemporary review. J Am Coll Cardiol Sep 23;64(12): Chronic oral anticoagulant therapy is recommended (class I) in patients with mechanical heart valves and in patients with atrial fibrillation with a CHA2DS2-VASc (Congestive heart failure, Hypertension, Age 75 years, Diabetes mellitus, prior Stroke or transient ischemic attack or thromboembolism, Vascular disease, Age 65 to 74 years, Sex category) score 1. When these patients undergo percutaneous coronary intervention with stenting, treatment with aspirin and a P2Y12 receptor inhibitor also becomes indicated. Before 2014, guidelines recommended the use of triple therapy (vitamin K antagonists, aspirin, and clopidogrel) for these patients. However, major bleeding is increasingly recognized as the Achilles heel of the triple therapy regimen. Lately, various studies have investigated this topic, including a prospective randomized trial, and the evidence for adding aspirin to the regimen of vitamin K antagonists and clopidogrel seems to be weakened. In this group of patients, the challenge is finding the optimal equilibrium to prevent thromboembolic events, such as stent thrombosis and thromboembolic stroke, without increasing bleeding risk. PMID: Lamberts M, Dewilde W, Hansen ML. Atrial fibrillation and coronary artery disease: which antithrombotic treatment strategy? Curr Opin Cardiol Nov;29(6): PURPOSE OF REVIEW: The optimal antithrombotic therapy in patients with atrial fibrillation and coronary artery disease is controversial. The benefit of the combination of antithrombotic therapies remains debatable, and, as the bleeding risk is substantial, this calls for knowledge of the duration, and which and how many agents should be used. RECENT FINDINGS: The first randomized trial to challenge current recommendations of triple therapy (oral anticoagulation plus clopidogrel plus aspirin) examined patients on warfarin undergoing percutaneous coronary intervention with stent implantation. A reduced risk of any bleeding (hazard ratio 0.36) was found with combination of clopidogrel compared with triple therapy without increasing major cardiovascular events. In real-life patients, a nationwide Danish registry supported these findings, and, relative to triple therapy, no significant difference was found for recurrent myocardial infarction when adding only clopidogrel (hazard ratio 0.69) or aspirin (hazard ratio 0.96) to vitamin K antagonist. However, the latter regimen was associated with significantly increased risk of death. SUMMARY: Within 1 year after myocardial infarction and/or percutaneous coronary intervention in patients with atrial fibrillation, current consensus papers endorse use of dual antiplatelet therapy on top of oral anticoagulation. A regimen consisting of oral anticoagulation and clopidogrel (without aspirin) could provide an alternative from a benefit and safety perspective. PMID: Cardiologie 25

27 Bergmeijer TO, Janssen PW, Schipper JC, Qaderdan K, Ishak M, Ruitenbeek RS, Asselbergs FW, van t Hof AW, Dewilde WJ, Spanó F, Herrman JP, Kelder JC, Postma MJ, de Boer A, Deneer VH, ten Berg JM. CYP2C19 genotype-guided antiplatelet therapy in ST-segment elevation myocardial infarction patients-rationale and design of the Patient Outcome after primary PCI (POPular) Genetics study. Am Heart J Jul;168(1):16-22.e1. Epub 2014 Mar 21. RATIONALE: In patients with ST-segment elevation myocardial infarction (STEMI) who undergo primary percutaneous coronary intervention (ppci), the use of dual antiplatelet therapy is essential to prevent atherothrombotic complications. Therefore, patients are treated with acetylsalicylic acid and clopidogrel, prasugrel, or ticagrelor. Clopidogrel, however, shows a major interindividual variation in antiplatelet effect, which is correlated to an increase in atherothrombotic events in patients with high platelet reactivity. This interindividual variation is partly a result of CYP2C19 genetic variants. Ticagrelor and prasugrel reduce atherothrombotic events but increase bleeding rate and drug costs, as compared with clopidogrel. CYP2C19-based tailoring of antiplatelet therapy might be beneficial to STEMI patients. STUDY DESIGN: POPular Genetics (NCT ) is a randomized, open-label, multicenter trial involving 2,700 STEMI patients who undergo ppci. Patients are randomized to CYP2C19 genotyping or routine ticagrelor or prasugrel treatment. In the genotyping group, *1/*1 (wildtype) patients receive clopidogrel, and patients carrying 1 or 2 *2 or *3 loss-of-function alleles receive ticagrelor or prasugrel. The primary net clinical benefit end point is the composite of death, (recurrent) myocardial infarction, definite stent thrombosis, stroke, and Platelet Inhibition and Patient Outcomes (PLATO) major bleeding at 1 year. Primary safety end point is the composite of (PLATO) major and minor bleeding. Cost-effectiveness and quality of life will be assessed by calculating quality-adjusted life-years, net costs per life-year, and per quality-adjusted life-year gained. CONCLUSION: The POPular Genetics study is the first large-scale trial comparing CYP2C19 genotype-guided antiplatelet therapy to a nontailored strategy in terms of net clinical benefit, safety, and cost-effectiveness. PMID: Valente MA, Hillege HL, Navis G, Voors AA, Dunselman PH, van Veldhuisen DJ, Damman K. The Chronic Kidney Disease Epidemiology Collaboration equation outperforms the Modification of Diet in Renal Disease equation for estimating glomerular filtration rate in chronic systolic heart failure. Eur J Heart Fail Jan;16(1): Epub 2013 Dec 3. AIMS: The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula estimates glomerular filtration rate (GFR) better than the simplified Modification of Diet in Renal Disease (smdrd) formula in numerous populations. It has not previously been validated in heart failure patients. METHODS AND RESULTS: The GFR was measured in 120 patients with chronic systolic heart 26 Publicaties Medische Staf

28 failure (CHF) using [(125)I]iothalamate clearance (GFR(IOTH)) and estimated using the smdrd and CKD-EPI equations. Accuracy, bias, and prognostic performance were compared. Cockcroft- Gault, CKD-EPI serum cystatin C, and CKD-EPI creatinine-serum cystatin C equations were compared in secondary analyses. Mean age was 59 ± 12 years, 80% were male. Mean LVEF was 29 ± 10%. Mean GFR(IOTH) was 74 ± 27 ml/min/1.73 m(2), and mean estimated GFR was 66 ± 23 ml/ min/1.73 m(2) (CKD-EPI) and 63 ± 21 ml/min/1.73m(2) (smdrd). CKD-EPI showed less bias than smdrd (-8 ± 15 vs. -11 ± 16 ml/min/1.73 m(2), P < 0.001). Both equations underestimate at higher and overestimate at lower GFR(IOTH). Eleven patients (9%) were accurately reclassified into lower CKD classes with CKD-EPI. Cockcroft-Gault showed lower bias (-3 ± 16 ml/min/1.73 m(2)) but worse precision and accuracy. Cystatin C-based estimation showed the lowest bias (-3 ± 14 ml/min/1.73 m(2)) and the best precision and accuracy. Prognostic value did not differ between all GFR estimates. CONCLUSION: The CKD-EPI equation more accurately estimates measured GFR than the smdrd equation in CHF patients, with less bias and greater accuracy and precision. The prognostic power of all GFR assessments was equivalent. Based on better performance and equal risk prediction, we believe the CKI-EPI equation should be the preferred creatinine-based GFR estimation method in heart failure patients, particularly those with preserved or moderately impaired renal function. First published online by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. The Author PMID: McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau J, Shi VC, Solomon SD, Swedberg K, Zile MR; PARADIGM-HF Committees and Investigators* [Dunselman PH et al...]. Dual angiotensin receptor and neprilysin inhibition as an alternative to angiotensin-converting enzyme inhibition in patients with chronic systolic heart failure: rationale for and design of the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF). Eur J Heart Fail Sep;15(9): Epub 2013 Apr 5. AIMS: Although the focus of therapeutic intervention has been on neurohormonal pathways thought to be harmful in heart failure (HF), such as the renin-angiotensin-aldosterone system (RAAS), potentially beneficial counter-regulatory systems are also active in HF. These promote vasodilatation and natriuresis, inhibit abnormal growth, suppress the RAAS and sympathetic nervous system, and augment parasympathetic activity. The best understood of these mediators are the natriuretic peptides which are metabolized by the enzyme neprilysin. LCZ696 belongs to a new class of drugs, the angiotensin receptor neprilysin inhibitors (ARNIs), which both block the RAAS and augment natriuretic peptides. METHODS: Patients with chronic HF, NYHA class II-IV symptoms, an elevated plasma BNP or NT-proBNP level, and an LVEF of 40% were enrolled in the Prospective comparison of ARNI with Cardiologie 27

29 ACEI to Determine Impact on Global Mortailty and morbidity in Heart Failure trial (PARADIGM- HF). Patients entered a single-blind enalapril run-in period (titrated to 10 mg b.i.d.), followed by an LCZ696 run-in period (100 mg titrated to 200 mg b.i.d.). A total of 8436 patients tolerating both periods were randomized 1:1 to either enalapril 10 mg b.i.d. or LCZ mg b.i.d. The primary outcome is the composite of cardiovascular death or HF hospitalization, although the trial is powered to detect a 15% relative risk reduction in cardiovascular death. PERSPECTIVES: PARADIGM-HF will determine the place of the ARNI LCZ696 as an alternative to enalapril in patients with systolic HF. PARADIGM-HF may change our approach to neurohormonal modulation in HF. TRIAL REGISTRATION: NCT * Collaborators (1045) PMID: PMCID: PMC Maggioni AP, Dahlström U, Filippatos G, Chioncel O, Crespo Leiro M, Drozdz J, Fruhwald F, Gullestad L, Logeart D, Fabbri G, Urso R, Metra M, Parissis J, Persson H, Ponikowski P, Rauchhaus M, Voors AA, Nielsen OW, Zannad F, Tavazzi L; Heart Failure Association of the European Society of Cardiology (HFA)* [Dunselman PH et al...]. EURObservational Research Programme: regional differences and 1-year follow-up results of the Heart Failure Pilot Survey (ESC-HF Pilot). Eur J Heart Fail Jul;15(7): Epub 2013 Mar 28. AIMS: The ESC-HF Pilot survey was aimed to describe clinical epidemiology and 1-year outcomes of outpatients and inpatients with heart failure (HF). The pilot phase was also specifically aimed at validating structure, performance, and quality of the data set for continuing the survey into a permanent Registry. METHODS: The ESC-HF Pilot study is a prospective, multicentre, observational survey conducted in 136 Cardiology Centres in 12 European countries selected to represent the different health systems across Europe. All outpatients with HF and patients admitted for acute HF on 1 day per week for eight consecutive months were included. From October 2009 to May 2010, 5118 patients were included: 1892 (37%) admitted for acute HF and 3226 (63%) patients with chronic HF. The all-cause mortality rate at 1 year was 17.4% in acute HF and 7.2% in chronic stable HF. One-year hospitalization rates were 43.9% and 31.9%, respectively, in hospitalized acute and chronic HF patients. Major regional differences in 1-year mortality were observed that could be explained by differences in characteristics and treatment of the patients. CONCLUSION: The ESC-HF Pilot survey confirmed that acute HF is still associated with a very poor medium-term prognosis, while the widespread adoption of evidence-based treatments in patients with chronic HF seems to have improved their outcome profile. Differences across countries may be due to different local medical practice as well to differences in healthcare 28 Publicaties Medische Staf

30 systems. This pilot study also offered the opportunity to refine the organizational structure for a long-term extended European network. * Collaborators: 277 PMID: Daniels LB, Grady D, Mosca L, Collins P, Mitlak BH, Amewou-Atisso MG, Wenger NK, Barrett- Connor E; Raloxifene Use for the Heart (RUTH) Trial Investigators* [Dunselman PH et al...] Is diabetes mellitus a heart disease equivalent in women? Results from an international study of postmenopausal women in the Raloxifene Use for the Heart (RUTH) Trial. Circ Cardiovasc Qual Outcomes Mar 1;6(2): Epub 2013 Mar 12. BACKGROUND: Several studies have concluded that diabetes mellitus and heart disease carry similar risk for future cardiovascular disease (CVD). Most of these studies were too small to quantify independent risks specific to women. The purpose of this study was to determine whether diabetes mellitus is a coronary heart disease (CHD) risk equivalent for prediction of future CHD and CVD events in women. METHODS AND RESULTS: The Raloxifene Use for the Heart (RUTH) trial was an international, multicenter, double-blind, randomized, placebo-controlled trial of raloxifene and CVD outcomes in postmenopausal women selected for high CHD risk. Of these, 3672 had a history of diabetes mellitus without known CHD, and 3265 had a history of CHD without known diabetes mellitus. Cox proportional hazard models were used to compare cardiovascular outcomes in these 2 groups. Mean age at baseline was 67.5 years; median follow-up was 5.6 years. There were 725 deaths, including 450 cardiovascular deaths. In age-adjusted analyses, diabetic women had an increased risk of all-cause mortality compared with women with CHD. Although the overall risk of CHD and CVD was lower in diabetic women compared with women with CHD, the risk of fatal CHD, fatal CVD, and all-cause mortality was similar (hazard ratio [95% confidence interval]: 0.85 [ ], 0.99 [ ], and 1.18 [ ], respectively, after adjusting for age, lifestyle factors, CHD risk factors, statin use, and treatment assignment). CONCLUSIONS: In the RUTH trial, diabetes mellitus was a CHD risk equivalent in women for fatal, but not nonfatal, CHD and CVD. Clinical Trial Registration: URL: Unique identifier: NCT Comment in: Diabetes mellitus in women can be RUTHless: lessons from the Raloxifene Use for The Heart (RUTH) Trial. [Circ Cardiovasc Qual Outcomes. 2013] PMID: Cardiologie 29

31 Swedberg K, Young JB, Anand IS, Cheng S, Desai AS, Diaz R, Maggioni AP, McMurray JJ, O Connor C, Pfeffer MA, Solomon SD, Sun Y, Tendera M, van Veldhuisen DJ; RED-HF Committees; RED-HF Investigators* [Dunselman PH et al...]. Treatment of anemia with darbepoetin alfa in systolic heart failure. N Engl J Med Mar 28;368(13): Epub 2013 Mar 10. BACKGROUND: Patients with systolic heart failure and anemia have worse symptoms, functional capacity, and outcomes than those without anemia. We evaluated the effects of darbepoetin alfa on clinical outcomes in patients with systolic heart failure and anemia. METHODS: In this randomized, double-blind trial, we assigned 2278 patients with systolic heart failure and mild-to-moderate anemia (hemoglobin level, 9.0 to 12.0 g per deciliter) to receive either darbepoetin alfa (to achieve a hemoglobin target of 13 g per deciliter) or placebo. The primary outcome was a composite of death from any cause or hospitalization for worsening heart failure. RESULTS: The primary outcome occurred in 576 of 1136 patients (50.7%) in the darbepoetin alfa group and 565 of 1142 patients (49.5%) in the placebo group (hazard ratio in the darbepoetin alfa group, 1.01; 95% confidence interval, 0.90 to 1.13; P=0.87). There was no significant betweengroup difference in any of the secondary outcomes. The neutral effect of darbepoetin alfa was consistent across all prespecified subgroups. Fatal or nonfatal stroke occurred in 42 patients (3.7%) in the darbepoetin alfa group and 31 patients (2.7%) in the placebo group (P=0.23). Thromboembolic adverse events were reported in 153 patients (13.5%) in the darbepoetin alfa group and 114 patients (10.0%) in the placebo group (P=0.01). Cancer-related adverse events were similar in the two study groups. CONCLUSIONS: Treatment with darbepoetin alfa did not improve clinical outcomes in patients with systolic heart failure and mild-to-moderate anemia. Our findings do not support the use of darbepoetin alfa in these patients. (Funded by Amgen; RED-HF ClinicalTrials.gov number, NCT ). Comment in: Haemodilution is a mechanism of anaemia in patients with heart failure. [Eur J Heart Fail. 2013] Heart failure: the end of the road for darbepoetin alfa in heart failure? [Nat Rev Cardiol. 2013] Darbepoetin alfa in systolic heart failure. [N Engl J Med. 2013] * Collaborators: 778 PMID: Publicaties Medische Staf

32 McMurray JJ, Anand IS, Diaz R, Maggioni AP, O Connor C, Pfeffer MA, Solomon SD, Tendera M, van Veldhuisen DJ, Albizem M, Cheng S, Scarlata D, Swedberg K, Young JB; RED-HF Committees Investigators* [Dunselman PH et al...]. Baseline characteristics of patients in the Reduction of Events with Darbepoetin alfa in Heart Failure trial (RED-HF). Eur J Heart Fail Mar;15(3): Epub 2013 Jan 17. AIMS: This report describes the baseline characteristics of patients in the Reduction of Events with Darbepoetin alfa in Heart Failure trial (RED-HF) which is testing the hypothesis that anaemia correction with darbepoetin alfa will reduce the composite endpoint of death from any cause or hospital admission for worsening heart failure, and improve other outcomes. METHODS AND RESULTS: Key demographic, clinical, and laboratory findings, along with baseline treatment, are reported and compared with those of patients in other recent clinical trials in heart failure. Compared with other recent trials, RED-HF enrolled more elderly [mean age 70 (SD 11.4) years], female (41%), and black (9%) patients. RED-HF patients more often had diabetes (46%) and renal impairment (72% had an estimated glomerular filtration rate < 60 ml/min/1.73 m2). Patients in RED-HF had heart failure of longer duration [5.3 (5.4) years], worse NYHA class (35% II, 63% III, and 2% IV), and more signs of congestion. Mean EF was 30% (6.8%). RED-HF patients were well treated at randomization, and pharmacological therapy at baseline was broadly similar to that of other recent trials, taking account of study-specific inclusion/exclusion criteria. Median (interquartile range) haemoglobin at baseline was 112 ( ) g/l. CONCLUSION: The anaemic patients enrolled in RED-HF were older, moderately to markedly symptomatic, and had extensive co-morbidity. *Collaborators: 666 PMID: PMCID: PMC Fernández-Rodríguez D, Regueiro A, Brugaletta S, Martín-Yuste V, Masotti M, Cequier A, Iñíguez A, Serra A, Hernández-Antolín R, Mainar V, Valgimigli M, Tespili M, den Heijer P, Bethencourt A, Vázquez N, Serruys PW, Sabaté M; EXAMINATION investigators. Optimization in stent implantation by manual thrombus aspiration in ST-segment-elevation myocardial infarction: findings from the EXAMINATION trial. Circ Cardiovasc Interv Jun;7(3): Epub 2014 May 27. BACKGROUND: Manual thrombus aspiration (TA) is effective to reduce the thrombus burden during primary percutaneous coronary intervention for ST-elevation myocardial infarction. The objective of this study is to assess the impact of manual TA on stent implantation during primary percutaneous coronary intervention. METHODS AND RESULTS: Population of the EXAMINATION trial (n=1498) was divided into 2 groups according to the use of TA. Immediate angiographic results, primary patient-oriented end point (combination of all-cause death, myocardial infarction, and any revascularization) and Cardiologie 31

33 secondary device-oriented end point (combination of cardiac death, target vessel myocardial infarction, and clinically driven target lesion revascularization), definite/probable stent thrombosis, and major/minor bleeding were evaluated at 2 years. A total of 976 (65.2%) patients were classified into TA group and 522 (34.8%) patients into nonthrombus aspiration group. Manual TA was most frequently used in patients with worse initial thrombolysis in myocardial infarction flow. The TA group received less number of stents implanted (1.35 ± 0.62 versus 1.45 ± 0.71, P = 0.005) with bigger size (3.25 ± 0.44 versus 3.11 ± 0.46 mm, P < 0.001) compared with the nonthrombus aspiration group. A higher rate of direct stenting (69.2% versus 43.3%, P < 0.001) with lower rate of postdilatation (13.0% versus 18.0%, P < 0.009) was also present in the TA group compared with the nonthrombus aspiration group. At 2-year follow-up, no differences in clinical end point were observed between groups. CONCLUSIONS: Manual TA during primary percutaneous coronary intervention is associated with a higher rate of direct stenting, a lower rate of postdilatation, and larger and less stents in comparison with conventional primary percutaneous coronary intervention. Conversely, manual TA had no apparent impact on clinical outcomes at long-term follow-up. CLINICAL TRIAL REGISTRATION: Unique identifier: NCT PMID: Lenders GD, Collas V, Hernandez JM, Legrand V, Danenberg HD, den Heijer P, Rodrigus IE, Paelinck BP, Vrints CJ, Bosmans JM. Depth of valve implantation, conduction disturbances and pacemaker implantation with CoreValve and CoreValve Accutrak system for Transcatheter Aortic Valve Implantation, a multi-center study. Int J Cardiol Oct 20;176(3): Epub 2014 Aug 1. OBJECTIVES: This study sought to assess the 2-year outcomes of the population included in the EXAMINATION (Everolimus-Eluting Stents Versus Bare-Metal Stents in ST-Segment Elevation Myocardial Infarction) trial beyond the 1-year prescription period of dual antiplatelet therapy. BACKGROUND: The EXAMINATION trial compared the performance of everolimus-eluting stents (EES) versus bare-metal stents (BMS) in an all-comer ST-segment elevation myocardial infarction (STEMI) population. METHODS: This was a multicenter, multinational, prospective, randomized, single-blind, controlled trial in patients with STEMI. The primary endpoint, which was the combined endpoint of all-cause death, any recurrent myocardial infarction, and any revascularization, and the endpoints target lesion revascularization and stent thrombosis were assessed at 2 years. RESULTS: Between December 31, 2008, and May 15, 2010, 1,498 patients were randomized to receive EES (n = 751) or BMS (n = 747). Compliance with dual antiplatelet regimen was reduced at 2 years to a similar degree (17.3% vs. 17.2%, p = 0.91). At 2 years, the primary endpoint occurred in 108 (14.4%) patients of the EES group and in 129 (17.3%) patients of the BMS group (p = 0.11). Rate of target lesion revascularization was significantly lower in the EES group than in the BMS 32 Publicaties Medische Staf

34 group (2.9% vs. 5.6%; p = 0.009). Rates of definite and definite or probable stent thrombosis were also significantly reduced in the EES group (0.8% vs. 2.1%; p = 0.03, and 1.3% vs. 2.8%; p = 0.04, respectively). CONCLUSIONS: The 2-year follow-up of the EXAMINATION trial confirms the safety and efficacy of the EES compared with BMS in the setting of STEMI. Specifically, both rates of target lesion revascularization and stent thrombosis were reduced in recipients of EES without any signs of late attrition for either of these endpoints. (A Clinical Evaluation of Everolimus Eluting Coronary Stents in the Treatment of Patients With ST-Segment Elevation Myocardial Infarction: EXAMINATION Study; NCT ). PMID: Nijenhuis VJ, Stella PR, Baan J, Brueren BR, de Jaegere PP, den Heijer P, Hofma SH, Kievit P, Slagboom T, van den Heuvel AF, van der Kley F, van Garsse L, van Houwelingen KG, Van t Hof AW, Ten Berg JM. Antithrombotic therapy in patients undergoing TAVI: an overview of Dutch hospitals. Neth Heart J Feb;22(2):64-9. PURPOSE: To assess current antithrombotic treatment strategies in the Netherlands in patients undergoing transcatheter aortic valve implantation (TAVI). METHODS: For every Dutch hospital performing TAVI (n = 14) an interventional cardiologist experienced in performing TAVI was interviewed concerning heparin, aspirin, thienopyridine and oral anticoagulation treatment in patients undergoing TAVI. RESULTS: The response rate was 100%. In every centre, a protocol for antithrombotic treatment after TAVI was available. Aspirin was prescribed in all centres, concomitant clopidogrel was prescribed 13 of the 14 centres. Duration of concomitant clopidogrel was 3 months in over two-thirds of cases. In 2 centres, duration of concomitant clopidogrel was based upon type of prosthesis: 6 months versus 3 months for supra-annular and intra-annular prostheses, respectively. CONCLUSIONS: Leaning on a small basis of evidence and recommendations, the antithrombotic policy for patients undergoing TAVI is highly variable in the Netherlands. As a standardised regimen might further reduce haemorrhagic complications, large randomised clinical trials may help to establish the most appropriate approach. PMID: PMCID: PMC Cardiologie 33

35 Ielasi A, Brugaletta S, Silvestro A, Cequier A, Iñiguez A, Serra A, Hernandez-Antolin R, Mainar V, Valgimigli M, den Heijer P, Bethencourt A, Vazquez N, Serruys P, Sabate M, Tespili M. Everolimuseluting stent versus bare-metal stent in elderly ( 75years) versus non-elderly (<75years) patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention: Insights from the examination trial. Int J Cardiol Jan 20;179:73-8. Epub 2014 Oct 22. BACKGROUND: The elderly ( 75years) constitute a high-risk subset of patients who continue to have a poorer prognosis than non-elderly (<75years). Whether the effects of everolimus-eluting stent (EES) in ST-segment elevation myocardial infarction (STEMI) are independent of age has not been reported. We investigated the outcomes following primary PCI (PPCI) with bare-metal stent (BMS) or EES in elderly vs. non-elderly STEMI patients. METHODS: The EXAMINATION trial randomized 1498 STEMI patients to BMS or EES. The primary patient-oriented endpoint (POCE) was the combined of all-cause death, any-recurrent myocardial infarction (MI) and any-revascularization at 1-year. The secondary endpoint included the deviceoriented combined (DOCE) of cardiac death, target-vessel MI and target-lesion revascularization. These endpoints and their components were compared between elderly and non-elderly. RESULTS: Among patients enrolled in the trial, 245 (16.3%) were elderly, allocated to BMS (n=132) or EES (n=113), while the remaining 1253 (83.7%) were non-elderly, allocated to BMS (n=615) or EES (n=638). At 1-year, both the POCE and DOCE were observed more frequently in elderly vs. nonelderly group (24.5% vs. 10.5%, p<0.001 and 15.9% vs. 5.1%, p<0.001). Whereas in non-elderly, both POCE and DOCE were lower in EES vs. BMS (12.4% vs. 8.8%, p=0.03 and 6.7% vs. 3.6%, p=0.01), no differences were found in elderly, with a tendency for interaction between age and stent type for POCE (p=0.05). On multivariate analysis age 75 years was an independent predictor of POCE (HR 2.19 [95%CI ], p<0.0001) and DOCE (HR 2.42 [95%CI ], p<0.001) at 1-year. CONCLUSIONS: In STEMI patients undergoing PPCI, advanced age ( 75 years) is associated with worse outcomes. The beneficial effects of EES over BMS tended to be age-dependent. PMID: Den Dekker WK, Houtgraaf JH, Rowland SM, Ligtenberg E, de Boer SP, de Jong R, de Winter RJ, den Heijer P, Zijlstra F, Serruys PW, Cheng C, Duckers HJ. Efficiency of Statin Treatment on EPC Recruitment Depends on Baseline EPC Titer and Does Not Improve Angiographic Outcome in Coronary Artery Disease Patients Treated With the Genous Stent. Cell Transplantation 2014;23: Epub 2013 Apr 3. The objective of this study was to assess the effect of high-dose atorvastatin treatment on endothelial progenitor cell (EPC) recruitment and angiographic and clinical outcome in coronary artery disease (CAD) patients treated with the Genous EPC-capturing stent. The HEALING IIB study was a multicenter, open-label, prospective trial that enrolled 100 patients. Patients were started on 80 mg atorvastatin qd, at least 2 weeks before the index procedure and continued for at least 4 weeks after the index procedure. Eighty-seven patients were included in this analysis. 34 Publicaties Medische Staf

36 EPC levels significantly increased as early as 2 weeks after the start of atorvastatin. Remarkably, among this group, 31 patients proved to be nonresponders to atorvastatin treatment (i.e., no increase in EPC levels), while 56 patients were responders (i.e., rise in EPC count between week -2 and 0). Compared to responders, nonresponders had a significantly higher baseline EPC count (76 ± 10 vs. 41± 5, p < 0.01) with a lower late luminal loss (LLL) at 6- and 18-month follow-up (FU) (0.61 ± 0.07 vs ± 0.08, p < 0.05, and 0.50 ± 0.08 vs ± 0.08, p < 0.01 respectively). Furthermore, baseline EPC count was inversely correlated with LLL at 6-month FU (R = -0.42, p < 0.001). Patients with a higher EPC count at baseline showed no increase in EPC recruitment in response to statin treatment but had favorable LLL at 6- and 18-month FU, whereas patients with lower EPC count were responsive to statin therapy, but EPCs might be less functional as they had higher LLL at 6- and 18-month FU. These data imply that although statin treatment can enhance EPC titer in patients with low baseline levels, there is no indication for a possible beneficial clinical effect with EPC capture stents. PMID: Petraco R, Al-Lamee R, Gotberg M, Sharp A, Hellig F, Nijjer SS, Echavarria-Pinto M, van de Hoef TP, Sen S, Tanaka N, Van Belle E, Bojara W, Sakoda K, Mates M, Indolfi C, De Rosa S, Vrints CJ, Haine S, Yokoi H, Ribichini FL, Meuwissen M, Matsuo H, Janssens L, Katsumi U, Di Mario C, Escaned J, Piek J, Davies JE. Real-time use of instantaneous wave-free ratio: results of the ADVISE in-practice: an international, multicenter evaluation of instantaneous wave-free ratio in clinical practice. Am Heart J Nov;168(5): Epub 2014 Jul 21. OBJECTIVES: To evaluate the first experience of real-time instantaneous wave-free ratio (ifr) measurement by clinicians. BACKGROUND: The ifr is a new vasodilator-free index of coronary stenosis severity, calculated as a trans-lesion pressure ratio during a specific period of baseline diastole, when distal resistance is lowest and stable. Because all previous studies have calculated ifr offline, the feasibility of realtime ifr measurement has never been assessed. METHODS: Three hundred ninety-two stenoses with angiographically intermediate stenoses were included in this multicenter international analysis. Instantaneous wave-free ratio and fractional flow reserve (FFR) were performed in real time on commercially available consoles. The classification agreement of coronary stenoses between ifr and FFR was calculated. RESULTS: Instantaneous wave-free ratio and FFR maintain a close level of diagnostic agreement when both are measured by clinicians in real time (for a clinical 0.80 FFR cutoff: area under the receiver operating characteristic curve [ROC(AUC)] 0.87, classification match 80%, and optimal ifr cutoff 0.90; for a ischemic 0.75 FFR cutoff: ifr ROC(AUC) 0.90, classification match 88%, and optimal ifr cutoff 0.85; if the FFR gray zone is accounted for: ROC(AUC) 0.93, classification match 92%). When ifr and FFR are evaluated together in a hybrid decision-making strategy, 61% of the population is spared from vasodilator while maintaining a 94% overall agreement with FFR lesion classification. Cardiologie 35

37 CONCLUSION: When measured in real time, ifr maintains the close relationship to FFR reported in offline studies. These findings confirm the feasibility and reliability of real-time ifr calculation by clinicians. PMID: PMCID: PMC Verloop WL, Agema WR, Allaart CP, Blankestijn PJ, Khan M, Meuwissen M, Muijs van de Moer WM, Rensing BJ, Spiering W, Voskuil M, Doevendans PA; working group for renal denervation. Renal denervation for the treatment of hypertension: the Dutch consensus. Neth J Med Nov;72(9): Since 2010, renal denervation (RDN) is being performed in the Netherlands. To make sure RDN is implemented with care and caution in the Netherlands, a multidisciplinary Working Group has been set up by the Dutch Society of Cardiology (NVVC). The main aim of this Working Group was to establish a consensus document that can be used as a guide for implementation of RDN in the Netherlands. This consensus document was prepared in consultation with the Dutch Association of Internal Medicine (NIV) and the Dutch Society of Radiology (NVVR). PMID: Publicaties Medische Staf

38 Van de Hoef TP, Meuwissen M, Escaned J, Sen S, Petraco R, van Lavieren MA, Echavarria-Pinto M, Nolte F, Nijjer S, Chamuleau SA, Voskuil M, van Eck-Smit BL, Verberne HJ, Henriques JP, Koch KT, de Winter RJ, Spaan JA, Siebes M, Tijssen JG, Davies JE, Piek JJ. Head-to-head comparison of basal stenosis resistance index, instantaneous wave-free ratio, and fractional flow reserve: diagnostic accuracy for stenosis-specific myocardial ischaemia. EuroIntervention Aug 30. [Epub ahead of print]. AIMS: We sought to compare the diagnostic accuracy of basal stenosis resistance index (BSR), instantaneous wave-free ratio (ifr) and fractional flow reserve (FFR) for stenosis-specific myocardial ischaemia identified by means of a combined reference standard of myocardial perfusion scintigraphy and the hyperaemic stenosis resistance index. METHODS AND RESULTS: BSR and FFR were determined for 299 coronary stenoses, ifr was determined for 85 coronary stenoses (ifr cohort). The discriminative value for stenosis-specific myocardial ischaemia was compared by means of the area under the receiver operating characteristic (ROC) curves (AUC). Classification agreement with the reference standard was determined according to ROC curve-derived ischaemic cut-off values, as well as according to clinical cut-off values, equivalent to the 0.80 FFR cut-off. Across all stenoses, the discriminative value of BSR and FFR was equivalent (AUC: 0.90 and 0.91, respectively, p=0.46). In the ifr cohort, the discriminative value was equivalent for BSR, ifr, and FFR (AUC: 0.88, 0.84, and 0.88, respectively; p 0.20 for all). At both ischaemic as well as clinical cut-off values, classification agreement with the reference standard was equivalent for BSR and FFR across all stenoses, as well as for BSR, ifr, and FFR in the ifr cohort. CONCLUSIONS: BSR, ifr, and FFR have equivalent diagnostic accuracy for the detection of ischaemia-generating coronary stenoses. PMID: Petraco R, van de Hoef TP, Nijjer S, Sen S, van Lavieren MA, Foale RA, Meuwissen M, Broyd C, Echavarria-Pinto M, Foin N, Malik IS, Mikhail GW, Hughes AD, Francis DP, Mayet J, Di Mario C, Escaned J, Piek JJ, Davies JE. Baseline instantaneous wave-free ratio as a pressure-only estimation of underlying coronary flow reserve: results of the JUSTIFY-CFR Study (Joined Coronary Pressure and Flow Analysis to Determine Diagnostic Characteristics of Basal and Hyperemic Indices of Functional Lesion Severity-Coronary Flow Reserve). Circ Cardiovasc Interv Aug;7(4): Epub 2014 Jul 1. BACKGROUND: Coronary flow reserve has extensive validation as a prognostic marker in coronary disease. Although pressure-only fractional flow reserve (FFR) improves outcomes compared with angiography when guiding percutaneous coronary intervention, it disagrees with coronary flow reserve classification 30% of the time. We evaluated whether baseline instantaneous wave-free ratio (ifr) could provide an improved pressure-only estimation of underlying coronary flow reserve. Cardiologie 37

39 METHODS AND RESULTS: Invasive pressure and flow velocity were measured in 216 stenoses from 186 patients with coronary disease. The diagnostic relationship between pressure-only indices (ifr and FFR) and coronary flow velocity reserve (CFVR) was compared using correlation coefficient and the area under the receiver operating characteristic curve. ifr showed a stronger correlation with underlying CFVR (ifr-cfvr,ρ=0.68 versus FFR-CFVR, ρ=0.50; P<0.001). ifr also agreed more closely with CFVR in stenosis classification (ifr area under the receiver operating characteristic curve, 0.82 versus FFR area under the receiver operating characteristic curve, 0.72; P<0.001, for a CFVR of 2). The closer relationship between ifr and CFVR was found for different CFVR cutoffs and was particularly marked in the 0.6 to 0.9 FFR range. Hyperemic FFR flow was similar to baseline ifr flow in functionally significant lesions (FFR 0.75; mean FFR flow, 25.8±13.7 cm/s versus mean ifr flow, 21.5±11.7 cm/s; P=0.13). FFR flow was higher than ifr flow in nonsignificant stenoses (FFR >0.75; mean FFR flow, 42.3±22.8 cm/s versus mean ifr flow, 26.1±15.5 cm/s; P<0.001). CONCLUSIONS: When compared with FFR, ifr shows stronger correlation and better agreement with CFVR. These results provide physiological evidence that ifr could potentially be used as a functional index of disease severity, independently from its agreement with FFR. Comment in: Reconciling poststenotic pressure with hyperemic flow: comparing coronary flow reserve, instantaneous wave-free ratio, and fractional flow reserve. [Circ Cardiovasc Interv. 2014] PMID: Nolte F, van de Hoef TP, Meuwissen M, Voskuil M, Chamuleau SA, Henriques JP, Verberne HJ, van Eck-Smit BL, Koch KT, de Winter RJ, Spaan JA, Tijssen JG, Siebes M, Piek JJ. Increased hyperaemic coronary microvascular resistance adds to the presence of myocardial ischaemia. EuroIntervention. 2014;9(12): AIMS: It has been argued that hyperaemic microvascular resistance (HMR), defined as the ratio of mean distal coronary pressure to flow velocity, is overestimated in the presence of a coronary stenosis compared to actual microvascular resistance (MR), due to neglecting collateral flow. We aimed to test the hypothesis that HMR allows accurate identification of microvascular functional abnormalities by evaluating the association between high or low HMR and the presence of myocardial ischaemia on non-invasive stress testing. METHODS AND RESULTS: Myocardial perfusion scintigraphy was performed in 228 patients, with 299 lesions to identify reversible myocardial ischaemia. Intracoronary distal pressure and flow velocity were assessed during adenosine-induced hyperaemia (20-40 µg, intracoronary) to determine hyperaemic stenosis resistance (HSR) and HMR. HMR >1.9 mmhg/cm/s was defined as high. The diagnostic odds ratio (OR) for myocardial ischaemia for lesions associated with high compared to low HMR was 2.6 (95% confidence interval [CI]: ; p<0.001) overall, 3.3 (95% CI: ; p=0.02) for lesions with HSR >0.8 mmhg/cm/s, and 1.3 (95% CI: ; p=0.52) for lesions with HSR 0.8 mmhg/cm/s. 38 Publicaties Medische Staf

40 CONCLUSIONS: The increased risk of myocardial ischaemia in the presence of high HMR, uncorrected for collateral flow, demonstrates that HMR is reflective of an increase in actual MR, identifying pertinent pathophysiological alterations in the microvasculature. PMID: Van de Hoef TP, Nolte F, EchavarrÍa-Pinto M, van Lavieren MA, Damman P, Chamuleau SA, Voskuil M, Verberne HJ, Henriques JP, van Eck-Smit BL, Koch KT, de Winter RJ, Spaan JA, Siebes M, Tijssen JG, Meuwissen M, Piek JJ. Impact of hyperaemic microvascular resistance on fractional flow reserve measurements in patients with stable coronary artery disease: insights from combined stenosis and microvascular resistance assessment. Heart Jun;100(12): Epub 2014 Apr 11. BACKGROUND: Fractional flow reserve (FFR) aims to identify the extent of epicardial disease, but may be obscured by involvement of the coronary microvasculature. We documented the impact of hyperaemic stenosis resistance (HSR) and hyperaemic microvascular resistance (HMR) on FFR, and its relationship with myocardial ischaemia in patients with stable coronary artery disease. METHODS AND RESULTS: We evaluated 255 coronary arteries with stenoses of intermediate severity by means of intracoronary pressure and flow measurements to determine FFR, HSR and HMR. Myocardial perfusion scintigraphy (MPS) was performed to identify inducible myocardial ischaemia. In 178 patients, HMR was additionally determined in a reference coronary artery. Target vessel HMR was stratified according to reference vessel HMR tertiles. The diagnostic OR for inducible ischaemia on MPS of a positive compared with a negative FFR was significantly higher only in the presence of a high HMR (at the 0.75 and 0.80 FFR cut-off). Among stenoses with a positive FFR, the prevalence of ischaemia was significantly higher when HMR was high despite equivalent FFR across the HMR groups. This was paralleled by a concomitant significant increase in HSR with increasing HMR across groups. The relation between FFR and HSR (r(2)=0.54, p<0.001) was modulated by the magnitude of HMR, and improved substantially after adjustment for HMR (adjusted-r(2)=0.73, p<0.001), where, for epicardial disease of equivalent severity, FFR increased with increasing HMR. CONCLUSIONS: Identification of epicardial disease severity by FFR is partly obscured by the microvascular resistance, which illustrates the necessity of combined pressure and flow measurements in daily practice. PMID: Van de Hoef TP, van Lavieren MA, Damman P, Delewi R, Piek MA, Chamuleau SA, Voskuil M, Henriques JP, Koch KT, de Winter RJ, Spaan JA, Siebes M, Tijssen JG, Meuwissen M, Piek JJ. Physiological basis and long-term clinical outcome of discordance between fractional flow reserve and coronary flow velocity reserve in coronary stenoses of intermediate severity. Circ Cardiovasc Interv Jun;7(3): Epub 2014 Apr 29. Cardiologie 39

41 BACKGROUND: Discordance between fractional flow reserve (FFR) and coronary flow velocity reserve (CFVR) may reflect important coronary pathophysiology but usually remains unnoticed in clinical practice. We evaluated the physiological basis and clinical outcome associated with FFR/CFVR discordance. METHODS AND RESULTS: We studied 157 intermediate coronary stenoses in 157 patients, evaluated by FFR and CFVR between April 1997 and September 2006 in which revascularization was deferred. Long-term follow-up was performed to document the occurrence of major adverse cardiac events: cardiac death, myocardial infarction, or target vessel revascularization. Discordance between FFR and CFVR occurred in 31% and 37% of stenoses at the 0.75, and 0.80 FFR cut-off value, respectively, and was characterized by microvascular resistances during basal and hyperemic conditions. Follow-up duration amounted to 11.7 years (Q1-Q3, years). Compared with concordant normal results of FFR and CFVR, a normal FFR with an abnormal CFVR was associated with significantly increased major adverse cardiac events rate throughout 10 years of follow-up, regardless of the FFR cut-off applied. In contrast, an abnormal FFR with a normal CFVR was associated with equivalent clinical outcome compared with concordant normal results: 3 years when FFR <0.75 was depicted abnormal and throughout 10 years of follow-up when FFR 0.80 was depicted abnormal. CONCLUSIONS: Discordance of CFVR with FFR originates from the involvement of the coronary microvasculature. Importantly, the risk for major adverse cardiac events associated with FFR/ CFVR discordance is mainly attributable to stenoses where CFVR is abnormal. This emphasizes the requirement of intracoronary flow assessment in addition to coronary pressure for optimal risk stratification in stable coronary artery disease. Comment in: Moving beyond coronary stenosis: has the time arrived to address important physiological questions not answered by fractional flow reserve alone? [Circ Cardiovasc Interv. 2014] PMID: Schaap J, de Groot JA, Nieman K, Meijboom WB, Boekholdt SM, Kauling RM, Post MC, Van der Heyden JA, de Kroon TL, Rensing BJ, Moons KG, Verzijlbergen JF. Added value of hybrid myocardial perfusion SPECT and CT coronary angiography in the diagnosis of coronary artery disease. Eur Heart J Cardiovasc Imaging Nov;15(11): Epub 2014 Jul 29. AIMS: Hybrid single photon emission computed tomography (SPECT)/coronary computed tomography angiography (CCTA) has only been evaluated for its diagnostic accuracy as a single test in patients suspected of significant coronary artery disease (CAD). Added value of hybrid SPECT/CCTA beyond usual clinical work-up, or use of each of these tests separately, remains unclear. We evaluated the added value of hybrid myocardial perfusion SPECT (SPECT) and CCTA, beyond pre-test likelihood and exercise stress ECG (X-ECG), in the diagnosis of CAD. 40 Publicaties Medische Staf

42 METHODS AND RESULTS: Two hundred and five patients with stable angina pectoris and intermediate-to-high pre-test likelihood were prospectively included. All patients underwent clinical history and examination, X-ECG, stress and rest SPECT, coronary calcium scoring (CCS) and CCTA. Fractional flow reserve measurement <0.80 or a lesion >50% on coronary angiography (CA) served as reference standard for significant CAD. Multiple imputation was used to correct for missing test results (17-20%). Added value of hybrid SPECT/CCTA to the basic model of pre-test likelihood plus X-ECG was quantified using logistic regression analysis. Model differences were then assessed using differences in C-index and in net reclassification improvement (NRI). The basic model had a C-index of 0.73 (95%CI ). This significantly increased to 0.85 (95%CI ) by addition of only SPECT, to 0.90 (95%CI ) when adding only CCTA, and to 0.96 (95%CI ) when adding hybrid SPECT/CCTA. The accompanying NRIs were 0.82 (95%CI ), 0.86 (95%CI ) and 1.57 (95%CI ) respectively. CONCLUSION: Current analysis resembles clinical routine of layered testing and shows that hybrid SPECT/CCTA imaging has a substantially higher yield than standalone SPECT or CCTA in the diagnostic workup of patients suspected of significant CAD. PMID: Schölzel BE, Snijder RJ, Mager JJ, van Es HW, Plokker HW, Reesink HJ, Morshuis WJ, Post MC. Chronic thromboembolic pulmonary hypertension. Neth Heart J Dec;22(12): Chronic pulmonary thromboembolic disease is an important cause of severe pulmonary hypertension, and as such is associated with significant morbidity and mortality. The prognosis of this condition reflects the degree of associated right ventricular dysfunction, with predictable mortality related to the severity of the underlying pulmonary hypertension. Left untreated, the prognosis is poor. Pulmonary endarterectomy is the treatment of choice to relieve pulmonary artery obstruction in patients with chronic thromboembolic pulmonary hypertension and has been remarkably successful. Advances in surgical techniques along with the introduction of pulmonary hypertension-specific medication provide therapeutic options for the majority of patients afflicted with the disease. However, a substantial number of patients are not candidates for pulmonary endarterectomy due to either distal pulmonary vascular obstruction or significant comorbidities. Therefore, careful selection of surgical candidates in expert centres is paramount. The current review focuses on the diagnostic approach to chronic thromboembolic pulmonary hypertension and the available surgical and medical therapeutic options. PMID: Cardiologie 41

43 Schölzel BE, Post MC, van de Bruaene A, Dymarkowski S, Wuyts W, Meyns B, Budts W, Delcroix M. Prediction of hemodynamic improvement after pulmonary endarterectomy in chronic thromboembolic pulmonary hypertension using non-invasive imaging. Int J Cardiovasc Imaging Jan;31(1): Epub 2014 Aug 22. Pulmonary endarterectomy (PEA) is the recommended treatment in chronic thromboembolic pulmonary hypertension (CTEPH). Prediction of outcome after PEA remains challenging. In search for pre-operative predictors we evaluated non-invasive parameters measured by chest CT-scan and echocardiography. Between May 2004 and January 2009, 52 consecutive patients with CTEPH who underwent PEA (59.6% female, mean age 58.9 ± 13.4 years) were included. Prior to surgery, pulmonary artery (PA) diameter indices were calculated by chest CT scan and different echocardiographic measurements to evaluate pulmonary hypertension were obtained. Hemodynamic improvement after PEA was defined as a pulmonary vascular resistance (PVR) <500 dyn s cm(-5) and a mean pulmonary artery pressure <35 mmhg 3 days after PEA. Mortality was evaluated at day 30. Mean pulmonary artery pressure (PAP) at baseline was 40.1 ± 8.5 mmhg, with a PVR of 971 ± 420 dyn s cm(-5). Persistent pulmonary hypertension was observed in 15 patients (28.8%). Gender, pre-operative mean PAP, PA diameter indices, and tricuspid annular plane systolic excursion were all predictors for hemodynamic improvement after PEA. The indexed PA diameter on CT was the only independent predictor for hemodynamic improvement: 19.4 ± 2.4 versus 22.9 ± 4.9 mm/m(2) in those without improvement (OR 0.76: 95% CI , p = 0.04). All patients who died within 30 days (9.6%) had persistent pulmonary hypertension, with a post-operative mean PAP of 51.6 ± 14.1 mmhg and PVR of 692 ± 216 dyn s cm(-5). The pre-operative PA diameter indexed for body surface area is the only independent predictor for hemodynamic improvement after PEA in CTEPH patients. In all patients who died within 30 days after PEA, persistent pulmonary hypertension was present. PMID: Schölzel BE, Post MC, Dymarkowski S, Wuyts W, Meyns B, Budts W, Morshuis W, Snijder RJ, Delcroix M. Prediction of outcome after PEA in chronic thromboembolic pulmonary hypertension using indexed pulmonary artery diameter. Eur Respir J Mar;43(3): No abstract available. PMID: Publicaties Medische Staf

44 Cardiothoracale Chirurgie Kerngegevens 6 cardiothoracaal chirurgen: M. (Mohamed) Bentala, S. (Sander) Bramer, C.A. (Connie) Boot, dr. A.(Ali) Falsafi, P.A.E. (Peter) Hiddema, M.M. (Ries) Vrakking 3 verpleegkundig specialisten (fte 3) Samenvattingen gepubliceerde artikelen Tolsma M, Bentala M, Rosseel P, Gerritse BM, Dijkstra H, Mulder P, van der Meer N. The value of routine chest radiographs after minimally invasive cardiac surgery: an observational cohort study. J Cardiothorac Surg Nov 11;9(1):174. [Epub ahead of print]. BACKGROUND: Chest radiographs (CXRs) are obtained frequently in postoperative cardiac surgery patients. The diagnostic and therapeutic efficacy of routine CXRs is known to be low and the discussion regarding the safety of abandoning these CXRs after cardiac surgery is still ongoing. We investigated the value of routine CXRs directly after minimally invasive cardiac surgery. METHODS: We prospectively included all patients who underwent minimally invasive cardiac surgery by port access, ministernotomy or bilateral video-assisted thoracoscopy (VATS) in the year A direct postoperative CXR was performed on all patients at ICU arrival. All CXR findings were noted, including whether they led to an intervention or not. RESULTS: The results were compared to the postoperative CXR results in patients who underwent conventional cardiac surgery by full median sternotomy over the same period.main resultsa total of 249 consecutive patients were included. Most of these patients underwent valve surgery, rhythm surgery or a combination of both. The diagnostic efficacy for minor findings was highest in the port access and bilateral VATS groups (56% and 63% versus 28% and 45%) (p < 0.005). The diagnostic efficacy for major findings was also higher in these groups (8.9% and 11% versus 4.3% and 3.8%) (p = 0.010). The need for an intervention was most common after minimally invasive surgery by port access, although this difference was not statistically significant (p = 0.056). CONCLUSION: The diagnostic efficacy of routine CXRs performed after minimally invasive cardiac surgery by port access or bilateral VATS is higher than the efficacy of CXRs performed after conventional cardiac surgery. A routine CXR after these procedures should still be considered. PMID: PMCID: PMC Cardiothoracale Chirurgie 43

45 Hogervorst E, Rosseel P, van der Bom J, Bentala M, Brand A, van der Meer N, van de Watering L. Tolerance of intraoperative hemoglobin decrease during cardiac surgery. Transfusion Oct;54(10 Pt 2): Epub 2014 Apr 14. BACKGROUND: It has been suggested that a decrease of at least 50% from the preoperative hemoglobin (Hb) level during cardiac surgery is associated with adverse outcomes even if the absolute Hb level remains above the commonly used transfusion threshold of 7.0 g/dl. In this study the relation between intraoperative Hb decline of at least 50% and a composite endpoint was analyzed. STUDY DESIGN AND METHODS: This single-center study comprised 11,508 patients who underwent cardiac surgery and had normal preoperative Hb levels ( g/dl in women, g/dl in men) between January 2001 and December Logistic regression modeling was used. The composite endpoint comprised in-hospital mortality, stroke, myocardial infarction, and renal failure. RESULTS: Patients whose Hb did not decrease at least 50% and remained above 7 g/dl were used as reference (n = 9672). A total of 363 (3.2%) patients had an intraoperative Hb of less than 7 g/dl during surgery but a Hb decrease of less than 50%; 876 patients (7.4%) showed both a nadir Hb less than 7 g/dl and a Hb decrease of at least 50%, while 597 (5.2%) had a Hb decrease of at least 50% and a nadir Hb of at least 7 g/dl. In this last group the incidence of the composite endpoint was higher than in patients in the reference group (adjusted odds ratio, 1.27; 95% confidence interval, ). CONCLUSIONS: Our findings show that a decrease of at least 50% from baseline Hb during cardiac surgery is associated with adverse outcomes, even if the absolute Hb level remains higher than the commonly used transfusion threshold of 7.0 g/dl. PMID: De Jonge M, van Boxtel A, Soliman Hamad M, Mokhles M, Bramer S, Osnabrugge R, van Straten A, Berreklouw E. Intermittent warm blood versus cold crystalloid cardioplegia for myocardial protection: a propensity score-matched analysis of 12-year single-center experience. Perfusion Jun 26. [Epub ahead of print]. OBJECTIVES: This study analyzes the efficacy in myocardial protection of two types of cardioplegia solutions, namely, blood and crystalloid cardioplegia, both given intermittently in patients undergoing coronary artery bypass grafting (CABG). 44 Publicaties Medische Staf

46 METHODS: Adult patients undergoing primary isolated coronary artery bypass grafting between January 1998 and January 2011 with cardiopulmonary bypass, using either blood or crystalloid cardioplegia, were identified in our database. Propensity score matching was performed to create comparable patient groups. Multivariate logistic regression analysis was performed to identify independent risk factors for perioperative myocardial damage. The primary endpoint of the study was the maximum creatine kinase-mb (CK-MB) value within 5 days postoperatively with a cut-off point of 100 U/L. Early mortality and perioperative low cardiac output syndrome in both groups were compared. RESULTS: The study included 7138 CABG patients: 3369 patients using crystalloid cardioplegia and 3769 using blood cardioplegia. After propensity score matching, 2585 patients per study group remained for the analysis. Wilcoxon signed-rank test revealed significantly higher CK-MB levels in patients operated with the use of blood cardioplegia. Multivariate regression analysis identified blood cardioplegia as an independent risk factor for elevated CK-MB levels. However, it was associated with lower aspartate aminotransferase (AST) levels. The type of cardioplegia had no influence on early mortality, postoperative low cardiac output syndrome or intensive care unit stay. CONCLUSIONS: Blood cardioplegia was identified as an independent risk factor for elevated levels of CK-MB after CABG, but was associated with lower AST levels. The authors conclude that the type of cardioplegia had no significant influence on clinical outcome. PMID: Hulsman N, Hiddema PA, Veen EJ, van der Meer NJ. Traumatic cardiac injury by gun nails. Int J Crit Illn Inj Sci Apr;4(2): No abstract available. PMID: Cardiothoracale Chirurgie 45

47 Chirurgie Kerngegevens 16 chirurgen: R.M.P.H. (Rogier) Crolla, dr. P.D. (Paul) Gobardhan, H.G.W. (Hans) de Groot, dr. G.H. (Gwan) Ho, dr. L. (Lijckle) van der Laan, dr. E.J.T. (Ernest) Luiten, dr. J.K.S. (Hans) Nuytinck, dr. E.J.H. (Eric) van Rhede van der Kloot, dr. A.M. (Arjen) Rijken, P.J.H.J. (Piet) Romme, G.P. (George) van der Schelling, dr. E.J. (Eelco) Veen, dr. D.I. (Dagmar) Vos, dr. J.P.A.M. (Jos) Vroemen, J.C.H. (Jan) van der Waal, dr. J.H. (Jan) Wijsman 1 chivo vaatchirurgie: dr. M.M.A. (Mare) Lensvelt vanaf 7 april fellows onco/ge: dr. E.V.E. (Eva) Madsen t/m 15 augustus 2014, H.W. (Hugo) Nijhof vanaf 6 oktober fellow traumachirurgie: C.A.S. (Niels) Berende vanaf 1 juli assistenten in opleiding (10 fte) 14 assistenten niet in opleiding (14 fte) Subspecialismen: GE-oncologische chirurgie, traumachirurgie, vaatchirurgie, longchirurgie, mammachirurgie, algemene chirurgie Samenvattingen gepubliceerde artikelen De Kruijf M, Vroemen JP, de Leur K, van der Voort EA, Vos DI, Van der Laan L. Proximal fractures of the humerus in patients older than 75 years of age: should we consider operative treatment? J Orthop Traumatol Jun;15(2): BACKGROUND: Over 75% of patients presenting with a proximal humerus fracture are 70 years or older. Very little is known about the outcome after operative treatment of these fractures in very old patients. This study was performed to gain more insight in safety and functional outcome of surgical treatment of proximal humerus fractures in the elderly. MATERIALS AND METHODS: In this observational study, we analyzed all operatively treated patients, aged 75 or older, with a proximal humerus fracture between January 2003 and December 2008 in our center. Patient selection was on clinical grounds, based on physical, mental, and social criteria. Complications were evaluated. We used the DASH Questionnaire to investigate functional outcome, pain, and ADL limitations. RESULTS: Sixty-four patients were treated surgically for a displaced proximal fracture of the humerus: 15 two-part, 32 three-part, and 17 four-part fractures. Mean DASH scores were 37.5, 36.9, and 48.6, respectively. Regarding the operative methods, overall good results were obtained with the modern locked plate osteosynthesis (mean DASH 34.4). Prosthetic treatment, mostly used in highly comminuted fractures, often resulted in poor function (mean DASH 72.9). Persistent pain and ADL limitations were more present in more comminuted fractures (64 and 50% in patients with 4-part fractures vs. 14% in 2-part fractures). There were no postoperative deaths within 3 months of surgery, and fracture-related and non-fracture-related complication rates were low (non-union 3%; 1 myocardial infarction). 46 Publicaties Medische Staf

48 CONCLUSION: This study shows that it is safe and justifiable to consider surgical treatment of a severely dislocated proximal humerus fracture in selected patients aged 75 and older. LEVEL OF EVIDENCE: According to OCEBM Working Group, Level IV. PMID: Van der Slegt J, Steunenberg SL, Donker JM, Veen EJ, Ho GH, de Groot HG, van der Laan L. The current position of precuffed expanded polytetrafluoroethylene bypass grafts in peripheral vascular surgery. J Vasc Surg Jul;60(1): Epub 2014 Mar 12. OBJECTIVE: Long-term results of precuffed expanded polytetrafluoroethylene (eptfe) grafts used for peripheral bypass surgery are lacking. The aim of this study was to obtain the long-term outcomes of precuffed eptfe grafts compared with autologous saphenous vein (ASV) grafts used in patients with peripheral arterial disease (PAD). METHODS: A single-institution retrospective study of precuffed eptfe and ASV graft performances in patients with PAD was undertaken between January 2004 and December Five-year primary patency, secondary patency, and limb salvage rates were determined by Kaplan-Meier analyses. RESULTS: A total of 467 bypass grafts were included in this study (169 precuffed eptfe grafts and 298 ASV grafts). Secondary patency rates of eptfe vs ASV at 1 and 5 years, respectively, were as follows: for 134 supragenicular femoropopliteal bypasses, 60% and 27% vs 89% and 85% (P <.05); for 190 infragenicular femoropopliteal bypasses, 40% and 25% vs 86% and 79% (P <.05); and for 84 femorocrural bypasses, 30% and 14% vs 50% and 50% (P <.05). Five-year limb salvage rates of eptfe vs ASV for supragenicular femoropopliteal bypasses were 82% vs 94% (P =.16); for infragenicular femoropopliteal bypasses, 41% vs 92% (P <.05); and for femorocrural bypasses, 43% vs 64% (P =.06). CONCLUSIONS: ASV bypasses are still the first-choice conduit in peripheral bypass surgery performed in patients with PAD. Precuffed eptfe bypasses are acceptable alternatives in the absence of adequate autologous vein. PMID: Te Slaa A, Dolmans D, Ho G, van der Laan L. Treatment strategies and clinical aspects of lower limb edema following peripheral bypass surgery. Phlebology May 19;29(1 suppl): [Epub ahead of print]. In selected patients who suffer from severe peripheral artery disease (PAD) a revascularization with a peripheral bypass might be considered. Postoperative edema is a well-known phenomenon following peripheral bypass surgery and is probably caused by multiple factors. Chirurgie 47

49 Although postoperative edema causes discomfort to patients, the effects on the quality of life are unknown. Treatment and preventive strategies should nonetheless aim at achieving a net absorption of fluid from the interstitial space into the vascular or lymphatic compartment. A brief summarization of treatment strategies of lower limb edema will be presented that include the use of compression stocking and intermittent pneumatic compression. So far, the postoperative application of compression stockings seem to prevent and reduce edema as much as possible. Quality of life improves slightly following peripheral bypass surgery. However, a contribution of edema on the quality of life could not be detected. PMID: Van der Slegt J, Kluytmans JA, Mulder PG, Veen EJ, Ho GH, van der Laan L. Surgical site infection after multiple groin incisions in peripheral vascular surgery. Surg Infect (Larchmt) Dec;15(6): Abstract Background: Patients with peripheral arterial disease (PAD) are at risk for revision surgery in the groin and therefore at potential risk for surgical site infections (SSIs). In an observational study, a cohort of patients with peripheral arterial disease was followed to examine the effect of different incision intervals on SSI-free survival. METHODS: Patients, needing peripheral vascular surgery because of PAD, were retrieved from a prospectively collected database on SSIs after vascular surgery between March 2009 and January 2012, the group consisting of 720 patients. Of these, 255 patients were selected (age 71.9±10.4 y). Cox proportional hazards models were used for event-history analyses. The effect of incision interval was estimated with adjustment for a number of potential confounders. Effects were quantified by means of hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: No significant effect on the incision interval on SSI-free survival was observed. After separating incisional SSIs into superficial- and deep-seated, a significant linear trend effect of the groin incision interval on deep-incisional SSI development was observed: the shorter the interval, the higher the event rate (HR 1.5 per category, 95% CI , p=0.22). Besides the incision interval, the Rutherford classification was a significant risk factor for SSI development (HR 3.0; 95% CI ; p<0.0005). CONCLUSION: Revision surgery in the groin puts patients at risk for deep-incisional SSI. No effect on superficial incisional SSI development was observed. Besides the incision interval, the Rutherford classification was a significant risk factor for both superficial- and deep-incisional SSI. Quality improvement and better risk stratification schemes are suggested. PMID: Publicaties Medische Staf

50 Raats JW, Flu HC, Ho GH, Veen EJ, Vos LD, Steyerberg EW, van der Laan L. Long-term outcome of ruptured abdominal aortic aneurysm: impact of treatment and age. Clin Interv Aging Oct 13;9: ecollection BACKGROUND: Despite advances in operative repair, ruptured abdominal aortic aneurysm (raaa) remains associated with high mortality and morbidity rates, especially in elderly patients. The purpose of this study was to evaluate the outcomes of emergency endovascular aneurysm repair (eevar), conventional open repair (OPEN), and conservative treatment in elderly patients with raaa. METHODS: We conducted a retrospective study of all raaa patients treated with OPEN or eevar between January 2005 and December 2011 in the vascular surgery department at Amphia Hospital, the Netherlands. The outcome in patients treated for raaa by eevar or OPEN repair was investigated. Special attention was paid to patients who were admitted and did not receive operative intervention due to serious comorbidity, extremely advanced age, or poor physical condition. We calculated the 30-day raaa-related mortality for all raaa patients admitted to our hospital. RESULTS: Twelve patients did not receive operative emergency repair due to extreme fragility (mean age 87 years, median time to mortality 27 hours). Twenty-three patients had eevar and 82 had OPEN surgery. The 30-day mortality rate in operated patients was 30% (7/23) in the eevar group versus 26% (21/82) in the OPEN group (P=0.64). No difference in mortality was noted between eevar and OPEN over 5 years of follow-up. There were more cardiac adverse events in the OPEN group (n=25, 31%) than in the eevar group (n=2, 9%; P=0.035). Reintervention after discharge was more frequent in patients who received eevar (35%) than in patients who had OPEN (6%, P<0.001). Advancing age was associated with increasing mortality (hazard ratio 1.05 [95% confidence interval ]) per year for patients who received operative repair, with a 67%, 76%, and 100% 5-year mortality rate in the 34 patients aged <70 years, 59 patients aged years, and 12 octogenarians, respectively; 30-day raaa-related mortality was also associated with increasing age (21%, 30%, and 61%, respectively; P=0.008). CONCLUSION: The 30-day and 5-year mortality in patients who survived raaa was equal between the treatment options of eevar and OPEN. Particularly fragile and very elderly patients did not receive operative repair. The decision to intervene in raaa should not be made on the basis of patient age alone, but also in relation to comorbidity and patient preference. PMID: PMCID: PMC De Danschutter SJ, Schreinemakers JM, Smit LH, van der Laan L, Nuytinck HK. Thyroid surgery and the usefulness of intraoperative neuromonitoring, a single center study. J Invest Surg Nov 10. [Epub ahead of print] Purpose/Aim of study: To compare the use of intraoperative neuromonitoring (IONM) versus visualization of the recurrent laryngeal nerve (RLN) alone in thyroid surgery with regard Chirurgie 49

51 to incidence in postoperative RLN injury and operation time. Materials and Methods: This retrospective cohort study was performed in the Amphia Hospital, the Netherlands. All thyroid gland operations were collected from September 2009 to October For each case we recorded the patient characteristics, indication for surgery, intraoperative data, complications, results of pathological evaluation, and consultation of a ENT-surgeon. Research of current literature and statistical analysis was performed. RESULTS: In total, 147 patients were included and classified into an IONM and non-ionm group. Both groups were similar in demographical aspects and indications for surgery. In total, we had 170 nerves at risk (NAR). In both groups, there were 85 (50%) NAR. Overall injury to the RLN was 6%. A statistical significant decrease of permanent RLN injuries was noticed in the IONM group compared to the non-ionm group (n = 0 vs n = 6; p =.044). In transient RLN injury, no difference was noticed (n = 2 vs n = 2). Operation time with or without IONM was not significantly different for hemithyroidectomies, neither for total thyroidectomies. CONCLUSION: IONM is a useful tool as an adjunct in thyroid surgery to prevent RLN injury. A statistical significant decrease in permanent RLN injury with the use of IONM was found, but it did not significantly decrease time of operation. PMID: Van der Slegt J, Flu HC, Veen EJ, Ho GH, de Groot HG, Vos LD, van der Laan L. Adverse events after treatment of patients with acute limb ischemia. Ann Vasc Surg Feb;29(2): Epub 2014 Nov 28. BACKGROUND: To assess the outcome and the occurrence and consequences of adverse events (AEs) after treatment of acute limb ischemia (ALI). METHODS: Retrospective analysis on intra-arterial thrombolysis (group I) and thromboembolectomy (group II). Outcome measures were primary patency and limb salvage rates. AEs and consequences were registered during admission and 30 days after discharge. RESULTS: A total of 238 procedures were included (group I, 173 vs. group II, 65). The primary patency (P = 0.144) and limb salvage rates (P = 0.166) were not significantly different between both groups. A total of 195 AEs were registered. Most AEs were procedure related and resulted in surgical reintervention (77% vs. 76%). Some AEs resulted in irreversible physical damage (15% vs. 25%) and death (6% vs. 12%). CONCLUSIONS: Both, intra-arterial thrombolysis and thromboembolectomies are adequate therapies; however, they result in a wide variety of AEs resulting in serious morbidity and even death. PMID: Publicaties Medische Staf

52 Beek MA, Gobardhan PD, Klompenhouwer EG, Rutten HJ, Voogd AC, Luiten EJ. Axillary reverse mapping (ARM) in clinically node positive breast cancer patients. Eur J Surg Oncol Jan;41(1): Epub 2014 Oct 29. BACKGROUND: Axillary reverse mapping (ARM) is a technique to map and preserve upper extremity lymphatic drainage during axillary lymph node dissection (ALND) in breast cancer patients. We prospectively evaluated the metastatic involvement of ARM-nodes in patients who underwent an ALND for clinically node positive disease following (neo)adjuvant chemotherapy (NAC) in comparison to patients in whom primary ALND was performed without NAC. PATIENTS AND METHODS: Patients with clinically node positive invasive breast cancer, confirmed by fine needle aspiration cytology and scheduled for primary ALND were enrolled in the study. Patients were separated into two groups: one group treated with NAC (NAC+ group) and one group not treated with NAC (NAC- group). ARM was performed in all patients by injecting blue dye into the ipsilateral upper extremity. During ALND, ARM-nodes were first identified and removed separately, followed by a standard ALND. RESULTS: 91 patients were included in the NAC+ and 21 patients in the NAC- group. There was no difference in the ARM visualization rate between the two groups (86.8% for NAC+ group versus 90.5% for NAC- group, P = 0.647). In the NAC+ group 16.5% of the patients had metastatic involvement of the ARM-nodes versus 36.8% of the patients in the NAC- group (P = 0.048). CONCLUSION: The risk of metastatic involvement of ARM-nodes in clinically node positive breast cancer patients is significantly lower in patients who have received NAC. Copyright 2014 Elsevier Ltd. All rights reserved. PMID: Van Baal MC, Bollen TL, Bakker OJ, van Goor H, Boermeester MA, Dejong CH, Gooszen HG, van der Harst E, van Eijck CH, van Santvoort HC, Besselink MG; Dutch Pancreatitis Study Group*. [Wijsman J, Crolla R, van der Schelling GP et al...]. The role of routine fine-needle aspiration in the diagnosis of infected necrotizing pancreatitis. Surgery Mar;155(3): Epub 2013 Oct 12. BACKGROUND: Diagnosing infected necrotizing pancreatitis (INP) may be challenging. The aim of this study was to determine the added value of routine fine-needle aspiration (FNA) in addition to clinical and imaging signs of infection in patients who underwent intervention for suspected INP. METHODS: We conducted a post hoc analysis of 208 consecutive patients from a prospective, multicenter database who underwent intervention because of suspected INP. In retrospect, 3 groups were constructed based on the patients preoperative characteristics: Clinical, imaging, and FNA. Patients in the clinical group had clinical signs of infection but no gas on preoperative computed tomography (CT) and no FNA performed before intervention. Patients in the imaging group had gas bubbles on the preoperative CT but no was FNA performed, whereas patients in Chirurgie 51

53 the FNA group had a positive FNA before intervention. The reference standard for infection was the culture taken during the first intervention (either catheter drainage or necrosectomy). RESULTS: The initial intervention for INP was performed a median of 27 days (interquartile range, 20-39) after admission without difference between the 3 groups (P =.15). Infection was confirmed in 80% of 92 patients of the clinical group, in 94% of 88 patients of the imaging group, and in 86% of 28 patients of the FNA group (P =.07). Mortality was 19% and was not different between groups (P =.39). CONCLUSION: INP can generally be diagnosed based on clinical or imaging signs of infection. FNA may be useful in patients with unclear clinical signs and no imaging signs of INP. *Collaborators: Boermeester M, Bollen T, Dejong C, van Eijck C, van Goor H, Gooszen H, Hofker H, Laméris J, van Leeuwen M, Schaapherder A, Timmer R, Nieuwenhuijs V, van Dam R, Rutten J, Stoot J, Keulemans Y, Vliegen R, Roeterdink A, Ali U, Schrijver A, Rijnhart H, Cirkel G, van Erpecum K, Vleggaar F, Akkermans L, van Leeuwen M, Rijkers G, Wiezer M, Weusten B, Biemond H, van Ramshorst B, Ploeg R, Buitenhuis H, van Vliet S, Ramcharan S, van Dullemen H, Hofker H, Nieuwenhuijs V, van Ruler O, Laméris W, Laméris J, Gouma D, Busch O, Fockens P, Haasnoot A, Veenendaal R, Schaapherder A, Witteman B, Kruyt P, Pierie J, Spoelstra P, Dol J, Gerritsen R, Manusama E, Lange J, Wijffels N, van Walraven L, Coene P, Kubben F, Wijsman J, Crolla R, van Milligen de Wit AW, Rijk M, van der Schelling G, Stassen L, Karsten T, Buscher H, Hesselink E, Heisterkamp J, van Oostvogel H, Grubben M, Tan A, Rosman C, van der Wal J, Morak M, Kuipers E, Poley J, Bruno M, Jansen J, Hermans J, P S, van Laarhoven C, Zeguers V, Wahab P, Lips D, Olsman J, van Munster I, Bosscha K, Kolkman J, Huisman A, de Wit R, Tuynman H, Wiarda B, Houdijk A, Consten E, Schwartz M, Brink M, van der Peet D, Mulder C, Questa M. PMID: Van Erning FN, Crolla RM, Rutten HJ, Beerepoot LV, van Krieken JH, Lemmens VE. No change in lymph node positivity rate despite increased lymph node yield and improved survival in colon cancer. Eur J Cancer Dec;50(18): AIM: To analyse trends over time in the number of lymph nodes evaluated and in the proportion of node positivity and to investigate the impact on survival for patients with colon cancer. PATIENTS AND METHODS: 8616 patients resected for M0 colon cancer diagnosed in the southern Netherlands between 2000 and 2011 were included in this study. Trends in nodal evaluation and node positivity were analysed. Multivariable logistic regressions were used to assess the influence of period of diagnosis on adequate nodal evaluation (P12 lymph nodes) and no depositivity after adjusting for patient and tumour characteristics. Crude 5-year relative survival was used as an estimate for disease-specific survival. 52 Publicaties Medische Staf

54 RESULTS: Overall, the proportion adequate nodal evaluation increased from 13% in to 59% in (p < ), whereas the proportion node positivity remained similar across study periods (approximately 35%). Patients diagnosed in later periods were more likely to have received adequate nodal yield (adjusted Odds ratio (OR) versus , 95% Confidence interval (CI) ). However, the adjusted odds of having node positive disease did not differ between periods of diagnosis. Relative excess risk of dying was independently correlated with the number of lymph nodes evaluated (1 8 LNs versus P12 LNs, N0: 2.2, 95% CI ; N+: 1.7, 95% CI ) and period of diagnosis ( versus , N+ only: 0.8, 95% CI ). CONCLUSION: The reason for improved survival with increased nodal yield is different from simple understaging as the proportion of lymph node positivity remained constant. PMID: Chirurgie 53

55 Barentsz MW, Postma EL, van Dalen T, van den Bosch MA, Miao H, Gobardhan PD, van den Hout LE, Pijnappel RM, Witkamp AJ, van Diest PJ, van Hillegersberg R, Verkooijen HM. Prediction of positive resection margins in patients with non-palpable breast cancer. Eur J Surg Oncol Jan;41(1): Epub 2014 Sep 2. BACKGROUND: In patients undergoing breast conserving surgery for non-palpable breast cancer, obtaining tumour free resection margins is important to prevent reexcision and local recurrence. We developed a model to predict positive resection margins in patients undergoing breast conserving surgery for non-palpable invasive breast cancer. METHODS: A total of 576 patients with non-palpable invasive breast cancer underwent breast conserving surgery in five hospitals in the Netherlands. A prediction model for positive resection margins was developed using multivariate logistic regression. Calibration and discrimination of the model were assessed and the model was internally validated by bootstrapping. RESULTS: Positive resection margins were present in 69/576 (12%) patients. Factors independently associated with positive resection margins included mammographic microcalcifications (OR 2.14, ), tumour size (OR 1.75, ), presence of DCIS (OR 2.61, ), Bloom and Richardson grade 2/3 (OR 1.82, ), and caudal location of the lesion (OR 2.4, ). The model was well calibrated and moderately able to discriminate between patients with positive versus negative resection margins (AUC 0.70, 95% CI, , and 0.69 after internal validation). CONCLUSION: The presented prediction model is moderately able to differentiate between women with high versus low risk of positive margins, and may be useful for surgical planning and preoperative patient counselling. PMID: Hopmans CJ, den Hoed PT, van der Laan L, van der Harst E, van der Elst M, Mannaerts GH, Dawson I, Timman R, Wijnhoven BP, IJzermans JN. Assessment of surgery residents operative skills in the operating theater using a modified Objective Structured Assessment of Technical Skills (OSATS): A prospective multicenter study. Surgery Nov;156(5): Epub 2014 Sep 16. BACKGROUND: With the implementation of competency-based curricula, Objective Structured Assessment of Technical Skills (OSATS) increasingly is being used for the assessment of operative skills. Although evidence for its usefulness has been demonstrated in experimental study designs, data supporting OSATS application in the operating room are limited. This study evaluates the validity and reliability of the OSATS instrument to assess the operative skills of surgery residents in the operating theater. METHODS: Twenty-four residents were recruited from seven hospitals within a general surgical training region and classified equally into three groups according to postgraduate training year (PGY). Each resident had to perform five different types of operations. Surgical performance was measured using a modified OSATS consisting of three scales: Global Rating 54 Publicaties Medische Staf

56 Scale, Overall Performance Scale, and Alphabetic Summary Scale. Validity and reliability metrics included construct validity (Kruskal-Wallis test) and internal consistency reliability (Cronbach s a coefficient). Spearman s correlation coefficients were calculated to determine correlations between the different scales. RESULTS: Eighteen residents (PGY 1-2 [n = 7]; PGY 3-4 [n = 8]; PGY 5-6 [n = 3]) performed 249 operations. Comparisons of the performance scores revealed that evidence for construct validity depended on the difficulty level of the selected procedures. For individual operations, internal consistency reliability of the Global Rating Scale ranged from 0.93 to Scores on the different scales correlated strongly (r = , P <.001). CONCLUSION: Assessment of operative skills in the operating theater using this modified OSATS instrument has the potential to establish learning curves, allowing adequate monitoring of residents progress in achieving operative competence. The Alphabetic Summary Scale seems to be of additional value. Use of the Overall Performance Scale should be reconsidered. PMID: Raats JW, Donker JM, van der Laan L. Een jongen met pijn links onder in de buik. [A 15-year old boy with abdominal pain]. Ned Tijdschr Geneeskd. 2014;158:A6854. A 15-year-old boy came to the emergency department with abdominal pain in the left lower quadrant. The medical history included surgery for malrotation of bowel in two of his brothers. A CT-abdomen showed malrotation of the colon with a left-sided appendicitis and polysplenia. An emergency laparoscopic appendectomy was performed. Recovery was uneventful. PMID: Van Verschuer VM, van Deurzen CH, Westenend PJ, Rothbarth J, Verhoef C, Luiten EJ, Menke-Pluijmers MB, Koppert LB. Prophylactic nipple-sparing mastectomy leaves more terminal duct lobular units in situ as compared with skin-sparing mastectomy. Am J Surg Pathol May;38(5): Prophylactic skin-sparing mastectomy (SSM) is associated with major breast cancer risk reduction in high-risk patients. In prophylactic nipple-sparing mastectomy (NSM) it is unknown how many terminal duct lobular units (TDLUs) remain behind the nipple-areola complex (NAC) additionally to those behind the skin flap. Therefore, safety of NSM can be doubted. We compared amounts of TDLUs behind the NAC as compared with the skin. In prophylactic SSM and conventional therapeutic mastectomy patients, the NAC and an adjacent skin island (SI) were resected as if it were an NSM. NAC and SI were serially sectioned perpendicularly to the skin and analyzed for the amount of TDLUs present. Slides of NAC and SI were scanned, and slide surface areas (cm) were measured. TDLUs/cm in NAC versus SI specimen, representing TDLU density, were analyzed pairwise. In total, 105 NACs and SIs of 90 women were analyzed. Sixty- Chirurgie 55

57 four NACs (61%) versus 25 SIs (24%) contained 1 TDLUs. Median TDLU density was higher in NAC specimens (0.2 TDLUs/cm) as compared with SI specimens (0.0 TDLUs/cm; P<0.01). Independent risk factors for the presence of TDLUs in the NAC specimen were younger age and parity (vs. nulliparity). The finding of higher TDLU density behind the NAC as compared with the skin flap suggests that sparing the NAC in prophylactic NSM in high-risk patients possibly may increase postoperative breast cancer risk as compared with prophylactic SSM. Studies with long-term follow-up after NSM are warranted to estimate the level of residual risk. PMID: Sloothaak DA, van den Berg MW, Dijkgraaf MG, Fockens P, Tanis PJ, van Hooft JE, Bemelman WA; collaborative Dutch Stent-In study group [Rijken AM et al...]. Oncological outcome of malignant colonic obstruction in the Dutch Stent-In 2 trial. Br J Surg Dec;101(13): BACKGROUND: The Stent-In 2 trial randomized patients with malignant colonic obstruction to emergency surgery or stent placement as a bridge to elective surgery. The aim of this study was to compare the oncological outcomes. METHODS: Disease recurrence, and disease-free, disease-specific and overall survival were evaluated, including a subgroup analysis of patients with a stent- or guidewire-related perforation. RESULTS: Of 98 patients included in the original Stent-In 2 trial, patients with benign (16) or incurable (23) disease were excluded from this study, along with a patient who had withdrawn from the trial. Of the remaining 58 patients, 32 were randomized to emergency surgery (31 resection, 1 stoma only) and 26 to stenting. Unsuccessful stenting required emergency surgery in six patients owing to wire or stent perforation. Locoregional or distant disease recurrence developed in nine of 32 patients in the emergency surgery group and 13 of 26 in the stent group. Disease-free survival was worse in the subgroup with stent- or guidewire-related perforation. Five of six patients in this subgroup developed a recurrence, compared with nine of 32 in the emergency surgery group and eight of 20 who had unperforated stenting. CONCLUSION: Stent placement for malignant colonic obstruction was associated with a risk of recurrence in this trial, but the numbers are small. There is not enough evidence to refute the approach strongly. REGISTRATION NUMBER: ISRCTN ( * Van Hooft JE, Fockens P, Bemelman WA, Dijkgraaf MG, Sprangers MA, Buskens CJ, Jansen JM, Gerhards MF, Timmer R, van Ramshorst B, Oldenburg B, van Hilligersberg R, Bakker CM, Sosef M, Witteman P, Kruyt P, Ten Hove WR, Tseng LN, van der Linde K, Koopal SA, Marinelli AW, Perk L, Lutke Holzik MF, Grubben MJ, Heisterkamp J, Depla AC, Derksen E, Naber AH, van Geloven AA, Breumelhof R, Davids PH, Akol H, van der Zaag E, Schenk E, Patijn GA, Veenendaal RA, Tollenaar RA, van Berkel A, Gilissen LP, Nieuwenhuijzen GA, van der Waaij LA, Baas PC, Cense H, Scholten 56 Publicaties Medische Staf

58 P, van Wagensveld B, Koornstra JJ, Havenga K, van Milligen de Wit M, Rijken AM, Cazemier M, Guicherit OR, Houben MH, Steup WH. PMID: Goos JA, Hiemstra AC, Coupé VM, Diosdado B, Kooijman W, Delis-Van Diemen PM, Karga C, Beliën JA, Menke-van der Houven van Oordt CW, Geldof AA, Meijer GA, Hoekstra OS, Fijneman RJ; DeCoDe PET group; DeCoDe PET group. [Rijken AM et al...]. Epidermal growth factor receptor (EGFR) and prostaglandin-endoperoxide synthase 2 (PTGS2) are prognostic biomarkers for patients with resected colorectal cancer liver metastases. Br J Cancer Aug 12;111(4): Epub 2014 Jul 1. BACKGROUND: Resection of colorectal cancer liver metastasis (CRCLM) with curative intent has long-term benefit in ~40% of cases. Prognostic biomarkers are needed to improve clinical management and reduce futile surgeries. Expression of epidermal growth factor receptor (EGFR) and prostaglandin-endoperoxide synthase 2 (PTGS2; also known as cyclooxygenase-2) has been associated with carcinogenesis and survival. We investigated the prognostic value of EGFR and PTGS2 expression in patients with resected CRCLM. METHODS: Formalin-fixed paraffin-embedded CRCLM tissue and corresponding primary tumour specimens from a multi-institutional cohort of patients who underwent liver resection between 1990 and 2010 were incorporated into tissue microarrays (TMAs). TMAs were stained for EGFR and PTGS2 by immunohistochemistry. The hazard rate ratio (HRR) for the association between expression in CRCLM and overall survival was calculated using a 500-fold cross-validation procedure. RESULTS: EGFR and PTGS2 expression could be evaluated in 323 and 351 patients, respectively. EGFR expression in CRCLM was associated with poor prognosis (HRR 1.54; P<0.01) with a crossvalidated HRR of 1.47 (P=0.03). PTGS2 expression was also associated with poor prognosis (HRR 1.60; P<0.01) with a cross-validated HRR of 1.63 (P<0.01). Expression of EGFR and PTGS2 remained prognostic after multivariate analysis with standard clinicopathological variables (cross-validated HRR 1.51; P=0.02 and cross-validated HRR 1.59; P=0.01, respectively). Stratification for the commonly applied systemic therapy regimens demonstrated prognostic value for EGFR and PTGS2 only in the subgroup of patients who were not treated with systemic therapy (HRR 1.78; P<0.01 and HRR 1.64; P=0.04, respectively), with worst prognosis when both EGFR and PTGS2 were highly expressed (HRR 3.08; P<0.01). Expression of PTGS2 in CRCLM was correlated to expression in patient-matched primary tumours (P=0.02, 69.2% concordance). CONCLUSIONS: EGFR and PTGS2 expressions are prognostic molecular biomarkers with added value to standard clinicopathological variables for patients with resectable CRCLM. *Collaborators: Van Grieken NC, Perk LR, van den Tol MP, Te Velde EA, Windhorst AD, Baas J, Rijken AM, van Beek MW, Pijpers HJ, Bril H, Stockmann HB, Zwijnenburg A, Bosscha K, van den Brule AJ, Chirurgie 57

59 Hoekstra CJ, van der Linden JC, Borel Rinkes IH, van Diest PJ, van Hillegersberg R, Kranenburg O, Lam MG, Snoeren N, Liem IH, Roumen RM, Vening W. PMID: PMCID: PMC Ruitenbeek K, Ayez N, Verhoef C, de Wilt JH, Bottema J, Rijken AM, van Rij M, Koopman J, Zuckerman LA, Frohna P, Porte RJ. Safety and efficacy of a novel, dry powder fibrin sealant for hemostasis in hepatic resection. Dig Surg. 2014;31(6): Epub 2015 Jan 14. BACKGROUND/AIMS: Fibrocaps is a dry powder fibrin sealant containing human plasma-derived fibrinogen and thrombin. The safety, efficacy, and application methods for Fibrocaps were evaluated in an exploratory, first-in-human, noncomparative, clinical study. METHODS: Patients with minor bleeding/oozing after elective partial hepatic resection had Fibrocaps applied to the bleeding site either directly from the vial or from a spray device, with manual pressure applied using a cellulose, collagen, or gelatin sponge, if needed. Safety was evaluated at screening and postoperative days 1, 2, and 5, and weeks 4 and 12. The formation of anti-thrombin antibodies was assessed at baseline, and after 4 and 12 weeks. Time to hemostasis (TTH) within 10 min was determined. RESULTS: Twenty-nine patients were treated with Fibrocaps; 6 experienced serious adverse events that were not related to the course of treatment. Adverse events occurring in >10% of patients were nausea, constipation, hypotension, obstipation, hypokalemia, and postoperative pain. Most adverse events were mild or moderate in severity. No patient developed anti-thrombin antibodies. The percentage of patients who achieved hemostasis was 93%; the median TTH was 3.8 min (range ). Manual pressure was applied with Fibrocaps in 19 patients and considered beneficial in most. CONCLUSION: Fibrocaps was well tolerated in patients undergoing elective hepatic resection and resulted in rapid hemostasis. These safety and efficacy results support further clinical testing of this ready-to-use fibrin sealant as an adjunct to surgical hemostasis S. Karger AG, Basel. PMID: De Rooij T, Jilesen AP, Boerma D, Bonsing BA, Bosscha K, van Dam RM, van Dieren S, Dijkgraaf MG, van Eijck CH, Gerhards MF, van Goor H, van der Harst E, de Hingh IH, Kazemier G, Klaase JM, Molenaar IQ, Nieveen van Dijkum EJ, Patijn GA, van Santvoort HC, Scheepers JJ, van der Schelling GP, Sieders E, Vogel JA, Busch OR, Besselink MG; Dutch Pancreatic Cancer Group. A nationwide comparison of laparoscopic and open distal pancreatectomy for benign and malignant disease. J Am Coll Surg Mar;220(3): e1. Epub 2014 Nov 20. BACKGROUND: Cohort studies from expert centers suggest that laparoscopic distal pancreatectomy (LDP) is superior to open distal pancreatectomy (ODP) regarding postoperative 58 Publicaties Medische Staf

60 morbidity and length of hospital stay. But the generalizability of these findings is unknown because nationwide data on LDP are lacking. STUDY DESIGN: Adults who had undergone distal pancreatectomy in 17 centers between 2005 and 2013 were analyzed retrospectively. First, all LDPs were compared with all ODPs. Second, groups were matched using a propensity score. Third, the attitudes of pancreatic surgeons toward LDP were surveyed. The primary outcome was major complications (Clavien-Dindo grade III). RESULTS: Among 633 included patients, 64 patients (10%) had undergone LDP and 569 patients (90%) had undergone ODP. Baseline characteristics were comparable, except for previous abdominal surgery and mean tumor size. In the full cohort, LDP was associated with fewer major complications (16% vs 29%; p = 0.02) and a shorter median [interquartile range, IQR] hospital stay (8 days [7-12 days] vs 10 days [8-14 days]; p = 0.03). Of all LDPs, 33% were converted to ODP. Matching succeeded for 63 LDP patients. After matching, the differences in major complications (9 patients [14%] vs 19 patients [30%]; p = 0.06) and median [IQR] length of hospital stay (8 days [7-12 days] vs 10 days [8-14 days]; p = 0.48) were not statistically significant. The survey demonstrated that 85% of surgeons welcomed LDP training. CONCLUSIONS: Despite nationwide underuse and an impact of selection bias, outcomes of LDP seemed to be at least noninferior to ODP. Specific training is welcomed and could improve both the use and outcomes of LDP. PMID: Bakker OJ, van Brunschot S, van Santvoort HC, Besselink MG, Bollen TL, Boermeester MA, Dejong CH, van Goor H, Bosscha K, Ahmed Ali U, Bouwense S, van Grevenstein WM, Heisterkamp J, Houdijk AP, Jansen JM, Karsten TM, Manusama ER, Nieuwenhuijs VB, Schaapherder AF, van der Schelling GP, Schwartz MP, Spanier BW, Tan A, Vecht J, Weusten BL, Witteman BJ, Akkermans LM, Bruno MJ, Dijkgraaf MG, van Ramshorst B, Gooszen HG; Dutch Pancreatitis Study Group. Early versus on-demand nasoenteric tube feeding in acute pancreatitis. N Engl J Med Nov 20;371(21): BACKGROUND: Early enteral feeding through a nasoenteric feeding tube is often used in patients with severe acute pancreatitis to prevent gut-derived infections, but evidence to support this strategy is limited. We conducted a multicenter, randomized trial comparing early nasoenteric tube feeding with an oral diet at 72 hours after presentation to the emergency department in patients with acute pancreatitis. METHODS: We enrolled patients with acute pancreatitis who were at high risk for complications on the basis of an Acute Physiology and Chronic Health Evaluation II score of 8 or higher (on a scale of 0 to 71, with higher scores indicating more severe disease), an Imrie or modified Glasgow score of 3 or higher (on a scale of 0 to 8, with higher scores indicating more severe disease), or a serum C-reactive protein level of more than 150 mg per liter. Patients were randomly assigned Chirurgie 59

61 to nasoenteric tube feeding within 24 hours after randomization (early group) or to an oral diet initiated 72 hours after presentation (on-demand group), with tube feeding provided if the oral diet was not tolerated. The primary end point was a composite of major infection (infected pancreatic necrosis, bacteremia, or pneumonia) or death during 6 months of follow-up. RESULTS: A total of 208 patients were enrolled at 19 Dutch hospitals. The primary end point occurred in 30 of 101 patients (30%) in the early group and in 28 of 104 (27%) in the on-demand group (risk ratio, 1.07; 95% confidence interval, 0.79 to 1.44; P=0.76). There were no significant differences between the early group and the on-demand group in the rate of major infection (25% and 26%, respectively; P=0.87) or death (11% and 7%, respectively; P=0.33). In the on-demand group, 72 patients (69%) tolerated an oral diet and did not require tube feeding. CONCLUSIONS: This trial did not show the superiority of early nasoenteric tube feeding, as compared with an oral diet after 72 hours, in reducing the rate of infection or death in patients with acute pancreatitis at high risk for complications. (Funded by the Netherlands Organization for Health Research and Development and others; PYTHON Current Controlled Trials number, ISRCTN ). Comment in: Early versus on-demand tube feeding in pancreatitis. [N Engl J Med Feb 12;372(7):685. Bakker OJ, Besselink MG, Gooszen HG.] Early versus on-demand tube feeding in pancreatitis. [N Engl J Med Feb 12;372(7):684. Moran RA, Hernaez R, Singh VK.] Early versus on-demand tube feeding in pancreatitis. [N Engl J Med Feb 12;372(7): Petrov MS, Windsor JA.] PMID: Hulsman N, Hiddema PA, Veen EJ, van der Meer NJ. Traumatic cardiac injury by gun nails. Int J Crit Illn Inj Sci Apr;4(2): No abstract available. PMID: Tiren D, Vos DI. Correction osteotomy of distal radius malunion stabilised with dorsal locking plates without grafting. Strategies Trauma Limb Reconstr Apr;9(1):53-8. Epub 2014 Mar 8. The purpose of this study was to evaluate the results of our correction osteotomies of distal radial malunions without a bone graft. Eleven consecutive patients (mean age 52 years, range 18-71) were treated. A dorsal approach was utilised to perform an opening-wedge osteotomy which then was stabilised with two dorsal columnar plates without filling the osteotomy gap. All patients went on to radiographic union with a filling of the osteotomy gap within a mean 60 Publicaties Medische Staf

62 period of 3 months (range 2-6 months). All patients had satisfactory results in terms of function and pain. Correction osteotomy and stabilisation with bicolumnar locked plate fixation without a bone graft provides sufficient stability to allow the highly vascularised metaphysis to heal. In patients without risk factors predisposing to non-union, this procedure is safe and feasible. PMID: PMCID: PMC Schotanus M, van Hout N, Vos D. Pyoderma gangrenosum of the hand. Adv Skin Wound Care Feb;27(2):61-4. Pyoderma gangrenosum is a rare, painful, ulcerative neutrophilic dermatosis that is not usually seen on the hands. Pyoderma gangrenosum is a diagnosis of exclusion, as there are no specific laboratory or histopathologic findings to confirm the diagnosis. Heightened awareness and early recognition are needed to decrease morbidity in these patients. PMID: Bruinsma W, Kodde I, de Muinck Keizer RJ, Kloen P, Lindenhovius AL, Vroemen JP, Haverlag R, van den Bekerom MP, Bolhuis HW, Bullens PH, Meylaerts SA, van der Zwaal P, Steller PE, Hageman M, Ring DC, den Hartog D, Hammacher ER, King GJ, Athwal GS, Faber KJ, Drosdowech D, Grewal R, Goslings JC, Schep NW, Eygendaal D. A randomized controlled trial of nonoperative treatment versus open reduction and internal fixation for stable, displaced, partial articular fractures of the radial head: the RAMBO trial. BMC Musculoskelet Disord May 6;15:147. BACKGROUND: The choice between operative or nonoperative treatment is questioned for partial articular fractures of the radial head that have at least 2 millimeters of articular step-off on at least one radiograph (defined as displaced), but less than 2 millimeter of gap between the fragments (defined as stable) and that are not associated with an elbow dislocation, interosseous ligament injury, or other fractures. These kinds of fractures are often classified as Mason type-2 fractures. Retrospective comparative studies suggest that operative treatment might be better than nonoperative treatment, but the long-term results of nonoperative treatment are very good. Most experts agree that problems like reduced range of motion, painful crepitation, nonunion or bony ankylosis are infrequent with both nonoperative and operative treatment of an isolated displaced partial articular fracture of the radial head, but determining which patients will have problems is difficult. A prospective, randomized comparison would help minimize bias and determine the balance between operative and nonoperative risks and benefits. METHODS/DESIGN: The RAMBO trial (Radial Head - Amsterdam - Amphia - Boston - Others) is an international prospective, randomized, multicenter trial. The primary objective of this study is to compare patient related outcome defined by the Disabilities of Arm, Shoulder and Hand (DASH) score twelve months after injury between operative and nonoperative treated patients. Adult patients with partial articular fractures of the radial head that comprise at least 1/3rd Chirurgie 61

63 of the articular surface, have 2 millimeters of articular step-off but less than 2 millimeter of gap between the fragments will be enrolled. Secondary outcome measures will be the Mayo Elbow Performance Index (MEPI), the Oxford Elbow Score (OES), pain intensity through the Numeric Rating Scale, range of motion (flexion arc and rotational arc), radiographic appearance of the fracture (heterotopic ossification, radiocapitellar and ulnohumeral arthrosis, fracture healing, and signs of implant loosening or breakage) and adverse events (infection, nerve injury, secondary interventions) after one year. DISCUSSION: The successful completion of this trial will provide evidence on the best treatment for stable, displaced, partial articular fractures of the radial head. TRIAL REGISTRATION: The trial is registered at the Dutch Trial Register: NTR3413. PMID: PMCID: PMC Mahabier KC, Van Lieshout EM, Bolhuis HW, Bos PK, Bronkhorst MW, Bruijninckx MM, De Haan J, Deenik AR, Dwars BJ, Eversdijk MG, Goslings JC, Haverlag R, Heetveld MJ, Kerver AJ, Kolkman KA, Leenhouts PA, Meylaerts SA, Onstenk R, Poeze M, Poolman RW, Punt BJ, Roerdink WH, Roukema GR, Sintenie JB, Soesman NM, Tanka AK, Ten Holder EJ, Van der Elst M, Van der Heijden FH, Van der Linden FM, Van der Zwaal P, Van Dijk JP, Van Jonbergen HP, Verleisdonk EJ, Vroemen JP, Waleboer M, Wittich P, Zuidema WP, Polinder S, Verhofstad MH, Den Hartog D. HUMeral shaft fractures: measuring recovery after operative versus non-operative treatment (HUMMER): a multicenter comparative observational study. BMC Musculoskelet Disord Feb 11;15:39. BACKGROUND: Fractures of the humeral shaft are associated with a profound temporary (and in the elderly sometimes even permanent) impairment of independence and quality of life. These fractures can be treated operatively or non-operatively, but the optimal tailored treatment is an unresolved problem. As no high-quality comparative randomized or observational studies are available, a recent Cochrane review concluded there is no evidence of sufficient scientific quality available to inform the decision to operate or not. Since randomized controlled trials for this injury have shown feasibility issues, this study is designed to provide the best achievable evidence to answer this unresolved problem. The primary aim of this study is to evaluate functional recovery after operative versus non-operative treatment in adult patients who sustained a humeral shaft fracture. Secondary aims include the effect of treatment on pain, complications, generic health-related quality of life, time to resumption of activities of daily living and work, and cost-effectiveness. The main hypothesis is that operative treatment will result in faster recovery. METHODS/DESIGN: The design of the study will be a multicenter prospective observational study of 400 patients who have sustained a humeral shaft fracture, AO type 12A or 12B. Treatment decision (i.e., operative or non-operative) will be left to the discretion of the treating surgeon. Critical elements of treatment will be registered and outcome will be monitored at regular intervals over the subsequent 12 months. The primary outcome measure is the Disabilities of the Arm, Shoulder, and Hand score. Secondary outcome measures are the Constant score, pain 62 Publicaties Medische Staf

64 level at both sides, range of motion of the elbow and shoulder joint at both sides, radiographic healing, rate of complications and (secondary) interventions, health-related quality of life (Short- Form 36 and EuroQol-5D), time to resumption of ADL/work, and cost-effectiveness. Data will be analyzed using univariate and multivariable analyses (including mixed effects regression analysis). The cost-effectiveness analysis will be performed from a societal perspective. DISCUSSION: Successful completion of this trial will provide evidence on the effectiveness of operative versus non-operative treatment of patients with a humeral shaft fracture. TRIAL REGISTRATION: The trial is registered at the Netherlands Trial Register (NTR3617). PMID: PMCID: PMC Van Gestel YR, de Hingh IH, van Herk-Sukel MP, van Erning FN, Beerepoot LV, Wijsman JH, Slooter GD, Rutten HJ, Creemers GJ, Lemmens VE. Patterns of metachronous metastases after curative treatment of colorectal cancer. Cancer Epidemiol. 2014;38(4): Epub 2014 May 16. BACKGROUND: This study aimed to provide information on timing, anatomical location, and predictors for metachronous metastases of colorectal cancer based on a large consecutive series of non-selected patients. METHODS: All patients operated on with curative intent for colorectal cancer (TanyNanyM0) between 2003 and 2008 in the Dutch Eindhoven Cancer Registry were included (N=5671). By means of active follow-up by the Cancer Registry staff within ten hospitals, data on development of metastatic disease were collected. Median follow-up was 5.0 years. RESULTS: Of the 5671 colorectal cancer patients, 1042 (18%) were diagnosed with metachronous metastases. Most common affected sites were the liver (60%), lungs (39%), extra-regional lymph nodes (22%), and peritoneum (19%). 86% of all metastases was diagnosed within three years and the median time to diagnosis was 17 months (interquartile range months). Male gender (HR=1.2, 95%CI ), an advanced primary T-stage (T4 vs. T3 HR=1.6, 95%CI ) and N-stage (N1 vs. N0 HR=2.8, 95%CI and N2 vs. N0 HR=4.5, 95%CI ), highgrade tumour differentiation (HR=1.4, 95%CI ), and a positive (HR=2.1, 95%CI ) and unknown (HR=1.7, 95%CI ) resection margin were predictors for metachronous metastases. CONCLUSIONS: Different patterns of metastatic spread were observed for colon and rectal cancer patients and differences in time to diagnosis were found. Knowledge on these patterns and predictors for metachronous metastases may enhance tailor-made follow-up schemes leading to earlier detection of metastasized disease and increased curative treatment options. Copyright 2014 Elsevier Ltd. All rights reserved. PMID: Chirurgie 63

65 Dermatologie Kerngegevens 7 dermatologen: dr. A. (Angelina) Barentsen-Erceg, S.J. (Sarah) Caers, W.J.A. (Wim) de Kort, dr. J.E.M. (John) Körver, dr. D.I.M. (Danielle) Kuijpers, J. Molhoek De Rooij, L.C.C. Wijne 3,2 fte assistenten niet in opleiding 3,2 fte assistenten in opleiding 2 fte co-assistenten Subspecialismen: flebologie, dermato-oncologie Samenvattingen gepubliceerde artikelen Rozendaal AM, Erceg A, Kuijpers D. Een vergeten en ongewenste reisgezel. Ned Tijdschr Dermatol Veneorol okt. De Kort WJ, El Seady-Rol M, Fisscher L. De visjestherapie bij psoriasis Ned Tijdschr Dermatol Venereol mrt;24(3): Publicaties Medische Staf

66 Gynaecologie / Verloskunde Kerngegevens 16 gynaecologen: J. (Jeroen) van Bavel, dr. P.F.J. (Peter) van Bommel, dr. M.G.K. (Marja) Dijksterhuis, dr. D.A. (Dirk) Gietelink, dr. D. (Dennis) van Hamont, dr. D.J. (Dave) Hendriks, dr. R. (Roger) Heydanus, J.C.M (Anneke) Jeurgens-Borst, G.J.A. (Gerhard) Knol, A.L.M. (Angela) Kok, dr. M.S. (Simone) Lunshof, dr. D.N.M. (Dimitri) Papatsonis, M.F.M. (Mariska) Shekary-Moonen, J. (Jantien) Visser, dr. H.J. (Henk) Vonsée, J.A.W.M. (Jeff) van Zijl 3,6 fte assistenten niet in opleiding 3,3 fte assistent in opleiding 2 fte baios 1,7 fte fertiliteitsartsen Subspecialismen: benigne gynaecologie, prenatale diagnostiek, fertiliteit, bekkenbodem, oncologie, psychosomatiek, seksuologie, verloskunde: pre-partum, intra-partum en post-partum Wetenschap bij Gynaecologie / Verloskunde Binnen de vakgroep Gynaecologie en Verloskunde participeren wij in wetenschappelijk onderzoek op diverse deelgebieden, zoals verloskunde, voortplantingsgeneeskunde, oncologie en bekkenbodem. We werken vooral mee aan landelijke studies vanuit het NVOG consortium 2.0. Hiervoor zijn een drietal research nurses werkzaam (0,4 FTE) binnen onze afdeling. Zij zorgen voor de coördinatie, indiening van studies bij de lokale goedkeuringscommissie, randomisatie van patiënten, voorlichting op de afdelingen en follow-up. Ook de gehele invoering van vaak uitgebreide CRF s, correspondentie rondom studies en het implementeren van studies op de werkvloer wordt door hun verricht. Het participeren in de landelijke studies wordt bij voldoende inclusie beloond met mede auteurschap. Naast de landelijke studies verrichten we onderzoek vanuit onze eigen databases van de diverse deelgebieden. Hiermee proberen we antwoorden te geven op een vragen uit de klinische praktijk. Vaak wordt samengewerkt met een A(N)IOS met interesse voor wetenschap en graag een publicatie wil voor zijn of haar CV. Ook samenwerking op wetenschappelijk gebied met de derde lijn is belangrijk binnen de maatschap. Ondanks het feit dat wij het verrichten van wetenschappelijk onderzoek binnen de vakgroep toejuichen, blijft er altijd een spanningsveld tussen productie in het ziekenhuis en het verrichten van wetenschappelijk onderzoek. Het laatste is weliswaar niet een primaire taakstelling in ons ziekenhuis maar als groot opleidings- en STZ ziekenhuis zijn we wel min of meer verplicht om ook hier voldoende tijd aan te besteden. Gynaecologie / Verloskunde 65

67 Een voorbeeld van een studie waaraan wij het afgelopen jaar deel zijn gaan nemen als satelliet centrum prenatale diagnostiek van het Erasmus MC is de landelijke TRIDENT studie. Dit staat voor Trial by Dutch laboratories for Evaluation of Non-Invasive Prenatal Testing. In deze Nederlandse studie, uitgevoerd in de 8 UMC s door het NIPT consortium, wordt de NIPT (Niet Invasieve Prenatale Test) geëvalueerd en wordt de plaats van NIPT binnen de prenatale diagnostiek onderzocht. NIPT is een nieuwe test, die per 7 april 2014 als proef in Nederland beschikbaar is in de TRIDENT studie, waarbij het bloed van de moeder wordt gebruikt om in het laboratorium te testen of het ongeboren kind mogelijk trisomie 21 (downsyndroom), trisomie 18 (edwardssyndroom) en trisomie 13 (patausyndroom) heeft. Tijdens de studie wordt de NIPT aangeboden aan vrouwen met een verhoogde kans op een kind met een trisomie na de combinatietest. Zwangere vrouwen die in aanmerking komen voor de TRIDENT studie kunnen kiezen uit: 1. Geen vervolgtest laten doen; 2. Een vlokkentest of een vruchtwaterpunctie laten doen; 3. Meedoen aan de TRIDENT studie. De verloskundige of gynaecoloog in het centrum voor prenatale diagnostiek begeleidt zwangere vrouwen bij het maken van een keuze. De zwangere bepaalt zelf wat zij wil doen. Doel van de studie is nagaan hoe we in Nederland kunnen komen tot een zo goed mogelijke inrichting van het aanbod van NIPT, en tot de uitvoering daarvan in de dagelijkse praktijk. Na afloop van de studie kan advies worden gegeven over de verdere invoering van NIPT in Nederland. We willen deze samenwerking en met diverse andere academische centra in Nederland op gebied van wetenschappelijk onderzoek behouden en zo mogelijk uitbreiden. 66 Publicaties Medische Staf

68 Samenvattingen gepubliceerde artikelen Broekman EA, Versteeg H, Vos LD, Dijksterhuis MG, Papatsonis DN. Temporary balloon occlusion of the internal iliac arteries to prevent massive hemorrhage during cesarean delivery among patients with placenta previa. Int J Gynaecol Obstet Feb;128(2): Epub 2014 Nov 5. OBJECTIVE: To evaluate the effectiveness of temporary balloon occlusion of the internal iliac artery before uterine incision to prevent massive obstetric hemorrhage during cesarean delivery among patients with anterior placenta previa. METHODS: In a retrospective cohort study conducted at Amphia Hospital Breda (Breda, Netherlands), data were analyzed from women with anterior placenta previa who delivered by cesarean between January 1, 2001, and September 30, Cases with and without balloon occlusion of the internal iliac artery were included. The primary outcomes were the amount of blood loss during cesarean delivery, drop of hemoglobin level, and blood loss of more than 1000mL. RESULTS: Of 68 eligible women, 42 (62%) had temporary balloon occlusion and 26 (38%) had no balloon occlusion. Median blood loss was 800mL (interquartile range [IQR] ) in the balloon group and 1000mL (IQR ) in the no balloon group (P=0.06). Blood loss of 1000mL or more was recorded in 16 (38%) women in the balloon group and 18 (69%) in the no balloon group (P=0.01). CONCLUSION: Temporary balloon occlusion of the internal iliac artery before uterine incision during cesarean delivery could potentially reduce blood loss among patients with anterior placenta previa. Large, randomized controlled trials are needed to confirm the results. PMID: Jozwiak M, van de Lest HA, Burger NB, Dijksterhuis MG, De Leeuw JW. Cervical ripening with Foley catheter for induction of labor after cesarean section: a cohort study. Acta Obstet Gynecol Scand Mar;93(3): Epub 2014 Jan 13. OBJECTIVE: To evaluate spontaneous vaginal delivery and complication rates after induction of labor with a transcervical Foley catheter in women with a previous cesarean delivery. DESIGN: Retrospective cohort study. SETTING: Secondary teaching hospital in the second largest city of the Netherlands. POPULATION: Women with a history of cesarean delivery (n = 208), undergoing induction of labor with a Foley catheter in a subsequent pregnancy. MATERIAL AND METHODS: The women who had induction of labor with a transcervical Foley Gynaecologie / Verloskunde 67

69 catheter in the Ikazia Hospital, Rotterdam, between January 2003 and January 2012, were identified in a computerized database. Patient s records were checked for accuracy. MAIN OUTCOME MEASURES: Vaginal delivery rate, cesarean section rate, uterine rupture and maternal and neonatal (infectious) morbidity. RESULTS: Of the women 60% had a spontaneous vaginal delivery and 11% were delivered by vacuum extraction. Uterine rupture occurred in one woman. Postpartum hemorrhage was the most common maternal complication (12%). Maternal intrapartum and postpartum infections occurred in 5% and 1%. Proven neonatal infection was found in 3% of the cases. Two perinatal deaths occurred (1%), of which one was related to uterine rupture. CONCLUSION: Induction of labor with a transcervical Foley catheter is an effective method to achieve vaginal delivery in women with a previous cesarean delivery. There is a low risk of uterine rupture and maternal and neonatal (infectious) morbidity in this cohort. PMID: Dijksterhuis MG. De Nederlandse Voortgangstoets Obstetrie en Gynaecologie. Ned Tijdschr Obst Gyn Mar;127(3): Dijksterhuis MGK. Assessment to optimise postgraduate medical training [S.l.]: [s.n.], Proefschrift Vrije Universiteit Amsterdam. ISBN Van Doorn DE, van Leuken M, Rijnders RJ. Embolization of a left uterine artery mycotic aneurysm after a neglected, perforated appendicitis before delivery. Clin Case Rep Oct;2(5): Epub 2014 Jun 30. KEY CLINICAL MESSAGE: We report a case of a successful embolization of a mycotic aneurysm of the left uterine artery in the puerperium after a neglected perforated appendicitis. A mycotic aneurysm, meaning an infection of the vessel wall which leads to an aneurysmatic dilatation of the vessel, is potentially life threatening if rupture occurs. PMID: PMCID: PMC Monen L, van der Putten HW, van Hamont D. Een metastatisch proces na supra-cervicale laparoscopische hysterectomie. Ned Tijdschr Obst Gyn. 2014;127(3): Publicaties Medische Staf

70 Wij beschrijven een casus van een patiënte met multipele solide massa s in het kleine bekken, imponerend als een ovariumcarcinoom. Het blijkt te gaan om een relatief zeldzame complicatie van een eerder uitgevoerde laparoscopische supracervicale hysterectomie met morcellator. Srebniak MI, Bos MJ, de Vries FA, Heydanus R, Wessels MW, Van Opstal D. SNP array detects chromosome aberrations that we thought do not exist: the first case of an isochromosome Xp (i(x)(p10)). Prenat Diagn Aug;34(8): Epub 2014 Apr 27. No abstract available. PMID: Nieuwenhuyzen-De Boer GM, Hoogeboom AJ, Smit LS, Heydanus R, Eggink AJ. Pfeiffer syndrome: the importance of prenatal diagnosis. Eur J Obstet Gynecol Reprod Biol Oct;181: Epub 2014 Aug 13. No abstract available. PMID: Hitzerd E, Jeurgens-Borst AJ, Pijnenborg JM. Peritoneal inclusion cysts in pregnancy, a diagnostic challenge. BMJ Case Rep Jun 13;2014. pii: bcr A cystic pelvic mass detected during pregnancy is not uncommon, but can be a diagnostic challenge. Most of these pelvic masses are benign ovarian cysts and resolve spontaneously. However, rare non-ovarian causes can complicate the diagnostic and therapeutic management. In this report an unusual case is presented of a 27-year-old pregnant woman with an atypical multicystic lesion in the pelvis, seen on routine first trimester ultrasound. A laparoscopic exploration was performed to rule out ovarian malignancy, and after histological analysis she was diagnosed with peritoneal inclusion cysts. The diagnostic and therapeutic challenges inherent to this rare non-ovarian disease are addressed in this case report. PMID: Ter Laak MA, Roos C, Touw DJ, van Hattum PR, Kwee A, Lotgering FK, J Mol BW, van Pampus MG, Porath MM, Spaanderman ME, van der Post JA, Papatsonis DN, van t Veer NE. Pharmacokinetics of nifedipine slow-release during sustained tocolysis. Int J Clin Pharmacol Ther Jan;53(1): Epub 2014 Nov 19. OBJECTIVE: The pharmacokinetics of nifedipine as a tocolytic agent has not been studied in great detail in pregnant women and has instead focused on immediate release tablets and Gynaecologie / Verloskunde 69

71 gastrointestinal therapeutic system (GITS) tablets. The aim of this study was to determine nifedipine slowrelease half-life and distribution volume in pregnant women and to compare these with pharmacokinetic parameters of nifedipine in non-pregnant subjects described in the literature. MATERIALS: This is a study parallel to a trial studying women with threatened preterm labor between and weeks after initial tocolysis and a completed course of corticosteroids, who were randomly allocated to maintenance nifedipine (slow-release tablets 20 mg 4 times daily) or placebo. Exclusion criteria for the pharmacokinetic study were contra-indications for nifedipine, impaired liver function, and concomitant intake of inhibitors or inducers of the cytochrome P450 3A4 isoenzyme. Blood samples for measuring nifedipine plasma concentrations were drawn at t = 0, t = 12 hours, t = 24 hours, t = 48 hours, t = 72 hours, t = 7 days, and t = 9 days. METHODS: Pharmacokinetic parameters were estimated using iterative two-stage Bayesian population pharmacokinetic analysis by MWPharm software. The study was designed to establish a correlation between body weight and nifedipine plasma level. RESULTS: The pharmacokinetic parameters of nifedipine slow-release tablets were determined from the data of 8 pregnant women. Nifedipine slow-release had a half-life of 2-5 hours, a mean distribution volume of 6.2 ± 1.9 L/kg (calculated while using a fixed biological availability of 0.45 taken from the literature due to lack of intravenous data in this population) compared to a halflife of 6-11 hours, and a distribution volume of L/kg described in non-pregnant subjects in the literature. None of the women delivered during study medication. Study medication was continued for the duration of the pharmacokinetic study (9 days) in all women. A correlation between nifedipine plasma levels and maternal body weight was not demonstrated. This may have been caused by lack of power. CONCLUSION: Pregnant subjects in this study, using nifedipine slow-release tablets, showed a larger volume of distribution and a shorter elimination half-life than for non-pregnant subjects as published in the literature. PMID: Flenady V, Reinebrant HE, Liley HG, Tambimuttu EG, Papatsonis DN. Oxytocin receptor antagonists for inhibiting preterm labour. Cochrane Database Syst Rev Jun 6;6:CD BACKGROUND: Preterm birth, defined as birth between 20 and 36 completed weeks, is a major contributor to perinatal morbidity and mortality globally. Oxytocin receptor antagonists (ORA), such as atosiban, have been specially developed for the treatment of preterm labour. ORA have been proposed as effective tocolytic agents for women in preterm labour to prolong pregnancy with fewer side effects than other tocolytic agents. OBJECTIVES: To assess the effects on maternal, fetal and neonatal outcomes of tocolysis with ORA for women with preterm labour compared with placebo or any other tocolytic agent. 70 Publicaties Medische Staf

72 SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group s Trials Register (1 December 2013). SELECTION CRITERIA: We included all randomised controlled trials (published and unpublished) of ORA for tocolysis of labour between 20 and 36 completed weeks gestation. DATA COLLECTION AND ANALYSIS: Two review authors independently evaluated methodological quality and extracted trial data. When required, we sought additional data from trial authors. Results are presented as risk ratio (RR) for categorical and mean difference (MD) for continuous data with the 95% confidence intervals (CI). Where appropriate, the number needed to treat for benefit (NNTB) and the number needed to treat for harm (NNTH) were calculated. MAIN RESULTS: This review update includes eight additional studies (790 women), giving a total of 14 studies involving 2485 women.four studies (854 women) compared ORA (three used atosiban and one barusiban) with placebo. Three studies were considered at low risk of bias in general (blinded allocation to treatment and intervention), the fourth study did not adequately blind the intervention. No difference was shown in birth less than 48 hours after trial entry (average RR 1.05, 95% CI 0.15 to 7.43; random-effects, (two studies, 152 women), perinatal mortality (RR 2.25, 95% CI 0.79 to 6.38; two studies, 729 infants), or major neonatal morbidity. ORA (atosiban) resulted in a small reduction in birthweight (MD g, 95% CI to ; two studies with 676 infants). In one study, atosiban resulted in an increase in extremely preterm birth (before 28 weeks gestation) (RR 3.11, 95% CI 1.02 to 9.51; NNTH 31, 95% CI 8 to 3188) and infant deaths (up to 12 months) (RR 6.13, 95% CI 1.38 to 27.13; NNTH 28, 95% CI 6 to 377). However, this finding may be confounded due to randomisation of more women with pregnancy less than 26 weeks gestation to atosiban. ORA also resulted in an increase in maternal adverse drug reactions requiring cessation of treatment in comparison with placebo (RR 4.02, 95% CI 2.05 to 7.85; NNTH 12, 95% CI 5 to 33). No differences were shown in preterm birth less than 37 weeks gestation or any other adverse neonatal outcomes. No differences were evident by type of ORA, although data were limited.eight studies (1402 women) compared ORA (atosiban only) with betamimetics; four were considered of low risk of bias (blinded allocation to treatment and to intervention). No statistically significant difference was shown in birth less than 48 hours after trial entry (RR 0.89, 95% CI 0.66 to 1.22; eight studies with 1389 women), very preterm birth (RR 1.70, 95% CI 0.89 to 3.23; one study with 145 women), extremely preterm birth (RR 0.84, 95% CI 0.37 to 1.92; one study with 244 women) or perinatal mortality (RR 0.55, 95% CI 0.21 to 1.48; three studies with 816 infants). One study (80 women), of unclear methodological quality, showed an increase in the interval between trial entry and birth (MD days, 95% CI to 27.77). No difference was shown in any reported measures of major neonatal morbidity (although numbers were small). ORA (atosiban) resulted in less maternal adverse effects requiring cessation of treatment (RR 0.05, 95% CI 0.02 to 0.11; NNTB 6, 95% CI 6 to 6; five studies with 1161 women).two studies including (225 women) compared ORA (atosiban) with calcium channel blockers (CCB) (nifedipine only). The studies were considered as having high risk of bias as neither study blinded the intervention and in one study it was not known if allocation was blinded. No difference was shown in birth less than 48 hours after trial entry (average RR 1.09, 95% CI 0.44 to 2.73, randomeffects; two studies, 225 women) and extremely preterm birth (RR 2.14, 95% CI 0.20 to 23.11; one study, 145 women). No data were available for the outcome of perinatal mortality. One small Gynaecologie / Verloskunde 71

73 trial (145 women), which did not employ blinding of the intervention, showed an increase in the number of preterm births (before 37 weeks gestation) (RR 1.56, 95% CI 1.13 to 2.14; NNTH 5, 95% CI 3 to 19), a lower gestational age at birth (MD weeks, 95% CI to -0.25) and an increase in admission to neonatal intensive care unit (RR 1.70, 95% CI 1.17 to 2.47; NNTH 5, 95% CI 3 to 20). ORA (atosiban) resulted in less maternal adverse effects (RR 0.38, 95% CI 0.21 to 0.68; NNTB 6, 95% CI 5 to 12; two studies, 225 women) but not maternal adverse effects requiring cessation of treatment (RR 0.36, 95% CI 0.01 to 8.62; one study, 145 women). No longer-term outcome data were included. AUTHORS CONCLUSIONS: This review did not demonstrate superiority of ORA (largely atosiban) as a tocolytic agent compared with placebo, betamimetics or CCB (largely nifedipine) in terms of pregnancy prolongation or neonatal outcomes, although ORA was associated with less maternal adverse effects than treatment with the CCB or betamimetics. The finding of an increase in infant deaths and more births before completion of 28 weeks of gestation in one placebo-controlled study warrants caution. However, the number of women enrolled at very low gestations was small. Due to limitations of small numbers studied and methodological quality, further well-designed randomised controlled trials are needed. Further comparisons of ORA versus CCB (which has a better side-effect profile than betamimetics) are needed. Consideration of further placebo-controlled studies seems warranted. Future studies of tocolytic agents should measure all important short- and long-term outcomes for women and infants, and costs. Update of: Oxytocin receptor antagonists for inhibiting preterm labour. [Cochrane Database Syst Rev. 2005] PMID: Flenady V, Wojcieszek AM, Papatsonis DN, Stock OM, Murray L, Jardine LA, Carbonne B. Calcium channel blockers for inhibiting preterm labour and birth. Cochrane Database Syst Rev Jun 5;6:CD BACKGROUND: Preterm birth is a major contributor to perinatal mortality and morbidity, affecting around 9% of births in high-income countries and an estimated 13% of births in lowand middle-income countries. Tocolytics are drugs used to suppress uterine contractions for women in preterm labour. The most widely used tocolytic are the betamimetics, however, these are associated with a high frequency of unpleasant and sometimes severe maternal side effects. Calcium channel blockers (CCBs) (such as nifedipine) may have similar tocolytic efficacy with less side effects than betamimetics. Oxytocin receptor antagonists (ORAs) (e.g. atosiban) also have a low side-effect profile. OBJECTIVES: To assess the effects on maternal, fetal and neonatal outcomes of CCBs, administered as a tocolytic agent, to women in preterm labour. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group s Trials Register (12 November 2013). 72 Publicaties Medische Staf

74 SELECTION CRITERIA: All published and unpublished randomised trials in which CCBs were used for tocolysis for women in labour between 20 and 36 completed weeks gestation. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility, undertook quality assessment and data extraction. Results are presented using risk ratio (RR) for categorical data and mean difference (MD) for data measured on a continuous scale with the 95% confidence interval (CI). The number needed to treat to benefit (NNTB) and the number needed to treat to harm (NNTH) were calculated for categorical outcomes that were statistically significantly different. MAIN RESULTS: This update includes 26 additional trials involving 2511 women, giving a total of 38 included trials (3550 women). Thirty-five trials used nifedipine as the CCB and three trials used nicardipine. Blinding of intervention and outcome assessment was undertaken in only one of the trials (a placebo controlled trial). However, objective outcomes defined according to timing of birth and perinatal mortality were considered to have low risk of detection bias.two small trials comparing CCBs with placebo or no treatment showed a significant reduction in birth less than 48 hours after trial entry (RR 0.30, 95% CI 0.21 to 0.43) and an increase in maternal adverse effects (RR 49.89, 95% CI 3.13 to , one trial of 89 women). Due to substantial heterogeneity, outcome data for preterm birth (less than 37 weeks) were not combined; one placebo controlled trial showed no difference (RR 0.96, 95% CI 0.89 to 1.03) while the other (non-placebo controlled trial) reported a reduction (RR 0.44, 95% CI 0.31 to 0.62). No other outcomes were reported. Comparing CCBs (mainly nifedipine) with other tocolytics by type (including betamimetics, glyceryl trinitrate (GTN) patch, non-steriodal anti inflammatories (NSAID), magnesium sulphate and ORAs), no significant reductions were shown in primary outcome measures of birth within 48 hours of treatment or perinatal mortality.comparing CCBs with betamimetics, there were fewer maternal adverse effects (average RR 0.36, 95% CI 0.24 to 0.53) and fewer maternal adverse effects requiring discontinuation of therapy (average RR 0.22, 95% CI 0.10 to 0.48). Calcium channel blockers resulted in an increase in the interval between trial entry and birth (average MD 4.38 days, 95% CI 0.25 to 8.52) and gestational age (MD 0.71 weeks, 95% CI 0.34 to 1.09), while decreasing preterm and very preterm birth (RR 0.89, 95% CI 0.80 to 0.98 and RR 0.78, 95% CI 0.66 to 0.93); respiratory distress syndrome (RR 0.64, 95% CI 0.48 to 0.86); necrotising enterocolitis (RR 0.21, 95% CI 0.05 to 0.96); intraventricular haemorrhage (RR 0.53, 95% CI 0.34 to 0.84); neonatal jaundice (RR 0.72, 95% CI 0.57 to 0.92); and admissions to neonatal intensive care unit (NICU) (average RR 0.74, 95% CI 0.63 to 0.87). No difference was shown in one trial of outcomes at nine to twelve years of age.comparing CCBs with ORA, data from one study (which did blind the intervention) showed an increase in gestational age at birth (MD 1.20 completed weeks, 95% CI 0.25 to 2.15) and reductions in preterm birth (RR 0.64, 95% CI 0.47 to 0.89); admissions to the NICU (RR 0.59, 95% CI 0.41 to 0.85); and duration of stay in the NICU (MD days,95% CI to 0.04). Maternal adverse effects were increased in the CCB group (average RR 2.61, 95% CI 1.43 to 4.74).Comparing CCBs with magnesium sulphate, maternal adverse effects were reduced (average RR 0.52, 95% CI 0.40 to 0.68), as was duration of stay in the NICU (days) (MD -4.55, 95% CI to -0.92). No differences were shown in the comparisons with GTN patch or NSAID, although numbers were small.no differences in outcomes were shown in trials comparing nicardipine with other tocolytics, although with limited data no strong conclusions can be drawn. No differences were evident in a small trial that compared higher- versus lower- Gynaecologie / Verloskunde 73

75 dose nifedipine, though findings tended to favour a high dose on some measures of neonatal morbidity. AUTHORS CONCLUSIONS: Calcium channel blockers (mainly nifedipine) for women in preterm labour have benefits over placebo or no treatment in terms of postponement of birth thus, theoretically, allowing time for administration of antenatal corticosteroids and transfer to higher level care. Calcium channel blockers were shown to have benefits over betamimetics with respect to prolongation of pregnancy, serious neonatal morbidity, and maternal adverse effects. Calcium channel blockers may also have some benefits over ORAs and magnesium sulphate, although ORAs results in fewer maternal adverse effects. However, it must be noted that no difference was shown in perinatal mortality, and data on longer-term outcomes were limited. Further, the lack of blinding of the intervention diminishes the strength of this body of evidence. Further well-designed tocolytic trials are required to determine short- and longerterm infant benefit of CCBs over placebo or no treatment and other tocolytics, particularly ORAs. Another important focus for future trials is identifying optimal dosage regimens of different types of CCBs (high versus low, particularly addressing speed of onset of uterine quiescence) and formulation (capsules versus tablets). All future trials on tocolytics for women in preterm labour should employ blinding of the intervention and outcome assessment, include measurement of longer-term effects into early childhood, and also costs. Comment in: Calcium channel blockers are effective as first line for tocolysis in the management of preterm labour. [Evid Based Med. 2014] Update of: Calcium channel blockers for inhibiting preterm labour. [Cochrane Database Syst Rev. 2003] PMID: Wilmink FA, Hukkelhoven CW, van der Post JA, Steegers EA, Mol BW, Papatsonis DN. Timing van electieve keizersneden à terme: trends in Nederland. [Timing of elective term caesarean sections; trends in the Netherlands]. Ned Tijdschr Geneeskd. 2014;158:A6951. OBJECTIVE: To analyse if from the rate of elective caesarean sections (CS) before 39 0/7 weeks of gestation declined when compared with all elective CS, and to evaluate the possible associated factors. DESIGN: Retrospective cohort study. METHOD: Using data from The Netherlands Perinatal Registry, all term elective CS (n = 59,653) from were selected. Trends in patient characteristics and in performing an elective CS before 39 0/7 weeks were analysed using regression analysis, and differences between hospitals using the x 2 test. Using multiple logistic regression analysis it was analysed which factors were associated with performing an elective CS before 39 0/7 weeks. 74 Publicaties Medische Staf

76 RESULTS: The percentage of elective CS before 39 0/7 weeks decreased from 56% in 2000 to 43% in 2010 (p < ). In peripheral hospitals an elective SC was performed more often before 39+0 weeks than in academic hospitals; 53% in peripheral teaching hospitals, 57% in peripheral non-teaching hospitals, and 46% in academic hospitals. Adjusted odds ratios and 95% confidence intervals were 1.38 ( ) in peripheral teaching hospitals, and 1.55 ( ) in peripheral non-teaching hospitals. In hospitals where the number of deliveries per year was situated in the lower quartile, elective CS before 39 0/7 weeks was carried out more often than in hospitals where deliveries per year were in the upper quartile, 60% versus 52% (p < ). CONCLUSION: In the period the timing of elective CS improved marginally. In 2010 the trend began to decline, even though 43% of elective caesarean sections were still carried out before 39 0/7 weeks. This results in a higher risk of neonatal morbidity and health problems in long-term. PMID: Gynaecologie / Verloskunde 75

77 Van de Mheen L, Schuit E, Lim AC, Porath MM, Papatsonis D, Erwich JJ, van Eyck J, van Oirschot CM, Hummel P, Duvekot JJ, Hasaart TH, Groenwold RH, Moons KG, de Groot CJ, Bruinse HW, van Pampus MG, Mol BW. Prediction of preterm birth in multiple pregnancies: development of a multivariable model including cervical length measurement at 16 to 21 weeks gestation. J Obstet Gynaecol Can Apr;36(4): OBJECTIVE: To develop a multivariable prognostic model for the risk of preterm delivery in women with multiple pregnancy that includes cervical length measurement at 16 to 21 weeks gestation and other variables. METHODS: We used data from a previous randomized trial. We assessed the association between maternal and pregnancy characteristics including cervical length measurement at 16 to 21 weeks gestation and time to delivery using multivariable Cox regression modelling. Performance of the final model was assessed for the outcomes of preterm and very preterm delivery using calibration and discrimination measures. RESULTS: We studied 507 women, of whom 270 (53%) delivered < 37 weeks (preterm) and 66 (13%) < 32 weeks (very preterm). Women with cervical length < 30 mm delivered more often preterm (hazard ratio 1.9; 95% CI 0.7 to 4.8). Other independently contributing predictors were previous preterm delivery, monochorionicity, smoking, educational level, and triplet pregnancy. Prediction models for preterm and very preterm delivery had a c-index of 0.68 (95% CI 0.63 to 0.72) and 0.68 (95% CI 0.62 to 0.75), respectively, and showed good calibration. CONCLUSION: In women with a multiple pregnancy, the risk of preterm delivery can be assessed with a multivariable model incorporating cervical length and other predictors. PMID: Quispel C, Bangma M, Kazemier BM, Steegers EA, Hoogendijk WJ, Papatsonis DN, Paarlberg KM, Lambregtse-Van Den Berg MP, Bonsel GJ. The role of depressive symptoms in the pathway of demographic and psychosocial risks to preterm birth and small for gestational age. Midwifery Aug;30(8): Epub 2014 Mar 19. OBJECTIVE: depressive symptoms during pregnancy are associated with preterm birth (PTB) and small for gestational age (SGA). Depressive symptoms and PTB and SGA, however, share similar demographic and psychosocial risk factors. Therefore, we investigated whether depressive symptomatology is an independent risk factor, or a mediator in the pathway of demographic and psychosocial risks to PTB and SGA. DESIGN: multicentre follow-up study. PARTICIPANTS AND SETTING: pregnant women (n=1013) from midwifery practices, secondary hospitals and a tertiary hospital in three urban areas in the Netherlands. 76 Publicaties Medische Staf

78 MEASUREMENTS: initial risk factors and depressive symptoms were assessed with the Mind2Care instrument, including Edinburgh Depression Scale (EDS) during early pregnancy. Pregnancy outcomes were extracted from medical records. A formal mediation analysis was conducted to investigate the role of depressive symptoms in the pathway to PTB and SGA. FINDINGS: a univariate association between depressive symptoms and PTB (OR:1.04; 95% CI: ) was observed. After adjusting for the risk factors educational level and smoking in the mediation analysis, this association disappeared. One educational aspect remained associated: low education OR: 1.06; 95%-CI: KEY CONCLUSIONS: depressive symptomatology appeared no mediator in the pathway of demographic and psychosocial risks to PTB or SGA. The presumed association between depressive symptoms and PTB seems spurious and may be explained by demographic and psychosocial risk factors. IMPLICATIONS FOR PRACTICE: for the prevention of PTB and SGA, interventions directed at demographic and psychosocial risk factors are likely to be of primary concern for clinicians and public health initiatives. As depressive symptoms and PTB and SGA share similar risk factors, both will profit. PMID: Van der Ham DP, van Kuijk S, Opmeer BC, Willekes C, van Beek JJ, Mulder AL, van Loon AJ, Groenewout M, Mantel GD, Bloemenkamp KW, Porath M, Kwee A, Akerboom BM, Papatsonis DN, Metz GC, Nijhuis JG, Mol BW; PPROMEXIL trial group. Can neonatal sepsis be predicted in late preterm premature rupture of membranes? Development of a prediction model. Eur J Obstet Gynecol Reprod Biol May;176:90-5. Epub 2014 Feb 13. OBJECTIVE: Women with late preterm premature rupture of membranes (PROM) have an increased risk that their child will develop neonatal sepsis. We evaluated whether neonatal sepsis can be predicted from antepartum parameters in these women. STUDY DESIGN: We used multivariable logistic regression to develop a prediction model. Data were obtained from two recent randomized controlled trials on induction of labor versus expectant management in late preterm PROM (PPROMEXIL trials, (ISRCTN and ISRCTN ). Data from randomized as well as non-randomized women, who consented to the use of their medical data, were used. We evaluated 13 potential antepartum predictors for neonatal sepsis. Missing data were imputed. Discriminative ability of the model was expressed as the area under the receiver operating characteristic (ROC) curve and a calibration with both a calibration plot and the Hosmer and Lemeshow goodness-of-fit test. Overall performance of the prediction model was quantified as the scaled Brier score. RESULTS: We studied 970 women. Thirty-three (3.4%) neonates suffered neonatal sepsis. Maternal age (OR 1.09 per year), maternal CRP level (OR 1.01 per mmol/l), maternal temperature Gynaecologie / Verloskunde 77

79 (OR 1.80 per C) and positive GBS culture (OR 2.20) were associated with an increased risk of neonatal sepsis. The model had an area under the ROC-curve of The model had both a good calibration and accuracy. CONCLUSIONS: Antepartum parameters aid in the more precise prediction of the risk of neonatal sepsis in women with late preterm PPROM. PMID: Prick BW, Jansen AJ, Steegers EA, Hop WC, Essink-Bot ML, Uyl-de Groot CA, Akerboom BM, van Alphen M, Bloemenkamp KW, Boers KE, Bremer HA, Kwee A, van Loon AJ, Metz GC, Papatsonis DN, van der Post JA, Porath MM, Rijnders RJ, Roumen FJ, Scheepers HC, Schippers DH, Schuitemaker NW, Stigter RH, Woiski MD, Mol BW, van Rhenen DJ, Duvekot JJ. Transfusion policy after severe postpartum haemorrhage: a randomised non-inferiority trial. BJOG Jul;121(8): Epub 2014 Jan 10. OBJECTIVE: To assess the effect of red blood cell (RBC) transfusion on quality of life in acutely anaemic women after postpartum haemorrhage. DESIGN: Randomised non-inferiority trial. SETTING: Thirty-seven Dutch university and general hospitals. POPULATION: Women with acute anaemia (haemoglobin g/dl [ mmol/l] hours postpartum) without severe anaemic symptoms or severe comorbidities. METHODS: Women were allocated to RBC transfusion or non-intervention. MAIN OUTCOME MEASURES: Primary outcome was physical fatigue 3 days postpartum (Multidimensional Fatigue Inventory, scale 4-20; 20 represents maximal fatigue). Non-inferiority was demonstrated if the physical fatigue difference between study arms was maximal 1.3. Secondary outcomes were health-related quality of life and physical complications. Healthrelated quality of life questionnaires were completed at five time-points until 6 weeks postpartum. RESULTS: In all, 521 women were randomised to non-intervention (n = 262) or RBC transfusion (n = 259). Mean physical fatigue score at day 3 postpartum, adjusted for baseline and mode of delivery, was 0.8 lower in the RBC transfusion arm (95% confidence interval: , P = 0.02) and at 1 week postpartum was 1.06 lower (95% confidence interval: , P = 0.01). A median of two RBC units was transfused in the RBC transfusion arm. In the non-intervention arm, 33 women received RBC transfusion, mainly because of anaemic symptoms. Physical complications were comparable. 78 Publicaties Medische Staf

80 CONCLUSIONS: Statistically, non-inferiority could not be demonstrated as the confidence interval crossed the non-inferiority boundary. Nevertheless, with only a small difference in physical fatigue and no differences in secondary outcomes, implementation of restrictive management seems clinically justified. PMID: Van Oostwaard MF, Langenveld J, Schuit E, Wigny K, Van Susante H, Beune I, Ramaekers R, Papatsonis DN, Mol BW, Ganzevoort W. Prediction of recurrence of hypertensive disorders of pregnancy in the term period, a retrospective cohort study. Pregnancy Hypertension 2014 apr 22;4(3): OBJECTIVES: To assess the recurrence risk of term hypertensive disease of pregnancy and to determine which potential risk factors are predictive of recurrence. STUDY DESIGN: We performed a retrospective cohort study in two secondary and one tertiary care hospitals in the Netherlands. We identified women with a hypertensive disorder in the index pregnancy and delivery after 37 weeks of gestation between January 2000 and December Data were extracted from medical files and women were approached for additional information on subsequent pregnancies. Adverse outcome was defined as recurrence of a hypertensive disorder in the next subsequent pregnancy. MAIN OUTCOME MEASURES: The absolute risk of recurrence and a prediction model containing demographic and clinical factors predictive of recurrence. RESULTS: We identified 638 women for potential inclusion, of whom 503 could be contacted. Of these women, 312 (62%) had a subsequent pregnancy. Hypertensive disorders recurred in 120 (38%, 95% CI 33 44) women, of whom 15 (5%, 95% CI 3 7) delivered preterm. Women undergoing recurrence were more at risk to develop chronic hypertension after pregnancy (35% versus 16%, OR 2.8, 95% CI ). Body mass index, non-white European origin, chronic hypertension, maximum diastolic blood pressure, no use of anticonvulsive medication and interpregnancy interval were predictors for recurrence. CONCLUSIONS: Women with hypertensive disorders and term delivery have a substantial chance of recurrence, but a small risk of preterm delivery. A number of predictors for recurrence could be identified and women with a recurrence more often developed chronic hypertension. Gynaecologie / Verloskunde 79

81 Huisman C, Oude Rengerink K, Jozwiak M, Duvekot H, van Eyck J, Gaugler I, Franssen M, van Gemund N, Heres M, Langeveld J, de Leeuw JW, Oude Lohuis E, Oudijk M, Papatsonis D, van Pampus M, Porath M, van de Salm P, Scheepers L, Sikkema M, Sporken J, Stigter R, van Wijngaarden W, Woiski M, Mol BW, Bloemenkamp K. Effectiveness and safety of different methods for induction of labor in women with a previous cesarean section. [P682]. Am J Obstet Gynecol jan;210(suppl 1):S To study the effectiveness and safety of induction of labor and elective repeat cesarean section (CS) in women with prior CS and indication for delivery. Van Oostwaard M, Langenveld J, Schuit E, Wigny K, van Susante H, Beune I, Ramaekers R, Papatsonis D, Mol BW, Ganzevoort W. Prediction of recurrence of hypertensive disorders of pregnancy in the term period, a retrospective cohort study.[p291]. Am J Obstet Gynecol jan;210 (suppl 1):S To assess the recurrence risk of term hypertensive disease of pregnancy and to determine whether potential risk factors are predictive. Broekhuijsen K, van Baaren GJ, van Pampus M, Sikkema M, Woiski M, Oudijk M, Bloemenkamp K, Scheepers H, Bremer H, Rijnders R, van Loon A, Perquin D, Sporken J, Papatsonis D, van Huizen M, Vredevoogd C, Brons J, van Kaam A, Groen H, Porath M, Mol B, Franssen M, Langenveld J. Delivery versus expectant monitoring for late preterm hypertensive disorders of pregnancy (HYPITAT-II): a multicenter, open label, randomized controlled trial. [P2]. Am J Obstet Gynecol jan;210(suppl 1): S2-3. There is limited evidence on the effectiveness of immediate delivery for women with hypertensive disorders in late preterm pregnancy. We evaluated whether delivery could reduce adverse maternal outcomes in this group without compromising neonatal outcomes. Freeman L, Bloemenkamp K, Franssen M, Papatsonis D, Hollmann M, Woiski M, Porath, van den Berg H, van Beek E, Schuitemaker N, Sikkema M, Logtenberg S, Oudijk M, Bax C, van der Salm P, van den Akker-van Marle E, le Cessie S, van Lith J, Struys M, Dahan A, Mol BW, Middeldorp J. Remifentanil patient controlled analgesia versus epidural analgesia in labor; a randomized controlled equivalence trial. [P54]. Am J Obstet Gynecol jan;210(suppl 1):S36-7. Recent studies suggest that remifentanil patient controlled analgesia (RPCA) is equivalent to epidural analgesia (EA) with respect to pain appreciation (satisfaction with pain relief). These studies were underpowered to detect a difference in pain appreciation. The aim of our study was to compare the effectiveness of RPCA with EA regarding pain appreciation. 80 Publicaties Medische Staf

82 Interne Geneeskunde en Maag-, Darm-, Levergeneeskunde Kerngegevens 19 Internisten: dr. R.C. (René) Bakker, R.S. (Rinske) Boersma, dr. P.W.G. (Peggy) du Buf-Vereijken, T.T. (Nynke) Cnossen, S.A.M. (Simone) Ennecker-Jans, dr. J.W.J. (Joost) van Esser, dr. R.W. (Ronald) van Etten (medisch manager), A.M. (Astrid) van Gent, dr. C. (Coen) van Guldener, J.B. (Joan) Heijns, dr. M.H.W. (Mariëtte) Kappers, dr. M.A. (Marika) van Leeuwen-Artz, O.J.L. (Olaf) Loosveld, dr. S.W. (Sjoerd) van Thiel, dr. A.J. (Bert Jan) ten Tije, B.F.E. (Bernard) Veldhuijzen, G.P. (Gerrit) Verburg, I.M.E. (Iris) Wentholt, P. (Peter) van Wijngaarden 7 MDL-artsen: A.G.L. (Alexander) Bodelier, I.M. (Ivar) Harkema, M.J. (Marianne) van Heerde, dr. A.W.M (Marc) van Milligen de Wit, dr. M.C.M. (Marno) Rijk, dr. T.C.J (Tom) Seerden, J.J.M. (Joris) van Gulick 14,49 fte assistenten niet in opleiding 14,03 fte assistenten in opleiding (waarvan 4,58 fte werkzaam voor ander specialisme in kader van opleiding) Subspecialismen: diabetes, endocrinologie, hematologie, infectieziekten, nefrologie, oncologie, maag- darm- leverziekten, vasculaire geneeskunde Samenvattingen gepubliceerde artikelen Wissing MD, Coenen JL, van den Berg P, Westgeest HM, van den Eertwegh AJ, van Oort IM, Bos MM, Bergman AM, Hamberg P, Ten Tije AJ, Los M, Lolkema MP, de Wit R, Gelderblom H. CAST: A retrospective analysis of cabazitaxel and abiraterone acetate sequential treatment in patients with metastatic castrate-resistant prostate cancer previously treated with docetaxel. Int J Cancer Mar 15;136(6):E Epub 2014 Oct 3. Cabazitaxel and abiraterone have both received approval for treating metastatic castrateresistant prostate cancer (mcrpc) patients after first-line docetaxel therapy. In the cabazitaxel and abiraterone sequential treatment (CAST) study, the clinical outcome of docetaxel-treated mcrpc patients treated sequentially with both cabazitaxel and abiraterone was studied. Data were collected retrospectively from mcrpc patients at 12 hospitals across the Netherlands who initiated cabazitaxel and/or abiraterone before December Primary outcome measure was overall survival (OS); secondary measures were progression-free survival (PFS), biochemical PFS, and best clinical and PSA response. Hospital admission data during treatment were collected, as well as toxicities resulting in treatment discontinuation or patient death. Sixty-three and 69 patients received Cab Abi (cabazitaxel prior to abiraterone) and Abi Cab before July 10th, 2013, respectively. Median OS was 19.1 months and 17.0 months in Cab Abi and Abi Cab treated patients, respectively (p = 0.369). Median PFS and biochemical PFS were significantly longer in Cab Abi treated patients: 8.1 versus 6.5 (p = 0.050) and 9.5 versus 7.7 months (p = 0.024), respectively. Although partial responses to cabazitaxel occurred in both groups, Abi Cab treated patients had a significantly decreased antitumor response from cabazitaxel than Cab Abi treated patients (median PFS 5.0 versus 2.6 months, p < 0.001). Minor differences in toxicities were observed based on therapy sequence; generally, toxicity from cabazitaxel Interne Geneeskunde en Maag-, Darm-, Levergeneeskunde 81

83 could be severe, while abiraterone toxicity was milder. This retrospective analysis indicates that primary progression on cabazitaxel or abiraterone did not preclude a response to the other agent in mcrpc patients. However, tumor response of both agents, particularly cabazitaxel, was lower when administered as higher-line therapy in the selected study population. PMID: Van Baal MC, Bollen TL, Bakker OJ, van Goor H, Boermeester MA, Dejong CH, Gooszen HG, van der Harst E, van Eijck CH, van Santvoort HC, Besselink MG; Dutch Pancreatitis Study Group*. [van Milligen de Wit M, Rijk M et al...]. The role of routine fine-needle aspiration in the diagnosis of infected necrotizing pancreatitis. Surgery Mar;155(3): Epub 2013 Oct 12. BACKGROUND: Diagnosing infected necrotizing pancreatitis (INP) may be challenging. The aim of this study was to determine the added value of routine fine-needle aspiration (FNA) in addition to clinical and imaging signs of infection in patients who underwent intervention for suspected INP. METHODS: We conducted a post hoc analysis of 208 consecutive patients from a prospective, multicenter database who underwent intervention because of suspected INP. In retrospect, 3 groups were constructed based on the patients preoperative characteristics: Clinical, imaging, and FNA. Patients in the clinical group had clinical signs of infection but no gas on preoperative computed tomography (CT) and no FNA performed before intervention. Patients in the imaging group had gas bubbles on the preoperative CT but no was FNA performed, whereas patients in the FNA group had a positive FNA before intervention. The reference standard for infection was the culture taken during the first intervention (either catheter drainage or necrosectomy). RESULTS: The initial intervention for INP was performed a median of 27 days (interquartile range, 20-39) after admission without difference between the 3 groups (P =.15). Infection was confirmed in 80% of 92 patients of the clinical group, in 94% of 88 patients of the imaging group, and in 86% of 28 patients of the FNA group (P =.07). Mortality was 19% and was not different between groups (P =.39). CONCLUSION: INP can generally be diagnosed based on clinical or imaging signs of infection. FNA may be useful in patients with unclear clinical signs and no imaging signs of INP. *Collaborators: Boermeester M, Bollen T, Dejong C, van Eijck C, van Goor H, Gooszen H, Hofker H, Laméris J, van Leeuwen M, Schaapherder A, Timmer R, Nieuwenhuijs V, van Dam R, Rutten J, Stoot J, Keulemans Y, Vliegen R, Roeterdink A, Ali U, Schrijver A, Rijnhart H, Cirkel G, van Erpecum K, Vleggaar F, Akkermans L, van Leeuwen M, Rijkers G, Wiezer M, Weusten B, Biemond H, van Ramshorst B, Ploeg R, Buitenhuis H, van Vliet S, Ramcharan S, van Dullemen H, Hofker H, Nieuwenhuijs V, van Ruler O, Laméris W, Laméris J, Gouma D, Busch O, Fockens P, Haasnoot A, Veenendaal R, Schaapherder A, Witteman B, Kruyt P, Pierie J, Spoelstra P, Dol J, Gerritsen R, Manusama E, Lange J, Wijffels N, van Walraven L, Coene P, Kubben F, Wijsman J, Crolla R, van Milligen de Wit AW, Rijk M, van der Schelling G, Stassen L, Karsten T, Buscher H, Hesselink E, 82 Publicaties Medische Staf

84 Heisterkamp J, van Oostvogel H, Grubben M, Tan A, Rosman C, van der Wal J, Morak M, Kuipers E, Poley J, Bruno M, Jansen J, Hermans J, P S, van Laarhoven C, Zeguers V, Wahab P, Lips D, Olsman J, van Munster I, Bosscha K, Kolkman J, Huisman A, de Wit R, Tuynman H, Wiarda B, Houdijk A, Consten E, Schwartz M, Brink M, van der Peet D, Mulder C, Questa M. PMID: Kant KM, Djamin RS, Belderbos HN, van den Berg B. Acute respiratoire insufficiëntie door COPD: Beslissen over wel of niet beademen. [Acute respiratory insufficiency due to COPD: invasive mechanical ventilation or not?]. Ned Tijdschr Geneeskd. 2014;158:A5276. The decision to move to a form of mechanical ventilation in patients with acute respiratory failure due to an acute exacerbation of COPD is influenced by expectations about survival and quality of life after discharge from the ICU. Physicians tend to be too pessimistic about the survival outcome of an ICU stay with invasive mechanical ventilation. The forced expiratory volume in 1 second (FEV1) is not an adequate prognostic parameter. In order to prevent undertreatment of patients with respiratory failure due to an exacerbation of COPD, knowledge of prognostic parameters and quality of life in these patients is very important. End of life care should be integrated into the standard care of COPD patients. PMID: Bodelier AG, Pierik MJ, van den Heuvel T, Bovee-Oudenhoven IM, de Boer E, Hameeteman W, Masclee AA, Jonkers D. Pancreatitis-associated protein has no additional value as a marker of disease activity in a real-life cohort of IBD patients. Eur J Gastroenterol Hepatol Aug;26(8): BACKGROUND AND AIM: Monitoring of mucosal inflammation in inflammatory bowel disease (IBD) is of major importance. New noninvasive markers for intestinal inflammation are needed. Previous studies have reported that pancreatitis-associated protein (PAP) correlates with clinical activity in IBD subgroups. Our aim was to investigate the correlation of serum and fecal PAP with clinical and biochemical parameters of disease activity in a real-life IBD cohort. PATIENTS AND METHODS: Two hundred and five consecutive IBD patients were enrolled. Clinical disease activity was scored by the Harvey-Bradshaw Index or the Simple Clinical Colitis Activity Index; also, C-reactive protein (CRP), erythrocyte sedimentation rate, and fecal calprotectin were determined. As surrogate for endoscopy, a combination score of clinical indices with CRP or calprotectin was used to define active disease. Fecal and serum PAP were measured by ELISA. Interne Geneeskunde en Maag-, Darm-, Levergeneeskunde 83

85 RESULTS: The median serum and fecal PAP did not differ in Crohn s disease (CD) or ulcerative colitis (UC) patients with active compared with inactive disease according to clinical activity indices. Defining active disease by a combination score of Harvey-Bradshaw Index of more than 4 and CRP of more than 5 mg/l or calprotectin more than 250 µg/g, serum PAP (P=0.01), but not fecal PAP (P=0.32), was significantly higher in active than inactive CD patients. Area under the curve of the corresponding receiver operating curve (ROC) was No differences were found in serum or fecal PAP levels using the combination score for active disease in UC. CONCLUSION: Serum but not fecal PAP was higher in active compared with nonactive CD and may reflect mucosal inflammation in CD, but not in UC. However, the accuracy of serum PAP for the diagnosis of active disease was poor, and therefore, serum PAP does not seem to have additional value compared with the current noninvasive markers. PMID: Boersma RS, Jie KS, Voogd AC, Hamulyak K, Verbon A, Schouten HC. Concentrated citrate locking in order to reduce the long-term complications of central venous catheters: a randomized controlled trial in patients with hematological malignancies. Support Care Cancer Jan;23(1): Epub 2014 Jun 20. PURPOSE AND METHODS: Central venous catheter (CVC)-related thrombosis and infections are frequently occurring complications in patients with hematological malignancies. At present, heparin is most often used as a locking solution. Trisodium citrate (TSC) had been shown to be a very effective antimicrobial catheter locking in hemodialysis patients. We performed a prospective randomized phase III multicenter trial to determine the efficacy of TSC as a locking solution compared to heparin in preventing CVC-related thrombosis and infections in patients with hematological malignancies. RESULTS: Thirty-four episodes of CVC-related bloodstream infections (CVC-BSI) occurred in the 108 patients who were randomized to locking with heparin compared with 35 episodes in the 99 patients who were randomized to locking with TSC (P = 0.654). We did find seven times more CVC-BSI with gram-negative rods in CVCs locked with heparin (P = 0.041). The cumulative incidence of symptomatic thrombosis was 10% in the heparin group and 5% in the TSC group (hazard ratio 0.525; 95% confidence interval ). CONCLUSION: This study shows that locking with TSC in patients with hematological malignancies significantly reduced the incidence of CVC-BSI with gram-negative rods. However, the incidence of CVC-BSI with coagulase-negative staphylococcus or CVC-related thrombosis was not reduced by TSC locking. PMID: Publicaties Medische Staf

86 Van Gammeren AJ, Alcala LS, Smolders M, Boersma RS. Numerous Russell bodies and Dutcher bodies in multiple myeloma. Br J Haematol Oct 14. [Epub ahead of print] No abstract available. PMID: Buiten MS, de Bie MK, Bouma-de Krijger A, van Dam B, Dekker FW, Jukema JW, Rabelink TJ, Rotmans JI. Soluble Klotho is not independently associated with cardiovascular disease in a population of dialysis patients. BMC Nephrol Dec 11;15:197. BACKGROUND: Dialysis patients suffer from a high burden of cardiovascular disease (CVD). Partly this is due to progressive deterioration of calcium-phosphate homeostasis. Previous studies suggested that besides FGF-23, low levels of Klotho, a protein linked to aging, might constitute a key factor in this detrimental relationship. The purpose of the present study was to determine the relationship between serum Klotho (sklotho) and the presence of CVD in dialysis patients. METHODS: Plasma levels of sklotho were measured in a cohort of dialysis patients and related to left ventricular (LV) dysfunction (defined as a LV ejection fraction<45%) and LV mass using echocardiography. Coronary artery disease (CAD) and calcification score were assessed using computed tomography angiography. Abdominal aortic calcification score (AACscore) was measured by abdominal X-ray. RESULTS: We included 127 dialysis patients, 67±7 years old, 76% male, 67% on hemodialysis, median sklotho 460 pg/ml (25th-75th percentile pg/ml). Patients with a low sklotho (<460 pg/ml) showed significantly more CAD (81% versus 61%; p=0.02) and LV dysfunction (19% versus 3%; p<0.01). However, after adjusting for confounders, sklotho was not independently associated with the presence of CVD or the AACscore. CONCLUSIONS: In the present cohort of dialysis patients, sklotho was not independently associated with CVD. However, patients with a low sklotho level (<460 pg/ml) did show CAD and LV dysfunction more frequently. Therefore, while sklotho might be a marker for CVD in dialysis patients, the current data does not support a direct cardioprotective effect of sklotho. PMID: Interne Geneeskunde en Maag-, Darm-, Levergeneeskunde 85

87 Van den Berg SA, Verwer PE, Idema RN, Van Guldener C. Transient cefuroxime/metronidazole treatment induced factor V antibodies. BMJ Case Rep Aug 19;2014. pii: bcr A 29-year-old patient presented with an appendicular infiltrate, initially treated with intravenous antibiotics, but later requiring percutaneous drainage. Both prothrombin time (PT) and activated partial thromboplastin time (aptt) were prolonged on 3 days of antibiotic treatment and unresponsive to vitamin K or prothrombin complex concentrate. Laboratory investigation ultimately showed reduced factor V activity and factor V antibodies. In contrast to previously described cases of factor V antibodies, PT and aptt were only mildly prolonged and residual factor V activity was still >20%. Draining of the abscess did not induce significant bleeding. Afterwards, no haemostatic medication was required. The patient was discharged from the hospital without complications. One week after cessation of the antibiotic treatment, PT and aptt were within normal range again, with a factor V activity level of 36%. In conclusion, we present a patient with transient factor V antibodies, induced by antibiotics, without clinical bleeding tendency. PMID: Van Heerde MJ, Buijs J, Rauws EA, de Buy Wenniger LJ, Hansen BE, Biermann K, Verheij J, Vleggaar FP, Brink MA, Beuers UH, Kuipers EJ, van Buuren HR, Bruno MJ. A comparative study of diagnostic scoring systems for autoimmune pancreatitis. Pancreas May;43(4): OBJECTIVE: Several diagnostic scoring systems for autoimmune pancreatitis (AIP) have been proposed including the Asian, HISORt (Histology, Imaging, Serology, Other organ involvement and Response to therapy), and International Consensus Diagnostic Criteria (ICDC), which have been compared by a few studies. We evaluated the diagnostic performance of these criteria in patients diagnosed with AIP between May 1992 and August METHODS: Scoring systems were applied retrospectively using data obtained in the initial evaluation period, before pancreatic resection was performed. RESULTS: One hundred fourteen cases with AIP were included. Eighty-two percent met the diagnostic criteria for AIP according to either the Asian, HISORt, or ICDC criteria. Only 33% met the Asian criteria, probably mainly related to a low rate of diagnostic pancreatography. In 18%, all scoring systems failed to confirm the diagnosis, even though these patients were considered to have a firm diagnosis of AIP. CONCLUSIONS: In this cohort of AIP patients, the 3 major diagnostic scoring systems for AIP proved to be complementary rather than overlapping. Our data indicate that one-fifth of our AIP patients do not meet any of these scoring systems. The ICDC, Asian, and HISORt criteria should be considered as useful clinical tools but not as criterion standard for the diagnosis. PMID: Publicaties Medische Staf

88 Buijs J, van Heerde MJ, Rauws EA, de Buy Wenniger LJ, Hansen BE, Biermann K, Verheij J, Vleggaar FP, Brink MA, Beuers UH, Kuipers EJ, Bruno MJ, van Buuren HR. Comparable efficacy of low- versus high-dose induction corticosteroid treatment in autoimmune pancreatitis. Pancreas Mar;43(2): OBJECTIVE: The objective of this study was to compare efficacy of high versus low doses of prednisone for induction of remission in autoimmune pancreatitis (AIP). METHODS: This is a retrospective, multicenter study including patients diagnosed with AIP between May 1992 and August Clinical, laboratory and imaging findings were assessed before treatment and at 1, 3, and 6 months after starting treatment. RESULTS: A total of 65 patients (57 males; median age, 63 years) were treated with an initial low dose (10-20 mg/d, n = 14), a medium dose (30 mg/d, n = 15), or a high dose (40-60 mg/d, n = 36) of prednisone. There were no significant differences in baseline characteristics between the treatment groups including age, presenting symptoms and laboratory results. During a follow-up period of 6 months, in nearly all patients, symptoms (jaundice, weight loss) resolved completely. After 6 months, treatment response with respect to symptomatic, radiological, and laboratory improvement was comparable for the different dosage groups. CONCLUSIONS: Response to therapy was comparable for AIP patients treated with doses of prednisone in the range of 10 to 60 mg/d. A prospective trial should be conducted to confirm efficacy of lower-dose prednisone treatment. PMID: Interne Geneeskunde en Maag-, Darm-, Levergeneeskunde 87

89 Van Heerde MJ, Buijs J, Hansen BE, de Waart M, van Eijck CH, Kazemier G, Pek CJ, Poley JW, Bruno MJ, Kuipers EJ, van Buuren HR. Serum level of Ca 19-9 increases ability of IgG4 test to distinguish patients with autoimmune pancreatitis from those with pancreatic carcinoma. Dig Dis Sci Jun;59(6): Epub 2014 Jan 3. BACKGROUND: Autoimmune pancreatitis (AIP) is often difficult to distinguish from pancreatic carcinoma or other pancreatobiliary diseases. High serum levels of carbohydrate antigen 19-9 (Ca 19-9) are indicative of malignancies, whereas high levels of immunoglobulin (Ig)G4 (>1.4 g/l) are characteristic of AIP. We investigated whether serum levels of these proteins can differentiate between these diseases. METHODS: We measured levels of Ca 19-9 and IgG4 in serum samples from 33 patients with AIP, 53 with pancreatic carcinoma, and 145 with other pancreatobiliary disorders. We determined cut-off levels for each assay. Logistic regression analysis was used to evaluate combined data on Ca 19-9, IgG4, and bilirubin levels. 88 Publicaties Medische Staf

90 RESULTS: Low levels of Ca 19-9 were independently associated with AIP, compared with pancreatic adenocarcinoma [odds ratio (OR) 0.28; 95% confidence interval (CI) ; p = ]. Using an upper level of 74 U/ml, the assay for Ca 19-9 identified patients with AIP with 73% sensitivity and 74% specificity. Using a lower level of 2.6 g/l, the assay for IgG4 identified these patients with 70% sensitivity and 100% specificity. Combining data, levels of Ca 19-9 < 74 U/ ml and IgG4 > 1.0 g/l identified patients with AIP with 94% sensitivity and 100% specificity. CONCLUSIONS: Patients with AIP have lower levels of Ca 19-9 than those patients with pancreatic carcinoma. Measurement of either the Ca 19-9 or the IgG4 level alone are not accurate enough for diagnosis. However, the combination of Ca 19-9 < 74 U/ml and IgG4 > 1.0 g/l distinguishes patients with AIP from those patients with pancreatic carcinoma with 94% sensitivity and 100% specificity. PMID: Boonstra K, Culver EL, de Buy Wenniger LM, van Heerde MJ, van Erpecum KJ, Poen AC, van Nieuwkerk KM, Spanier BW, Witteman BJ, Tuynman HA, van Geloven N, van Buuren H, Chapman RW, Barnes E, Beuers U, Ponsioen CY. Serum immunoglobulin G4 and immunoglobulin G1 for distinguishing immunoglobulin G4-associated cholangitis from primary sclerosing cholangitis. Hepatology May;59(5): Epub 2014 Apr 1. The recent addition of immunoglobulin (Ig)G4-associated cholangitis (IAC), also called IgG4- related sclerosing cholangitis (IRSC), to the spectrum of chronic cholangiopathies has created the clinical need for reliable methods to discriminate between IAC and the more common cholestatic entities, primary (PSC) and secondary sclerosing cholangitis. The current American Association for the Study of Liver Diseases practice guidelines for PSC advise on the measurement of specific Ig (sig)g4 in PSC patients, but interpretation of elevated sigg4 levels remains unclear. We aimed to provide an algorithm to distinguish IAC from PSC using sigg analyses. We measured total IgG and IgG subclasses in serum samples of IAC (n = 73) and PSC (n = 310) patients, as well as in serum samples of disease controls (primary biliary cirrhosis; n = 22). sigg4 levels were elevated above the upper limit of normal (ULN = >1.4 g/l) in 45 PSC patients (15%; 95% confidence interval [CI]: 11-19). The highest specificity and positive predictive value (PPV; 100%) for IAC were reached when applying the 4 x ULN (sigg4 > 5.6 g/l) cutoff with a sensitivity of 42% (95% CI: 31-55). However, in patients with a sigg4 between 1 x and 2 x ULN (n = 38/45), the PPV of sigg4 for IAC was only 28%. In this subgroup, the sigg4/sigg1 ratio cutoff of 0.24 yielded a sensitivity of 80% (95% CI: 51-95), a specificity of 74% (95% CI: 57-86), a PPV of 55% (95% CI: 33-75), and a negative predictive value of 90% (95% CI: 73-97). CONCLUSION: Elevated sigg4 (>1.4 g/l) occurred in 15% of patients with PSC. In patients with a sigg4 >1.4 and <2.8 g/l, incorporating the IgG4/IgG1 ratio with a cutoff at 0.24 in the diagnostic algorithm significantly improved PPV and specificity. We propose a new diagnostic algorithm based on IgG4/IgG1 ratio that may be used in clinical practice to distinguish PSC from IAC. PMID: Interne Geneeskunde en Maag-, Darm-, Levergeneeskunde 89

91 Charehbili A, van de Ven S, Smit VT, Meershoek-Klein Kranenbarg E, Hamdy NA, Putter H, Heijns JB, van Warmerdam LJ, Kessels L, Dercksen M, Pepels MJ, Maartense E, van Laarhoven HW, Vriens B, Wasser MN, van Leeuwen-Stok AE, Liefers GJ, van de Velde CJ, Nortier JW, Kroep JR; Dutch Breast Cancer Research Group (BOOG). Addition of zoledronic acid to neoadjuvant chemotherapy does not enhance tumor response in patients with HER2-negative stage II/III breast cancer: the NEOZOTAC trial (BOOG ). Ann Oncol May;25(5): Epub 2014 Feb 27. BACKGROUND: The role of zoledronic acid (ZA) when added to the neoadjuvant treatment of breast cancer (BC) in enhancing the clinical and pathological response of tumors is unclear. The effect of ZA on the antitumor effect of neoadjuvant chemotherapy has not prospectively been studied before. PATIENTS AND METHODS: NEOZOTAC is a national, multicenter, randomized study comparing the efficacy of TAC (docetaxel, adriamycin and cyclophosphamide i.v.) followed by granulocyte colony-stimulating factor on day 2 with or without ZA 4 mg i.v. q 3 weeks inpatients withstage II/ III, HER2-negative BC. We present data on the pathological complete response (pcr in breast and axilla), on clinical response using MRI, and toxicity. Post hoc subgroup analyses were undertaken to address the predictive value of menopausal status. RESULTS: Addition of ZA to chemotherapy did not improve pcr rates (13.2% for TAC+ZA versus 13.3% for TAC). Postmenopausal women (N = 96) had a numerical benefit from ZA treatment (pcr 14.0% for TAC+ZA versus 8.7% for TAC, P = 0.42). Clinical objective response did not differ between treatment arms (72.9% versus 73.7%). There was no difference in grade III/IV toxicity between treatment arms. CONCLUSIONS: Addition of ZA to neoadjuvant chemotherapy did not improve pathological or clinical response to chemotherapy. Further investigations are warranted in postmenopausal women with BC, since this subgroup might benefit from ZA treatment. PMID: Publicaties Medische Staf

92 Onstenk W, Kraan J, Mostert B, Timmermans MM, Charehbili A, Smit VT, Kroep JR, Nortier JW, van de Ven S, Heijns JB, Kessels LW, van Laarhoven HW, Bos MM, van de Velde CJ, Gratama JW, Sieuwerts AM, Martens JW, Foekens JA, Sleijfer S. Improved Circulating Tumor Cell Detection by a Combined EpCAM and MCAM CellSearch Enrichment Approach in Patients with Breast Cancer Undergoing Neoadjuvant Chemotherapy. Mol Cancer Ther Dec 31. [Epub ahead of print] Circulating tumor cells (CTC) are detected by the CellSearch System in 20% to 25% of patients with primary breast cancer (pbc). To improve CTC detection, we investigated melanoma cell adhesion molecule (MCAM) as enrichment marker next to epithelial cell adhesion molecule (EpCAM) and tested the clinical relevance of MCAM-positive CTCs in patients with HER2-negative stage II/III pbc starting neoadjuvant chemotherapy (NAC) in the NEOZOTAC trial. Using the CellSearch System, EpCAM-positive and MCAM-positive CTCs were separately enriched from 7.5 ml blood, at baseline and after the first NAC cycle. Circulating endothelial cells (CEC) were measured using flow cytometry. Primary objective was to improve the CTC detection rate to 40% combining EpCAM/MCAM. Correlations of CTC and CEC counts and pathologic complete response (pcr) were also explored. At baseline, we detected EpCAM-positive and MCAM-positive CTCs in 12 of 68 (18%) and 8 of 68 (12%) patients, respectively. After one cycle, this was 7 of 44 (16%) and 7 of 44 (16%) patients, respectively. The detection rate improved from 18% at baseline and 16% after one cycle with EpCAM to 25% (P = 0.08) and 30% (P = 0.02), respectively, with EpCAM/MCAM. No patients with MCAM-positive CTCs versus 23% of patients without MCAMpositive CTCs at baseline achieved pcr (P = 0.13). EpCAM-positive CTCs and CEC counts were not correlated to pcr. Combined EpCAM/MCAM CellSearch enrichment thus increased the CTC detection rate in stage II/III pbc. We found no associations of CTC and CEC counts with pcr to NAC. The clinical relevance of MCAM-positive CTCs deserves further study. PMID: Lankhorst S, Kappers MH, van Esch JH, Smedts FM, Sleijfer S, Mathijssen RH, Baelde HJ, Danser AH, van den Meiracker AH. Treatment of hypertension and renal injury induced by the angiogenesis inhibitor sunitinib: preclinical study. Hypertension Dec;64(6): Epub 2014 Sep 2. Common adverse effects of angiogenesis inhibition are hypertension and renal injury. To determine the most optimal way to prevent these adverse effects and to explore their interdependency, the following drugs were investigated in unrestrained Wistar Kyoto rats exposed to the angiogenesis inhibitor sunitinib: the dual endothelin receptor antagonist macitentan; the calcium channel blocker amlodipine; the angiotensin-converting enzyme inhibitor captopril; and the phosphodiesterase type 5 inhibitor sildenafil. Mean arterial pressure was monitored telemetrically. After 8 days, rats were euthanized and blood samples and kidneys were collected. In addition, 24-hour urine samples were collected. After sunitinib start, mean arterial pressure increased rapidly by 30 mm Hg. Coadministration of macitentan or amlodipine largely prevented this rise, whereas captopril or sildenafil did not. Macitentan, captopril, and sildenafil diminished the sunitinib-induced proteinuria and endothelinuria and glomerular intraepithelial protein deposition, whereas amlodipine did not. Changes in proteinuria and endothelinuria were unrelated. We conclude that in our experimental model, dual endothelin Interne Geneeskunde en Maag-, Darm-, Levergeneeskunde 91

93 receptor antagonism and calcium channel blockade are suitable to prevent angiogenesis inhibition-induced hypertension, whereas dual endothelin receptor antagonism, angiotensinconverting enzyme inhibitor, and phosphodiesterase type 5 inhibition can prevent angiogenesis inhibition-induced proteinuria. Moreover, the variable response of hypertension and renal injury to different antihypertensive agents suggests that these side effects are, at least in part, unrelated. PMID: Krol CG, Klok FA, de Koning EJ. Diplopia as the presenting symptom of type 1 diabetes. Diabetes Care Mar;37(3):e45-6. No abstract available. PMID: Krol CG, Dekkers OM, Kroon HM, Rabelink TJ, van Hoek B, Hamdy NA. Longitudinal changes in BMD and fracture risk in orthotopic liver transplant recipients not using bone-modifying treatment. J Bone Miner Res Aug;29(8): Osteoporosis is prevalent in end-stage liver disease, but data on long-term changes in bone mineral density (BMD) and related fracture incidence after orthotopic liver transplantation (OLT) are scarce. We evaluated BMD changes up to 5 years in consecutive recipients of a successful OLT at the Leiden University Medical Centre between 2000 and 2011, in whom sequential BMD data were available. Spinal radiographs were available at time of screening and at 6 and 12 months post-olt and were assessed for vertebral fractures by two independent observers using Genant s semiquantitative method. Patients were excluded from the study when started on bisphosphonates. A total of 201 patients (71% men), median age 53 years (range, years) were included in the study. Most common liver pathology was viral (27%) or alcoholic liver disease (25%). All patients received prednisone for at least 6 months after transplantation and the majority received either tacrolimus or cyclosporine for immunosuppression. At time of screening for OLT, osteoporosis and osteopenia were found in 18% and 36% of patients at the lumbar spine (LS), respectively, and in 9% and 42% at the femoral neck (FN), respectively. T-scores declined significantly at both sites 6 months after OLT, but increased thereafter at the LS, reaching pretransplantation values at 2 years and remaining stable thereafter. FN T-scores remained consistently lower than pretransplantation values. The prevalence of vertebral fractures increased from 56% at screening to 71% at 1 year after OLT, with a fracture incidence of 34%. BMD changes did not predict fracture risk. Osteoporosis, osteopenia, and vertebral fractures are prevalent in patients with end-stage liver disease. An overall decline in BMD is observed within the first 6 months after OLT, with subsequent recovery to pretransplantation values at the LS, but not at the FN. Vertebral fracture risk is high after OLT regardless of changes in BMD. PMID: Publicaties Medische Staf

94 Krol CG, Dekkers OM, Kroon HM, Rabelink TJ, van Hoek B, Hamdy NA. No association between BMD and prevalent vertebral fractures in liver transplant recipients at time of screening before transplantation. J Clin Endocrinol Metab Oct;99(10): Epub 2014 Jul 24. CONTEXT: Osteoporosis and fractures are prevalent after orthotopic liver transplantation (OLT), but data on these skeletal complications are scarce in patients with end-stage liver disease awaiting liver transplantation. OBJECTIVE: To evaluate the prevalence of vertebral fractures (VFs) in OLT recipients at the time of screening for transplantation and to establish the association between bone mineral density (BMD) and these fractures before transplantation. DESIGN AND SETTING: We conducted a retrospective study of consecutive OLT recipients at the Leiden University Medical Centre between 2000 and 2011 at the time of screening for transplantation. Clinical, laboratory, and BMD data were extracted from electronic hospital records. Conventional spinal radiographs were assessed for VF by two independent observers using Genant s semiquantitative method. PATIENTS: In total, 162 of the 223 OLT recipients (median age, 51 y; 75% men) who had available BMD and spinal radiographs but who were not receiving bone-modifying treatment at screening for OLT were included in the study. MAIN OUTCOME MEASURES: Association between BMD and VF before transplantation. RESULTS: Osteoporosis and osteopenia were prevalent at the lumbar spine in 19 and 38% of subjects, respectively, and in 10 and 42% at the femoral neck. VFs, mostly grade 1, were prevalent in 56% of the subjects. There was no association between BMD and prevalent VF before transplantation. CONCLUSIONS: VFs were prevalent in liver transplant recipients at the time of screening for transplantation, but there was no association between BMD and prevalent fractures. Spinal radiographs should be routinely performed as part of screening protocols before liver transplantation to enable identification of VF and allow timely intervention to potentially decrease or prevent skeletal morbidity after transplantation. PMID: Interne Geneeskunde en Maag-, Darm-, Levergeneeskunde 93

95 Sloothaak DA, van den Berg MW, Dijkgraaf MG, Fockens P, Tanis PJ, van Hooft JE, Bemelman WA; collaborative Dutch Stent-In study group [van Milligen de Wit M et al...]. Oncological outcome of malignant colonic obstruction in the Dutch Stent-In 2 trial. Br J Surg Dec;101(13): BACKGROUND: The Stent-In 2 trial randomized patients with malignant colonic obstruction to emergency surgery or stent placement as a bridge to elective surgery. The aim of this study was to compare the oncological outcomes. METHODS: Disease recurrence, and disease-free, disease-specific and overall survival were evaluated, including a subgroup analysis of patients with a stent- or guidewire-related perforation. RESULTS: Of 98 patients included in the original Stent-In 2 trial, patients with benign (16) or incurable (23) disease were excluded from this study, along with a patient who had withdrawn from the trial. Of the remaining 58 patients, 32 were randomized to emergency surgery (31 resection, 1 stoma only) and 26 to stenting. Unsuccessful stenting required emergency surgery in six patients owing to wire or stent perforation. Locoregional or distant disease recurrence developed in nine of 32 patients in the emergency surgery group and 13 of 26 in the stent group. Disease-free survival was worse in the subgroup with stent- or guidewire-related perforation. Five of six patients in this subgroup developed a recurrence, compared with nine of 32 in the emergency surgery group and eight of 20 who had unperforated stenting. CONCLUSION: Stent placement for malignant colonic obstruction was associated with a risk of recurrence in this trial, but the numbers are small. There is not enough evidence to refute the approach strongly. REGISTRATION NUMBER: ISRCTN ( *Collaborators: Van Hooft JE, Fockens P, Bemelman WA, Dijkgraaf MG, Sprangers MA, Buskens CJ, Jansen JM, Gerhards MF, Timmer R, van Ramshorst B, Oldenburg B, van Hilligersberg R, Bakker CM, Sosef M, Witteman P, Kruyt P, Ten Hove WR, Tseng LN, van der Linde K, Koopal SA, Marinelli AW, Perk L, Lutke Holzik MF, Grubben MJ, Heisterkamp J, Depla AC, Derksen E, Naber AH, van Geloven AA, Breumelhof R, Davids PH, Akol H, van der Zaag E, Schenk E, Patijn GA, Veenendaal RA, Tollenaar RA, van Berkel A, Gilissen LP, Nieuwenhuijzen GA, van der Waaij LA, Baas PC, Cense H, Scholten P, van Wagensveld B, Koornstra JJ, Havenga K, van Milligen de Wit M, Rijken AM, Cazemier M, Guicherit OR, Houben MH, Steup WH. PMID: De Boer YS, van Gerven NM, Zwiers A, Verwer BJ, van Hoek B, van Erpecum KJ, Beuers U, van Buuren HR, Drenth JP, den Ouden JW, Verdonk RC, Koek GH, Brouwer JT, Guichelaar MM, Vrolijk JM, Kraal G, Mulder CJ, van Nieuwkerk CM, Fischer J, Berg T, Stickel F, Sarrazin C, Schramm C, Lohse AW, Weiler-Normann C, Lerch MM, Nauck M, Völzke H, Homuth G, Bloemena E, Verspaget 94 Publicaties Medische Staf

96 HW, Kumar V, Zhernakova A, Wijmenga C, Franke L, Bouma G; Dutch Autoimmune Hepatitis Study Group* [van Milligen de Wit M et al...].; LifeLines Cohort Study; Study of Health in Pomerania. Genome-wide association study identifies variants associated with autoimmune hepatitis type 1. Gastroenterology Aug;147(2): e5. Epub 2014 Apr 23. BACKGROUND & AIMS: Autoimmune hepatitis (AIH) is an uncommon autoimmune liver disease of unknown etiology. We used a genome-wide approach to identify genetic variants that predispose individuals to AIH. METHODS: We performed a genome-wide association study of 649 adults in The Netherlands with AIH type 1 and 13,436 controls. Initial associations were further analyzed in an independent replication panel comprising 451 patients with AIH type 1 in Germany and 4103 controls. We also performed an association analysis in the discovery cohort using imputed genotypes of the major histocompatibility complex region. RESULTS: We associated AIH with a variant in the major histocompatibility complex region at rs (P = 1.5 x 10(-78)). Analysis of this variant in the discovery cohort identified HLA-DRB1*0301 (P = 5.3 x 10(-49)) as a primary susceptibility genotype and HLA-DRB1*0401 (P = 2.8 x 10(-18)) as a secondary susceptibility genotype. We also associated AIH with variants of SH2B3 (rs , 12q24; P = 7.7 x 10(-8)) and CARD10 (rs , 22q13.1; P = 3.0 x 10(-6)). In addition, strong inflation of association signal was found with single-nucleotide polymorphisms associated with other immune-mediated diseases, including primary sclerosing cholangitis and primary biliary cirrhosis, but not with single-nucleotide polymorphisms associated with other genetic traits. CONCLUSIONS: In a genome-wide association study, we associated AIH type 1 with variants in the major histocompatibility complex region, and identified variants of SH2B3and CARD10 as likely risk factors. These findings support a complex genetic basis for AIH pathogenesis and indicate that part of the genetic susceptibility overlaps with that for other immune-mediated liver diseases. Comment in: Genetic risks link autoimmune hepatitis to other autoimmune liver disease. [Gastroenterology. 2014] Collaborators: Baak L, Baven-Pronk A, Coenraad MJ, Klemt-Kropp M, van Meyel J, Linskens R, Spanier B, Kneppelhout J, Kuyvenhoven J, van Geenen E, Wagtmans M, Cahen D, Wolfhagen F, Kingma P, de Vree J, Loffeld R, de Man RA, Friederich W, Schreuder T, van Milligen de Wit A, Alleman M, Bhalla A, Stadhouders P, Verhagen M, Alizadeh B, de Boer R, Boezen H, Bruinenberg M, van der Harst P, Hillege H, van der Klauw M, Navis G, Ormel J, Postma D, Rosmalen J, Slaets J, Snieder H, Stolk R, Wolffenbuttel B, Mayerle J. PMID: Interne Geneeskunde en Maag-, Darm-, Levergeneeskunde 95

97 Van Gerven NM, Verwer BJ, Witte BI, van Erpecum KJ, van Buuren HR, Maijers I, Visscher AP, Verschuren EC, van Hoek B, Coenraad MJ, Beuers UH, de Man RA, Drenth JP, den Ouden JW, Verdonk RC, Koek GH, Brouwer JT, Guichelaar MM, Vrolijk JM, Mulder CJ, van Nieuwkerk CM, Bouma G; Dutch Autoimmune hepatitis STUDY group [van Milligen de Wit AWM et al...]. Epidemiology and clinical characteristics of autoimmune hepatitis in the Netherlands. Scand J Gastroenterol Oct;49(10): Epub 2014 Aug 15. BACKGROUND AND AIMS: Epidemiological data on autoimmune hepatitis (AIH) are scarce. In this study, we determined the clinical and epidemiological characteristics of AIH patients in the Netherlands (16.7 million inhabitants). METHODS: Clinical characteristics were collected from 1313 AIH patients (78% females) from 31 centers, including all eight academic centers in the Netherlands. Additional data on ethnicity, family history and symptoms were obtained by the use of a questionnaire. RESULTS: The prevalence of AIH was 18.3 (95% confidential interval [CI]: ) per 100,000 with an annual incidence of 1.1 (95% CI: 0.5-2) in adults. An incidence peak was found in middleaged women. At diagnosis, 56% of patients had fibrosis and 12% cirrhosis in liver biopsy. Overall, 1% of patients developed HCC and 3% of patients underwent liver transplantation. Overlap with primary biliary cirrhosis and primary sclerosing cholangitis was found in 9% and 6%, respectively. The clinical course did not differ between Caucasian and non-caucasian patients. Other autoimmune diseases were found in 26% of patients. Half of the patients reported persistent AIH-related symptoms despite treatment with a median treatment period of 8 years (range 1-44 years). Familial occurrence was reported in three cases. CONCLUSION: This is the largest epidemiological study of AIH in a geographically defined region and demonstrates that the prevalence of AIH in the Netherlands is uncommon. Although familial occurrence of AIH is extremely rare, our twin data may point towards a genetic predisposition. The high percentage of patients with cirrhosis or fibrosis at diagnosis urges the need of more awareness for AIH. Collaborators: Baak LC, Klemt-Kropp M, van Meyel JJ, Linskens RK, Kneppelhout JC, Kuyvenhoven JP, van Geenen EJ, Wagtmans MJ, Cahen DL, Wolfhagen FH, Kingma PJ, de Vree JM, Loffeld RJ, Vrolijk JM, Friederich PW, Schreuder TC, van Milligen de Wit A, Alleman MA, Bhalla A, Stadhouders PH, Verhagen MA. PMID: Barendse R, Musters G, Fockens P, Bemelman W, de Graaf E, van den Broek F, van der Linde K, Schwartz M, Houben M, van Milligen de Wit A, Witteman B, Winograd R, Dekker E; TREND study group. Endoscopic mucosal resection of large rectal adenomas in the era of centralization: Results of a multicenter collaboration. United European Gastroenterol J Dec;2(6): Publicaties Medische Staf

98 BACKGROUND AND OBJECTIVE: Endoscopic mucosal resection (EMR) of large rectal adenomas is largely being centralized. We assessed the safety and effectiveness of EMR in the rectum in a collaboration of 15 Dutch hospitals. METHODS: Prospective, observational study of patients with rectal adenomas >3cm, resected by piecemeal EMR. Endoscopic treatment of adenoma remnants at 3 months was considered part of the intervention strategy. Outcomes included recurrence after 6, 12 and 24 months and morbidity. RESULTS: Sixty-four patients (50% male, age 69±11, 96% ASA 1/2) presented with 65 adenomas (diameter 46±17mm, distance ab ano 4.5cm (IQR 1-8), 6% recurrent lesion). Sixty-two procedures (97%) were technically successful. Histopathology revealed invasive carcinoma in three patients (5%), who were excluded from effectiveness analyses. At 3 months follow-up, 10 patients showed adenoma remnants. Recurrence was diagnosed in 16 patients during follow-up (recurrence rate 25%). Fifteen of 64 patients (23%) experienced 17 postprocedural complications. CONCLUSION: In a multicenter collaboration, EMR was feasible in 97% of patients. Recurrence and postprocedural morbidity rates were 25% and 23%. Our results demonstrate the outcomes of EMR in the absence of tertiary referral centers. PMID: Ahmed Ali U, Issa Y, van Goor H, van Eijck CH, Nieuwenhuijs VB, Keulemans Y, Fockens P, Busch OR, Drenth JP, Dejong CH, van Dullemen HM, van Hooft JE, Siersema PD, Spanier BW, Poley JW, Poen AC, Timmer R, Seerden T, Tan AC, Thijs WJ, Witteman BJ, Romkens TE, Roeterdink AJ, Gooszen HG, van Santvoort HC, Bruno MJ, Boermeester MA; Dutch Pancreatitis Study Group. Dutch Chronic Pancreatitis Registry (CARE): Design and rationale of a nationwide prospective evaluation and follow-up. Pancreatology Jan-Feb;15(1): Epub 2014 Nov 29. BACKGROUND: Chronic pancreatitis is a complex disease with many unanswered questions regarding the natural history and therapy. Prospective longitudinal studies with long-term follow-up are warranted. METHODS: The Dutch Chronic Pancreatitis Registry (CARE) is a nationwide registry aimed at prospective evaluation and follow-up of patients with chronic pancreatitis. All patients with (suspected) chronic or recurrent pancreatitis are eligible for CARE. Patients are followed-up by yearly questionnaires and review of medical records. Study outcomes are pain, disease complications, quality of life, and pancreatic function. The target sample size was set at 500 for the first year and 1000 patients within 3 years. RESULTS: A total of 1218 patients were included from February 2010 until June 2013 by 76 participating surgeons and gastroenterologist from 33 hospitals. Participation rate was 90% of eligible patients. Eight academic centers included 761 (62%) patients, while 25 community hospitals included 457 (38%). Patient centered outcomes were assessed by yearly questionnaires, Interne Geneeskunde en Maag-, Darm-, Levergeneeskunde 97

99 which had a response rate of 85 and 82% for year 1 and 2, respectively. The median age of patients was 58 years, 814 (67%) were male, and 38% had symptoms for less than 5 years. DISCUSSION: The CARE registry has successfully recruited over 1200 patients with chronic and recurrent pancreatitis in about 3 years. The defined inclusion criteria ensure patients are included at an early disease stage. Participation and compliance rates are high. CARE offers a unique opportunity with sufficient power to investigate many clinical questions regarding natural course, complications, and efficacy and timing of treatment strategies. PMID: Ruff P, Ferry DR, Lakomỳ R, Prausová J, Van Hazel GA, Hoff PM, Cunningham D, Arnold D, Schmoll HJ, Moiseyenko VM, McKendrick JJ, Ten Tije AJ, Vishwanath RL, Bhargava P, Chevalier S, Macarulla T, Van Cutsem E. Time course of safety and efficacy of aflibercept in combination with FOLFIRI in patients with metastatic colorectal cancer who progressed on previous oxaliplatin-based therapy. Eur J Cancer Jan;51(1): Epub 2014 Nov 14. BACKGROUND: Patients with metastatic colorectal cancer (mcrc) previously-treated with oxaliplatin benefit significantly from the addition of aflibercept to FOLFIRI in relation to overall survival, progression-free survival and response rate. PATIENTS AND METHODS: The results for efficacy and safety over the time course of the VEGF Trap (aflibercept) with irinotecan in colorectal cancer after failure of oxaliplatin regimen trial were analysed based on data from 1226 patients randomised to receive FOLFIRI plus either aflibercept (n=612) or placebo (n=614). Hazard ratios (HR) by 6-month time period were estimated using a piecewise Cox proportional hazard model. Severity of adverse events (AEs) was graded using National Cancer Institute Common Terminology Criteria, version 3.0. RESULTS: The estimated probabilities of survival were 38.5% versus 30.9% at 18 months, 28.0% versus 18.7% at 24 months and 22.3% versus 12.0% at 30 months, for the aflibercept- and placebo-treated arms, respectively. The proportional improvement in the HR over time was consistent with the survival probability results; survival at 24 months was improved by 50% and almost doubled at 30 months. The majority of worst-grade AEs occurred within the first four cycles of treatment and in a small percent of treatment cycles and were mostly reversible. Common chemotherapy- and anti-vascular epithelial growth factor (VEGF)-associated AEs occurred rarely and in a small proportion of cycles with the majority being of single occurrence. CONCLUSIONS: The addition of aflibercept to FOLFIRI showed a continued and persistent improvement in overall survival over time in patients with mcrc. Although grade 3-4 AEs were more frequent in the aflibercept arm, they occurred in early treatment cycles and decreased sharply following initial presentation. PMID: Publicaties Medische Staf

100 Lam SW, de Groot SM, Honkoop AH, Jager A, ten Tije AJ, Bos MM, Linn SC, van den Bosch J, Kroep JR, Braun JJ, van Tinteren H, Boven E; Dutch Breast Cancer Research Group. Paclitaxel and bevacizumab with or without capecitabine as first-line treatment for HER2-negative locally recurrent or metastatic breast cancer: a multicentre, open-label, randomised phase 2 trial. Eur J Cancer Dec;50(18): BACKGROUND: The addition of bevacizumab to paclitaxel or capecitabine has demonstrated improved progression-free survival (PFS) and objective response rate (ORR) as compared with chemotherapy alone in patients with HER2-negative locally recurrent or metastatic breast cancer (LR/MBC). We evaluated the efficacy and safety of first-line therapy of paclitaxel and bevacizumab with or without capecitabine in patients with HER2-negative LR/MBC. METHODS: In this multicentre, open-label, randomised phase II trial, women with HER2-negative LR/MBC were randomly assigned in a 1:1 ratio to paclitaxel (90 mg/m2 intravenously [IV] on days 1, 8, and 15) and bevacizumab (10 mg/kg IV on days 1 and 15) every 4 weeks for six cycles, followed by bevacizumab (15 mg/kg IV on day 1) every 3 weeks (AT) or to paclitaxel (90 mg/m2 IV on days 1 and 8), bevacizumab (15 mg/kg IV on day 1) and capecitabine (825 mg/m2 orally twice daily on days 1 14) every 3 weeks for eight cycles, followed by bevacizumab and capecitabine at the same doses every 3 weeks (ATX). The primary end-point was investigator-assessed PFS. Secondary endpoints included ORR, duration of response, overall survival (OS) and safety. Exploratory analyses were conducted to evaluate the impact of capecitabine on OS and to validate a novel prognostic model. This trial is registered with EudraCT, number FINDINGS: Median PFS was significantly longer in ATX as compared with AT (11.2 months versus 8.4 months; stratified hazard ratio (HR), 0.52; 95% confidence interval (CI), ; p < ). The ORR in ATX patients with measurable disease (n = 268) was higher than that in AT (69% versus 51%; p = 0.01). The median duration of response was 6.8 versus 5.4 months for, respectively, ATX and AT (p < ). Median OS was 24.2 months for ATX and 23.1 months for AT (p = 0.53). The increased rate of grade 3 4 adverse events related to the addition of capecitabine, being hand-foot syndrome (34% versus 0% for AT) and neutropenia (20% versus 12% for AT), generally did not preclude continuation of treatment. Exploratory analyses indicated that (1) patients receiving capecitabine at some line for treatment have significantly improved OS and (2) a prognostic model can classify patients into three risk groups associated with OS. INTERPRETATION: In patients with HER2-negative LR/MBC, addition of capecitabine to paclitaxel and bevacizumab significantly improved PFS, ORR and response duration. This combination was reasonably well tolerated and may be considered of use as first-line treatment in rapidly progressive disease. FUNDING: F. Hoffmann-La Roche Ltd, the Netherlands. PMID: Interne Geneeskunde en Maag-, Darm-, Levergeneeskunde 99

101 Bosscher MR, Wentholt IM, Ackermans MT, Nieveen van Dijkum EJ. An adrenal mass and increased catecholamines: monoamine oxidase or pheochromocytoma effect? J Clin Med Res Mar;7(3): Epub 2014 Dec 29. Hormonal evaluation in patients with an adrenal incidentaloma can be difficult in patients with comorbidities or in patients using interfering drugs. We present a case of a 54-year-old man who was evaluated for an adrenal mass. The medical history reported treatment with a monoamine oxidase (MAO) inhibitor for recurrent psychoses. Hormonal screening showed elevated levels of normetanephrine and metanephrine in plasma and urine, suggesting a diagnosis of pheochromocytoma (PHEO), and an adrenalectomy was performed. Histologic examination showed that the tumor had an origin of the adrenal cortex. MAO inhibitors are also known to cause elevated levels of catecholamines. In this case, a PHEO seemed more likely the cause due to repeatedly elevated levels of metanephrines and normal levels of catecholamines. Since the tumor had an origin of the adrenal cortex, the use of MAO inhibitors was the most likely explanation for the elevated levels of metanephrines. This case illustrated the difficulties in diagnosing PHEO, especially in patients with comorbidities and interfering drugs. PMID: De Bree LC, Alings AM, van Wijngaarden P. Heparin-induced thrombocytopenia after ICD-lead flushing. Acta Cardiol Apr;69(2): Heparin-induced thrombocytopenia (HIT) is a potentially life-threatening prothrombotic complication following heparin administration. We describe a patient, known with idiopathic dilating cardiomyopathy, presenting nine days after a biventricular ICD implantation with dyspnoea and thrombocytopenia. Thirteen days after administration of a single heparin flush during ICD implantation, the patient developed venous thrombosis in two extremities and pulmonary embolism caused by HIT. HIT is the development of thrombocytopenia, caused by IgG antibodies against complexes of platelet factor 4 and heparin, leading to platelet aggregation. HIT may be accompanied by thrombosis in 20-50% of patients and untreated mortality rates are high. Once HIT is suspected, heparin should be replaced by an alternative anti-factor Xa or anti-factor II therapy. Regardless of the low incidence of HIT, because of the widespread use of heparin and the potentially life-threatening course of HIT, all physicians should be aware of it. PMID: Raven CF, van Wijngaarden P, Moen G, van Rijen MM. Clusteruitbraak MRSA buiten het ziekenhuis: Herkennen en aanpakken. [Cluster outbreak of MRSA in the community; recognition and approach]. Ned Tijdschr Geneeskd. 2014;158:A6812. BACKGROUND: Community-acquired infection with methicillin-resistant Staphylococcus aureus (CA-MRSA) mainly affects healthy young people, without health-care related risk factors for MRSA. Patients often present with skin and soft-tissue infections. 100 Publicaties Medische Staf

102 CASE DESCRIPTION: An 18-year-old woman presented at the casualty department with recurrent purulent skin infections. She proved to be MRSA-positive. Within 6 months, 2 people around her also developed an MRSA infection. Culture showed CA-MRSA, with an identical strain (spa type: t008). Additional screening within her immediate circle identified 4 carriers, 2 of whom had corresponding skin infections. CONCLUSION: Cluster outbreaks of CA-MRSA require a coordinated approach from both the treating physician and the public health services. The choice of additional investigation among the circle of contacts was the determining factor in breaking the cycle of transmission and reinfection within this cluster. PMID: Hendrikse WM, Grootenboers MJ, van Wijngaarden P. Type B lactic acidosis as initial presentation of acute myeloid leukaeemia. A case report. Neth J Crit Care apr;18(2):15-6. Lactic acidosis type B is a rare complication in patients with haematological malignancies. This article reports a single patient case with lactic acidosis as a first presentation of acute myeloid leukaemia. Finally, we briefly speculate on the pathogenesis of this disorder. Interne Geneeskunde en Maag-, Darm-, Levergeneeskunde 101

103 Keel-, Neus- en Oorheelkunde Kerngegevens 8 KNO-artsen: P.E. (Paul) Briët, J. (Jasper) Companjen, M.L.C.H. (Milou) Heiligers, E.A. (Eric) Janssen, G.L.E. (Geert) Küppers, A.J.M (Antoon) van der Rijt, dr. F.C.A. (Ferdinand) Timmer, dr. G.K.A. (Gijs) van Wermeskerken 1 arts-assistent (per half jaar, het gehele jaar door; 1,1 fte) 1 co-assistent (per 3 weken, het gehele jaar door; 1 fte) Samenvattingen gepubliceerde artikelen Bruintjes TD, Companjen J, van der Zaag-Loonen HJ, van Benthem PP. A randomised sham-controlled trial to assess the long-term effect of the Epley manoeuvre for treatment of posterior canal benign paroxysmal positional vertigo. Clin Otolaryngol Feb;39(1): OBJECTIVE: To evaluate the long-term efficacy of the Epley manoeuvre as a therapeutic procedure for posterior canal benign paroxysmal positional vertigo. DESIGN: Randomised, double-blind, sham-controlled trial. SETTING: A multidisciplinary dizziness unit in a non-academic Hospital. PARTICIPANTS: Forty-four patients with posterior canal benign paroxysmal positional vertigo (BPPV) with a duration of at least 1 month. Participants were randomised in two groups of 22 and treated with either the Epley manoeuvre or a sham manoeuvre and followed up for 1 year after treatment. MAIN OUTCOME MEASURES: Conversion of a positive Dix-Hallpike test to a negative Dix- Hallpike test, impairments perceived by the dizziness assessed by the Dizziness Handicap Inventory (DHI). STATISTICAL ANALYSIS: Absolute and relative risks were computed, and Fisher s exact test was used to compare the treatments. RESULTS: Six patients were lost to follow up (five in the sham group, one in the Epley group). The Epley procedure resulted in a treatment success in 20/22 patients (91%) after 12 months of follow-up, whereas the sham procedure had a positive effect in 10/22 patients (46%; P = 0.001). The DHI was significantly lower in the Epley group at all follow-up assessments (median scores 12 months 0 (0-51) versus 20 (0-76), P = 0.003). 102 Publicaties Medische Staf

104 CONCLUSION: The Epley manoeuvre provides long-term resolution of symptoms in patients with posterior canal BPPV. PMID: De Ru JA, Van Benthem PP, van Wermeskerken GK. Injudicious use of EBM: one step forward, two steps back. B-ENT. 2014;10(4): PROBLEM: The authors are concerned that an overrestrictive approach to evidence-based medicine could lead to the neglect of valuable treatment options. METHODOLOGY: We describe the need for a personalised approach to evidence-based medicine, and support this with examples from ENT practice. RESULTS: We concur with the point of view that evidence at all levels should be used in clinical decision-making and we suggest that fitness for purpose is more important than hierarchy of evidence. CONCLUSION: We conclude that the application of evidence-based medicine should involve trying to select the best therapy for individuals on the basis of the total spectrum of treatment options. Evidence and expertise should work synergistically. PMID: Keel-, Neus- en Oorheelkunde 103

105 Kindergeneeskunde Kerngegevens 12 kinderartsen: C.D. (Coranne) Aarts-Tesselaar, dr. R.H.T. (Ron) van Beek, dr. A.R. (Anthon) Hulsmann, M.H. (Marc) Jonkers, J. (Jaap) Kooijman, dr. S.A. (Stella) de Man, P.W.J. (Paul) van Mossevelde, S.M.H.B. (Saskia) de Pont, L. (Leo) Torn, dr. A.A.P.H. (Anja) Vaessen-Verberne, E.J.M. (Esther) Veldkamp, dr. H.M. (Herbert) Wering 3 assistenten in opleiding (2,83 fte) 2 assistenten niet in opleiding (0,88 fte) 4 baios (3,36 fte) 1 tagio (1,06 fte) Samenvattingen gepubliceerde artikelen De Man SA, Aarts-Tesselaar CD, Festen DA. Transitie van zorg bij jongeren met een verstandelijke beperking: van generalist naar generalist. [Health care transition in young people with intellectual disabilities: from generalist to generalist]. Ned Tijdschr Geneeskd. 2014;158:A8072. The transition of medical care in young people with intellectual disabilities is not well organised in the Netherlands. This heterogeneous group, with a high rate of comorbidity, needs regular medical follow-up. During adolescence the paediatrician should preferably transfer medical care to a generalist, such as a physician for people with intellectual disabilities. The guarantee of a safe and effective transition is an integral element in achieving quality of care in this special group of young people with regard to their long-term health and well-being. PMID: Hulsmann AR, Smid G, Landman JR, Schuur J, Langeveld-Wildschut EG. Van maat naar maatschap: Van IFMS naar GFMS. A & I jun;(2):53-8. Langeveld-Wildschut A, Joosten P, Nobruis O, Hulsmann A. Een goede maatschap, een goede specialist. Med Contact apr;69(15): De Wijs-Meijler DP, Jonkers MH, Ermens AA. Een neonaat met een navelstompbloeding. [A neonate with umbilical cord bleeding]. Ned Tijdschr Geneeskd. 2014;158:A7587. A 7-day-old neonate was admitted to our neonatal ward for umbilical stump bleeding. His medical history included hyperbilirubinaemia due to cephalic haematoma. Only after the administration of fresh frozen plasma, the bleeding stopped, suggesting coagulation factor deficiency. Elaborate coagulation tests showed factor XIII-deficiency. PMID: Publicaties Medische Staf

106 Mergler S, de Man SA. Breekbaar vanaf jonge leeftijd: Osteoporose bij een kind met ernstige meervoudige beperkingen. [Fragile from an early age: osteoporosis in a child with multiple severe disabilities]. Ned Tijdschr Geneeskd. 2014;158:A8017. BACKGROUND: In the general population osteoporosis and low impact fractures occur mainly in the elderly and in people at increased risk due to disorders. In children with severe intellectual impairment and multiple disabilities severe osteoporosis and fractures of the long bones may be present from an early age. CASE DESCRIPTION: We describe a case of a 14-year-old girl with Dravet syndrome and multiple low impact fractures arising from minimal or unknown trauma. CONCLUSION: In children with severe intellectual impairment and multiple disabilities the optimizing of bone quality and peak bone mass in order to prevent osteoporosis and fractures is recommended. PMID: De Man SA, Merkus PJ. Aandoeningen van de luchtwegen. In: Medische zorg voor patiënten met een verstandelijke beperking / Braam W, van Duinen-Maas MJ, Festen DA, van Gelderen I, S.A. Huisman SA, M.A.M. Tonino MA. [red.]. Leerboek AVG. Houten: Prelum, ISBN pag Teunissen J, Hochs AH, Vaessen-Verberne A, Boehmer AL, Smeets CC, Brackel H, van Gent R, Wesseling J, Logtens-Stevens D, de Moor R, Rosias PP, Potgieter S, Faber MR, Hendriks HJ, Janssen-Heijnen ML, Loza BF. The effect of 3% and 6% hypertonic saline in viral bronchiolitis: a randomised controlled trial. Eur Respir J Oct;44(4): Epub 2014 Jun 25. Bronchiolitis is a common disorder in young children that often results in hospitalisation. Except for a possible effect of nebulised hypertonic saline (sodium chloride), no evidence-based therapy is available. This study investigated the efficacy of nebulised 3% and 6% hypertonic saline compared with 0.9% hypertonic saline in children hospitalised with viral bronchiolitis. In this multicentre, double-blind, randomised, controlled trial, children hospitalised with acute viral bronchiolitis were randomised to receive either nebulised 3%, 6% hypertonic saline or 0.9% normal saline during their entire hospital stay. Salbutamol was added to counteract possible bronchial constriction. The primary endpoint was the length of hospital stay. Secondary outcomes were need for supplemental oxygen and tube feeding. From the 292 children included in the study (median age 3.4 months), 247 completed the study. The median length of hospital stay did not differ between the groups: 69 h (interquartile range 57), 70 h (IQR 69) and 53 h (IQR 52), for 3% (n = 84) and 6% (n = 83) hypertonic saline and 0.9% (n = 80) normal saline, respectively, (p = 0.29). The need for supplemental oxygen or tube feeding did not differ significantly. Adverse effects were similar in the three groups. Nebulisation with hypertonic saline (3% or 6% sodium chloride) although safe, did not reduce the length of stay in hospital, duration of supplemental oxygen or tube feeding in children hospitalised with moderate-to-severe viral bronchiolitis. PMID: Kindergeneeskunde 105

107 Van de Griend EJ, Vaessen-Verberne A, de Jongste JC. Astma. In: Werkboek kinderallergologie / Dubois E. [...et al.][red.]. Amsterdam: VU University Press, ISBN: Voorend-van Bergen S, Vaessen-Verberne AA, de Jongste JC, Pijnenburg MW. Asthma control questionnaires in the management of asthma in children: A review. Pediatr Pulmonol Feb;50(2): Epub 2014 Sep 3. Several self-administered questionnaires have been developed to assess childhood asthma control in a simple and standardized way. This review discusses the most commonly used questionnaires and explores their usefulness in asthma management in children. We conclude that the use of asthma control questionnaires in daily practice and in research contributes to the standardized evaluation of children with asthma and helps to track asthma symptoms, but validation studies in a wider range of settings are needed. PMID: Korterink JJ, Benninga MA, van Wering HM, Deckers-Kocken JM. Glucose Hydrogen Breath Test for Small Intestinal Bacterial Overgrowth in Children with Abdominal Pain-Related Functional Gastrointestinal Disorders. J Pediatr Gastroenterol Nutr Nov 17. [Epub ahead of print]. OBJECTIVES: A potential link between small intestinal bacterial overgrowth (SIBO) and abdominal pain related functional gastrointestinal disorders (AP-FGID) has been suggested by symptom similarities and by the reported prevalence of SIBO in children with irritable bowel syndrome and functional abdominal pain. The aim of this study is to evaluate the prevalence of SIBO using the glucose hydrogen breath test (GHBT), in a cohort of Dutch children with AP-FGID fulfilling the Rome III criteria, and to identify potential predictors. METHODS: Children aged 6-18 years with AP-FGID fulfilling the ROME III criteria were included. All children underwent a GHBT. SIBO was diagnosed if the fasting breath hydrogen concentration was > 20ppm or if an increase of H2 levels of > 12 ppm over the baseline value was measured after ingestion of glucose. Gastrointestinal symptoms were collected using a standardised abdominal pain questionnaire. RESULTS: 161 Dutch children with AP-FGID were enrolled. 23 patients (14.3%) were diagnosed with SIBO, as assessed by GHBT. 78% of the children diagnosed with SIBO had fasting hydrogen levels above 20 ppm. Irritable bowel syndrome (IBS) was significantly more found in children with SIBO compared to children without SIBO (p=0.001). An altered defecation pattern (i.e. change in frequency or form of stool) (p=0.013), loss of appetite (p=0.007) and belching (p=0.023) were significantly more found in children with SIBO compared to those without SIBO. 106 Publicaties Medische Staf

108 CONCLUSION: SIBO is present in 14.3% of children presenting with AP-FGID. IBS, altered defecation pattern, loss of appetite and belching were predictors for SIBO in children with AP-FGID. PMID: Rutten JM, Vlieger AM, Frankenhuis C, George EK, Groeneweg M, Norbruis OF, Tjon a Ten W, Van Wering H, Dijkgraaf MG, Merkus MP, Benninga MA. Gut-directed hypnotherapy in children with irritable bowel syndrome or functional abdominal pain (syndrome): a randomized controlled trial on self exercises at home using CD versus individual therapy by qualified therapists. BMC Pediatr Jun 4;14:140. BACKGROUND: Irritable bowel syndrome (IBS) and functional abdominal pain (syndrome) (FAP(S)) are common pediatric disorders, characterized by chronic or recurrent abdominal pain. Treatment is challenging, especially in children with persisting symptoms. Gut-directed hypnotherapy (HT) performed by a therapist has been shown to be effective in these children, but is still unavailable to many children due to costs, a lack of qualified child-hypnotherapists and because it requires a significant investment of time by child and parent(s). Home-based hypnotherapy by means of exercises on CD has been shown effective as well, and has potential benefits, such as lower costs and less time investment. The aim of this randomized controlled trial (RCT) is to compare cost-effectiveness of individual HT performed by a qualified therapist with HT by means of CD recorded self-exercises at home in children with IBS or FAP(S). METHODS/DESIGN: 260 children, aged 8-18 years with IBS or FAP(S) according to Rome III criteria are included in this currently conducted RCT with a follow-up period of one year. Children are randomized to either 6 sessions of individual HT given by a qualified therapist over a 3-month period or HT through self-exercises at home with CD for 3 months.the primary outcome is the proportion of patients in which treatment is successful at the end of treatment and after one year follow-up. Treatment success is defined as at least 50% reduction in both abdominal pain frequency and intensity scores. Secondary outcomes include adequate relief, cost-effectiveness and effects of both therapies on depression and anxiety scores, somatization scores, QoL, pain beliefs and coping strategies. DISCUSSION: If the effectiveness of home-based HT with CD is comparable to, or only slightly lower, than HT by a therapist, this treatment may become an attractive form of therapy in children with IBS or FAP(S), because of its low costs and direct availability. TRIAL REGISTRATION: Dutch Trial Register number NTR2725 (date of registration: 1 February 2011). PMID: Kindergeneeskunde 107

109 Klinisch Chemisch Hematologisch Laboratorium Kerngegevens 6 Laboratoriumspecialisten Klinisch Chemie: dr. K.J.M. (Kristel) Boonen, dr. J.M.A. (Judith) Emmen, dr. Ir. A.A.M. (Ton) Ermens, dr. A.J. (Adriaan) van Gammeren, dr. R.N. (René) Idema, dr. M.H.M. (Marc) Thelen 2 assistenten in opleiding (2 fte): dr. S.A.A. (Sjoerd) van den Berg, dr. A.M.C.P. (Annemiek) Joosen (tot ), dr. E. (Eline) van der Hagen (vanaf ) Samenvattingen gepubliceerde artikelen Joosen AM, Boonen K, Hulsman N, Schuitemaker FJ, Thelen MH. Hypernatraemia in disguise. Clin Chem Lab Med Nov;52(11):e No abstract available. PMID: Schmitz EM, Boonen K, van den Heuvel DJ, van Dongen JL, Schellings MW, Emmen JM, van der Graaf F, Brunsveld L, van de Kerkhof D. Determination of dabigatran, rivaroxaban and apixaban by ultra-performance liquid chromatography - tandem mass spectrometry (UPLC-MS/MS) and coagulation assays for therapy monitoring of novel direct oral anticoagulants. J Thromb Haemost Oct;12(10): BACKGROUND: Three novel direct oral anticoagulants (DOACs) have recently been registered by the Food and Drug Administration and European Medicines Agency Commission: dabigatran, rivaroxaban, and apixaban. To quantify DOACs in plasma, various dedicated coagulation assays have been developed. OBJECTIVE: To develop and validate a reference ultra-performance liquid chromatography - tandem mass spectrometry (UPLC-MS/MS) method and to evaluate the analytical performance of several coagulation assays for quantification of dabigatran, rivaroxaban, and apixaban. METHODS: The developed UPLC-MS/MS method was validated by determination of precision, accuracy, specificity, matrix effects, lower limits of detection, carry-over, recovery, stability, and robustness. The following coagulation assays were evaluated for accuracy and precision: laboratory-developed (LD) diluted thrombin time (dtt), Hemoclot dtt, Pefakit PiCT, ECA, Liquid anti-xa, Biophen Heparin (LRT), and Biophen DiXal anti-xa. Agreement between the various coagulation assays and UPLC-MS/MS was determined with random samples from patients using dabigatran or rivaroxaban. 108 Publicaties Medische Staf

110 RESULTS: The UPLC-MS/MS method was shown to be accurate, precise, sensitive, stable, and robust. The dabigatran coagulation assay showing the best precision, accuracy and agreement with the UPLC-MS/MS method was the LD dtt test. For rivaroxaban, the anti-factor Xa assays were superior to the PiCT-Xa assay with regard to precision, accuracy, and agreement with the reference method. For apixaban, the Liquid anti-xa assay was superior to the PiCT-Xa assay. CONCLUSIONS: Statistically significant differences were observed between the various coagulation assays as compared with the UPLC-MS/MS reference method. It is currently unknown whether these differences are clinically relevant. When DOACs are quantified with coagulation assays, comparison with a reference method as part of proficiency testing is therefore pivotal. PMID: Emmen JM, Heijboer AC, de Jong SM, Endert E. Glucagon stability anno Clin Chim Acta Feb 2;440:1-2. Epub 2014 Nov 11. No abstract available. PMID: Uzun S, Djamin RS, Kluytmans JA, Mulder PG, Van t Veer NE, Ermens AA, Pelle AJ, Hoogsteden HC, Aerts JG, van der Eerden MM. Azithromycin maintenance treatment in patients with frequent exacerbations of chronic obstructive pulmonary disease (COLUMBUS): a randomised, doubleblind, placebo-controlled trial. Lancet Respir Med May;2(5): Epub 2014 Apr 15. BACKGROUND: Macrolide resistance is an increasing problem; there is therefore debate about when to implement maintenance treatment with macrolides in patients with chronic obstructive pulmonary disease (COPD). We aimed to investigate whether patients with COPD who had received treatment for three or more exacerbations in the previous year would have a decrease in exacerbation rate when maintenance treatment with azithromycin was added to standard care. Klinisch Chemisch Hematologisch Laboratorium 109

111 METHODS: We did a randomised, double-blind, placebo-controlled, single-centre trial in the Netherlands between May 19, 2010, and June 18, Patients ( 18 years) with a diagnosis of COPD who had received treatment for three or more exacerbations in the previous year were randomly assigned, via a computer-generated randomisation sequence with permuted block sizes of ten, to receive 500 mg azithromycin or placebo three times a week for 12 months. Randomisation was stratified by use of long-term, low-dose prednisolone ( 10 mg daily). Patients and investigators were masked to group allocation. The primary endpoint was rate of exacerbations of COPD in the year of treatment. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT FINDINGS: We randomly assigned 92 patients to the azithromycin group (n=47) or the placebo group (n=45), of whom 41 (87%) versus 36 (80%) completed the study. We recorded 84 exacerbations in patients in the azithromycin group compared with 129 in those in the placebo group. The unadjusted exacerbation rate per patient per year was 1 94 (95% CI ) for the azithromycin group and 3 22 ( ) for the placebo group. After adjustment, azithromycin resulted in a significant reduction in the exacerbation rate versus placebo (0 58, 95% CI ; p=0 001). Three (6%) patients in the azithromycin group reported serious adverse events compared with five (11%) in the placebo group. During follow-up, the most common adverse event was diarrhoea in the azithromycin group (nine [19%] patients vs one [2%] in the placebo group; p=0 015). INTERPRETATION: Maintenance treatment with azithromycin significantly decreased the exacerbation rate compared with placebo and should therefore be considered for use in patients with COPD who have the frequent exacerbator phenotype and are refractory to standard care. FUNDING: SoLong Trust. PMID: Uzun S, Djamin RS, Veer NE van t, Kluytmans JA, Ermens AA, Hoogsteden HC, Aerts JG, Eerden MM van der. Macrolides to prevent COPD exacerbations. Clin Pulm Med. 2014;21(2): Chronic obstructive pulmonary disease (COPD) is one of the major health problems in the world. Long-term treatment with macrolide antibiotics is a recent development that has been reported to have beneficial effects on exacerbation frequency. These effects are not only attributed to the antimicrobial effect but also to the immune modulatory effect. Six randomized trials and 1 retrospective study have been performed to investigate the efficacy of macrolides in the prevention of acute exacerbations of COPD. Besides the beneficial effects on the occurrence of exacerbations of COPD, this treatment also seems to improve quality of life and is well tolerated. Antimicrobial resistance is one of the future issues to consider before implementing this therapy. 110 Publicaties Medische Staf

112 De Wijs-Meijler DP, Jonkers MH, Ermens AA. Een neonaat met een navelstompbloeding. [A neonate with umbilical cord bleeding]. Ned Tijdschr Geneeskd. 2014;158:A7587. A 7-day-old neonate was admitted to our neonatal ward for umbilical stump bleeding. His medical history included hyperbilirubinaemia due to cephalic haematoma. Only after the administration of fresh frozen plasma, the bleeding stopped, suggesting coagulation factor deficiency. Elaborate coagulation tests showed factor XIII-deficiency. PMID: Van Gammeren AJ, Alcala LS, Smolders M, Boersma RS. Numerous Russell bodies and Dutcher bodies in multiple myeloma. Br J Haematol Oct 14. [Epub ahead of print]. No abstract available. PMID: Van den Berg SA, Verwer PE, Idema RN, Van Guldener C. Transient cefuroxime/metronidazole treatment induced factor V antibodies. BMJ Case Rep Aug 19;2014. pii: bcr A 29-year-old patient presented with an appendicular infiltrate, initially treated with intravenous antibiotics, but later requiring percutaneous drainage. Both prothrombin time (PT) and activated partial thromboplastin time (aptt) were prolonged on 3 days of antibiotic treatment and unresponsive to vitamin K or prothrombin complex concentrate. Laboratory investigation ultimately showed reduced factor V activity and factor V antibodies. In contrast to previously described cases of factor V antibodies, PT and aptt were only mildly prolonged and residual factor V activity was still >20%. Draining of the abscess did not induce significant bleeding. Afterwards, no haemostatic medication was required. The patient was discharged from the hospital without complications. One week after cessation of the antibiotic treatment, PT and aptt were within normal range again, with a factor V activity level of 36%. In conclusion, we present a patient with transient factor V antibodies, induced by antibiotics, without clinical bleeding tendency. PMID: Klinisch Chemisch Hematologisch Laboratorium 111

113 Klinische Farmacie Kerngegevens 7 ziekenhuisapothekers: P.R.M. (Paul) van Hattum, V.S (Victorine) Koster, C.H.P. (Chris) Pellicaan, P.A.O. (Peter) Smithuis, N.E. (Nils) van t Veer, R.R.E.C.M. (Relin) Verzijl-Zeegers, M.F.G. (Marjolein) Winters 2 assistenten in opleiding (2,1 fte) 2 apothekers EMD 1 project apotheker Samenvattingen gepubliceerde artikelen Ter Laak MA, Roos C, Touw DJ, van Hattum PR, Kwee A, Lotgering FK, J Mol BW, van Pampus MG, Porath MM, Spaanderman ME, van der Post JA, Papatsonis DN, van t Veer NE. Pharmacokinetics of nifedipine slow-release during sustained tocolysis. Int J Clin Pharmacol Ther Jan;53(1): Epub 2014 Nov 19. OBJECTIVE: The pharmacokinetics of nifedipine as a tocolytic agent has not been studied in great detail in pregnant women and has instead focused on immediate release tablets and gastrointestinal therapeutic system (GITS) tablets. The aim of this study was to determine nifedipine slowrelease half-life and distribution volume in pregnant women and to compare these with pharmacokinetic parameters of nifedipine in non-pregnant subjects described in the literature. MATERIALS: This is a study parallel to a trial studying women with threatened preterm labor between and weeks after initial tocolysis and a completed course of corticosteroids, who were randomly allocated to maintenance nifedipine (slow-release tablets 20 mg 4 times daily) or placebo. Exclusion criteria for the pharmacokinetic study were contra-indications for nifedipine, impaired liver function, and concomitant intake of inhibitors or inducers of the cytochrome P450 3A4 isoenzyme. Blood samples for measuring nifedipine plasma concentrations were drawn at t = 0, t = 12 hours, t = 24 hours, t = 48 hours, t = 72 hours, t = 7 days, and t = 9 days. METHODS: Pharmacokinetic parameters were estimated using iterative two-stage Bayesian population pharmacokinetic analysis by MWPharm software. The study was designed to establish a correlation between body weight and nifedipine plasma level. RESULTS: The pharmacokinetic parameters of nifedipine slow-release tablets were determined from the data of 8 pregnant women. Nifedipine slow-release had a half-life of 2-5 hours, a mean distribution volume of 6.2 ± 1.9 L/kg (calculated while using a fixed biological availability of 0.45 taken from the literature due to lack of intravenous data in this population) compared to a halflife of 6-11 hours, and a distribution volume of L/kg described in non-pregnant subjects in the literature. None of the women delivered during study medication. Study medication was continued for the duration of the pharmacokinetic study (9 days) in all women. A correlation 112 Publicaties Medische Staf

114 between nifedipine plasma levels and maternal body weight was not demonstrated. This may have been caused by lack of power. CONCLUSION: Pregnant subjects in this study, using nifedipine slow-release tablets, showed a larger volume of distribution and a shorter elimination half-life than for non-pregnant subjects as published in the literature. PMID: Uzun S, Djamin RS, Kluytmans JA, Mulder PG, Van t Veer NE, Ermens AA, Pelle AJ, Hoogsteden HC, Aerts JG, van der Eerden MM. Azithromycin maintenance treatment in patients with frequent exacerbations of chronic obstructive pulmonary disease (COLUMBUS): a randomised, doubleblind, placebo-controlled trial. Lancet Respir Med May;2(5): Epub 2014 Apr 15. BACKGROUND: Macrolide resistance is an increasing problem; there is therefore debate about when to implement maintenance treatment with macrolides in patients with chronic obstructive pulmonary disease (COPD). We aimed to investigate whether patients with COPD who had received treatment for three or more exacerbations in the previous year would have a decrease in exacerbation rate when maintenance treatment with azithromycin was added to standard care. METHODS: We did a randomised, double-blind, placebo-controlled, single-centre trial in the Netherlands between May 19, 2010, and June 18, Patients ( 18 years) with a diagnosis of COPD who had received treatment for three or more exacerbations in the previous year were randomly assigned, via a computer-generated randomisation sequence with permuted block sizes of ten, to receive 500 mg azithromycin or placebo three times a week for 12 months. Randomisation was stratified by use of long-term, low-dose prednisolone ( 10 mg daily). Patients and investigators were masked to group allocation. The primary endpoint was rate of exacerbations of COPD in the year of treatment. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT FINDINGS: We randomly assigned 92 patients to the azithromycin group (n=47) or the placebo group (n=45), of whom 41 (87%) versus 36 (80%) completed the study. We recorded 84 exacerbations in patients in the azithromycin group compared with 129 in those in the placebo group. The unadjusted exacerbation rate per patient per year was 1 94 (95% CI ) for the azithromycin group and 3 22 ( ) for the placebo group. After adjustment, azithromycin resulted in a significant reduction in the exacerbation rate versus placebo (0 58, 95% CI ; p=0 001). Three (6%) patients in the azithromycin group reported serious adverse events compared with five (11%) in the placebo group. During follow-up, the most common adverse event was diarrhoea in the azithromycin group (nine [19%] patients vs one [2%] in the placebo group; p=0 015). Klinische Farmacie 113

115 INTERPRETATION: Maintenance treatment with azithromycin significantly decreased the exacerbation rate compared with placebo and should therefore be considered for use in patients with COPD who have the frequent exacerbator phenotype and are refractory to standard care. FUNDING: SoLong Trust. PMID: Uzun S, Djamin RS, Veer NE van t, Kluytmans JA, Ermens AA, Hoogsteden HC, Aerts JG, Eerden MM van der. Macrolides to prevent COPD exacerbations. Clin Pulm Med. 2014;21(2): Chronic obstructive pulmonary disease (COPD) is one of the major health problems in the world. Long-term treatment with macrolide antibiotics is a recent development that has been reported to have beneficial effects on exacerbation frequency. These effects are not only attributed to the antimicrobial effect but also to the immune modulatory effect. Six randomized trials and 1 retrospective study have been performed to investigate the efficacy of macrolides in the prevention of acute exacerbations of COPD. Besides the beneficial effects on the occurrence of exacerbations of COPD, this treatment also seems to improve quality of life and is well tolerated. Antimicrobial resistance is one of the future issues to consider before implementing this therapy. 114 Publicaties Medische Staf

116 Klinische Geriatrie Kerngegevens 5 geriaters: H.M. (Hanneke) Beerens-Tiebosch, J.I. (Jonneke) Eikelboom, I.C. (Iris) Jobse, R.A.M. (Richard) de Jonckheere, D.C. (Dominique) de Lange 4 assistenten in opleiding (3,75 fte) 2 assistenten niet in opleiding (1,60 fte) 1 HAIO/AVG 1 VAIO Samenvattingen gepubliceerde artikelen Jobse IC, de Jonckheere RA. Het effect van galantamine op de ecg- geleidingstijden [The effect of galantamine on cardiac conduction time] Tijdschr Gerontol Geriatr Dec;45(6): Galantamine, one of the acethylcholinesterase inhibitors (AChEI), is used in the treatment of Alzheimer s disease. However AChEI have been associated with adverse events, including cardiac events. The objective of this prospective, observational study is to evaluate the association between galantamine and incident cardiac conduction abnormalities. METHODS: A total of 64 patients, who visited an out - patient clinic of a geriatric department were enrolled in the study. All patients were diagnosed with Alzheimer s disease and started with a capsule containing 8 mg of galantamine. Subsequently, if galantamine was well tolerated, the dosage was raised every 4 weeks, to an eventual dosage of 24 mg/ day. The mean follow-up period was 4 months. ECG parameters were evaluated at baseline and after start of galantamine at each galantamine dose level (8, 16, 24 mg / day). RESULTS: No significant differences in electrocardiographic measurements before and during treatment with galantamine were found. CONCLUSION: No significant changes in ECG parameters relative to baseline were found with galantamine treatment. Also after adjustment for concomitant cardioactive medications and cardiovascular comorbidity, no significant changes were found. PMID: Klinische Geriatrie 115

117 Laboratorium voor Microbiologie en Infectiepreventie Kerngegevens 5 artsen-microbioloog: prof.dr. J.A.J.W. (Jan) Kluytmans, dr. C.M. (Kees) Verduin, drs. P.H.J. (Peter) van Keulen, dr. G.J. (Jolanda) van Hooydonk-Elving, dr. J.H. (Jan) Marcelis 2 stafmedewerkers: dr. L.E. (Ina) Willemsen, C. (Carlo) Verhulst 2 meewerkend teamleidinggevenden: A. (Angela) Vrolijk, dr. M.M.L. (Miranda) van Rijen 5 adviseurs infectiepreventie: A.B. (Gonny) Moen, Y.J.A.M. (Yvonne) Hendriks, V.A.T.C. (Veronica) Weterings, E. (Esther) Weterings, C.M. (Marie Louise) van Leest 5 research coördinatoren: H.P.M. (Henk) Coertjens, D.A.C.W. (Debbie) Gommers, R.M.T. (Renée) Ladestein, A.C.M. (Jannie) Romme, E.C.P. (Betty) Veeken 2 assistenten in opleiding Samenvattingen gepubliceerde artikelen Koningstein M, van der Bij AK, de Kraker ME, Monen JC, Muilwijk J, de Greeff SC, Geerlings SE, van Hall MA; ISIS-AR Study Group [van Keulen PH, Kluytmans JA et al...]. Recommendations for the empirical treatment of complicated urinary tract infections using surveillance data on antimicrobial resistance in the Netherlands. PLoS One Jan 28;9(1):e BACKGROUND: Complicated urinary tract infections (c-utis) are among the most common nosocomial infections and a substantial part of the antimicrobial agents used in hospitals is for the treatment of c-utis. Data from surveillance can be used to guide the empirical treatment choices of clinicians when treating c-utis. We therefore used nation-wide surveillance data to evaluate antimicrobial coverage of agents for the treatment of c-uti in the Netherlands. METHODS: We included the first isolate per patient of urine samples of hospitalised patients collected by the Infectious Disease Surveillance Information System for Antibiotic Resistance (ISIS-AR) in 2012, and determined the probability of inadequate coverage for antimicrobial agents based on species distribution and susceptibility. Analyses were repeated for various patient groups and hospital settings. RESULTS: The most prevalent bacteria in 27,922 isolates of 23,357 patients were Escherichia coli (47%), Enterococcus spp. (14%), Proteus mirabilis (8%), and Klebsiella pneumoniae (7%). For all species combined, the probability of inadequate coverage was <5% for amoxicillin or amoxicillinclavulanic acid combined with gentamicin and the carbapenems. When including gram-negative bacteria only, the probability of inadequate coverage was 4.0%, 2.7%, 2.3% and 1.7%, respectively, for amoxicillin, amoxicillin-clavulanic acid, a second or a third generation cephalosporin in combination with gentamicin, and the carbapenems (0.4%). There were only small variations in results among different patient groups and hospital settings. 116 Publicaties Medische Staf

118 CONCLUSIONS: When excluding Enterococcus spp., considered as less virulent, and the carbapenems, considered as last-resort drugs, empirical treatment for c-uti with the best chance of adequate coverage are one of the studied beta-lactam-gentamicin combinations. This study demonstrates the applicability of routine surveillance data for up-to-date clinical practice guidelines on empirical antimicrobial therapy, essential in patient care given the evolving bacterial susceptibility. PMID: PMCID: PMC Laboratorium voor Microbiologie en Infectiepreventie 117

119 Van Rijen MM, Bosch T, Verkade EJ, Schouls L, Kluytmans JA; CAM Study Group* [Verduin K et al...]. Livestock-associated MRSA carriage in patients without direct contact with livestock. PLoS One Jun 27;9(6):e BACKGROUND: Livestock-associated MRSA (MC398) has emerged and is related to an extensive reservoir in pigs and veal calves. Individuals with direct contact with these animals and their family members are known to have high MC398 carriage rates. Until now it was assumed that MC398 does not spread to individuals in the community without pig or veal calf exposure. To test this, we identified the proportion of MC398 in MRSA positive individuals without contact with pigs/veal calves or other known risk factors (MRSA of unknown origin; MUO). METHODS: In 17 participating hospitals, we determined during two years the occurrence of MC398 in individuals without direct contact with livestock and no other known risk factor (n = 271) and tested in a post analysis the hypothesis whether hospitals in pig-dense areas have higher proportions of MC398 of all MUO. RESULTS: Fifty-six individuals (20.7%) without animal contact carried MC398. In hospitals with high pig-densities in the adherence area, the proportion of MC398 of all MUO was higher than this proportion in hospitals without pigs in the surroundings. CONCLUSIONS: One fifth of the individuals carrying MUO carried MC398. So, MC398 is found in individuals without contact to pigs or veal calves. The way of transmission from the animal reservoir to these individuals is unclear, probably by human-to-human transmission or by exposure to the surroundings of the stables. Further research is needed to investigate the way of transmission. *Collaborators: van Cleef B, Hendriks Y, op den Kamp D, Kluytmans J, Kluytmans-van den Bergh M, Ladestein R, Punselie R, van Rijen M, Verkade E, Ernest M, Wulf M, Feingold B, Brekelmans M, Willemse P, ten Feld N, Wintermans R, Postma B, Terwee M, Thuy-Nga, de Ruiter T, van der Vorm E, Wijker A, Hamers H, Das P, Sanders E, Verduin K, van Dam D, Diederen J, ten Ham P, Nolles L, van der Vorm E, Smeulders A, Buiting A, Hörmann H, Nieuwkoop E, Muller Y, Haverkate D, Verweij P, Bonten M, van der Jagt-Zwetsloot M, Troelstra A, Berkhout H, van den Hout L, Kaiser A, Vandenbroucke-Grauls C. PMID: PMCID: PMC Kock R, Becker K, Cookson B, van Gemert-Pijnen JE, Harbarth S, Kluytmans J, Mielke M, Peters G, Skov RL, Struelens MJ, Tacconelli E, Witte W, Friedrich AW. Systematic literature analysis and review of targeted preventive measures to limit healthcare-associated infections by meticillin-resistant Staphylococcus aureus. Euro Surveill Jul 24;19(29). pii: Publicaties Medische Staf

120 Meticillin-resistant Staphylococcus aureus (MRSA) is a major cause of healthcare-associated infections in Europe. Many examples have demonstrated that the spread of MRSA within healthcare settings can be reduced by targeted infection control measures. The aim of this systematic literature analysis and review was to summarise the evidence for the use of bacterial cultures for active surveillance the benefit of rapid screening tests, as well as the use of decolonisation therapies and different types of isolation measures. We included 83 studies published between 2000 and Although the studies reported good evidence supporting the role of active surveillance followed by decolonisation therapy, the effectiveness of single-room isolation was mostly shown in non-controlled studies, which should inspire further research regarding this issue. Overall, this review highlighted that when planning the implementation of preventive interventions, there is a need to consider the prevalence of MRSA, the incidence of infections, the competing effect of standard control measures (e.g. hand hygiene) and the likelihood of transmission in the respective settings of implementation. PMID: Verkade E, Kluytmans-van den Bergh M, van Benthem B, van Cleef B, van Rijen M, Bosch T, Schouls L, Kluytmans J. Transmission of methicillin-resistant Staphylococcus aureus CC398 from livestock veterinarians to their household members. PLoS One Jul 25;9(7):e ecollection There are indications that livestock-associated MRSA CC398 has a reduced human-to-human transmissibility, limiting its impact on public health and justifying modified control measures. This study determined the transmissibility of MRSA CC398 from livestock veterinarians to their household members in the community as compared to MRSA non-cc398 strains. A oneyear prospective cohort study was performed to determine the presence of MRSA CC398 in four-monthly nasal and oropharyngeal samples of livestock veterinarians (n = 137) and their household members (n = 389). In addition, a cross-sectional survey was performed to detect the presence of MRSA non-cc398 in hospital derived control patients (n = 20) and their household members (n = 41). Staphylococcus aureus isolates were genotyped by staphylococcal protein A (spa) typing and multiple-locus variable-number tandem repeat analysis (MLVA). Mean MRSA CC398 prevalence over the study period was 44% (range %) in veterinarians and 4.0% (range %) in their household members. The MRSA CC398 prevalence in household members of veterinarians was significantly lower than the MRSA non-cc398 prevalence in household members of control patients (PRR 6.0; 95% CI ), indicating the reduced transmissibility of MRSA CC398. The impact of MRSA CC398 appears to be low at the moment. However, careful monitoring of the human-to-human transmissibility of MRSA CC398 remains important. PMID: PMCID: PMC Laboratorium voor Microbiologie en Infectiepreventie 119

121 Huijts SM, Boersma WG, Grobbee DE, Gruber WC, Jansen KU, Kluytmans JA, Kuipers BA, Palmen F, Pride MW, Webber C, Bonten MJ; The CAP Diagnostics investigators. Predicting Pneumococcal Community-Acquired Pneumonia in the Emergency Department Evaluation of clinical parameters. Clin Microbiol Infect Jun 30. [Epub ahead of print]. OBJECTIVE: To quantify the value of clinical predictors available in the emergency department (ED) in predicting Streptococcus pneumoniae as cause of community acquired pneumonia (CAP). METHODS: Prospective, observational, cohort study of patients with CAP presenting in the ED. Pneumococcal aetiology of CAP was based on either bacteraemia, or S. pneumoniae cultured from sputum, or urinary immunochromatographic assay (ICA) positivity or positivity of a novel serotype specific urinary antigen detection (UAD). Multivariate logistic regression was used to identify independent predictors and various cut-off values of probability scores were used to evaluate the usefulness of the model. RESULTS: 328 patients (31.0%) of 1,057 patients with CAP had pneumococcal CAP. Nine independent predictors for pneumococcal pneumonia were identified, but the clinical utility of this prediction model was disappointing because of low positive predictive values or a small yield. CONCLUSION: Clinical criteria have insufficient diagnostic capacity to predict pneumococcal CAP. Rapid antigen detecting tests are needed to diagnose S. pneumoniae at the time of hospital admission. PMID: Souverein D, Boers SA, Veenendaal D, Euser SM, Kluytmans J, Den Boer JW. Polyclonal spread and outbreaks with ESBL positive gentamicin resistant Klebsiella spp. in the region Kennemerland, The Netherlands. PLoS One Jun 27;9(6):e ecollection OBJECTIVE: The objective of this study was to analyze the transmission dynamics of ESBL positive Klebsiella spp. with an additional resistance towards gentamicin (ESBL-G) in a Dutch region of 650,000 inhabitants in METHODS: All patient related ESBL-G isolates isolated in 2012 were genotyped using both Amplification Fragment Length Polymorphism (AFLP) and High-throughput MultiLocus Sequence Typing (HiMLST). HiMLST was used to analyze the presence of (unidentified) clusters of ESBL-G positive patients. Furthermore, all consecutive ESBL-G isolates within patients were studied in order to evaluate the intra-patient variation of antibiotic phenotypes. RESULTS: There were 38 ESBL-G isolates, which were classified into 18 different sequence types (STs) and into 21 different AFLP types. Within the STs, four clusters were detected from which two were unknown resulting in a transmission index of An analysis of consecutive ESBL-G 120 Publicaties Medische Staf

122 isolates (with similar STs) within patients showed that for 68.8% of the patients at least one isolate had a different consecutive antibiotic phenotype. CONCLUSION: The transmission of ESBL-G in the region Kennemerland in 2012 was polyclonal with several outbreaks (with a high level of epidemiological linkage). Furthermore, clustering by antibiotic phenotype characterization seems to be an inadequate approach in this setting. The routine practice of molecular typing of collected ESBL-G isolates may help to detect transmission in an early stage, which opens the possibility of a rapid response. PMID: PMCID: PMC Reuland EA, Al Naiemi N, Raadsen SA, Savelkoul PH, Kluytmans JA, Vandenbroucke-Grauls CM. Prevalence of ESBL-producing Enterobacteriaceae in raw vegetables. Eur J Clin Microbiol Infect Dis May 22. [Epub ahead of print]. To determine whether extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae (ESBL-E) are present in retail raw vegetables in Amsterdam, the Netherlands, we collected 119 samples of 15 different types of vegetables from various sources. After culture, strain identification and susceptibility testing, ESBL-encoding genes were characterised by a microarray. Four of the 15 vegetable types were contaminated with ESBL-E. Seven samples (6%) yielded ESBL-E. Three bla CTX-M-15, one bla CTX-M-1, two genes of the CTX-M-9 group and one SHV ESBL-encoding gene were found. The ESBL genes were similar to what is found in enterobacterial strains from human origin. Therefore, raw vegetables might be a source of resistance genes for the enterobacterial strains found in humans. PMID: Perencevich EN, Skov R, Kluytmans J. Identifying livestock-associated methicillin-resistant Staphylococcus aureus in the United States. JAMA Intern Med May;174(5): Comment in: - Identifying livestock-associated methicillin-resistant staphylococcus aureus in the United States--reply. [JAMA Intern Med. 2014] Comment on: - High-density livestock operations, crop field application of manure, and risk of communityassociated methicillin-resistant Staphylococcus aureus infection in Pennsylvania. [JAMA Intern Med. 2013] PMID: Laboratorium voor Microbiologie en Infectiepreventie 121

123 Stewardson AJ, Renzi G, Maury N, Vaudaux C, Brossier C, Fritsch E, Pittet D, Heck M, van der Zwaluw K, Reuland EA, van de Laar T, Snelders E, Vandenbroucke-Grauls C, Kluytmans J, Edder P, Schrenzel J, Harbarth S. Extended-spectrum ß-lactamase-producing Enterobacteriaceae in hospital food: a risk assessment. Infect Control Hosp Epidemiol Apr;35(4): OBJECTIVE: Determine the prevalence of extended-spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae (ESBL-PE) contamination of food and colonization of food handlers in a hospital kitchen and compare retrieved ESBL-PE strains with patient isolates. DESIGN: Cross-sectional study. SETTING: A 2,200-bed tertiary care university hospital in Switzerland. PARTICIPANTS: Food handlers. METHODS: Raw and prepared food samples were obtained from the hospital kitchen, with a comparator group from local supermarkets. Fecal samples collected from food handlers and selectively pre-enriched homogenized food samples were inoculated onto selective chromogenic media. Phenotypic confirmation of ESBL production was performed using the double disk method. Representative ESBL-PE were characterized using polymerase chain reaction (PCR) and sequencing for blactx-m, blashv, and blatem genes, and Escherichia coli strains were typed using phylotyping, repetitive element palindromic PCR, and multilocus sequence typing. Meat samples were screened for antibiotic residues using liquid chromatography time-of-flight mass spectrometry. RESULTS: Sixty (92%) of the raw chicken samples were ESBL-PE positive, including 30 (86%) of the hospital samples and all supermarket samples. No egg, beef, rabbit, or cooked chicken samples were ESBL-PE positive. No antibiotic residues were detected. Six (6.5%) of 93 food handlers were ESBL-PE carriers. ESBL-PE strains from chicken meat more commonly possessed blactx-m-1 and blactx-m-2, whereas blactx-m-14 and blactx-m-15 were predominant among strains of human origin. There was partial overlap in the sequence type of E. coli strains of chicken and human origin. No E. coli ST131 strains or blactx-m-15 genes were isolated from meat. CONCLUSIONS: Although there is significant ESBL-PE contamination of delivered chicken meat, current preventive strategies minimize risks to food handlers, hospital staff, and patients. PMID: Publicaties Medische Staf

124 Bonten MJ, Friedrich A, Kluytmans JA, Vandenbroucke-Grauls CM, Voss A, Vos MC. Infectiepreventie in Nederlandse ziekenhuizen; resultaten zeggen meer dan procesindicatoren. [Infection prevention in Dutch hospitals; results say more than process indicators]. Ned Tijdschr Geneeskd. 2014;158:A7395. The Dutch Health Care Inspectorate investigated the preparedness of Dutch hospitals for the emergence of antibiotic resistance, and concluded that hospitals are not well prepared and are insufficiently aware that infection prevention is a prerequisite for patient safety. These conclusions are based on observations of process indicators of current practice guidelines, without including the available outcome indicators that demonstrate the persistently low incidence of infections with antibiotic resistant bacteria in Dutch hospitals. The conclusions may have negative effects on the quality of infection prevention in Dutch hospitals. Therefore, it is advisable to use outcome indicators rather than process indicators to evaluate the quality of infection prevention. PMID: Willemsen I, Hille L, Vrolijk A, Bergmans A, Kluytmans J. Evaluation of a commercial real-time PCR for the detection of extended spectrum ß-lactamase genes. J Med Microbiol Apr;63 (Pt 4): Epub 2014 Jan 28. We investigated the performance of a real-time PCR for the detection of extended spectrum ß-lactamase genes in Enterobacteriaceae (Check-MDR ESBL PCR). Results from micro-arrays were considered as the gold standard. An analysis on 489 isolates resulted in a sensitivity of 98.9 % and a specificity of 100 % for the PCR. PMID: Halaby T, Al Naiemi N, Kluytmans J, van der Palen J, Vandenbroucke-Grauls CM. Reply to colistin resistance during selective digestive tract decontamination is uncommon. Antimicrob Agents Chemother. 2014;58(1):627. No abstract available. Comment on: - Emergence of colistin resistance in Enterobacteriaceae after the introduction of selective digestive tract decontamination in an intensive care unit. [Antimicrob Agents Chemother. 2013] - Colistin resistance during selective digestive tract decontamination is uncommon. [Antimicrob Agents Chemother. 2014] PMID: Laboratorium voor Microbiologie en Infectiepreventie 123

125 Van Zanten AR, Brinkman S, Arbous MS, Abu-Hanna A, Levy MM, de Keizer NF; Netherlands Patient Safety Agency Sepsis Expert Group* [Kluytmans JA et al...]. Guideline bundles adherence and mortality in severe sepsis and septic shock. Crit Care Med Aug;42(8): OBJECTIVE: Surviving Sepsis Campaign bundles have been associated with reduced mortality in severe sepsis and septic shock patients. Case-mix adjusted mortality evaluations have not been performed to compare hospitals participating in sepsis bundle programs with those not participating. We aimed to achieve an individual bundle target adherence more than 80% and a relative mortality reduction of at least 15% (absolute mortality reduction 5.2%) at the end of DESIGN: Prospective multicenter cohort study in participating and nonparticipating centers. SETTING: Eighty-two ICUs in The Netherlands. PATIENTS: In total, 213,677 adult ICU patients admitted to all ICUs among which 8,387 severe sepsis patients at 52 participating ICUs and 8,031 severe sepsis patients at 30 nonparticipating ICUs. INTERVENTIONS: A national program to screen patients for severe sepsis and septic shock and implement Surviving Sepsis Campaign bundles to complete within 6 and 24 hours after ICU admission. MEASUREMENTS AND MAIN RESULTS: Bundle target adherence and case-mix adjusted in-hospital mortality were evaluated through odds ratios of time since program initiation by logistic generalized estimating equation analyses (July 2009 through January 2013). Outcomes were adjusted for age, gender, admission type, severity of illness, and sepsis diagnosis location. Participation duration was associated with improved bundle target adherence (adjusted odds ratio per month = [ ]) and decreased in-hospital mortality (adjusted odds ratio per month = [ ]) equivalent to 5.8% adjusted absolute mortality reduction over 3.5 years. Mortality reduced in screened patients with other diagnoses (1.9% over 3.5 yr, adjusted odds ratio per month = [ ]) and did not change in nonscreened patients in participating ICUs, nor in patients with sepsis or other diagnoses in nonparticipating ICUs. CONCLUSIONS: Implementation of a national sepsis program resulted in improved adherence to sepsis bundles in severe sepsis and septic shock patients and was associated with reduced adjusted in-hospital mortality only in participating ICUs, suggesting direct impact of sepsis screening and bundle application on in-hospital mortality. * Collaborators: Arbous MS, Biemond-Moeniralam HS, van Boxtel AJ, Bruns M, Dawson I, Heemskerk BT, Houtsma MM, Kluytmans JA, Schoonderbeek FJ, Trooster RM, van der Vorm ER, Wallenborg C, Wille J, Wittenberg J. PMID: Publicaties Medische Staf

126 Uzun S, Djamin RS, Kluytmans JA, Mulder PG, Van t Veer NE, Ermens AA, Pelle AJ, Hoogsteden HC, Aerts JG, van der Eerden MM. Azithromycin maintenance treatment in patients with frequent exacerbations of chronic obstructive pulmonary disease (COLUMBUS): a randomised, doubleblind, placebo-controlled trial. Lancet Respir Med May;2(5): Epub 2014 Apr 15. BACKGROUND: Macrolide resistance is an increasing problem; there is therefore debate about when to implement maintenance treatment with macrolides in patients with chronic obstructive pulmonary disease (COPD). We aimed to investigate whether patients with COPD who had received treatment for three or more exacerbations in the previous year would have a decrease in exacerbation rate when maintenance treatment with azithromycin was added to standard care. METHODS: We did a randomised, double-blind, placebo-controlled, single-centre trial in the Netherlands between May 19, 2010, and June 18, Patients ( 18 years) with a diagnosis of COPD who had received treatment for three or more exacerbations in the previous year were randomly assigned, via a computer-generated randomisation sequence with permuted block sizes of ten, to receive 500 mg azithromycin or placebo three times a week for 12 months. Randomisation was stratified by use of long-term, low-dose prednisolone ( 10 mg daily). Patients and investigators were masked to group allocation. The primary endpoint was rate of exacerbations of COPD in the year of treatment. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT FINDINGS: We randomly assigned 92 patients to the azithromycin group (n=47) or the placebo group (n=45), of whom 41 (87%) versus 36 (80%) completed the study. We recorded 84 exacerbations in patients in the azithromycin group compared with 129 in those in the placebo group. The unadjusted exacerbation rate per patient per year was 1 94 (95% CI ) for the azithromycin group and 3 22 ( ) for the placebo group. After adjustment, azithromycin resulted in a significant reduction in the exacerbation rate versus placebo (0 58, 95% CI ; p=0 001). Three (6%) patients in the azithromycin group reported serious adverse events compared with five (11%) in the placebo group. During follow-up, the most common adverse event was diarrhoea in the azithromycin group (nine [19%] patients vs one [2%] in the placebo group; p=0 015). INTERPRETATION: Maintenance treatment with azithromycin significantly decreased the exacerbation rate compared with placebo and should therefore be considered for use in patients with COPD who have the frequent exacerbator phenotype and are refractory to standard care. FUNDING: SoLong Trust. PMID: Laboratorium voor Microbiologie en Infectiepreventie 125

127 Uzun S, Djamin RS, Veer NE van t, Kluytmans JA, Ermens AA, Hoogsteden HC, Aerts JG, Eerden MM van der. Macrolides to prevent COPD exacerbations. Clin Pulm Med. 2014;21(2): Chronic obstructive pulmonary disease (COPD) is one of the major health problems in the world. Long-term treatment with macrolide antibiotics is a recent development that has been reported to have beneficial effects on exacerbation frequency. These effects are not only attributed to the antimicrobial effect but also to the immune modulatory effect. Six randomized trials and 1 retrospective study have been performed to investigate the efficacy of macrolides in the prevention of acute exacerbations of COPD. Besides the beneficial effects on the occurrence of exacerbations of COPD, this treatment also seems to improve quality of life and is well tolerated. Antimicrobial resistance is one of the future issues to consider before implementing this therapy. Van Rijen MM, Kluytmans JA. Adjustment of the MRSA Search and Destroy policy for outpatients in the Netherlands: a prospective cohort study with repeated prevalence measurements. Antimicrob Resist Infect Control Jan 15;3(1):3. BACKGROUND: In the Netherlands a successful MRSA Search and Destroy policy is applied in healthcare institutes. We determined the effect of an adjustment in the MRSA Search and Destroy policy for patients in the outpatient clinic on the MRSA transmission to health care workers (HCW). METHODS: In June 2008 an adjustment in the policy for outpatients was introduced in a large teaching hospital. Following this adjustment MRSA positive patients and patients at risk could be seen and treated applying general precautions, without additional protective measures. Also, disinfection of the room after the patient had left was abandoned. To monitor the effect of this policy on the transmission of MRSA all physicians and health care workers of the outpatient clinic were screened for MRSA carriage repeatedly. RESULTS: Before the introduction of the adjusted policy all physicians and HCW of the outpatient clinic were screened (=0-measurement, n = 1,073). None of them was found to be MRSA positive. After introduction of the policy in June 2008 the screening was repeated in October 2008 (n = 1,170) and April 2009 (n = 1,128). In April 2009 one health care worker was MRSA positive resulting in a mean prevalence of 0.09%. This is lower than the known prevalence in HCW. The health care worker was colonized with the livestock-related Spa type t011. As far as we could verify, no patients with this Spa-type had been cared for by the health care worker. CONCLUSIONS: The adjusted MRSA policy did not lead to detectable transmission of MRSA to HCW and was associated with less disturbances in the work flow. PMID: Publicaties Medische Staf

128 Veenemans J, Overdevest IT, Snelders E, Willemsen I, Hendriks Y, Adesokan A, Doran G, Bruso S, Rolfe A, Pettersson A, Kluytmans JA. Next-generation sequencing for typing and detection of resistance genes: performance of a new commercial method during an outbreak of extended-spectrum-beta-lactamase-producing Escherichia coli. J Clin Microbiol Jul;52(7): Epub 2014 Apr 30. Next-generation sequencing (NGS) has the potential to provide typing results and detect resistance genes in a single assay, thus guiding timely treatment decisions and allowing rapid tracking of transmission of resistant clones. We evaluated the performance of a new NGS assay (Hospital Acquired Infection BioDetection System; Pathogenica) during an outbreak of sequence type 131 (ST131) Escherichia coli infections in a nursing home in The Netherlands. The assay was performed on 56 extended-spectrum-beta-lactamase (ESBL) E. coli isolates collected during 2 prevalence surveys (March and May 2013). Typing results were compared to those of amplified fragment length polymorphism (AFLP), whereby we visually assessed the agreement of the BioDetection phylogenetic tree with clusters defined by AFLP. A microarray was considered the gold standard for detection of resistance genes. AFLP identified a large cluster of 31 indistinguishable isolates on adjacent departments, indicating clonal spread. The BioDetection phylogenetic tree showed that all isolates of this outbreak cluster were strongly related, while the further arrangement of the tree also largely agreed with other clusters defined by AFLP. The BioDetection assay detected ESBL genes in all but 1 isolate (sensitivity, 98%) but was unable to discriminate between ESBL and non-esbl TEM and SHV beta-lactamases or to specify CTX-M genes by group. The performance of the hospital-acquired infection (HAI) BioDetection System for typing of E. coli isolates compared well with the results of AFLP. Its performance with larger collections from different locations, and for typing of other species, was not evaluated and needs further study. PMID: Reuland EA, Hays JP, de Jongh DM, Abdelrehim E, Willemsen I, Kluytmans JA, Savelkoul PH, Vandenbroucke-Grauls CM, al Naiemi N. Detection and occurrence of plasmid-mediated AmpC in highly resistant gram-negative rods. PLoS One Mar 18;9(3):e ecollection OBJECTIVES: The aim of this study was to compare the current screening methods and to evaluate confirmation tests for phenotypic plasmidal AmpC (pampc) detection. METHODS: For this evaluation we used 503 Enterobacteriaceae from 18 Dutch hospitals and 21 isolates previously confirmed to be pampc positive. All isolates were divided into three groups: isolates with 1) reduced susceptibility to ceftazidime and/or cefotaxime; 2) reduced susceptibility to cefoxitin; 3) reduced susceptibility to ceftazidime and/or cefotaxime combined with reduced susceptibility to cefoxitin. Two disk-based tests, with cloxacillin or boronic acid as inhibitor, and Etest with cefotetan-cefotetan/cloxacillin were used for phenotypic AmpC confirmation. Finally, presence of pampc genes was tested by multiplex and singleplex PCR. Laboratorium voor Microbiologie en Infectiepreventie 127

129 RESULTS: We identified 13 pampc producing Enterobacteriaceae isolates among the 503 isolates (2.6%): 9 CMY-2, 3 DHA-1 and 1 ACC-1 type in E. coli isolates. The sensitivity and specificity of reduced susceptibility to ceftazidime and/or cefotaxime in combination with cefoxitin was 97% (33/34) and 90% (289/322) respectively. The disk-based test with cloxacillin showed the best performance as phenotypic confirmation method for AmpC production. CONCLUSIONS: For routine phenotypic detection of pampc the screening for reduced susceptibility to third generation cephalosporins combined with reduced susceptibility to cefoxitin is recommended. Confirmation via a combination disk diffusion test using cloxacillin is the best phenotypic option. The prevalence found is worrisome, since, due to their plasmidal location, pampc genes may spread further and increase in prevalence. PMID: PMCID: PMC Knox J, Van Rijen M, Uhlemann AC, Miller M, Hafer C, Vavagiakis P, Shi Q, Johnson PD, Coombs G, Kluytmans-Van den Bergh M, Kluytmans J, Bennett CM, Lowy FD. Community-associated methicillin-resistant Staphylococcus aureus transmission in households of infected cases: a pooled analysis of primary data from three studies across international settings. Epidemiol Infect Apr 24:1-12. [Epub ahead of print]. SUMMARY Diverse strain types of methicillin-resistant Staphylococcus aureus (MRSA) cause infections in community settings worldwide. To examine heterogeneity of spread within households and to identify common risk factors for household transmission across settings, primary data from studies conducted in New York (USA), Breda (The Netherlands), and Melbourne (Australia) were pooled. Following MRSA infection of the index patient, household members completed questionnaires and provided nasal swabs. Swabs positive for S. aureus were genotyped by spa sequencing. Poisson regression with robust error variance was used to estimate prevalence odds ratios for transmission of the clinical isolate to non-index household members. Great diversity of strain types existed across studies. Despite differences between studies, the index patient being colonized with the clinical isolate at the home visit (P < 0 01) and the percent of household members aged <18 years (P < 0 01) were independently associated with transmission. Targeted decolonization strategies could be used across geographical settings to limit household MRSA transmission. PMID: Publicaties Medische Staf

130 Van Cleef BA, van Benthem BH, Verkade EJ, van Rijen M, Kluytmans-van den Bergh MF, Schouls LM, Duim B, Wagenaar JA, Graveland H, Bos ME, Heederik D, Kluytmans JA. Dynamics of methicillin-resistant Staphylococcus aureus and methicillin-susceptible Staphylococcus aureus carriage in pig farmers: a prospective cohort study. Clin Microbiol Infect Oct;20(10): Epub 2014 May 15. Our purpose was to determine the dynamics of livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) carriage and its determinants in persons working at pig farms, in order to identify targets for interventions. This prospective cohort study surveyed 49 pig farms in the Netherlands on six sampling dates in 1 year ( ). Nasal and oropharyngeal swabs were collected, as well as environmental surface samples from stables and house. Of 110 pig farmers, 38% were persistent MRSA nasal carriers. The average cross-sectional MRSA prevalence was 63%. Methicillin-susceptible S. aureus (MSSA) nasal carriage was associated with fewer MRSA acquisitions (prevalence rate (PR) = 0.47, p 0.02). In multivariate analysis, an age of years (PR = 2.13, p 0.01), a working week of 40 h (PR=1.89, p 0.01), giving birth assistance to sows (PR=2.26, p 0.03), removing manure of finisher pigs (PR=0.48, p 0.02), and wearing a facemask (PR = 0.13, p 0.02) were significantly related with persistent MRSA nasal carriage. A higher MRSA exposure in stables was associated with MRSA in pig farmers (p <0.0001). This study describes a very high prevalence of LA-MRSA carriage in pig farmers, reflecting extensive exposure during work. We identified the possible protective effects of MSSA carriage and of continuously wearing a facemask during work. PMID: Van der Mee-Marquet NL, Corvaglia A, Haenni M, Bertrand X, Franck JB, Kluytmans J, Girard M, Quentin R, François P. Emergence of a novel subpopulation of CC398 Staphylococcus aureus infecting animals is a serious hazard for humans. Front Microbiol Dec 5;5:652. ecollection. Until recently, Staphylococcus aureus from clonal complex (CC)398 were mostly described as colonizing asymptomatic raised pigs and pig-farmers. Currently, the epidemiology of the CC398 lineage is becoming more complex. CC398 human-adapted isolates are increasingly being identified in bloodstream infections in humans living in animal-free environments. In addition, CC398 isolates are increasingly responsible for invasive infections in various animals. CC398 isolates that colonize asymptomatic pigs and the isolates that infect humans living in animal-free environments (human-adapted isolates) both lack several clinically important S. aureus-associated virulence factors but differ on the basis of their prophage content. Recent findings have provided insight into the influence of a φmr11-like helper prophage on the ability of CC398 isolates to infect humans. To assess the recent spread of the CC398 lineage to various animal species and to investigate the links between the φmr11-like prophage and the emergence of CC398 isolates infecting animals, we studied 277 isolates causing infections in unrelated animals. The prevalence of CC398 isolates increased significantly between 2007 and 2013 (p < 0.001); 31.8% of the animal isolates harbored the φmr11-like prophage. High-density DNA microarray experiments with 37 representative infected-animal isolates positive for φmr11-like DNA established that most infected-animal isolates carried many genetic elements related to Laboratorium voor Microbiologie en Infectiepreventie 129

131 antimicrobial resistance and virulence genes, and a φ3 prophage encoding immune-modulating proteins and associated with animal-to-human jumps. Our findings suggest recent clonal expansion and dissemination of a new subpopulation of CC398 isolates, responsible for invasive infections in various animals, with a considerable potential to colonize and infect humans, probably greater than that of human-adapted CC398 isolates, justifying active surveillance. PMID: PMCID: PMC Bos ME, Verstappen KM, van Cleef BA, Dohmen W, Dorado-García A, Graveland H, Duim B, Wagenaar JA, Kluytmans JA, Heederik DJ. Transmission through air as a possible route of exposure for MRSA. J Expo Sci Environ Epidemiol Dec 17. [Epub ahead of print]. Livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) is highly prevalent in pigs and veal calves. The environment and air in pig and veal calf barns is often contaminated with LA-MRSA, and can act as a transmission source for humans. This study explores exposureresponse relationships between sequence type 398 (ST398) MRSA air exposure level and nasal ST398 MRSA carriage in people working and/or living on farms. Samples and data were used from three longitudinal field studies in pig and veal calf farm populations. Samples consisted of nasal swabs from the human participants and electrostatic dust fall collectors capturing airborne settled dust in barns. In both multivariate and mutually adjusted analyses, a strong association was found between nasal ST398 MRSA carriage in people working in the barns for >20 h per week and MRSA air levels. In people working in the barns < 20 h per week there was a strong association between nasal carriage and number of working hours. Exposure to ST398 MRSA in barn air seems to be an important determinant for nasal carriage, especially in the highly exposed group of farmers, next to duration of contact with animals. Intervention measures should therefore probably also target reduction of ST398 MRSA air levels. PMID: Bosch T, Verkade E, van Luit M, Landman F, Kluytmans J, Schouls LM. Transmission and Persistence of Livestock-Associated Methicillin-Resistant Staphylococcus aureus among Veterinarians and Their Household Members. Appl Environ Microbiol Jan 1;81(1): Epub After the first isolation of livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) in 2003, this MRSA variant quickly became the predominant MRSA obtained from humans as part of the Dutch national MRSA surveillance. Previous studies have suggested that human-to-human transmission of LA-MRSA, compared to that of other MRSA lineages, rarely occurs. However, these reports describe the transmission of LA-MRSA based on epidemiology and limited molecular characterization of isolates, making it difficult to assess whether transmission actually occurred. In this study, we used whole-genome maps (WGMs) to identify possible transmission of LA-MRSA between humans. For this, we used LA-MRSA isolates originating from a 2-year prospective longitudinal cohort study in which livestock veterinarians and their household members were repeatedly sampled for the presence of S. aureus. A considerable 130 Publicaties Medische Staf

132 degree of genotypic variation among LA-MRSA strains was observed. However, there was very limited variability between the maps of the isolates originating from the same veterinarian, indicating that each of the veterinarians persistently carried or had reacquired the same LA-MRSA strain. Comparison of WGMs revealed that LA-MRSA transmission had likely occurred within virtually every veterinarian household. Yet only a single LA-MRSA strain per household appeared to be involved in transmission. The results corroborate our previous finding that LA-MRSA is genetically diverse. Furthermore, this study shows that transmission of LA-MRSA between humans occurs and that carriage of LA-MRSA can be persistent, thus posing a potential risk for spread of this highly resistant pathogen in the community. PMID: PMCID: PMC Djamin RS, Uzun S, Snelders E, Kluytmans JA, Hoogsteden HC, Aerts JG, van der Eerden MM. Occurrence of virus-induced COPD exacerbations during four seasons. Scand J Infect Dis Nov 26:1-5. [Epub ahead of print]. In this study, we investigated the occurrence of viral infections in acute exacerbations of chronic obstructive pulmonary disease (COPD) during four seasons. Viral infections were detected by the use of real-time reverse transcriptase polymerase chain reaction on pharyngeal swabs. During a 12-month period pharyngeal swabs were obtained in 136 exacerbations of 63 patients. In 35 exacerbations (25.7%) a viral infection was detected. Most viral infections occurred in the winter (n = 14, 40.0%), followed by summer (n = 9, 25.7%), autumn (n = 6, 17.1%), and spring (n = 6, 17.1%). Rhinovirus was the most frequently isolated virus (n = 19, 51.4%), followed by respiratory syncytial virus (n = 6, 16.2%), human metapneumovirus (n = 5, 13.5%), influenza A (n = 4, 10.8%), parainfluenza 4 (n = 2, 5.4%), and parainfluenza 3 (n = 1, 2.7%). This study showed that virus-induced COPD exacerbations occur in all four seasons with a peak in the winter months. However, the distribution of rhinovirus infections showed a different pattern, with most infections occurring in July. PMID: Van der Slegt J, Kluytmans JA, Mulder PG, Veen EJ, Ho GH, van der Laan L. Surgical site infection after multiple groin incisions in peripheral vascular surgery. Surg Infect (Larchmt) Dec;15(6): Abstract Background: Patients with peripheral arterial disease (PAD) are at risk for revision surgery in the groin and therefore at potential risk for surgical site infections (SSIs). In an observational study, a cohort of patients with peripheral arterial disease was followed to examine the effect of different incision intervals on SSI-free survival. METHODS: Patients, needing peripheral vascular surgery because of PAD, were retrieved from a prospectively collected database on SSIs after vascular surgery between March 2009 and January 2012, the group consisting of 720 patients. Of these, 255 patients were selected (age 71.9±10.4 y). Laboratorium voor Microbiologie en Infectiepreventie 131

133 Cox proportional hazards models were used for event-history analyses. The effect of incision interval was estimated with adjustment for a number of potential confounders. Effects were quantified by means of hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: No significant effect on the incision interval on SSI-free survival was observed. After separating incisional SSIs into superficial- and deep-seated, a significant linear trend effect of the groin incision interval on deep-incisional SSI development was observed: the shorter the interval, the higher the event rate (HR 1.5 per category, 95% CI , p=0.22). Besides the incision interval, the Rutherford classification was a significant risk factor for SSI development (HR 3.0; 95% CI ; p<0.0005). CONCLUSION: Revision surgery in the groin puts patients at risk for deep-incisional SSI. No effect on superficial incisional SSI development was observed. Besides the incision interval, the Rutherford classification was a significant risk factor for both superficial- and deep-incisional SSI. Quality improvement and better risk stratification schemes are suggested. PMID: Willemsen I, Nelson-Melching J, Hendriks Y, Mulders A, Verhoeff S, Kluytmans-Vandenbergh M, Kluytmans J. Measuring the quality of infection control in Dutch nursing homes using a standardized method; the Infection prevention RIsk Scan (IRIS). Antimicrob Resist Infect Control Aug 18;3:26. BACKGROUND: We developed a standardised method to assess the quality of infection control in Dutch Nursing Home (NH), based on a cross-sectional survey that visualises the results. The method was called the Infection control RIsk Infection Scan (IRIS). We tested the applicability of this new tool in a multicentre surveillance executed June and July METHODS: The IRIS includes two patient outcome-variables, i.e. the prevalence of healthcare associated infections (HAI) and rectal carriage of Extended-Spectrum Beta-Lactamase (ESBL) producing Enterobacteriaceae (ESBL-E); two patient-related risk factors, i.e. use of medical devices, and antimicrobial therapy; and three ward-related risk factors, i.e. environmental contamination, availability of local guidelines, and shortcomings in infection prevention preconditions. Results were categorised as low-, intermediate- and high risk, presented in an easy-to-read graphic risk spider-plot. This plot was given as feedback to management and healthcare workers of the NH. RESULTS: Large differences were found among most the variables in the different NH. Common shortcomings were the availability of infection control guidelines and the level of environmental cleaning. Most striking differences were observed in the prevalence of ESBL carriage, ranged from zero to 20.6% (p < 0.001). 132 Publicaties Medische Staf

134 CONCLUSIONS: The IRIS provided a rapid and easy to understand assessment of the infection control situation of the participating NH. The results can be used to improve the quality of infection control based on the specific needs of a NH but needs further validation in future studies. Repeated measurement can determine the effectiveness of the interventions. This makes the IRIS a useful tool for quality systems. PMID: PMCID: PMC Laboratorium voor Microbiologie en Infectiepreventie 133

135 Longgeneeskunde Kerngegevens 10 Longartsen: dr. J.G.J.V. (Joachim) Aerts, J. (Jerryll) Asin, T.A. (Theo) Bantje, H.N.A. (Huub) Belderbos, R.S. (Remco) Djamin, dr. M.J.J.H. (Marco) Grootenboers, A.M. (André) Janssens, V.M.J. (Vic) Linsen, K.M. (Merijn) Kant, C. van der Leest, N.C. (Nico) van Walree 1 chef de clinique: S.A. Gajadin, longarts 6 assistenten in opleiding (6,14 fte) 6 assistenten niet in opleiding (6,14 fte) 4 research medewerkers Subspecialismen: astma en allergologie, COPD, interstitiële longziekten, longziekten, longkanker, slaapapneu en niet-invasieve beademing Samenvattingen gepubliceerde artikelen Kant KM, Djamin RS, Belderbos HN, van den Berg B. Acute respiratoire insufficiëntie door COPD: Beslissen over wel of niet beademen. [Acute respiratory insufficiency due to COPD: invasive mechanical ventilation or not?]. Ned Tijdschr Geneeskd. 2014;158:A5276. The decision to move to a form of mechanical ventilation in patients with acute respiratory failure due to an acute exacerbation of COPD is influenced by expectations about survival and quality of life after discharge from the ICU. Physicians tend to be too pessimistic about the survival outcome of an ICU stay with invasive mechanical ventilation. The forced expiratory volume in 1 second (FEV1) is not an adequate prognostic parameter. In order to prevent undertreatment of patients with respiratory failure due to an exacerbation of COPD, knowledge of prognostic parameters and quality of life in these patients is very important. End of life care should be integrated into the standard care of COPD patients. PMID: Uzun S, Djamin RS, Kluytmans JA, Mulder PG, Van t Veer NE, Ermens AA, Pelle AJ, Hoogsteden HC, Aerts JG, van der Eerden MM. Azithromycin maintenance treatment in patients with frequent exacerbations of chronic obstructive pulmonary disease (COLUMBUS): a randomised, doubleblind, placebo-controlled trial. Lancet Respir Med May;2(5): Epub 2014 Apr 15. BACKGROUND: Macrolide resistance is an increasing problem; there is therefore debate about when to implement maintenance treatment with macrolides in patients with chronic obstructive pulmonary disease (COPD). We aimed to investigate whether patients with COPD who had received treatment for three or more exacerbations in the previous year would have a decrease in exacerbation rate when maintenance treatment with azithromycin was added to standard care. METHODS: We did a randomised, double-blind, placebo-controlled, single-centre trial in the Netherlands between May 19, 2010, and June 18, Patients ( 18 years) with a diagnosis of 134 Publicaties Medische Staf

136 COPD who had received treatment for three or more exacerbations in the previous year were randomly assigned, via a computer-generated randomisation sequence with permuted block sizes of ten, to receive 500 mg azithromycin or placebo three times a week for 12 months. Randomisation was stratified by use of long-term, low-dose prednisolone ( 10 mg daily). Patients and investigators were masked to group allocation. The primary endpoint was rate of exacerbations of COPD in the year of treatment. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT FINDINGS: We randomly assigned 92 patients to the azithromycin group (n=47) or the placebo group (n=45), of whom 41 (87%) versus 36 (80%) completed the study. We recorded 84 exacerbations in patients in the azithromycin group compared with 129 in those in the placebo group. The unadjusted exacerbation rate per patient per year was 1 94 (95% CI ) for the azithromycin group and 3 22 ( ) for the placebo group. After adjustment, azithromycin resulted in a significant reduction in the exacerbation rate versus placebo (0 58, 95% CI ; p=0 001). Three (6%) patients in the azithromycin group reported serious adverse events compared with five (11%) in the placebo group. During follow-up, the most common adverse event was diarrhoea in the azithromycin group (nine [19%] patients vs one [2%] in the placebo group; p=0 015). INTERPRETATION: Maintenance treatment with azithromycin significantly decreased the exacerbation rate compared with placebo and should therefore be considered for use in patients with COPD who have the frequent exacerbator phenotype and are refractory to standard care. FUNDING: SoLong Trust. PMID: Uzun S, Djamin RS, Veer NE van t, Kluytmans JA, Ermens AA, Hoogsteden HC, Aerts JG, Eerden MM van der. Macrolides to prevent COPD exacerbations. Clin Pulm Med. 2014;21(2): Chronic obstructive pulmonary disease (COPD) is one of the major health problems in the world. Long-term treatment with macrolide antibiotics is a recent development that has been reported to have beneficial effects on exacerbation frequency. These effects are not only attributed to the antimicrobial effect but also to the immune modulatory effect. Six randomized trials and 1 retrospective study have been performed to investigate the efficacy of macrolides in the prevention of acute exacerbations of COPD. Besides the beneficial effects on the occurrence of exacerbations of COPD, this treatment also seems to improve quality of life and is well tolerated. Antimicrobial resistance is one of the future issues to consider before implementing this therapy. Djamin RS, Uzun S, Snelders E, Kluytmans JA, Hoogsteden HC, Aerts JG, van der Eerden MM. Occurrence of virus-induced COPD exacerbations during four seasons. Scand J Infect Dis Nov 26:1-5. [Epub ahead of print]. Longgeneeskunde 135

137 In this study, we investigated the occurrence of viral infections in acute exacerbations of chronic obstructive pulmonary disease (COPD) during four seasons. Viral infections were detected by the use of real-time reverse transcriptase polymerase chain reaction on pharyngeal swabs. During a 12-month period pharyngeal swabs were obtained in 136 exacerbations of 63 patients. In 35 exacerbations (25.7%) a viral infection was detected. Most viral infections occurred in the winter (n = 14, 40.0%), followed by summer (n = 9, 25.7%), autumn (n = 6, 17.1%), and spring (n = 6, 17.1%). Rhinovirus was the most frequently isolated virus (n = 19, 51.4%), followed by respiratory syncytial virus (n = 6, 16.2%), human metapneumovirus (n = 5, 13.5%), influenza A (n = 4, 10.8%), parainfluenza 4 (n = 2, 5.4%), and parainfluenza 3 (n = 1, 2.7%). This study showed that virus-induced COPD exacerbations occur in all four seasons with a peak in the winter months. However, the distribution of rhinovirus infections showed a different pattern, with most infections occurring in July. PMID: Lievense LA, Hegmans JP, Aerts JG. Biomarkers for immune checkpoint inhibitors. Lancet Oncol Jan;15(1):e1. No abstract available. Comment in: - Biomarkers for immune checkpoint inhibitors--authors reply. [Lancet Oncol. 2014] Comment on: - Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial. [Lancet Oncol. 2013] PMID: Stolz D, Boersma W, Blasi F, Louis R, Milenkovic B, Kostikas K, Aerts JG, Rohde G, Lacoma A, Rakic J, Boeck L, Castellotti P, Scherr A, Marin A, Hertel S, Giersdorf S, Torres A, Welte T, Tamm M. Exertional hypoxemia in stable COPD is common and predicted by circulating proadrenomedullin. Chest Apr 10. [Epub ahead of print]. BACKGROUND: The prevalence of exertional hypoxemia in unselected COPD patients is unknown. Intermittent hypoxia leads to adrenomedullin (ADM) up regulation through the HIF-1 pathway. We aimed to assess the prevalence and the annual probability to develop exertional hypoxemia in stable COPD. We also hypothesized that increased ADM might be associated with exertional hypoxemia and envisioned that adding ADM to clinical variables might improve its prediction in COPD. 136 Publicaties Medische Staf

138 METHODS: minute walking tests and circulating proadrenomedullin levels from 574 patients with clinically stable, moderate to very severe COPD enrolled in a multinational cohort study and followed-up for 2 years were concomitantly analyzed. RESULTS: The prevalence of exertional hypoxemia was 29.1%. In a matrix derived from a fittedmulti-state model, the annual probability to develop exertional hypoxemia was 21.6%. Exertional hypoxemia was associated with greater deterioration of specific domains of health-related QoL, higher severe exacerbation and death annual rates. In the logistic linear and conditional Cox-regression multivariable analyses, both FEV1% predicted and proadm proved independent predictors of exertional hypoxemia (p < for both). Adjustment for comorbidities, including cardiovascular disorders, and exacerbation-rate did not influence results. Relative to using FEV1% pred alone, adding proadm resulted in a significant improvement of the predictive properties (p=0.018). Based on the suggested non-linear nomogram, patients with moderate COPD (FEV1 predicted=50%) but high proadm levels (> 2 nmol/l) presented increased risk (> 30%) for exertional desaturation. CONCLUSIONS: Exertional desaturation is common and associated with poorer clinical outcomes in COPD. Adrenomedullin improves prediction of exertional desaturation as compared to the use of FEV1%pred alone. PMID: Barlesi F, Scherpereel A, Gorbunova V, Gervais R, Vikström A, Chouaid C, Chella A, Kim JH, Ahn MJ, Reck M, Pazzola A, Kim HT, Aerts JG, Morando C, Loundou A, Groen HJ, Rittmeyer A. Maintenance bevacizumab-pemetrexed after first-line cisplatin-pemetrexed-bevacizumab for advanced nonsquamous nonsmall-cell lung cancer: updated survival analysis of the AVAPERL (MO22089) randomized phase III trial. Ann Oncol May;25(5): Epub 2014 Feb 27. BACKGROUND: The randomized, phase III AVAPERL trial evaluated the safety and efficacy of bevacizumab maintenance with or without pemetrexed in nonsquamous nonsmall-cell lung cancer (nsnsclc). Progression-free survival (PFS) was significantly prolonged with bevacizumabpemetrexed, but overall survival (OS) data were immature. In this article, we report an independent, updated analysis of survival outcomes in AVAPERL. PATIENTS AND METHODS: Patients with advanced nsnsclc received first-line bevacizumab (7.5 mg/kg), cisplatin (75 mg/m(2)), and pemetrexed (500 mg/m(2)) every 3 weeks (q3w) for four cycles. Nonprogressing patients were randomized to maintenance bevacizumab (7.5 mg/ kg) or bevacizumab-pemetrexed (500 mg/m(2)) q3w until progression or consent withdrawal. The primary end point of the trial was PFS; in this independent OS analysis, participating study centers were contacted to collect survival data on patients still alive at the time of the first analysis. RESULTS: A total of 376 patients received induction treatment. Disease control was confirmed in 71.9% of patients; 253 patients were randomized to maintenance treatment with bevacizumab Longgeneeskunde 137

139 (n = 125) or bevacizumab-pemetrexed (n = 128). At a median follow-up of 14.8 months, patients allocated to bevacizumab-pemetrexed had significantly improved PFS versus those on bevacizumab when measured from randomization [7.4 versus 3.7 months, hazard ratio (HR), 0.57, 95% confidence interval (CI) ); P < ]. OS events occurred in 58% of all patients. OS was numerically longer with bevacizumab-pemetrexed versus bevacizumab when measured from randomization [17.1 versus 13.2 months, HR 0.87 ( ); P = 0.29]. Second-line therapy was administered in 77% and 70% of patients in the bevacizumab and bevacizumab-pemetrexed arms, respectively. No new adverse events were reported during this updated analysis. CONCLUSION: In an unselected population of nsnsclc patients achieving disease control on platinum-based induction therapy, maintenance with bevacizumab-pemetrexed was associated with a nonsignificant increase in OS over bevacizumab alone. PMID: Mokhles S, Nuyttens JJ, Maat AP, Birim O, Aerts JG, Bogers AJ, Takkenberg JJ. Survival and Treatment of Non-small Cell Lung Cancer Stage I-II Treated Surgically or with Stereotactic Body Radiotherapy: Patient and Tumor-Specific Factors Affect the Prognosis. Ann Surg Oncol Jun 25. [Epub ahead of print]. BACKGROUND: This study was designed to define clinical baseline parameters associated with impaired survival of patients with stage I or II non-small cell lung cancer (NSCLC) who underwent surgery or stereotactic body radiotherapy (SBRT). METHODS: From January 2001 to January 2011, 425 patients (216 surgery, 209 SBRT) were identified with clinical stage I or II NSCLC. Cox proportional-hazards regression analyses were used to investigate risk factors for mortality. RESULTS: Median age of patients in the surgery and SBRT groups was 65 and 74 years, respectively. A smaller proportion of the surgical group had Charlson Comorbidity Index (CCI) score 1 compared with the SBRT group: 52 and 72% (p < 0.001), respectively. Overall survival in the surgical group at 2 and 4 years was 79 and 65%, respectively. In the SBRT group, this was 65% at 2 years and 44% at 4 years. In the surgical group older age, CCI score = 4 and clinical stage = IIB were associated with long-term mortality. In the SBRT group, this was CCI score 5 and clinical stage >IA. The area under the curve was calculated for the model with clinical and tumor factors: 0.77 for the surgery and 0.85 for the SBRT group. CONCLUSIONS: Both patient characteristics and survival of NSCLC I-II patients undergoing surgical treatment or SBRT differ considerably. Long-term survival as a result of treatment strategy of NSCLC patients might be optimized by focusing on patient and tumor specific factors. In addition to TNM staging, the consideration of patient age and CCI can be useful for prognostication of NSCLC patients. PMID: Publicaties Medische Staf

140 Hegmans JP, Aerts JG. Immunomodulation in cancer. Curr Opin Pharmacol Aug;17C: Epub 2014 Jul 8. We have to strengthen our chess-playing skills when using immunotherapeutic approaches in cancer treatment: know the cancerous opponent, study its evolution and have an eye for its weaknesses. Besides tumor cells, other pieces on the board are stromal cells, endothelial cells and different immune cells. Some of these immune cells, like helper and cytotoxic T cells, natural killer (T) cells and mature dendritic cells are of help, others like regulatory T cells and myeloid-derived suppressor cells belong to the opponent, while macrophages and neutrophils can belong to both. A personalized approach, by selecting the optimal treatment from the myriad of possibilities based on biomarker findings, is essential to attack that particular cancer at that moment. We have to adapt the strategy to the changing positions created by the opponent. Using all these skills, we might control cancer growth in the future. PMID: Cornelissen R, Lievense LA, Maat AP, Hendriks RW, Hoogsteden HC, Bogers AJ, Hegmans JP, Aerts JG. Ratio of intratumoral macrophage phenotypes is a prognostic factor in epithelioid malignant pleural mesothelioma. PLoS One Sep 5;9(9):e ecollection HYPOTHESIS: The tumor micro-environment and especially the different macrophage phenotypes appear to be of great influence on the behavior of multiple tumor types. M1 skewed macrophages possess anti-tumoral capacities, while the M2 polarized macrophages have protumoral capacities. We analyzed if the macrophage count and the M2 to total macrophage ratio is a discriminative marker for outcome after surgery in malignant pleural mesothelioma (MPM) and studied the prognostic value of these immunological cells. METHODS: 8 MPM patients who received induction chemotherapy and surgical treatment were matched on age, sex, tumor histology, TNM stage and EORTC score with 8 patients who received chemotherapy only. CD8 positive T-cells and the total macrophage count, using the CD68 panmacrophage marker, and CD163 positive M2 macrophage count were determined in tumor specimens prior to treatment. RESULTS: The number of CD68 and CD163 cells was comparable between the surgery and the nonsurgery group, and was not related to overall survival (OS) in both the surgery and non-surgery group. However, the CD163/CD68 ratio did correlate with OS in both in the total patient group (Pearson r -0.72, p<0.05). No correlation between the number of CD8 cells and prognosis was found. CONCLUSIONS: The total number of macrophages in tumor tissue did not correlate with OS in both groups, however, the CD163/CD68 ratio correlates with OS in the total patient group. Our data revealed that the CD163/CD68 ratio is a potential prognostic marker in epithelioid mesothelioma patients independent of treatment but cannot be used as a predictive marker for outcome after surgery. PMID: PMCID: PMC Longgeneeskunde 139

141 Aarts MJ, van den Borne BE, Biesma B, Kloover JS, Aerts JG, Lemmens VE. Improvement in population-based survival of stage IV NSCLC due to increased use of chemotherapy. Int J Cancer Sep 15. [Epub ahead of print]. This study aimed to investigate which factors were associated with the administration of chemotherapy for patients with stage IV non-small cell lung cancer (NSCLC), and their relation to survival at a population-based level. All patients with NSCLC stage IV from 2001 to 2012 were identified in the Netherlands Cancer Registry in the Eindhoven area (n=5,428). Chemotherapy use and survival were evaluated by logistic and Cox regression analyses, respectively. The proportion of patients receiving chemotherapy increased from 30% in 2001 to 48% in Higher rates were found among younger patients [multivariable odds ratio (OR 64 vs. 75 years ): 1.8 (95%CI )], high socioeconomic status [OR high vs. low : 1.8 (95%CI )], no comorbidity [OR 0 vs. 2 : 1.5 (95%CI )], diagnosed in recent years [OR vs : 2.0 (95%CI )] and adenocarcinoma [OR squamous vs. adenocarcinoma : 0.8 (95%CI )]. Having liver metastasis was associated with reduced odds (OR liver vs. brain : 0.8 (95%CI ). The variation between hospitals was large, up to OR 2.0 (95%CI ). Median survival increased from 18 weeks in to 21 weeks in (log-rank p=0.007), and was 35 weeks in patients with and 10 weeks without chemotherapy. The multivariable hazard of death reduced significantly over time [HR vs : 1.1 (95%CI ), HR vs : 1.2 (95%CI )] and only remained significant for after additional adjustment for chemotherapy [final multivariable model, HR vs : 1.1 (95%CI )]. Besides, prognostic factors were having chemotherapy [final multivariable model: HR 0.4 (95%CI )], female sex [HR male vs. female : 1.1 (95%CI )], socioeconomic status [HR intermediate and high vs. low both 0.9 (95%CI )], comorbidity [HR unknown vs. 2 : 1.3 (95%CI )], histology [HR other vs. adenocarcinoma : 1.1 (95%CI )], and location of metastasis [range: 1.2 (HR lymph nodes vs. brain ) (HR liver vs. brain )]. In conclusion, population-based survival increased due to increasing administration rates of chemotherapy. The administration of chemotherapy was affected by hospital of diagnosis and both patient and tumour characteristics. Identifying patients who benefit from chemotherapy should become a key issue. Struik FM, Sprooten RT, Kerstjens HA, Bladder G, Zijnen M, Asin J, Cobben NA, Vonk JM, Wijkstra PJ. Nocturnal non-invasive ventilation in COPD patients with prolonged hypercapnia after ventilatory support for acute respiratory failure: a randomised, controlled, parallel-group study. Thorax Sep;69(9): Epub 2014 Apr 29. INTRODUCTION: The effectiveness of non-invasive positive pressure ventilation (NIV) in COPD patients with prolonged hypercapnia after ventilatory support for acute respiratory failure (ARF) remains unclear. We investigated if nocturnal NIV in these patients prolongs the time to readmission for respiratory causes or death (primary endpoint) in the following 12 months. 140 Publicaties Medische Staf

142 METHODS: 201 COPD patients admitted to hospital with ARF and prolonged hypercapnia >48 h after termination of ventilatory support were randomised to NIV or standard treatment. Secondary outcomes were daytime arterial blood gasses, transcutaneous PCO2 during the night, lung function, health-related quality-of-life (HRQL), mood state, daily activities and dyspnoea. RESULTS: 1 year after discharge, 65% versus 64% of patients (NIV vs standard treatment) were readmitted to hospital for respiratory causes or had died; time to event was not different (p=0.85). Daytime PaCO2 was significantly improved in NIV versus standard treatment (PaCO2 0.5 kpa (95% CI 0.04 to 0.90, p=0.03)) as was transcutaneous PCO2 during the night. HRQL showed a trend (p=0.054, Severe Respiratory Insufficiency questionnaire) in favour of NIV. Number of exacerbations, lung function, mood state, daily activity levels or dyspnoea was not significantly different. DISCUSSIONS: We could not demonstrate an improvement in time to readmission or death by adding NIV for 1 year in patients with prolonged hypercapnia after an episode of NIV for ARF. There is no reason to believe the NIV was not effective since daytime PaCO2 and night-time PCO2 improved. The trend for improvement in HRQL favouring NIV we believe nevertheless should be explored further. TRIAL REGISTRATION NUMBER: NTR1100. PMID: Righini M, Van Es J, Den Exter PL, Roy PM, Verschuren F, Ghuysen A, Rutschmann OT, Sanchez O, Jaffrelot M, Trinh-Duc A, Le Gall C, Moustafa F, Principe A, Van Houten AA, Ten Wolde M, Douma RA, Hazelaar G, Erkens PM, Van Kralingen KW, Grootenboers MJ, Durian MF, Cheung YW, Meyer G, Bounameaux H, Huisman MV, Kamphuisen PW, Le Gal G. Age-adjusted D-dimer cutoff levels to rule out pulmonary embolism: the ADJUST-PE study. JAMA Mar 19;311(11): Erratum in: JAMA Apr 23-30;311(16):1694. IMPORTANCE: D-dimer measurement is an important step in the diagnostic strategy of clinically suspected acute pulmonary embolism (PE), but its clinical usefulness is limited in elderly patients. OBJECTIVE: To prospectively validate whether an age-adjusted D-dimer cutoff, defined as age x 10 in patients 50 years or older, is associated with an increased diagnostic yield of D-dimer in elderly patients with suspected PE. DESIGN, SETTINGS, AND PATIENTS: A multicenter, multinational, prospective management outcome study in 19 centers in Belgium, France, the Netherlands, and Switzerland between January 1, 2010, and February 28, INTERVENTIONS: All consecutive outpatients who presented to the emergency department with clinically suspected PE were assessed by a sequential diagnostic strategy based on the clinical probability assessed using either the simplified, revised Geneva score or the 2-level Wells Longgeneeskunde 141

143 score for PE; highly sensitive D-dimer measurement; and computed tomography pulmonary angiography (CTPA). Patients with a D-dimer value between the conventional cutoff of 500 µg/l and their age-adjusted cutoff did not undergo CTPA and were left untreated and formally followed-up for a 3-month period. MAIN OUTCOMES AND MEASURES: The primary outcome was the failure rate of the diagnostic strategy, defined as adjudicated thromboembolic events during the 3-month follow-up period among patients not treated with anticoagulants on the basis of a negative age-adjusted D-dimer cutoff result. RESULTS: Of the 3346 patients with suspected PE included, the prevalence of PE was 19%. Among the 2898 patients with a nonhigh or an unlikely clinical probability, 817 patients (28.2%) had a D-dimer level lower than 500 µg/l (95% CI, 26.6%-29.9%) and 337 patients (11.6%) had a D-dimer between 500 µg/l and their age-adjusted cutoff (95% CI, 10.5%-12.9%). The 3-month failure rate in patients with a D-dimer level higher than 500 µg/l but below the age-adjusted cutoff was 1 of 331 patients (0.3% [95% CI, 0.1%-1.7%]). Among the 766 patients 75 years or older, of whom 673 had a nonhigh clinical probability, using the age-adjusted cutoff instead of the 500 µg/l cutoff increased the proportion of patients in whom PE could be excluded on the basis of D-dimer from 43 of 673 patients (6.4% [95% CI, 4.8%-8.5%) to 200 of 673 patients (29.7% [95% CI, 26.4%-33.3%), without any additional false-negative findings. CONCLUSIONS AND RELEVANCE: Compared with a fixed D-dimer cutoff of 500 µg/l, the combination of pretest clinical probability assessment with age-adjusted D-dimer cutoff was associated with a larger number of patients in whom PE could be considered ruled out with a low likelihood of subsequent clinical venous thromboembolism. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT Comment in: Age-adjusted D-dimer cutoff levels and pulmonary embolism. [JAMA. 2014] In suspected PE, an age-adjusted D-dimer cutpoint improved ability to exclude PE. [Ann Intern Med. 2014] Is it time to raise the bar? Age-adjusted D-dimer cutoff levels to exclude pulmonary embolism. [Ann Emerg Med. 2014] PMID: Publicaties Medische Staf

144 Hendrikse WM, Grootenboers MJ, van Wijngaarden P. Type B lactic acidosis as initial presentation of acute myeloid leukaeemia. A case report. Neth J Crit Care apr;18(2):15-6. Van Ranst D, Stoop WA, Meijer JW, Otten HJ, van de Port IG. Reduction of exacerbation frequency in patients with COPD after participation in a comprehensive pulmonary rehabilitation program. Int J Chron Obstruct Pulmon Dis Oct 3;9: ecollection BACKGROUND: Pulmonary rehabilitation (PR) is an important treatment option for chronic obstructive pulmonary disease (COPD) patients and might contribute to a reduction in exacerbation and exacerbation-related hospitalization rate. METHODS: In this prospective study, all COPD patients that completed a comprehensive pulmonary rehabilitation program (PRP) between June 2006 and December 2012 were included. Self-reported exacerbation and hospitalization frequency 1 year before PR was retrospectively recorded. During the year following PR, exacerbation and hospitalization frequency was recorded with questionnaires. RESULTS: For 343 patients, complete information on exacerbation and hospitalization rate was obtained. The mean number of exacerbations decreased significantly after participating in a PRP by 1.37 exacerbations/year (95% confidence interval to 1.717) from 4.56±3.26 exacerbations in the year preceding PR to 3.18±2.53 in the year following PR (P<0.0005). The number of hospitalizations due to exacerbations decreased significantly by 0.68 hospitalizations/year (95% confidence interval to 0.903) from 1.48±1.84 in the year preceding PR to 0.80±1.31 hospitalizations/year in the year following PR (P<0.0005). The proportion of patients with a frequent exacerbation type (more than two exacerbations/year) was reduced by 24%. Multivariate regression analysis to explore determinants that might predict reduction in exacerbation frequency or change in exacerbation pattern did not reveal clinically useful predictors, although patients with more exacerbations before PR had the highest potential for reduction. CONCLUSION: In a large population of severely impaired COPD patients with high exacerbation rates, a significant reduction in exacerbation and hospitalization frequency was observed after participation in a comprehensive PRP. PMID: Longgeneeskunde 143

145 Mondziekten, Kaak- en Aangezichtschirurgie Kerngegevens 6 kaakchirurgen: dr. J.E. (Eelco) Bergsma, J.T.M. (Jan) van Gemert, dr. P.J.J (Peter) Gooris, E. (Eric) van Hooft, dr. G. (Gertjan) Mensink, dr. A.B.E. (Bert) Voûte Waarnemend kaakchirurg (0,4 fte) Arts-assistenten in opleiding (2 fte) Arts-assistenten niet in opleiding (0,4 fte) Subspecialismen: dento-alveolaire chirurgie, implantologie, orthognatische chirurgie; oncologie; reconstructieve chirurgie; traumatologie; orale pathologie; orbitopathie; aangezichtschirurgie; kaakgewrichtspathologie Samenvattingen gepubliceerde artikelen Mensink G, Gooris PJ, Bergsma JE, van Hooft E, van Merkesteyn JP. Influence of BSSO surgical technique on postoperative inferior alveolar nerve hypoesthesia: A systematic review of the literature. J Craniomaxillofac Surg Sep;42(6): Epub 2014 Jan 14. OBJECTIVE: The aim of this study was to evaluate the influence of different splitting techniques, namely, mallet and chisel versus spreading and prying, used during bilateral sagittal split osteotomy (BSSO) on postoperative hypoesthesia outcomes. STUDY DESIGN: We systematically searched the PubMed and Cochrane databases (from January 1957 to November 2012) for studies that examined postoperative neurosensory disturbance (NSD) of the inferior alveolar nerve (IAN) after BSSO. RESULTS: Our initial PubMed search identified 673 studies, of which, 14 met our inclusion criteria. From these 14 studies, 3 groups were defined: (1) no chisel use (4.1% NSD/site), (2) undefined chisel use (18.4% NSD/site), and (3) explicit chisel use along the buccal cortex (37.3% NSD/site). CONCLUSION: Study heterogeneity and a frequent lack of surgical detail impeded our ability to make precise comparisons between studies. However, the group of studies explicitly describing chisel use along the buccal cortex showed the highest incidence of NSD. Moreover, comparison of the study that did not use chisels with the 2 studies that explicitly described chisel use revealed a possible disadvantage of the mallet and chisel group (4.1% versus 37.3% NSD/site). These results suggest that chisel use increases NSD risk after BSSO. Copyright 2014 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved. PMID: Publicaties Medische Staf

146 Gooris PJ, Zijlmans JC, Bergsma JE, Mensink G. A Case of Mental Nerve Paresthesia Due to Dynamic Compression of Alveolar Inferior Nerve Along an Elongated Styloid Process. J Oral Maxillofac Surg Jul;72(7):1267.e1-7. Epub 2014 Jan 16. Spontaneous paresthesia of the mental nerve is considered an ominous clinical sign. Mental nerve paresthesia has also been referred to as numb chin syndrome. Several potentially different factors have been investigated for their role in interfering with the inferior alveolar nerve (IAN) and causing mental nerve neuropathy. In the present case, the patient had an elongated calcified styloid process that we hypothesized had caused IAN irritation during mandibular movement. This eventually resulted in progressive loss of sensation in the mental nerve region. To our knowledge, this dynamic irritation, with complete recovery after resection of the styloid process, has not been previously reported. PMID: Mensink G, Gooris P, Mulder F, Gooris-Kuipers C, van Merkesteyn R. Experiencing your own orthognathic surgery: A personal case report. Angle Orthod Nov 4. [Epub ahead of print]. Abstract There has been much research on minimizing the side effects of orthognathic surgery. However, there are very few doctors and researchers who themselves have undergone this surgery. This case report describes the findings of a maxillofacial surgeon who underwent combined orthodontic and orthognathic treatment for correction of Class II malocclusion. In March 2012, the surgeon was referred to an orthodontist, and an orthodontic examination revealed a Class II, division 2, malocclusion with a traumatic palatal bite and attrition of the lower front teeth. The patient underwent alignment of the upper and lower arches, followed by a bilateral sagittal split osteotomy. During this treatment, he made many interesting observations and learned much as a patient, which can have implications in improving the outcomes and quality of care for patients receiving such treatment. Thus, this case report aims to provide a critical perspective of the surgical procedure and treatment from the viewpoint of a maxillofacial surgeon who himself experienced the surgery as a patient. PMID: Van Bakelen NB, Boermans BD, Buijs GJ, Jansma J, Pruim GJ, Hoppenreijs TJ, Bergsma JE, Stegenga B, Bos RR. Comparison of the long-term skeletal stability between a biodegradable and a titanium fixation system following BSSO advancement - a cohort study based on a multicenter randomised controlled trial. Br J Oral Maxillofac Surg Oct;52(8): Epub 2014 Aug 16. Biodegradable fixation systems could reduce or eliminate the problems associated with removal of titanium plates. A multicenter randomised controlled trial (RCT) was performed in the Netherlands from December 2006-July 2009, and originally 230 injured and orthognathic patients were included. The patients were randomly assigned to either a titanium control group (KLS Martin) or to a biodegradable test group (Inion CPS). The aim of the present study was to Mondziekten, Kaak- en Aangezichtschirurgie 145

147 compare the long-term skeletal stability of advancement bilateral sagittal split osteotomies (BSSO) of a biodegradable system and a titanium system. Only patients from the original RCT who were at least 18 years old and who had a BSSO advancement osteotomy were included. Those who had simultaneous Le Fort I osteotomy or genioplasty were excluded. Analysis of skeletal stability was made by digital tracing of lateral cephalograms. Long-term skeletal stability in BSSO advancement did not differ significantly between patients treated with biodegradable plates and screws and those treated with titanium plates and screws. Given the comparable amount of relapse, the general use of Inion CPS in the treatment of BSSO advancement should not be discouraged. On the basis of other properties a total picture of the clinical use can be obtained; the short-term stability, the intraoperative switches, the number of plates removed and cost-effectiveness. Trial registration of original RCT: ISRCTN PMID: Verweij JP, Houppermans PN, Mensink G, van Merkesteyn JP. Removal of bicortical screws and other osteosynthesis material that caused symptoms after bilateral sagittal split osteotomy: a retrospective study of 251 patients, and review of published papers. Br J Oral Maxillofac Surg Oct;52(8): Epub 2014 Jun 19. Rigid fixation with either bicortical screws or miniplates is the current standard way to stabilise the mandibular segments after bilateral sagittal split osteotomy (BSSO). Both techniques are widely used and the superiority of one or other method is still debatable. One complication of rigid fixation is the need to remove the osteosynthesis material because of associated complaints. The main aim of this retrospective study was to analyse how often we needed to remove bicortical screws because they caused symptoms after BSSO in our clinic. Review of other published papers also enabled us to investigate the reported rates of removal of screws and miniplates at other centres. The mean (SD) duration of follow-up of 251 patients (502 sites) was 432 (172) days, and the number of bicortical screws removed in our clinic was 14/486 sites (3%). Other methods of fixation were used at 16 sites. We found no significant association between removal of bicortical screws and age, sex, presence of third molars, or bad splits. Published rates of removal of bicortical screws and miniplates are 3.1%-7.2% and 6.6%-22.2% per site, respectively. These findings show that fixation with bicortical screws after BSSO is associated with a low rate of removal of osteosynthesis material. Reported incidences imply a lower rate of removal for screws than for miniplates. PMID: Publicaties Medische Staf

148 Verweij JP, Mensink G, Fiocco M, van Merkesteyn JP. Presence of mandibular third molars during bilateral sagittal split osteotomy increases the possibility of bad split but not the risk of other post-operative complications. J Craniomaxillofac Surg Oct;42(7):e Epub 2014 Apr 4. Timing of third molar removal in relation to bilateral sagittal split osteotomy (BSSO) is controversial, especially with regard to post-operative complications. We investigated the influence of mandibular third molar presence on complications after BSSO with sagittal splitters and separators, by a retrospective record review of 251 patients (502 surgical sites). Mandibular third molars were present during surgery at 169 sites and removed at least 6 months preoperatively in 333 sites. Bad splits occurred at 3.0% (5/169) and 1.5% (5/333) of the respective sites. Presence of mandibular third molars significantly increased the risk of bad splits (OR 1.08, CI , p < 0.01). The mean incidences of permanent neurosensory disturbances, post-operative infection, and symptomatic removal of the osteosynthesis material were 5.4% (OR, 0.89; 95% CI, ; p = 0.06), 8.2% (OR, 1.09; 95% CI, ; p = 0.63), and 3.4% (OR, 0.97; 95% CI, ; p = 0.35) per site, respectively, without a significant influence of mandibular third molar status. In conclusion, the presence of mandibular third molars during surgery increases the possibility of bad split but does not affect the risk of other complications. Therefore, third molars can be removed concomitantly with BSSO using sagittal splitters and separators. PMID: Mondziekten, Kaak- en Aangezichtschirurgie 147

149 Neurologie / Neurochirurgie Kerngegevens 15 neurologen: R. (Ron) van Dijl,, M.W.J. (Jiske) Fermont, R.J. (Robert-Jan) de Graaf, dr. N. (Naghmeh) Jafari (vanaf 2015), dr. I.A.W. (Irene) Kotsopoulos, H.B.M. (Hans) van Lieshout, dr. D. (David) van Nieuwenhuizen, dr. A.G.W. (Anouk) van Norden, C.A.M.M. (Casper) van Oers, M.J.M. (Michel) Remmers, dr. J.F. (Johanneke) de Rijk - van Andel, J-P.M. (Jan-Pieter) Stroy, H.B.C. (Henk) Verbiest, dr. J.E. (Jasper) Visser, dr. J.C.M. (Jan) Zijlmans 2 neurologen/kinderneurologen: dr. I.A.W. (Irene) Kotsopoulos, dr. J.F. (Johanneke) de Rijk - van Andel 2 neurochirurgen vanuit St. Elisabeth Ziekenhuis verbonden aan zorgkern: dr. P.R.A.M. (Paul) Depauw, dr. B. (Bram) van der Pol 7 assistenten niet in opleiding (7,39 fte) 3 research verpleegkundigen Subspecialismen: kinderneurologie, parkinson(ismen), dementiesyndromen, multiple sclerose, CVA, neuro-oncologie Samenvattingen gepubliceerde artikelen Arntz RM, van Alebeek ME, Synhaeve NE, Brouwers PJ, van Dijk GW, Gons RA, den Heijer T, de Kort PL, de Laat KF, van Norden AG, Vermeer SE, van der Vlugt MJ, Kessels RP, van Dijk EJ, de Leeuw FE. Observational Dutch Young Symptomatic StrokE study (ODYSSEY): study rationale and protocol of a multicentre prospective cohort study. BMC Neurol Mar 22;14:55. BACKGROUND: The proportion of strokes occurring in younger adults has been rising over the past decade. Due to the far longer life expectancy in the young, stroke in this group has an even larger socio-economic impact. However, information on etiology and prognosis remains scarce. METHODS/DESIGN: ODYSSEY is a multicentre prospective cohort study on the prognosis and risk factors of patients with a first-ever TIA, ischemic stroke or intracerebral hemorrhage aged 18 to 49 years. Our aim is to include 1500 patients. Primary outcome will be all cause mortality and risk of recurrent vascular events. Secondary outcome will be the risk of post-stroke epilepsy and cognitive impairment. Patients will complete structured questionnaires on outcome measures and risk factors. Both well-documented and less well-documented risk factors and potentially acute trigger factors will be investigated. Patients will be followed every 6 months for at least 3 years. In addition, an extensive neuropsychological assessment will be administered both at baseline and 1 year after the stroke/tia. Furthermore we will include 250 stroke-free controls, who will complete baseline assessment and one neuropsychological assessment. DISCUSSION: ODYSSEY is designed to prospectively determine prognosis after a young stroke and get more insight into etiology of patients with a TIA, ischemic stroke and intracerebral hemorrhage in patients aged 18 to 49 years old in a large sample size. PMID: Publicaties Medische Staf

150 Göttle M, Prudente CN, Fu R, Sutcliffe D, Pang H, Cooper D, Veledar E, Glass JD, Gearing M, Visser JE, Jinnah HA. Loss of dopamine phenotype among midbrain neurons in Lesch-Nyhan disease. Ann Neurol Jul;76(1): Epub 2014 Jun 20. OBJECTIVE: Lesch-Nyhan disease (LND) is caused by congenital deficiency of the purine recycling enzyme, hypoxanthine-guanine phosphoribosyltransferase (HGprt). Affected patients have a peculiar neurobehavioral syndrome linked with reductions of dopamine in the basal ganglia. The purpose of the current studies was to determine the anatomical basis for the reduced dopamine in human brain specimens collected at autopsy. METHODS: Histopathological studies were conducted using autopsy tissue from 5 LND cases and 6 controls. Specific findings were replicated in brain tissue from an HGprt-deficient knockout mouse using immunoblots, and in a cell model of HGprt deficiency by flow-activated cell sorting (FACS). RESULTS: Extensive histological studies of the LND brains revealed no signs suggestive of a degenerative process or other consistent abnormalities in any brain region. However, neurons of the substantia nigra from the LND cases showed reduced melanization and reduced immunoreactivity for tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis. In the HGprt-deficient mouse model, immunohistochemical stains for TH revealed no obvious loss of midbrain dopamine neurons, but quantitative immunoblots revealed reduced TH expression in the striatum. Finally, 10 independent HGprt-deficient mouse MN9D neuroblastoma lines showed no signs of impaired viability, but FACS revealed significantly reduced TH immunoreactivity compared to the control parent line. INTERPRETATION: These results reveal an unusual phenomenon in which the neurochemical phenotype of dopaminergic neurons is not linked with a degenerative process. They suggest an important relationship between purine recycling pathways and the neurochemical integrity of the dopaminergic phenotype. PMID: Gooris PJ, Zijlmans JC, Bergsma JE, Mensink G. A Case of Mental Nerve Paresthesia Due to Dynamic Compression of Alveolar Inferior Nerve Along an Elongated Styloid Process. J Oral Maxillofac Surg Jul;72(7):1267.e1-7. Epub 2014 Jan 16. Spontaneous paresthesia of the mental nerve is considered an ominous clinical sign. Mental nerve paresthesia has also been referred to as numb chin syndrome. Several potentially different factors have been investigated for their role in interfering with the inferior alveolar nerve (IAN) and causing mental nerve neuropathy. In the present case, the patient had an elongated calcified styloid process that we hypothesized had caused IAN irritation during mandibular movement. This eventually resulted in progressive loss of sensation in the mental nerve region. To our knowledge, this dynamic irritation, with complete recovery after resection of the styloid process, has not been previously reported. PMID: Neurologie / Neurochirurgie 149

151 Oogheelkunde Kerngegevens 13 oogartsen: G.A. (Bert) Bakker, dr. T.P. (Thomas) Colen, dr. B.T.H. (Bart) van Dooren, G. (Trudy) de Grip, L.J.C. (Lidy) Hartman, O. (Olivera) Jovanovic, M.J.C. (Marjolein) Kooijman-de Groot I.L.A. (Irene) van Liempt, dr. G.L. (Giorgio) Porro, dr. N.J. (Nic) Reus, O.A.M. (Odette) Tigchelaar-Besling, dr. J.J.M. (Jacqueline) Willemse-Assink, C. (Christien) Weenen 3 assistenten in opleiding (2,78 fte) 1 assistent niet in opleiding (1 fte) Subspecialismen: cornea, refractiechirurgie en laserbehandeling, traanwegchirurgie, ooglidchirurgie, Graves, glaucoom, medische retina, kinderoogheelkunde, neurophthalmologie, strabismus en ophthalmogenetica Samenvattingen gepubliceerde artikelen Koenraads Y, van der Linden DC, van Schooneveld MM, Imhof SM, Gosselaar PH, Porro GL, Braun KP. Visual function and compensatory mechanisms for hemianopia after hemispherectomy in children. Epilepsia Jun;55(6): Epub 2014 Apr 22. OBJECTIVE: Little is known about the functional visual outcome of children after hemispherectomy. Several case reports have described an anomalous head posture (AHP) and exotropia (XT) contralateral to the side of early brain damage, as possible compensatory mechanisms (CMs) for homonymous hemianopia (HH). The aim of this study was to determine visual outcome and the prevalence of such CMs in hemispherectomized children. METHODS: Patient files from all children who underwent hemispherectomy and had a postoperative ophthalmologic examination in the University Medical Center (UMC) Utrecht up to October 2012 were retrospectively reviewed. Preoperative and postoperative clinical information on visual fixation, visual acuity, visual fields, optic discs, head posturing, ocular alignment, and cognitive development was collected. Clinical characteristics were compared between children who developed CMs and those who did not. RESULTS: Forty-five children (21 male) underwent a hemispherectomy (22 right) at a median age of 2.1 years. Median ophthalmologic follow-up was 2.3 years. After hemispherectomy, visual fixation was present in all children, and 87% of the examined children had a normal visual acuity or a mild visual impairment. All children who underwent a visual field measurement had an HH. Anomalous head posturing and continuous or intermittent XT contralateral to the side of hemispherectomy were found in 53% and 38% of children, respectively. Children with CMs had more frequently right-sided surgery and earlier onset of epilepsy, and they tended to be younger when they underwent hemispherectomy than children without. SIGNIFICANCE: Despite HH, the majority of children who undergo hemispherectomy have a good visual outcome. Furthermore, they frequently develop AHP and continuous or intermittent XT contralateral to the hemispherectomy as part of a coping strategy to optimize the functional 150 Publicaties Medische Staf

152 visual field. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here. PMID: Koenraads Y, Braun KP, van der Linden DC, Imhof SM, Porro GL. Perimetry in Young and Neurologically Impaired Children: The Behavioral Visual Field (BEFIE) Screening Test Revisited. JAMA Ophthalmol Dec 26. [Epub ahead of print]. IMPORTANCE: Visual field examination in young or neurologically impaired children is a challenge. As a result, the Behavioral Visual Field (BEFIE) Screening Test was developed in OBJECTIVES: To evaluate the applicability of the BEFIE test in a large population of young or neurologically impaired children, its reliability and consistency of findings across time, and its potential diagnostic value compared with standard conventional perimetry. DESIGN, SETTING, AND PARTICIPANTS: The BEFIE tests were performed at an academic tertiary center and measured the peripheral visual field extension in degrees by observing an individual s response to a stimulus on a graded arc that moved from the periphery to the center of the visual field along different meridians. Patient files from all children who underwent this test were retrospectively analyzed. In total, 1788 BEFIE tests were performed in 835 children (median age, 3.4 years). MAIN OUTCOMES AND MEASURES: Reliability and results of all tests were longitudinally evaluated. The diagnostic value of the BEFIE test was assessed by comparing monocular BEFIE test results with those of standard conventional perimetry in children who underwent both. RESULTS: Of 1788 tests, 74% (95% CI, 72%-76%) were considered reliable from the age of 4 months and older, with increasing success with higher ages; 56% reliable in children younger than 1 year; 71% reliable in children between 1 and 2 years; and more than 75% reliable in children 2 years and older (Spearman r = 0.506; P =.11). Peripheral visual field defects were found in 28% (95% CI, 25%-31%) of all first reliable tests. In 75% of children who underwent serial testing, results were consistent and there were good explanations in the case of discrepancies. Comparison of monocular BEFIE tests with standard conventional perimetry results in 147 eyes yielded a positive predictive value of 98% (95% CI, 94%-100%), negative predictive value of 66% (95% CI, 56%-75%), specificity of 98% (95% CI, 95%-100%), sensitivity of 60% (95% CI, 50%-71%), and superior sensitivity of 80% (95% CI, 70%-91%) when only absolute peripheral visual field defects at standard conventional perimetry were accounted for. CONCLUSIONS AND RELEVANCE: These data suggest that the BEFIE test is a valuable tool to detect peripheral visual field defects when standard conventional perimetry cannot be performed in young or neurologically impaired children. PMID: Oogheelkunde 151

153 Orthopedie Kerngegevens 15 orthopedisch chirurgen: dr. A. Beumer (Annechien), A.F.A. (Ad) van Beurden, R. (Ronald) Boer, dr. S.B.T. (Stefan) Bolder, M.P.J. (Maaike) van den Borne, L.H.G.J. (Leon) Elmans, dr. D. (Denise) Eygendaal, dr. R.C.I. (Rutger) van Geenen, W.H.J.C. (Wim) van Heeswijk, E.A. (Eric) Hoebink, J.A.A.M. (Joost) van den Hout, A.J.P. (Peter) Joosten, dr. A.F.C.M. (Sjors) Moonen, dr. B. (Bertram) The (per 1 sept. 2014), dr. R. (Robert) Wagenmakers 3 assistenten niet in opleiding (2,57 fte) 3 assistent in opleiding (2,92 fte) 1 fellow orthopedie (1,65 fte) 3 verpleegkundig specialisten MA-NP, waarvan 1 in opleiding Subspecialismen: wervelkolom, kinderorthopedie, bovenste extremiteit, onderste extremiteit, traumatologie, sport orthopedie Samenvattingen gepubliceerde artikelen Thoomes-de Graaf M, Scholten-Peeters GG, Duijn E, Karel YH, van den Borne MP, Beumer A, Ottenheijm RP, Dinant GJ, Tetteroo E, Lucas C, Koes BW, Verhagen AP. Inter-professional agreement of ultrasound-based diagnoses in patients with shoulder pain between physical therapists and radiologists in the Netherlands. Man Ther Oct;19(5): Epub 2014 May 14. STUDY DESIGN: Reliability study. OBJECTIVES: The aim of this study was to evaluate the interrater-reliability of the interpretation of diagnostic ultrasound in patients with shoulder pain between physical therapists and radiologists. BACKGROUND: Although physical therapists in The Netherlands increasingly use diagnostic ultrasound in clinical practice, there is no evidence available on its reliability. METHODS: A cohort study included patients with shoulder pain from primary care physiotherapy. Patients followed the usual diagnostic pathway of which diagnostic ultrasound could be a part. Patients that received diagnostic ultrasound also visited a radiologist within one week for a second one. Patients and radiologists were blinded for the diagnostic ultrasound diagnosis of the physical therapists. Agreement was assessed using Cohen s kappa statistics. Subgroup analysis was performed on education and experience. RESULTS: A total of 65 patients were enrolled and 13 physical therapists and 9 radiologists performed diagnostic ultrasound. We found substantial agreement (0.63 K) between physical therapists and radiologists on the assessment of full thickness tears. The overall kappa of all four diagnostic categories was 0.36, indicating fair agreement. The more experienced and highly trained physical therapists showed moderate agreement (0.43 K) compared to only slight agreement (0.17 and 0.09 K) from the less experienced and trained physical therapists with radiologists. 152 Publicaties Medische Staf

154 CONCLUSION: The reliability between physical therapists and radiologist on diagnostic ultrasound of shoulder patients in primary care is borderline substantial (Kappa = 0.63) for full thickness tears only. This level of reliability is relatively low when compared with the high reliability between radiologists. More experience and training of physical therapists may increase the reliability of diagnostic ultrasound. PMID: Van Heeswijk EJ, Beumer A, Eygendaal D. Injuries of elbow and forearm. In: Nuclear Medicine and Radiologic Imaging in Sports Injuries / Glaudemans AW, Dierckx RA, Gielen J, Zwerver H. (Eds.). Berlin; Heidelberg: Springer, ISBN Walenkamp MM, Goslings JC, Beumer A, Haverlag R, Leenhouts PA, Verleisdonk EJ, Liem RS, Sintenie JB, Bronkhorst MW, Winkelhagen J, Schep NW. Surgery versus conservative treatment in patients with type A distal radius fractures, a randomized controlled trial. BMC Musculoskelet Disord Mar 19;15(1):90. BACKGROUND: Fractures of the distal radius are common and account for an estimated 17% of all fractures diagnosed. Two-thirds of these fractures are displaced and require reduction. Although distal radius fractures, especially extra-articular fractures, are considered to be relatively harmless, inadequate treatment may result in impaired function of the wrist. Initial treatment according to Dutch guidelines consists of closed reduction and plaster immobilisation. If fracture redisplacement occurs, surgical treatment is recommended. Recently, the use of volar locking plates has become more popular. The aim of this study is to compare the functional outcome following surgical reduction and fixation with a volar locking plate with the functional outcome following closed reduction and plaster immobilisation in patients with displaced extraarticular distal radius fractures. DESIGN: This single blinded randomised controlled trial will randomise between open reduction and internal fixation with a volar locking plate (intervention group) and closed reduction followed by plaster immobilisation (control group). The study population will consist of all consecutive adult patients who are diagnosed with a displaced extra-articular distal radius fracture, which has been adequately reduced at the Emergency Department. The primary outcome (functional outcome) will be assessed by means of the Disability Arm Shoulder Hand Score (DASH). Secondary outcomes comprise the Patient-Rated Wrist Evaluation score (PRWE), quality of life, pain, range of motion, radiological parameters, complications and cross-overs. Since the treatment allocated involves a surgical procedure, randomisation status will not be blinded. However, the researcher assessing the outcome at one year will be unaware of the treatment allocation. In total, 90 patients will be included and this trial will require an estimated time of two years to complete and will be conducted in the Academic Medical Centre Amsterdam and its partners of the regional trauma care network. Orthopedie 153

155 DICUSSION: Ideally, patients would be randomised before any kind of treatment has been commenced. However, we deem it not patient-friendly to approach possible participants before adequate reduction has been obtained. TRIAL REGISTRATION: This study is registered at the Netherlands Trial Register (NTR3113) and was granted permission by the Medical Ethical Review Committee of the Academic Medical Centre on PMID: Beumer A, Lindau TR. Grip strength ratio: a grip strength measurement that correlates well with DASH score in different hand/wrist conditions. BMC Musculoskelet Disord Oct 6;15:336. BACKGROUND: Grip strength correlates with personal factors such as gender, age and nutritional status and has a good inter-rater reliability. It reflects fairly well how much people can use their hands.the Disabilities of the Arm, Shoulder and Hand (DASH) Outcome Measure 3 is a 30-item, self-report, questionnaire that reflects the patients opinion on their disability due to upper-limb disorders. We assessed if grip strength and grip strength ratio correlate with DASH score. METHODS: In 3 groups (20 healthy volunteers, 17 patients after distal radius fractures, 12 patients with different hand/wrist conditions) grip strength and DASH scores (items 1-21, and total) were assessed. To exclude personal factors grip strengths in the injured or non-dominant hand and grip strength ratios (grip strength in the injured or non-dominant hand divided by grip strength in the non-injured or dominant hand) were assessed too. Results were analyzed groups using Pearson Correlation Coefficients and with a multivariate ANOVA. RESULTS: Grip strength ratio was 0.97 in healthy volunteers, 0.52 in patients after distal radius fracture and 0.74 in patients with various other hand/wrist disorders.significant correlations were found between the grip strength ratio and DASH as well as DASH subsections in all groups and between DASH scores and grip strength in some. The correlations between the ratio of the grip strength (GSR) and DASH were much stronger than the correlation between grip strength and DASH. This emphasizes the value of the GSR. Age showed no correlation with grip strength ratio using a multivariate ANOVA. CONCLUSION: Grip strength ratio correlates well with the DASH score in different hand and wrist conditions. It is a valuable tool to assess patients that speak a different language and have problems with the non-dominant hand and probably easier to follow over time than the DASH score, which is time consuming to fill in and process. PMID: Publicaties Medische Staf

156 Spaans AJ, van Heeswijk EJ, Arnold DE, Beumer A. Foreign body reaction associated with polyethylene mesh interposition used for treatment of trapeziometacarpal osteoarthritis: report of 8 cases. J Hand Surg Am Oct;39(10): Epub 2014 Aug 27. PURPOSE: To report the incidence of foreign body reactions associated with placement of a polyethylene mesh implant in patients treated with trapiezectomy for trapeziometacarpal osteoarthritis. METHODS: Between November 2008 and September 2012, 70 hands in 66 adults with stage IV trapeziometacarpal osteoarthritis had a trapiezectomy with interposition of a spacer made of polyethylene terephthalate mesh (Anchois Ligastic, Orthomed SA, St Jeannet, France). Out of these 70 implants, 8 implants (11%) in 8 patients (mean age, 60 y; range, y) were removed because of persistent swelling, synovitis, and pain. RESULTS: The mean interval between primary and revision surgery was 14 (range, 5-27) months. Histological analysis in all cases showed a foreign body giant cell reaction. Two hands showed bone resorption or carpal bone cysts similar to silicone particle synovitis. The cysts resolved after implant removal and bone grafting. CONCLUSIONS: In the light of these results and the available literature, we recommend not using this material for interposition in the treatment of osteoarthritis of the trapeziometacarpal joint. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID: Kodde IF, Rahusen FT, Eygendaal D. Arthroscopic techniques in the elbow. In: Surgical Orthopaedics and Traumatology / George Bentley [ed.]. Berlin, Heidelberg: Springer-Verlag, ISBN: De Vos MJ, Verdonschot N, Luites JW, Anderson PG, Eygendaal D. Stable fixation of the IBP humeral component implanted without cement in total elbow replacement: a radiostereometric analysis study of 16 elbows at two-year follow-up. Bone Joint J Feb;96-B(2): We determined the short-term clinical outcome and migration within the bone of the humeral cementless component of the Instrumented Bone Preserving (IBP) total elbow replacement in a series of 16 patients. There were four men and 12 women with a mean age at operation of 63 years (40 to 81). Migration was calculated using radiostereometric analysis. There were no intra-operative complications and no revisions. At two-year follow-up, all patients showed a significant reduction in pain and functional improvement of the elbow (both p < 0.001). Although ten components (63%) showed movement or micromovement during the first six weeks, 14 (88%) were stable at one year post-operatively. Translation was primarily found in the proximal direction (median 0.3 mm (interquartile range (IQR) to 0.8); the major rotational Orthopedie 155

157 movement was an anterior tilt (median 0.7 (IQR 0.4 to 1.6 )). One malaligned component continued to migrate during the second year, and one component could not be followed beyond three months because migration had caused the markers to break off the prosthesis. This study shows promising early results for the cementless humeral component of the IBP total elbow replacement. All patients had a good clinical outcome, and most components stabilised within six months of the operation. PMID: De Vos MJ, Wagener ML, Verdonschot N, Eygendaal D. An extensive posterior approach of the elbow with osteotomy of the medial epicondyle. J Shoulder Elbow Surg Mar;23(3): BACKGROUND: This study describes a posterior approach to the elbow for placement of a total elbow prosthesis. METHODS: Release of the medial collateral ligament is achieved by performing an osteotomy of the medial epicondyle. This allows anatomic refixation of the origin of the medial collateral ligament. A description of the posterior approach is given. Standard radiographs were used to analyze the bone-to-bone refixation of the osteotomy of the medial epicondyle in 13 elbows. RESULTS: Radiographs showed proper bone healing in all elbows, with restoration of the anatomic origin of the medial collateral ligament. DISCUSSION: The described approach provides a good exposure of the elbow necessary for the placement of modern total elbow prostheses, without compromising the stability of the elbow. Refixation of stabilizing structures is relatively easy and results in an anatomic position of the ligaments. PMID: Kaas L, Eygendaal D. Regarding Ligamentous repair of acute lateral collateral ligament rupture of the elbow. J Shoulder Elbow Surg Apr;23(4):e94. No abstract available. Comment in: Response to Ligamentous repair of acute lateral collateral ligament rupture of the elbow. Kim BS, Park KH, Song HS, Park SY. J Shoulder Elbow Surg Apr; 23(4):e95. Epub 2014 Jan Publicaties Medische Staf

158 Comment on: Ligamentous repair of acute lateral collateral ligament rupture of the elbow. [J Shoulder Elbow Surg. 2013] PMID: Bruinsma W, Kodde I, de Muinck Keizer RJ, Kloen P, Lindenhovius AL, Vroemen JP, Haverlag R, van den Bekerom MP, Bolhuis HW, Bullens PH, Meylaerts SA, van der Zwaal P, Steller PE, Hageman M, Ring DC, den Hartog D, Hammacher ER, King GJ, Athwal GS, Faber KJ, Drosdowech D, Grewal R, Goslings JC, Schep NW, Eygendaal D. A randomized controlled trial of nonoperative treatment versus open reduction and internal fixation for stable, displaced, partial articular fractures of the radial head: the RAMBO trial. BMC Musculoskelet Disord May 6;15:147. BACKGROUND: The choice between operative or nonoperative treatment is questioned for partial articular fractures of the radial head that have at least 2 millimeters of articular step-off on at least one radiograph (defined as displaced), but less than 2 millimeter of gap between the fragments (defined as stable) and that are not associated with an elbow dislocation, interosseous ligament injury, or other fractures. These kinds of fractures are often classified as Mason type-2 fractures. Retrospective comparative studies suggest that operative treatment might be better than nonoperative treatment, but the long-term results of nonoperative treatment are very good. Most experts agree that problems like reduced range of motion, painful crepitation, nonunion or bony ankylosis are infrequent with both nonoperative and operative treatment of an isolated displaced partial articular fracture of the radial head, but determining which patients will have problems is difficult. A prospective, randomized comparison would help minimize bias and determine the balance between operative and nonoperative risks and benefits. METHODS/DESIGN: The RAMBO trial (Radial Head - Amsterdam - Amphia - Boston - Others) is an international prospective, randomized, multicenter trial. The primary objective of this study is to compare patient related outcome defined by the Disabilities of Arm, Shoulder and Hand (DASH) score twelve months after injury between operative and nonoperative treated patients. Adult patients with partial articular fractures of the radial head that comprise at least 1/3rd of the articular surface, have 2 millimeters of articular step-off but less than 2 millimeter of gap between the fragments will be enrolled. Secondary outcome measures will be the Mayo Elbow Performance Index (MEPI), the Oxford Elbow Score (OES), pain intensity through the Numeric Rating Scale, range of motion (flexion arc and rotational arc), radiographic appearance of the fracture (heterotopic ossification, radiocapitellar and ulnohumeral arthrosis, fracture healing, and signs of implant loosening or breakage) and adverse events (infection, nerve injury, secondary interventions) after one year. DISCUSSION: The successful completion of this trial will provide evidence on the best treatment for stable, displaced, partial articular fractures of the radial head. TRIAL REGISTRATION: The trial is registered at the Dutch Trial Register: NTR3413. PMID: PMCID: PMC Orthopedie 157

159 Luites JW, Wymenga AB, Blankevoort L, Eygendaal D, Verdonschot N. Accuracy of a computerassisted planning and placement system for anatomical femoral tunnel positioning in anterior cruciate ligament reconstruction. Int J Med Robot Dec;10(4): Epub 2013 Oct 24. BACKGROUND: Femoral tunnel positioning is a difficult, but important factor in successful anterior cruciate ligament (ACL) reconstruction. Computer navigation can improve the anatomical planning procedure besides the tunnel placement procedure. METHODS: The accuracy of the computer-assisted femoral tunnel positioning method for anatomical double bundle ACL-reconstruction with a three-dimensional template was determined with respect to both aspects for AM and PL bundles in 12 cadaveric knees. RESULTS: The accuracy of the total tunnel positioning procedure was 2.7 mm (AM) and 3.2 mm (PL). These values consisted of the accuracies for planning (AM:2.9 mm; PL:3.2 mm) and for placement (about 0.4 mm). The template showed a systematic bias for the PL-position. CONCLUSIONS: The computer-assisted templating method showed high accuracy for tunnel placement and has promising capacity for application in anatomical tunnel planning. Improvement of the template will result in an accurate and robust navigation system for femoral tunnel positioning in ACL-reconstruction. PMID: Heijink A, Morrey BF, Eygendaal D. Radiocapitellar prosthetic arthroplasty: a report of 6 cases and review of the literature. J Shoulder Elbow Surg Jun;23(6): Epub 2014 Apr 13. BACKGROUND: Radiocapitellar prosthetic arthroplasty has recently been introduced to treat isolated degenerative arthritis of the radiocapitellar joint. Although this procedure is conceptually attractive and sound in situations in which radial head resection is inadequate, clinical experience is still limited. Its role in the treatment of isolated radiocapitellar degenerative arthritis in the ligamentous-intact elbow and forearm is not yet defined. Our purpose was to report the short-term results of 6 patients who were treated by radiocapitellar prosthetic arthroplasty for isolated radiocapitellar degenerative arthritis in the ligamentous-intact elbow, as well as to provide a review of the literature. METHODS: Six patients were treated by radiocapitellar prosthetic arthroplasty for isolated degenerative arthritis of the radiocapitellar joint in the ligamentous-intact elbow. Their medical records were reviewed, and each patient was seen in the office. The mean follow-up period was 50 months (range, months). RESULTS: The implant survival rate was 100%. Pain improved in all patients and all patients were satisfied. The mean flexion-extension arc increased from 98 (range, ) to 110 (range, ) (P =.17), and the mean pronation-supination arc increased from 133 (range, ) to 143 (range, ) (P =.34). The mean Disabilities of the Arm, Shoulder and Hand score was Publicaties Medische Staf

160 (range, ). According to the Mayo Elbow Performance Score, there were 3 excellent and 3 good results. CONCLUSION: The short-term follow-up results of radiocapitellar prosthetic arthroplasty for isolated radiocapitellar degenerative arthritis in the ligamentous-intact elbow and forearm seem favorable. LEVEL OF EVIDENCE: Level IV, case series, treatment study. PMID: Van den Bekerom MP, van Hooft MA, Eygendaal D. Osteoid osteoma of the elbow mimicking hemophilic arthropathy. World J Clin Cases Apr 16;2(4): A case of osteoid osteoma of the elbow in a patient with hemophilia A is described. This male patient presented with chronic and nocturnal pain of the left elbow which was alleviated with acetaminophen. Besides pain, he also complained of stiffness. Before these complaints, he had recurrent bleedings in the elbow because of hemophilia. A delayed diagnosis of osteoid osteoma in the proximal part of the left ulna was established by a bone scan and a multislice spiral computed tomography (CT) scan. The lesion was surgically removed under CT-guidance. The histopathological analyses did not show specific features of osteoid osteoma. Two months after the operation, the complaints decreased and the range of motion of the left elbow improved. A diagnosis of osteoid osteoma of the elbow should be considered in young adult patients with persistent elbow pain and histological confirmation is not always necessary. PMID: Van den Bekerom MP, Eygendaal D. Posterior elbow problems in the overhead athlete. Sports Med Arthrosc Sep;22(3): The overhead athlete is defined as an athlete who uses his/her hand in an overhead position. The motion in the overhead athlete is a highly skilled movement performed at extremely high velocity, which requires flexibility, muscular strength, coordination, synchronicity, and neuromuscular control of the whole body. In this overview, we will discuss the most common pathologies seen at the posterior side of the elbow such as posteromedial impingement, proximal ulnar stress fractures, and triceps pathology. Specific nonsurgical and operative treatment guidelines for the overhead athlete s elbow are also discussed. PMID: Orthopedie 159

161 Van den Bekerom MP, Doornberg JN, Eygendaal D. Letter to the editor: anconeus interposition arthroplasty: mid- to long-term results. Clin Orthop Relat Res Nov;472(11): Epub 2014 Aug 12. No abstract available. PMID: Van den Bekerom MP, Kodde IF, Aster A, Bleys RL, Eygendaal D. Clinical relevance of distal biceps insertional and footprint anatomy. Knee Surg Sports Traumatol Arthrosc Sep 18. [Epub ahead of print]. PURPOSE: The aim of this review was to present an overview, based on a literature search, of surgical anatomy for distal biceps tendon repairs, based on the current literature. METHODS: A narrative review was performed using Pubmed/Medline using key words: Search terms were distal biceps, insertional, and anatomy. RESULTS: Last decade, the interest in both reconstruction techniques, as well as surgical anatomy of the distal biceps tendon, has increased. The insights into various aspects of distal biceps tendon anatomy (two tendons, bicipital tuberosity, lacertus fibrosis, bicipital-radial bursa, posterior interosseous nerve, and lateral antebrachial cutaneous nerve) have evolved significantly in the last years. CONCLUSION: Thorough knowledge of the anatomy is essential for the surgeon in order to understand the biomechanics of rupture and reconstruction of the distal biceps tendon and to avoid injuries of the nerves. Some tips and tricks are provided, and some pitfalls were described to avoid complications and optimize surgical outcome. LEVEL OF EVIDENCE: IV. PMID: Arrigoni P, van Tongel A, Eygendaal D, Adamczyk G, Pederzini L. Elbow Arthroscopy: From Basic to Advance. In: ESSKA Instructional Course Lecture Book. Berlin; Heidelberg: Springer, Chapter 4: ISBN Tosti R, Ilyas AM, Mellema JJ, Guitton TG, Ring D; Science of Variation Group [Eygendaal D et al...]. Interobserver variability in the treatment of little finger metacarpal neck fractures. J Hand Surg Am Sep;39(9): Epub 2014 Jul 14. PURPOSE: To address the null hypothesis that surgeons shown radiographs of little finger 160 Publicaties Medische Staf

162 metacarpal neck fractures with measured fracture angulation would recommend surgery as often as surgeons shown unmarked radiographs. METHODS: Members of the Science of Variation Group, an international collaboration of fully trained orthopedic and trauma surgeons, were asked to review 20 little finger metacarpal neck fracture cases, which included a vignette and 3 high-quality radiographs. Members were then randomized to review radiographs with or without measured fracture angulation on the lateral view and select operative or nonoperative management. RESULTS: Surgeons shown radiographs with measured angulation were more likely to recommend surgery, and there was less variability among these surgeons, particularly for fractures with less angular deformity. CONCLUSIONS: Measured fracture angulation has a small but significant influence on treatment recommendations for little finger metacarpal neck fractures. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic III. PMID: Bruinsma WE, Guitton T, Ring D; Science of Variation Group [Eygendaal D et al...]. Radiographic loss of contact between radial head fracture fragments is moderately reliable. Clin Orthop Relat Res Jul;472(7): BACKGROUND: Loss of contact between radial head fracture fragments is strongly associated with other elbow or forearm injuries. If this finding has adequate interobserver reliability, it could help examiners identify and treat associated ligament injuries and fractures (eg, forearm interosseous ligament injury or elbow dislocation). QUESTIONS/PURPOSES: (1) What is the interobserver agreement on radiographic loss of contact between radial head fracture fragments? (2) Are there factors associated with the observer such as location of practice or subspecialization that increase interobserver reliability? METHODS: Fully trained practicing orthopaedic and trauma surgeons from around the world evaluated 27 anteroposterior and lateral radiographs of radial head fractures on a web-based platform for the following characteristics: (1) loss of contact between at least one radial head fracture fragment and the remaining radial head and neck; (2) a gap between fragments of 2 mm or greater; (3) anticipated fracture instability (mobility) on operative exposure; (4) anticipated associated ligament injuries; and (5) recommendation for treatment. Agreement among observers was measured using the multirater kappa measure. Kappas for various observer characteristics were compared using 95% confidence intervals. RESULTS: The overall interobserver agreement was moderate (range, ) for each question except associated ligament injury, which was fair (0.33). Shoulder and elbow surgeons Orthopedie 161

163 had substantial agreement (range, ) in many areas, but kappas were generally in the moderate range ( ) based on number of years in practice, radial head fractures treated per year, and trainee supervision. CONCLUSIONS: Radiographic signs of radial head fracture instability such as loss of contact have moderate reliability. This characteristic seems clinically useful, because loss of contact between at least one radial head fracture fragment and the remaining radial head and neck is strongly associated with associated ligament injury or other fractures. LEVEL OF EVIDENCE: Level III, diagnostic study. See Guidelines for Authors for a complete description of levels of evidence. PMID: PMCID: PMC Keijsers R, Eygendaal D, van den Bekerom MP. Should we really abandon PRP in the treatment of lateral epicondylar tendinopathy? BJSM Blog oct. In response to: Robert-Jan de Vos, Johann Windt, Adam Weir. Strong evidence against platelet-rich plasma injections for chronic lateral epicondylar tendinopathy: a systematic review. Br J Sports Med. 2014;48(12): Keijsers R, Eygendaal D, van den Bekerom MP. Letter to the editor in response to review by De Vos, Windt and Weir. BJSM Blog dec. Common ground and continued debate: further response to: Strong evidence against platelet-rich plasma injections for chronic lateral epicondylar tendinopathy: a systematic review. De Vos RJ, Windt J, Weir A. Br J Sports Med. 2014;48(12): Kievit AJ, van Geenen RC, Kuijer PP, Pahlplatz TM, Blankevoort L, Schafroth MU. Total knee arthroplasty and the unforeseen impact on return to work: a cross-sectional multicenter survey. J Arthroplasty Jun;29(6): Epub 2014 Jan 10. The number of patients receiving a TKA during working life is increasing but little is known about the impact of TKA on patients reintegration into the workplace. In this cross-sectional survey it was found that 173 of 480 responders worked within 2 years prior to surgery. Sixty-three percent of the working patients stopped within two weeks prior to surgery and 102 patients returned within 6 months. One third never returned to work. Activities that most improved were operating foot pedals, operating vehicles, standing and walking on level terrain. Activities that least improved were kneeling, crouching and clambering. Fifty patients scored 5 or less on the 162 Publicaties Medische Staf

164 Work Ability Index. Thirty patients were dissatisfied. TKA significantly, but unequally, reduces difficulties in carrying out knee-burdening work activities. PMID: Ten Brinke B, de Haan LJ, Koenraadt KL, van Geenen RC. Medial femoral condyle fracture as an intraoperative complication of Oxford unicompartmental knee replacement. Knee Surg Sports Traumatol Arthrosc Dec 6. [Epub ahead of print]. Oxford unicompartmental knee replacement (OUKR) is associated with a low perioperative complication rate. This case report describes a periprosthetic fracture of the medial femoral condyle that occurred during an OUKR. The patient was treated with a non-weight-bearing long leg cast for 6 weeks. Afterwards, the fracture had healed, and 3 months postoperatively, there was a full range of motion. Factors leading to this complication could be the impaction force or direction, or a diminished load resistance of the distal femur. Minimally displaced coronal periprosthetic fractures after OUKR can be managed conservatively without residual functional impairment. LEVEL OF EVIDENCE: Case report, Level IV. PMID: Hoebink E, Journée H, Rácz I, Berends H, van Hal C. Evoked movements in transcranial electrical stimulation on 4 locations of the body at different stimulation electrode montages and stimulation paradigms. Clin Neurophysiol may;125(5):e16. INTRODUCTION: Muscle contraction from transcranial electrical stimulation (TES) induces seismic potentials: smep. These movements may be of discomfort to the surgeon or address safety issues. In this study smeps at the chin, occiput, at mid thoracic and thoracic-lumbar levels are studied at single and multipulse TES with 2 TES montage pairs. METHODS: Eight patients (5f/3 m, 22 ± 12 y) underwent TES-mMEP monitoring during spinal deformity surgery. smeps were recorded by 2-vector accelero transducers on 4 locations during the set-up procedure for TES-mMEP monitoring at the selected TES voltage for monitoring. The smepampl vector pairs were summed before analysis. Single and multi-pulse trains (1 or 5 ppt) TES was performed at Cz- Fz and C3-C4 montages. RESULTS: At CzFz (Cz anode), the latencies increase from chin and occiput to mid thoracic and thoraco-lumbar from 3.8 ± 0.6 ms to 12.4 ± 2.3 ms when 1 ppt is used. smepampl decrease from 1.7 ± 1.3 mv (chin) to ± mv (thoraco-lumbar). When using 5 ppt, latencies increase from 4.1 ± 0.6 ms (chin) to 12.9 ± 2.30 ms (thoraco-lumbar). smepampl decrease from 2.3 ± 1.0 mv (chin) to 0.05 ± 0.03 mv (thoraco-lumbar). At C3C4, latencies are similar to CzFz. smepampl at the chin is higher at C3C4 than at CzFz, where smepampl at the chin is 2.0 ± 1.6 mv and at thoraco- Orthopedie 163

165 lumbar level ± mv for 1ppt, and 2.9 ± 2.1 (chin) to 0.42 ± 0.44(thoraco-lumbar) for 55pt. The higher smep amplitudes at the chin could result from stronger electrical fields from the C3/C4 electrodes close to the masseter muscle. CONCLUSION: Because of the short latency times at 1 and 5 ppt, the movements of the jaw and head most likely result from extracranial stimulation, while smepampl at thoracic and lumbar locations apparently originate from the cortico-spinal route. Langeveld-Wildschut A, Joosten P, Nobruis O, Hulsmann A. Een goede maatschap, een goede specialist. Med Contact apr;69(15): The B, Brutty M, Wang A, Wambeek ND, Campbell P, Halliday MJ, Ackland TR. Biceps muscle fatty infiltration and atrophy. A midterm review after arthroscopic tenotomy of the long head of the biceps. Arthroscopy Oct 29. pii: S (14) [Epub ahead of print]. PURPOSE: Pathology of the long head of the biceps (LHB) tendon is commonly treated by tenotomy. High levels of clinical function and patient satisfaction are reported in the short-term. The purpose of this study was to investigate the midterm effects of tenotomy on biceps fatty infiltration and atrophy in active working-age male patients. METHODS: Twenty-five men (mean age, 57 years) were evaluated at a mean follow-up of 6.7 years after tenotomy. Bilateral magnetic resonance imaging (MRI) was performed, and fatty infiltration of the biceps was assessed relative to the ipsilateral triceps. Seventeen participants had an intact contralateral LHB tendon. To assess atrophy, anterior muscle compartment volume was measured by serial cross-sectional area measurements on MRI. The tenotomized side was then compared to the healthy side in these 17 participants. Clinical scores were obtained using the QuickDASH and Oxford Elbow Score, and the occurrence of a Popeye sign and residual pain were recorded. RESULTS: Good clinical function was maintained at a mean follow-up time of 6.7 years (range, 4 to 10 years) (QuickDASH score of 7.1; standard error [SE], 1.8) and Oxford Elbow Score of 97.9 [SE 1.2]). Eleven of the 25 participants had a Popeye deformity. Four participants showed signs of fatty infiltration, and all were minor (grade 1). The mean decrease in total volume of the anterior musculature was 3.6%. In participants without a Popeye deformity, it was 3.3%, whereas it was 4.1% in participants with a Popeye sign (P =.8). CONCLUSIONS: In the midterm, LHB tenotomy in active men of working age does not result in fatty degeneration or substantial atrophy in the anterior musculature of the arm. Clinical function remains good. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID: Publicaties Medische Staf

166 The B, Brutty M, Wang A, Campbell PT, Halliday MJ, Ackland TR. Long-term functional results and isokinetic strength evaluation after arthroscopic tenotomy of the long head of biceps tendon. Int J Shoulder Surg Jul;8(3): INTRODUCTION: The objective of this study is to evaluate the biomechanical function of the upper arm after arthroscopic long head of biceps (LHB) tenotomy at long-term follow-up. MATERIALS AND METHODS: Twenty-five male subjects ranging from 30 to 63 years old were evaluated at a mean follow-up of 7.0 years after tenotomy. Bilateral isokinetic testing was performed to obtain peak torque values, as well as total work done throughout the full range of elbow flexion and supination. RESULTS: Magnetic resonance imaging scans revealed nine unrecognized LHB ruptures in the contralateral arm, leaving 16 subjects to complete the testing protocol. The mean quickdash score was 8.1 (standard error [SE] 2.5). The mean oxford elbow score was 97.9 (SE 1.6). The tenotomy arm recorded a decrease in peak flexion torque of 7.0% (confidence interval [CI] ), and a decrease in the peak supination torque of 9.1% (CI ) relative to the contralateral arm. The total work carried out through the full range of joint motion was reduced in elbow flexion by 5.1% (CI ) and in forearm supination by 5.7% (CI ). DISCUSSION: Maximum strength in elbow flexion and forearm supination is significantly reduced compared with the contralateral arm. However, this impairment is partially compensated for by relatively greater strength sustained through the latter stages of joint motion. This results in comparable total work measurements between the tenotomised and contralateral side, potentially accounting for ongoing high levels of patient satisfaction and clinical function in the long term after LHB tenotomy. LEVEL OF EVIDENCE IV: Case series without comparison group. PMID: PMCID: PMC Neuhaus V, Bot AG, Guitton TG, Ring DC; Science of Variation Group, Abdel-Ghany MI, Abrams J, Abzug JM, Adolfsson LE, Balfour GW, Bamberger HB, Barquet A, Baskies M, Batson WA, Baxamusa T, Bayne GJ, Begue T, Behrman M, Beingessner D, Biert J, Bishop J, Alves MB, Boyer M, Brilej D, Brink PR, Brunton LM, Buckley R, Cagnone JC, Calfee RP, Campinhos LA, Cassidy C, Catalano L 3rd, Chivers K, Choudhari P, Cimerman M, Conflitti JM, Costanzo RM, Crist BD, Cross BJ, Dantuluri P, Darowish M, de Bedout R, DeCoster T, Dennison DG, DeNoble PH, DeSilva G, Dienstknecht T, Duncan SF, Duralde XA, Durchholz H, Egol K, Ekholm C, Elias N, Erickson JM, Esparza JD, Fernandes CH, Fischer TJ, Fischmeister M, Forigua Jaime E, Getz CL, Gilbert RS, Giordano V, Glaser DL, Gosens T, Grafe MW, Filho JE, Gray RR, Gulotta LV, Gummerson NW, Hammerberg EM, Harvey E, Haverlag R, Henry PD, Hobby JL, Hofmeister EP, Hughes T, Itamura J, Jebson P, Jenkinson R, Jeray K, Jones CM, Jones J, Jubel A, Kaar SG, Kabir K, Kaplan FT, Kennedy SA, Kessler MW, Kimball HL, Kloen P, Klostermann C, Kohut G, Kraan GA, Kristan A, Loebenberg MI, Malone KJ, Marsh L, Martineau PA, McAuliffe J, McGraw I, Mehta S, Merchant M, Metzger C, Meylaerts SA, Miller AN, Wolf JM, Orthopedie 165

167 Murachovsky J, Murthi A, Nancollas M, Nolan BM, Omara T, Omid R, Ortiz JA, Overbeck JP, Castillo AP, Pesantez R, Polatsch D, Porcellini G, Prayson M, Quell M, Ragsdell MM, Reid JG, Reuver JM, Richard MJ, Richardson M, Rizzo M, Rowinski S, Rubio J, Guerrero CG, Satora W, Schandelmaier P, Scheer JH, Schmidt A, Schubkegel TA, Schulte LM, Schumer ED, Sears BW, Shafritz AB, Shortt NL, Siff T, Silva DM, Smith RM, Spruijt S, Stein JA, Pemovska ES, Streubel PN, Swigart C, Swiontkowski M, Thomas G, Tolo ET, Turina M, Tyllianakis M, van den Bekerom MP, van der Heide H, van de Sande MA, van Eerten PV, Verbeek DO, Hoffmann DV, Vochteloo AJ, Wagenmakers R, Wall CJ, Wallensten R, Wascher DC, Weiss L, Wiater JM, Wills BP, Wint J, Wright T, Young JP, Zalavras C, Zura RD, Zyto K. Scapula fractures: interobserver reliability of classification and treatment. J Orthop Trauma Mar;28(3): OBJECTIVES: There is substantial variation in the classification and management of scapula fractures. The first purpose of this study was to analyze the interobserver reliability of the OTA/ AO classification and the New International Classification for Scapula Fractures. The second purpose was to assess the proportion of agreement among orthopaedic surgeons on operative or nonoperative treatment. DESIGN: Web-based reliability study. SETTING: Independent orthopaedic surgeons from several countries were invited to classify scapular fractures in an online survey. PARTICIPANTS: One hundred three orthopaedic surgeons evaluated 35 movies of threedimensional computerized tomography reconstruction of selected scapular fractures, representing a full spectrum of fracture patterns. MAIN OUTCOME MEASUREMENTS: Fleiss kappa (k) was used to assess the reliability of agreement between the surgeons. RESULTS: The overall agreement on the OTA/AO classification was moderate for the types (A, B, and C, k = 0.54) with a 71% proportion of rater agreement (PA) and for the 9 groups (A1 to C3, k = 0.47) with a 57% PA. For the New International Classification, the agreement about the intraarticular extension of the fracture (Fossa (F), k = 0.79) was substantial and the agreement about a fractured body (Body (B), k = 0.57) or process was moderate (Process (P), k = 0.53); however, PAs were more than 81%. The agreement on the treatment recommendation was moderate (k = 0.57) with a 73% PA. CONCLUSIONS: The New International Classification was more reliable. Body and process fractures generated more disagreement than intraarticular fractures and need further clear definitions. PMID: Publicaties Medische Staf

168 Mellema JJ, Doornberg JN, Guitton TG, Ring D; Science of Variation Group [R. Wagenmakers et al...]. Biomechanical studies: science (f)or common sense? Injury Dec;45(12): Epub 2014 Sep 28. INTRODUCTION: It is our impression that many biomechanical studies invest substantial resources studying the obvious: that more and larger metal is stronger. The purpose of this study is to evaluate if a subset of biomechanical studies comparing fixation constructs just document common sense. METHODS: Using a web-based survey, 274 orthopaedic surgeons and 81 medical students predicted the results of 11 biomechanical studies comparing fracture fixation constructs (selected based on the authors sense that the answer was obvious prior to performing the study). Sensitivity, specificity, and accuracy were calculated according to standard formulas. The agreement among the observers was calculated by using a multirater kappa, described by Siegel and Castellan. RESULTS: The accuracy of predicting outcomes was 80% or greater for 10 of 11 studies. Accuracy was not influenced by level of experience (i.e., time in practice and medical students vs. surgeons). There were substantial differences in accuracy between observers from different regions. The overall categorical rating of inter-observer reliability according to Landis and Koch was moderate (k=0.55; standard error (SE)=0.01). CONCLUSION: The results of a subset of biomechanical studies comparing fracture fixation constructs can be predicted prior to doing the study. As these studies are time and resource intensive, one criterion for proceeding with a biomechanical study should be that the answer is not simply a matter of common sense. PMID: Orthopedie 167

169 Pathologisch Anatomisch Laboratorium Kerngegevens 5 Pathologen: L.S.M. (Luthy) Alcalá, dr. D.E. (Dorothee) Arnold, K.E.S. (Kristoff) Duthoi, J. (Jan) Los (per uit dienst), dr. C.P.H. (Celien) Vreuls (per in dienst), dr. P.E.J. (Peter) de Wit Samenvattingen gepubliceerde artikelen Van Gammeren AJ, Alcala LS, Smolders M, Boersma RS. Numerous Russell bodies and Dutcher bodies in multiple myeloma. Br J Haematol Oct 14. [Epub ahead of print]. No abstract available. PMID: Publicaties Medische Staf

170 Radiologie Kerngegevens 18 radiologen: R.A.H.M. (Ruud) Aarts, K. (Koen) Borsje, H.F.C.M. (Hein) Brands, H.A.J. (Homme) Dijkstra, G.P.J. (Gé) Geenen, H.A.W. (Dirk) Haans, Th.E.A.M. (Thijs) de Jong, P.A.M. (Peter) Kint, M.M. (Mark) Krouwels, I. (Ilse) Niers-Stobbe, P.A.M. (Peter) Raaijmakers, E. (Evert) Sanders, M.F.A.M. (Maarten) Sturm, dr. E. (Eric) Tetteroo, J.L. (Jeroen) Turkenburg, R.J. (Rob) Versteylen, L.D. (Douwe) Vos, T.T. (Thomas) de Weert Subspecialismen: interventieradiologie, mammaradiologie Samenvattingen gepubliceerde artikelen Tolsma M, Bentala M, Rosseel P, Gerritse BM, Dijkstra H, Mulder P, van der Meer N. The value of routine chest radiographs after minimally invasive cardiac surgery: an observational cohort study. J Cardiothorac Surg Nov 11;9(1):174. [Epub ahead of print]. BACKGROUND: Chest radiographs (CXRs) are obtained frequently in postoperative cardiac surgery patients. The diagnostic and therapeutic efficacy of routine CXRs is known to be low and the discussion regarding the safety of abandoning these CXRs after cardiac surgery is still ongoing. We investigated the value of routine CXRs directly after minimally invasive cardiac surgery. METHODS: We prospectively included all patients who underwent minimally invasive cardiac surgery by port access, ministernotomy or bilateral video-assisted thoracoscopy (VATS) in the year A direct postoperative CXR was performed on all patients at ICU arrival. All CXR findings were noted, including whether they led to an intervention or not. RESULTS: The results were compared to the postoperative CXR results in patients who underwent conventional cardiac surgery by full median sternotomy over the same period.main resultsa total of 249 consecutive patients were included. Most of these patients underwent valve surgery, rhythm surgery or a combination of both. The diagnostic efficacy for minor findings was highest in the port access and bilateral VATS groups (56% and 63% versus 28% and 45%) (p < 0.005). The diagnostic efficacy for major findings was also higher in these groups (8.9% and 11% versus 4.3% and 3.8%) (p = 0.010). The need for an intervention was most common after minimally invasive surgery by port access, although this difference was not statistically significant (p = 0.056). CONCLUSION: The diagnostic efficacy of routine CXRs performed after minimally invasive cardiac surgery by port access or bilateral VATS is higher than the efficacy of CXRs performed after conventional cardiac surgery. A routine CXR after these procedures should still be considered. PMID: PMCID: PMC Radiologie 169

171 Thoomes-de Graaf M, Scholten-Peeters GG, Duijn E, Karel YH, van den Borne MP, Beumer A, Ottenheijm RP, Dinant GJ, Tetteroo E, Lucas C, Koes BW, Verhagen AP. Inter-professional agreement of ultrasound-based diagnoses in patients with shoulder pain between physical therapists and radiologists in the Netherlands. Man Ther Oct;19(5): Epub 2014 May 14. STUDY DESIGN: Reliability study. OBJECTIVES: The aim of this study was to evaluate the interrater-reliability of the interpretation of diagnostic ultrasound in patients with shoulder pain between physical therapists and radiologists. BACKGROUND: Although physical therapists in The Netherlands increasingly use diagnostic ultrasound in clinical practice, there is no evidence available on its reliability. METHODS: A cohort study included patients with shoulder pain from primary care physiotherapy. Patients followed the usual diagnostic pathway of which diagnostic ultrasound could be a part. Patients that received diagnostic ultrasound also visited a radiologist within one week for a second one. Patients and radiologists were blinded for the diagnostic ultrasound diagnosis of the physical therapists. Agreement was assessed using Cohen s kappa statistics. Subgroup analysis was performed on education and experience. RESULTS: A total of 65 patients were enrolled and 13 physical therapists and 9 radiologists performed diagnostic ultrasound. We found substantial agreement (0.63 K) between physical therapists and radiologists on the assessment of full thickness tears. The overall kappa of all four diagnostic categories was 0.36, indicating fair agreement. The more experienced and highly trained physical therapists showed moderate agreement (0.43 K) compared to only slight agreement (0.17 and 0.09 K) from the less experienced and trained physical therapists with radiologists. CONCLUSION: The reliability between physical therapists and radiologist on diagnostic ultrasound of shoulder patients in primary care is borderline substantial (Kappa = 0.63) for full thickness tears only. This level of reliability is relatively low when compared with the high reliability between radiologists. More experience and training of physical therapists may increase the reliability of diagnostic ultrasound. PMID: Publicaties Medische Staf

172 Raats JW, Flu HC, Ho GH, Veen EJ, Vos LD, Steyerberg EW, van der Laan L. Long-term outcome of ruptured abdominal aortic aneurysm: impact of treatment and age. Clin Interv Aging Oct 13;9: ecollection BACKGROUND: Despite advances in operative repair, ruptured abdominal aortic aneurysm (raaa) remains associated with high mortality and morbidity rates, especially in elderly patients. The purpose of this study was to evaluate the outcomes of emergency endovascular aneurysm repair (eevar), conventional open repair (OPEN), and conservative treatment in elderly patients with raaa. METHODS: We conducted a retrospective study of all raaa patients treated with OPEN or eevar between January 2005 and December 2011 in the vascular surgery department at Amphia Hospital, the Netherlands. The outcome in patients treated for raaa by eevar or OPEN repair was investigated. Special attention was paid to patients who were admitted and did not receive operative intervention due to serious comorbidity, extremely advanced age, or poor physical condition. We calculated the 30-day raaa-related mortality for all raaa patients admitted to our hospital. RESULTS: Twelve patients did not receive operative emergency repair due to extreme fragility (mean age 87 years, median time to mortality 27 hours). Twenty-three patients had eevar and 82 had OPEN surgery. The 30-day mortality rate in operated patients was 30% (7/23) in the eevar group versus 26% (21/82) in the OPEN group (P=0.64). No difference in mortality was noted between eevar and OPEN over 5 years of follow-up. There were more cardiac adverse events in the OPEN group (n=25, 31%) than in the eevar group (n=2, 9%; P=0.035). Reintervention after discharge was more frequent in patients who received eevar (35%) than in patients who had OPEN (6%, P<0.001). Advancing age was associated with increasing mortality (hazard ratio 1.05 [95% confidence interval ]) per year for patients who received operative repair, with a 67%, 76%, and 100% 5-year mortality rate in the 34 patients aged <70 years, 59 patients aged years, and 12 octogenarians, respectively; 30-day raaa-related mortality was also associated with increasing age (21%, 30%, and 61%, respectively; P=0.008). CONCLUSION: The 30-day and 5-year mortality in patients who survived raaa was equal between the treatment options of eevar and OPEN. Particularly fragile and very elderly patients did not receive operative repair. The decision to intervene in raaa should not be made on the basis of patient age alone, but also in relation to comorbidity and patient preference. PMID: PMCID: PMC Radiologie 171

173 Van der Slegt J, Flu HC, Veen EJ, Ho GH, de Groot HG, Vos LD, van der Laan L. Adverse events after treatment of patients with acute limb ischemia. Ann Vasc Surg Feb;29(2): Epub 2014 Nov 28. BACKGROUND: To assess the outcome and the occurrence and consequences of adverse events (AEs) after treatment of acute limb ischemia (ALI). METHODS: Retrospective analysis on intra-arterial thrombolysis (group I) and thromboembolectomy (group II). Outcome measures were primary patency and limb salvage rates. AEs and consequences were registered during admission and 30 days after discharge. RESULTS: A total of 238 procedures were included (group I, 173 vs. group II, 65). The primary patency (P = 0.144) and limb salvage rates (P = 0.166) were not significantly different between both groups. A total of 195 AEs were registered. Most AEs were procedure related and resulted in surgical reintervention (77% vs. 76%). Some AEs resulted in irreversible physical damage (15% vs. 25%) and death (6% vs. 12%). CONCLUSIONS: Both, intra-arterial thrombolysis and thromboembolectomies are adequate therapies; however, they result in a wide variety of AEs resulting in serious morbidity and even death. PMID: Broekman EA, Versteeg H, Vos LD, Dijksterhuis MG, Papatsonis DN. Temporary balloon occlusion of the internal iliac arteries to prevent massive hemorrhage during cesarean delivery among patients with placenta previa. Int J Gynaecol Obstet Feb;128(2): Epub 2014 Nov 5. OBJECTIVE: To evaluate the effectiveness of temporary balloon occlusion of the internal iliac artery before uterine incision to prevent massive obstetric hemorrhage during cesarean delivery among patients with anterior placenta previa. METHODS: In a retrospective cohort study conducted at Amphia Hospital Breda (Breda, Netherlands), data were analyzed from women with anterior placenta previa who delivered by cesarean between January 1, 2001, and September 30, Cases with and without balloon occlusion of the internal iliac artery were included. The primary outcomes were the amount of blood loss during cesarean delivery, drop of hemoglobin level, and blood loss of more than 1000mL. 172 Publicaties Medische Staf

174 RESULTS: Of 68 eligible women, 42 (62%) had temporary balloon occlusion and 26 (38%) had no balloon occlusion. Median blood loss was 800mL (interquartile range [IQR] ) in the balloon group and 1000mL (IQR ) in the no balloon group (P=0.06). Blood loss of 1000mL or more was recorded in 16 (38%) women in the balloon group and 18 (69%) in the no balloon group (P=0.01). CONCLUSION: Temporary balloon occlusion of the internal iliac artery before uterine incision during cesarean delivery could potentially reduce blood loss among patients with anterior placenta previa. Large, randomized controlled trials are needed to confirm the results. PMID: Urologie 173

175 Urologie Kerngegevens 6 urologen: P.J. (Pieter) van den Broeke, H. (Harald) Jansen, I. E.W. (Ilze) van Onna, E.H.G.M. (Eric) Oomens, P.J. (Péjé) Posthumus, D.K.E. (Deric) van der Schoot 2 assistenten in opleiding (1,8 fte) 1 assistent niet in opleiding (1 fte) Subspecialismen: oncologie (kwaadaardige aandoeningen), stenen (in nieren, urineleiders of blaas), functionele urologie (incontinentie, plasklachten en neurologische blaasproblemen), andrologie (erectiestoornissen, fertiliteit en ouder wordende man), kinderen (aangeboren afwijkingen), algemeen (vergrote prostaat en plasbuisafwijkingen) Samenvattingen gepubliceerde artikelen Buijs J, Maillette de Buy Wenniger L, van Leenders G, Verheij J, van Onna I, Hansen B, van Heerde M, Krak N, Beuers U, Bruno M, van Buuren H. Immunoglobulin G4-related prostatitis: a casecontrol study focusing on clinical and pathologic characteristics. Urology Mar;83(3): OBJECTIVE: To evaluate the occurrence and histopathologic characteristics of immunoglobulin G4 (IgG4)-related prostatic involvement in patients diagnosed with autoimmune pancreatitis. METHODS: Nine cases of IgG4-related prostatitis were identified among 117 men in the autoimmune pancreatitis and IgG4-associated cholangitis patient databases in 2 tertiary hospitals. Clinical information was retrieved, and available prostatic tissue samples and 18 prostatitis control samples were evaluated for characteristic IgG4-related disease (IgG4-RD) features: maximum number of IgG4-positive cells per high-power field; dense lymphoplasmacytic infiltrate; fibrosis, arranged at least focally in a storiform pattern; phlebitis with or without obliteration of the lumen; and increased number of eosinophils. RESULTS: The aspecific sign of urine retention was commonly present in IgG4-RD patients with prostatic involvement. In these patients with IgG4-related prostatitis, the median number of IgG4-positive cells in prostatic tissue was 150 (interquartile range, ) per high-power field compared with a median of 3 (interquartile range, 1-11) in control patients (P =.008). Dense lymphoplasmacytic infiltrate was observed in most (86% in cases and 72% in control patients) tissue samples independent of the underlying cause of prostatitis. Fibrosis in at least a focally storiform pattern was seen rarely in both groups, and (obliterative) phlebitis was absent in all patients. Furthermore, eosinophil numbers were more often elevated in patients with IgG4- RD compared with controls (P <.001). In 2 cases, amelioration of the prostatitis symptoms on corticosteroid treatment was documented. CONCLUSION: Prostatic involvement might not be rare in patients with pancreatic or biliary IgG4-RD. Clinicians should consider this disease entity in patients with IgG4-RD and prostatic symptoms. PMID: Publicaties Medische Staf

176 Richters A, Derks J, Husson O, Van Onna IE, Fossion LM, Kil PJ, Verhoeven RH, Aarts MJ. Effect of surgical margin status after radical prostatectomy on health-related quality of life and illness perception in patients with prostate cancer. Urol Oncol Jan;33(1):16.e9-15. Epub 2014 Nov 14. OBJECTIVE: The aim of the study was to evaluate the effect of positive surgical margins (PSM) on health-related quality of life and illness perception after radical prostatectomy in patients with prostate cancer. METHODS: Of all patients with prostate cancer diagnosed between 2006 and 2009 in 7 participating hospitals in the Eindhoven region of the Netherlands Cancer Registry, 197 patients who underwent radical prostatectomy were invited to fill in a questionnaire. Data from the Netherlands Cancer Registry were combined with questionnaire data (including European Organization for Research and Treatment of Cancer quality of life questionnaire-c30, quality of life questionnaire-prostate Module 25, and the Brief Illness Perception Questionnaire). Mean scores per margin status group were compared in multivariate linear regression. RESULTS: Of the addressed patients, 166 (84%) responded to the questionnaire. At time of questioning, their surgery was 1.7 to 6.4 years ago. The prevalence of PSM was 34%. On most scales, patients with PSM reported more favorable scores than patients with negative surgical margins. However, differences were mostly trivial (<5 points on 100-point scales), or of small (5-10) to medium (10-20) clinical importance. Only differences on hormonal complaints and illness comprehensibility were statistically significant. Effect of PSM on scores did not vary between patients who were at different time points after surgery. CONCLUSION: Although patients with PSM showed a trend toward more favorable scores, these differences were of little or no clinical importance. Additional research is needed to evaluate how patients value these differences with respect to oncological outcomes. PMID: Van der Schoot DKE. Van eunuch tot ageing male. in: Canon van de Urologie / Fons Ypma [red.]. Haarlem: DCHG Medische Communicatie, Hfdst 27. ISBN: Urologie 175

177 Publicaties arts-assistenten Anesthesiologie Samenvattingen gepubliceerde artikelen Joosen AM, Boonen K, Hulsman N, Schuitemaker FJ, Thelen MH. Hypernatraemia in disguise. Clin Chem Lab Med Nov;52(11):e No abstract available. PMID: Chirurgie Samenvattingen gepubliceerde artikelen Beek MA, Gobardhan PD, Klompenhouwer EG, Rutten HJ, Voogd AC, Luiten EJ. Axillary reverse mapping (ARM) in clinically node positive breast cancer patients. Eur J Surg Oncol Jan;41(1): Epub 2014 Oct 29. BACKGROUND: Axillary reverse mapping (ARM) is a technique to map and preserve upper extremity lymphatic drainage during axillary lymph node dissection (ALND) in breast cancer patients. We prospectively evaluated the metastatic involvement of ARM-nodes in patients who underwent an ALND for clinically node positive disease following (neo)adjuvant chemotherapy (NAC) in comparison to patients in whom primary ALND was performed without NAC. PATIENTS AND METHODS: Patients with clinically node positive invasive breast cancer, confirmed by fine needle aspiration cytology and scheduled for primary ALND were enrolled in the study. Patients were separated into two groups: one group treated with NAC (NAC+ group) and one group not treated with NAC (NAC- group). ARM was performed in all patients by injecting blue dye into the ipsilateral upper extremity. During ALND, ARM-nodes were first identified and removed separately, followed by a standard ALND. RESULTS: 91 patients were included in the NAC+ and 21 patients in the NAC- group. There was no difference in the ARM visualization rate between the two groups (86.8% for NAC+ group versus 90.5% for NAC- group, P = 0.647). In the NAC+ group 16.5% of the patients had metastatic involvement of the ARM-nodes versus 36.8% of the patients in the NAC- group (P = 0.048). 176 Publicaties arts-assistenten

178 CONCLUSION: The risk of metastatic involvement of ARM-nodes in clinically node positive breast cancer patients is significantly lower in patients who have received NAC. Copyright 2014 Elsevier Ltd. All rights reserved. PMID: Van der Slegt J, Steunenberg SL, Donker JM, Veen EJ, Ho GH, de Groot HG, van der Laan L. The current position of precuffed expanded polytetrafluoroethylene bypass grafts in peripheral vascular surgery. J Vasc Surg Jul;60(1): Epub 2014 Mar 12. OBJECTIVE: Long-term results of precuffed expanded polytetrafluoroethylene (eptfe) grafts used for peripheral bypass surgery are lacking. The aim of this study was to obtain the long-term outcomes of precuffed eptfe grafts compared with autologous saphenous vein (ASV) grafts used in patients with peripheral arterial disease (PAD). METHODS: A single-institution retrospective study of precuffed eptfe and ASV graft performances in patients with PAD was undertaken between January 2004 and December Five-year primary patency, secondary patency, and limb salvage rates were determined by Kaplan-Meier analyses. RESULTS: A total of 467 bypass grafts were included in this study (169 precuffed eptfe grafts and 298 ASV grafts). Secondary patency rates of eptfe vs ASV at 1 and 5 years, respectively, were as follows: for 134 supragenicular femoropopliteal bypasses, 60% and 27% vs 89% and 85% (P <.05); for 190 infragenicular femoropopliteal bypasses, 40% and 25% vs 86% and 79% (P <.05); and for 84 femorocrural bypasses, 30% and 14% vs 50% and 50% (P <.05). Five-year limb salvage rates of eptfe vs ASV for supragenicular femoropopliteal bypasses were 82% vs 94% (P =.16); for infragenicular femoropopliteal bypasses, 41% vs 92% (P <.05); and for femorocrural bypasses, 43% vs 64% (P =.06). CONCLUSIONS: ASV bypasses are still the first-choice conduit in peripheral bypass surgery performed in patients with PAD. Precuffed eptfe bypasses are acceptable alternatives in the absence of adequate autologous vein. PMID: Raats JW, Donker JM, van der Laan L. Een jongen met pijn links onder in de buik. [A 15-year old boy with abdominal pain]. Ned Tijdschr Geneeskd. 2014;158:A6854. A 15-year-old boy came to the emergency department with abdominal pain in the left lower quadrant. The medical history included surgery for malrotation of bowel in two of his brothers. A CT-abdomen showed malrotation of the colon with a left-sided appendicitis and polysplenia. An emergency laparoscopic appendectomy was performed. Recovery was uneventful. PMID: Chirurgie 177

179 Hopmans CJ, den Hoed PT, van der Laan L, van der Harst E, van der Elst M, Mannaerts GH, Dawson I, Timman R, Wijnhoven BP, IJzermans JN. Assessment of surgery residents operative skills in the operating theater using a modified Objective Structured Assessment of Technical Skills (OSATS): A prospective multicenter study. Surgery Nov;156(5): Epub 2014 Sep 16. BACKGROUND: With the implementation of competency-based curricula, Objective Structured Assessment of Technical Skills (OSATS) increasingly is being used for the assessment of operative skills. Although evidence for its usefulness has been demonstrated in experimental study designs, data supporting OSATS application in the operating room are limited. This study evaluates the validity and reliability of the OSATS instrument to assess the operative skills of surgery residents in the operating theater. METHODS: Twenty-four residents were recruited from seven hospitals within a general surgical training region and classified equally into three groups according to postgraduate training year (PGY). Each resident had to perform five different types of operations. Surgical performance was measured using a modified OSATS consisting of three scales: Global Rating Scale, Overall Performance Scale, and Alphabetic Summary Scale. Validity and reliability metrics included construct validity (Kruskal-Wallis test) and internal consistency reliability (Cronbach s a coefficient). Spearman s correlation coefficients were calculated to determine correlations between the different scales. RESULTS: Eighteen residents (PGY 1-2 [n = 7]; PGY 3-4 [n = 8]; PGY 5-6 [n = 3]) performed 249 operations. Comparisons of the performance scores revealed that evidence for construct validity depended on the difficulty level of the selected procedures. For individual operations, internal consistency reliability of the Global Rating Scale ranged from 0.93 to Scores on the different scales correlated strongly (r = , P <.001). CONCLUSION: Assessment of operative skills in the operating theater using this modified OSATS instrument has the potential to establish learning curves, allowing adequate monitoring of residents progress in achieving operative competence. The Alphabetic Summary Scale seems to be of additional value. Use of the Overall Performance Scale should be reconsidered. PMID: Publicaties arts-assistenten

180 De Kruijf M, Vroemen JP, de Leur K, van der Voort EA, Vos DI, Van der Laan L. Proximal fractures of the humerus in patients older than 75 years of age: should we consider operative treatment? J Orthop Traumatol Jun;15(2): BACKGROUND: Over 75% of patients presenting with a proximal humerus fracture are 70 years or older. Very little is known about the outcome after operative treatment of these fractures in very old patients. This study was performed to gain more insight in safety and functional outcome of surgical treatment of proximal humerus fractures in the elderly. MATERIALS AND METHODS: In this observational study, we analyzed all operatively treated patients, aged 75 or older, with a proximal humerus fracture between January 2003 and December 2008 in our center. Patient selection was on clinical grounds, based on physical, mental, and social criteria. Complications were evaluated. We used the DASH Questionnaire to investigate functional outcome, pain, and ADL limitations. RESULTS: Sixty-four patients were treated surgically for a displaced proximal fracture of the humerus: 15 two-part, 32 three-part, and 17 four-part fractures. Mean DASH scores were 37.5, 36.9, and 48.6, respectively. Regarding the operative methods, overall good results were obtained with the modern locked plate osteosynthesis (mean DASH 34.4). Prosthetic treatment, mostly used in highly comminuted fractures, often resulted in poor function (mean DASH 72.9). Persistent pain and ADL limitations were more present in more comminuted fractures (64 and 50% in patients with 4-part fractures vs. 14% in 2-part fractures). There were no postoperative deaths within 3 months of surgery, and fracture-related and non-fracture-related complication rates were low (non-union 3%; 1 myocardial infarction). CONCLUSION: This study shows that it is safe and justifiable to consider surgical treatment of a severely dislocated proximal humerus fracture in selected patients aged 75 and older. LEVEL OF EVIDENCE: According to OCEBM Working Group, Level IV. PMID: De Kruijf M, Vroemen JP, de Leur K, van der Voort EA, Vos DI, Van der Laan L. Proximal fractures of the humerus in patients older than 75 years of age: should we consider operative treatment? J Orthop Traumatol Jun;15(2): BACKGROUND: Over 75% of patients presenting with a proximal humerus fracture are 70 years or older. Very little is known about the outcome after operative treatment of these fractures in very old patients. This study was performed to gain more insight in safety and functional outcome of surgical treatment of proximal humerus fractures in the elderly. Chirurgie 179

181 MATERIALS AND METHODS: In this observational study, we analyzed all operatively treated patients, aged 75 or older, with a proximal humerus fracture between January 2003 and December 2008 in our center. Patient selection was on clinical grounds, based on physical, mental, and social criteria. Complications were evaluated. We used the DASH Questionnaire to investigate functional outcome, pain, and ADL limitations. RESULTS: Sixty-four patients were treated surgically for a displaced proximal fracture of the humerus: 15 two-part, 32 three-part, and 17 four-part fractures. Mean DASH scores were 37.5, 36.9, and 48.6, respectively. Regarding the operative methods, overall good results were obtained with the modern locked plate osteosynthesis (mean DASH 34.4). Prosthetic treatment, mostly used in highly comminuted fractures, often resulted in poor function (mean DASH 72.9). Persistent pain and ADL limitations were more present in more comminuted fractures (64 and 50% in patients with 4-part fractures vs. 14% in 2-part fractures). There were no postoperative deaths within 3 months of surgery, and fracture-related and non-fracture-related complication rates were low (non-union 3%; 1 myocardial infarction). CONCLUSION: This study shows that it is safe and justifiable to consider surgical treatment of a severely dislocated proximal humerus fracture in selected patients aged 75 and older. LEVEL OF EVIDENCE: According to OCEBM Working Group, Level IV. PMID: Nanninga GL, de Leur K, Panneman MJ, van der Elst M, Hartholt KA. Increasing rates of pelvic fractures among older adults: The Netherlands, Age Ageing Jan 12. [Epub ahead of print]. BACKGROUND: age-related issues are expected to rise in the coming decades. Osteoporosis, falls and fractures are major public health issues among elderly. Pelvic fractures are associated with a serious morbidity and hospitalisation rate. We therefore performed a study to determine trends in incidence and age-specific rates of pelvic fracture-related hospitalisations among elderly ( 65 years). METHODS: a secular trend analysis of all hospitalisations due to a pelvic fracture among older adults, using the National Medical Registration, , The Netherlands. RESULTS: the total number of hospitalisations due to a pelvic fracture increased from 887 in 1986 to 2,013 admissions in 2011 (127% increase). The overall age-adjusted incidence rate increased from 5.19 in 1986 to 7.14 per 10,000 population in 2011 (37.5% increase). The incidence rate increased with age and was higher for females. The Percentual Annual Change was 1.2% (95% CI: 0.9;1.5) for older males, and 1.0% (95% CI: 0.9;1.2) for females, respectively. The mean length of hospital stay decreased between 1991 and 2011 to 12.0 days (53.4% decrease). The total number of hospital-bed-days decreased from 29,002 days in 1991 to 17,283 days in 2011 (40.4% decrease), despite an increase in absolute number of admissions. 180 Publicaties arts-assistenten

182 CONCLUSION: absolute numbers and incidence rates of pelvic fractures are increasing among the older Dutch population. Considering the fact the general population is growing older, an increasing number of elderly suffer from pelvic fractures. Attention on osteoporosis screening and prevention of falls in elderly remains important, in order to limit-related healthcare costs in the future. KEYWORDS: The Netherlands, falls, older adults, older people, pelvic fractures, trends PMID: Raats JW, Donker JM, van der Laan L. Een jongen met pijn links onder in de buik. [A 15-year old boy with abdominal pain]. Ned Tijdschr Geneeskd. 2014;158:A6854. A 15-year-old boy came to the emergency department with abdominal pain in the left lower quadrant. The medical history included surgery for malrotation of bowel in two of his brothers. A CT-abdomen showed malrotation of the colon with a left-sided appendicitis and polysplenia. An emergency laparoscopic appendectomy was performed. Recovery was uneventful. PMID: Raats JW, Flu HC, Ho GH, Veen EJ, Vos LD, Steyerberg EW, van der Laan L. Long-term outcome of ruptured abdominal aortic aneurysm: impact of treatment and age. Clin Interv Aging Oct 13;9: ecollection BACKGROUND: Despite advances in operative repair, ruptured abdominal aortic aneurysm (raaa) remains associated with high mortality and morbidity rates, especially in elderly patients. The purpose of this study was to evaluate the outcomes of emergency endovascular aneurysm repair (eevar), conventional open repair (OPEN), and conservative treatment in elderly patients with raaa. METHODS: We conducted a retrospective study of all raaa patients treated with OPEN or eevar between January 2005 and December 2011 in the vascular surgery department at Amphia Hospital, the Netherlands. The outcome in patients treated for raaa by eevar or OPEN repair was investigated. Special attention was paid to patients who were admitted and did not receive operative intervention due to serious comorbidity, extremely advanced age, or poor physical condition. We calculated the 30-day raaa-related mortality for all raaa patients admitted to our hospital. RESULTS: Twelve patients did not receive operative emergency repair due to extreme fragility (mean age 87 years, median time to mortality 27 hours). Twenty-three patients had eevar and 82 had OPEN surgery. The 30-day mortality rate in operated patients was 30% (7/23) in the eevar group versus 26% (21/82) in the OPEN group (P=0.64). No difference in mortality was noted between eevar and OPEN over 5 years of follow-up. There were more cardiac adverse events in Chirurgie 181

183 the OPEN group (n=25, 31%) than in the eevar group (n=2, 9%; P=0.035). Reintervention after discharge was more frequent in patients who received eevar (35%) than in patients who had OPEN (6%, P<0.001). Advancing age was associated with increasing mortality (hazard ratio 1.05 [95% confidence interval ]) per year for patients who received operative repair, with a 67%, 76%, and 100% 5-year mortality rate in the 34 patients aged <70 years, 59 patients aged years, and 12 octogenarians, respectively; 30-day raaa-related mortality was also associated with increasing age (21%, 30%, and 61%, respectively; P=0.008). CONCLUSION: The 30-day and 5-year mortality in patients who survived raaa was equal between the treatment options of eevar and OPEN. Particularly fragile and very elderly patients did not receive operative repair. The decision to intervene in raaa should not be made on the basis of patient age alone, but also in relation to comorbidity and patient preference. PMID: PMCID: PMC Van der Slegt J, Steunenberg SL, Donker JM, Veen EJ, Ho GH, de Groot HG, van der Laan L. The current position of precuffed expanded polytetrafluoroethylene bypass grafts in peripheral vascular surgery. J Vasc Surg Jul;60(1): Epub 2014 Mar 12. OBJECTIVE: Long-term results of precuffed expanded polytetrafluoroethylene (eptfe) grafts used for peripheral bypass surgery are lacking. The aim of this study was to obtain the longterm outcomes of precuffed eptfe grafts compared with autologous saphenous vein (ASV) grafts used in patients with peripheral arterial disease (PAD). METHODS: A single-institution retrospective study of precuffed eptfe and ASV graft performances in patients with PAD was undertaken between January 2004 and December Five-year primary patency, secondary patency, and limb salvage rates were determined by Kaplan-Meier analyses. RESULTS: A total of 467 bypass grafts were included in this study (169 precuffed eptfe grafts and 298 ASV grafts). Secondary patency rates of eptfe vs ASV at 1 and 5 years, respectively, were as follows: for 134 supragenicular femoropopliteal bypasses, 60% and 27% vs 89% and 85% (P <.05); for 190 infragenicular femoropopliteal bypasses, 40% and 25% vs 86% and 79% (P <.05); and for 84 femorocrural bypasses, 30% and 14% vs 50% and 50% (P <.05). Five-year limb salvage rates of eptfe vs ASV for supragenicular femoropopliteal bypasses were 82% vs 94% (P =.16); for infragenicular femoropopliteal bypasses, 41% vs 92% (P <.05); and for femorocrural bypasses, 43% vs 64% (P =.06). CONCLUSIONS: ASV bypasses are still the first-choice conduit in peripheral bypass surgery performed in patients with PAD. Precuffed eptfe bypasses are acceptable alternatives in the absence of adequate autologous vein. PMID: Publicaties arts-assistenten

184 Te Slaa A, Dolmans D, Ho G, van der Laan L. Treatment strategies and clinical aspects of lower limb edema following peripheral bypass surgery. Phlebology May 19;29(1 suppl): [Epub ahead of print]. In selected patients who suffer from severe peripheral artery disease (PAD) a revascularization with a peripheral bypass might be considered. Postoperative edema is a well-known phenomenon following peripheral bypass surgery and is probably caused by multiple factors. Although postoperative edema causes discomfort to patients, the effects on the quality of life are unknown. Treatment and preventive strategies should nonetheless aim at achieving a net absorption of fluid from the interstitial space into the vascular or lymphatic compartment. A brief summarization of treatment strategies of lower limb edema will be presented that include the use of compression stocking and intermittent pneumatic compression. So far, the postoperative application of compression stockings seem to prevent and reduce edema as much as possible. Quality of life improves slightly following peripheral bypass surgery. However, a contribution of edema on the quality of life could not be detected. PMID: Van der Slegt J, Steunenberg SL, Donker JM, Veen EJ, Ho GH, de Groot HG, van der Laan L. The current position of precuffed expanded polytetrafluoroethylene bypass grafts in peripheral vascular surgery. J Vasc Surg Jul;60(1): Epub 2014 Mar 12. OBJECTIVE: Long-term results of precuffed expanded polytetrafluoroethylene (eptfe) grafts used for peripheral bypass surgery are lacking. The aim of this study was to obtain the long-term outcomes of precuffed eptfe grafts compared with autologous saphenous vein (ASV) grafts used in patients with peripheral arterial disease (PAD). METHODS: A single-institution retrospective study of precuffed eptfe and ASV graft performances in patients with PAD was undertaken between January 2004 and December Five-year primary patency, secondary patency, and limb salvage rates were determined by Kaplan-Meier analyses. RESULTS: A total of 467 bypass grafts were included in this study (169 precuffed eptfe grafts and 298 ASV grafts). Secondary patency rates of eptfe vs ASV at 1 and 5 years, respectively, were as follows: for 134 supragenicular femoropopliteal bypasses, 60% and 27% vs 89% and 85% (P <.05); for 190 infragenicular femoropopliteal bypasses, 40% and 25% vs 86% and 79% (P <.05); and for 84 femorocrural bypasses, 30% and 14% vs 50% and 50% (P <.05). Five-year limb salvage rates of eptfe vs ASV for supragenicular femoropopliteal bypasses were 82% vs 94% (P =.16); for infragenicular femoropopliteal bypasses, 41% vs 92% (P <.05); and for femorocrural bypasses, 43% vs 64% (P =.06). Chirurgie 183

185 CONCLUSIONS: ASV bypasses are still the first-choice conduit in peripheral bypass surgery performed in patients with PAD. Precuffed eptfe bypasses are acceptable alternatives in the absence of adequate autologous vein. PMID: Van der Slegt J, Kluytmans JA, Mulder PG, Veen EJ, Ho GH, van der Laan L. Surgical site infection after multiple groin incisions in peripheral vascular surgery. Surg Infect (Larchmt) Dec;15(6): Abstract Background: Patients with peripheral arterial disease (PAD) are at risk for revision surgery in the groin and therefore at potential risk for surgical site infections (SSIs). In an observational study, a cohort of patients with peripheral arterial disease was followed to examine the effect of different incision intervals on SSI-free survival. METHODS: Patients, needing peripheral vascular surgery because of PAD, were retrieved from a prospectively collected database on SSIs after vascular surgery between March 2009 and January 2012, the group consisting of 720 patients. Of these, 255 patients were selected (age 71.9±10.4 y). Cox proportional hazards models were used for event-history analyses. The effect of incision interval was estimated with adjustment for a number of potential confounders. Effects were quantified by means of hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: No significant effect on the incision interval on SSI-free survival was observed. After separating incisional SSIs into superficial- and deep-seated, a significant linear trend effect of the groin incision interval on deep-incisional SSI development was observed: the shorter the interval, the higher the event rate (HR 1.5 per category, 95% CI , p=0.22). Besides the incision interval, the Rutherford classification was a significant risk factor for SSI development (HR 3.0; 95% CI ; p<0.0005). CONCLUSION: Revision surgery in the groin puts patients at risk for deep-incisional SSI. No effect on superficial incisional SSI development was observed. Besides the incision interval, the Rutherford classification was a significant risk factor for both superficial- and deep-incisional SSI. Quality improvement and better risk stratification schemes are suggested. PMID: Van der Slegt J, Flu HC, Veen EJ, Ho GH, de Groot HG, Vos LD, van der Laan L. Adverse events after treatment of patients with acute limb ischemia. Ann Vasc Surg Feb;29(2): Epub 2014 Nov 28. BACKGROUND: To assess the outcome and the occurrence and consequences of adverse events (AEs) after treatment of acute limb ischemia (ALI). 184 Publicaties arts-assistenten

186 METHODS: Retrospective analysis on intra-arterial thrombolysis (group I) and thromboembolectomy (group II). Outcome measures were primary patency and limb salvage rates. AEs and consequences were registered during admission and 30 days after discharge. RESULTS: A total of 238 procedures were included (group I, 173 vs. group II, 65). The primary patency (P = 0.144) and limb salvage rates (P = 0.166) were not significantly different between both groups. A total of 195 AEs were registered. Most AEs were procedure related and resulted in surgical reintervention (77% vs. 76%). Some AEs resulted in irreversible physical damage (15% vs. 25%) and death (6% vs. 12%). CONCLUSIONS: Both, intra-arterial thrombolysis and thromboembolectomies are adequate therapies; however, they result in a wide variety of AEs resulting in serious morbidity and even death. PMID: Chirurgie 185

187 Interne Geneeskunde en Maag-, Darm-, Levergeneeskunde Samenvattingen gepubliceerde artikelen De Bree LC, Alings AM, van Wijngaarden P. Heparin-induced thrombocytopenia after ICD-lead flushing. Acta Cardiol Apr;69(2): Heparin-induced thrombocytopenia (HIT) is a potentially life-threatening prothrombotic complication following heparin administration. We describe a patient, known with idiopathic dilating cardiomyopathy, presenting nine days after a biventricular ICD implantation with dyspnoea and thrombocytopenia. Thirteen days after administration of a single heparin flush during ICD implantation, the patient developed venous thrombosis in two extremities and pulmonary embolism caused by HIT. HIT is the development of thrombocytopenia, caused by IgG antibodies against complexes of platelet factor 4 and heparin, leading to platelet aggregation. HIT may be accompanied by thrombosis in 20-50% of patients and untreated mortality rates are high. Once HIT is suspected, heparin should be replaced by an alternative anti-factor Xa or anti-factor II therapy. Regardless of the low incidence of HIT, because of the widespread use of heparin and the potentially life-threatening course of HIT, all physicians should be aware of it. PMID: Hendrikse WM, Grootenboers MJ, van Wijngaarden P. Type B lactic acidosis as initial presentation of acute myeloid leukaeemia. A case report. Neth J Crit Care apr;18(2):15-6. Van den Berg SA, Verwer PE, Idema RN, Van Guldener C. Transient cefuroxime/metronidazole treatment induced factor V antibodies. BMJ Case Rep Aug 19;2014. pii: bcr A 29-year-old patient presented with an appendicular infiltrate, initially treated with intravenous antibiotics, but later requiring percutaneous drainage. Both prothrombin time (PT) and activated partial thromboplastin time (aptt) were prolonged on 3 days of antibiotic treatment and unresponsive to vitamin K or prothrombin complex concentrate. Laboratory investigation ultimately showed reduced factor V activity and factor V antibodies. In contrast to previously described cases of factor V antibodies, PT and aptt were only mildly prolonged and residual factor V activity was still >20%. Draining of the abscess did not induce significant bleeding. Afterwards, no haemostatic medication was required. The patient was discharged from the hospital without complications. One week after cessation of the antibiotic treatment, PT and aptt were within normal range again, with a factor V activity level of 36%. In conclusion, we present a patient with transient factor V antibodies, induced by antibiotics, without clinical bleeding tendency. PMID: Publicaties arts-assistenten

188 Klinisch Chemisch Hematologisch Laboratorium Samenvattingen gepubliceerde artikelen Van den Berg SA, Verwer PE, Idema RN, Van Guldener C. Transient cefuroxime/metronidazole treatment induced factor V antibodies. BMJ Case Rep Aug 19;2014. pii: bcr A 29-year-old patient presented with an appendicular infiltrate, initially treated with intravenous antibiotics, but later requiring percutaneous drainage. Both prothrombin time (PT) and activated partial thromboplastin time (aptt) were prolonged on 3 days of antibiotic treatment and unresponsive to vitamin K or prothrombin complex concentrate. Laboratory investigation ultimately showed reduced factor V activity and factor V antibodies. In contrast to previously described cases of factor V antibodies, PT and aptt were only mildly prolonged and residual factor V activity was still >20%. Draining of the abscess did not induce significant bleeding. Afterwards, no haemostatic medication was required. The patient was discharged from the hospital without complications. One week after cessation of the antibiotic treatment, PT and aptt were within normal range again, with a factor V activity level of 36%. In conclusion, we present a patient with transient factor V antibodies, induced by antibiotics, without clinical bleeding tendency. PMID: Joosen AM, Boonen K, Hulsman N, Schuitemaker FJ, Thelen MH. Hypernatraemia in disguise. Clin Chem Lab Med Nov;52(11):e No abstract available. PMID: Klinisch Chemisch Hematologisch Laboratorium 187

189 Laboratorium voor Microbiologie en Infectiepreventie Samenvattingen gepubliceerde artikelen Van Cleef BA, van Benthem BH, Verkade EJ, van Rijen M, Kluytmans-van den Bergh MF, Schouls LM, Duim B, Wagenaar JA, Graveland H, Bos ME, Heederik D, Kluytmans JA. Dynamics of methicillin-resistant Staphylococcus aureus and methicillin-susceptible Staphylococcus aureus carriage in pig farmers: a prospective cohort study. Clin Microbiol Infect Oct;20(10):O Epub 2014 May 15. Our purpose was to determine the dynamics of livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) carriage and its determinants in persons working at pig farms, in order to identify targets for interventions. This prospective cohort study surveyed 49 pig farms in the Netherlands on six sampling dates in 1 year ( ). Nasal and oropharyngeal swabs were collected, as well as environmental surface samples from stables and house. Of 110 pig farmers, 38% were persistent MRSA nasal carriers. The average cross-sectional MRSA prevalence was 63%. Methicillin-susceptible S. aureus (MSSA) nasal carriage was associated with fewer MRSA acquisitions (prevalence rate (PR) = 0.47, p 0.02). In multivariate analysis, an age of years (PR = 2.13, p 0.01), a working week of 40 h (PR=1.89, p 0.01), giving birth assistance to sows (PR=2.26, p 0.03), removing manure of finisher pigs (PR=0.48, p 0.02), and wearing a facemask (PR = 0.13, p 0.02) were significantly related with persistent MRSA nasal carriage. A higher MRSA exposure in stables was associated with MRSA in pig farmers (p <0.0001). This study describes a very high prevalence of LA-MRSA carriage in pig farmers, reflecting extensive exposure during work. We identified the possible protective effects of MSSA carriage and of continuously wearing a facemask during work. PMID: Verkade E, Kluytmans-van den Bergh M, van Benthem B, van Cleef B, van Rijen M, Bosch T, Schouls L, Kluytmans J. Transmission of methicillin-resistant Staphylococcus aureus CC398 from livestock veterinarians to their household members. PLoS One Jul 25;9(7):e ecollection There are indications that livestock-associated MRSA CC398 has a reduced human-to-human transmissibility, limiting its impact on public health and justifying modified control measures. This study determined the transmissibility of MRSA CC398 from livestock veterinarians to their household members in the community as compared to MRSA non-cc398 strains. A oneyear prospective cohort study was performed to determine the presence of MRSA CC398 in four-monthly nasal and oropharyngeal samples of livestock veterinarians (n = 137) and their household members (n = 389). In addition, a cross-sectional survey was performed to detect the presence of MRSA non-cc398 in hospital derived control patients (n = 20) and their household members (n = 41). Staphylococcus aureus isolates were genotyped by staphylococcal protein A (spa) typing and multiple-locus variable-number tandem repeat analysis (MLVA). Mean MRSA CC398 prevalence over the study period was 44% (range %) in veterinarians and 4.0% (range %) in their household members. The MRSA CC398 prevalence in household 188 Publicaties arts-assistenten

190 members of veterinarians was significantly lower than the MRSA non-cc398 prevalence in household members of control patients (PRR 6.0; 95% CI ), indicating the reduced transmissibility of MRSA CC398. The impact of MRSA CC398 appears to be low at the moment. However, careful monitoring of the human-to-human transmissibility of MRSA CC398 remains important. PMID: PMCID: PMC Van Rijen MM, Bosch T, Verkade EJ, Schouls L, Kluytmans JA; CAM Study Group* [van Cleef BA et al...]. Livestock-associated MRSA carriage in patients without direct contact with livestock. PLoS One Jun 27;9(6):e BACKGROUND: Livestock-associated MRSA (MC398) has emerged and is related to an extensive reservoir in pigs and veal calves. Individuals with direct contact with these animals and their family members are known to have high MC398 carriage rates. Until now it was assumed that MC398 does not spread to individuals in the community without pig or veal calf exposure. To test this, we identified the proportion of MC398 in MRSA positive individuals without contact with pigs/veal calves or other known risk factors (MRSA of unknown origin; MUO). METHODS: In 17 participating hospitals, we determined during two years the occurrence of MC398 in individuals without direct contact with livestock and no other known risk factor (n = 271) and tested in a post analysis the hypothesis whether hospitals in pig-dense areas have higher proportions of MC398 of all MUO. RESULTS: Fifty-six individuals (20.7%) without animal contact carried MC398. In hospitals with high pig-densities in the adherence area, the proportion of MC398 of all MUO was higher than this proportion in hospitals without pigs in the surroundings. CONCLUSIONS: One fifth of the individuals carrying MUO carried MC398. So, MC398 is found in individuals without contact to pigs or veal calves. The way of transmission from the animal reservoir to these individuals is unclear, probably by human-to-human transmission or by exposure to the surroundings of the stables. Further research is needed to investigate the way of transmission. *Collaborators: van Cleef B, Hendriks Y, op den Kamp D, Kluytmans J, Kluytmans-van den Bergh M, Ladestein R, Punselie R, van Rijen M, Verkade E, Ernest M, Wulf M, Feingold B, Brekelmans M, Willemse P, ten Feld N, Wintermans R, Postma B, Terwee M, Thuy-Nga, de Ruiter T, van der Vorm E, Wijker A, Hamers H, Das P, Sanders E, Verduin K, van Dam D, Diederen J, ten Ham P, Nolles L, van der Vorm E, Smeulders A, Buiting A, Hörmann H, Nieuwkoop E, Muller Y, Haverkate D, Verweij P, Bonten M, van der Jagt-Zwetsloot M, Troelstra A, Berkhout H, van den Hout L, Kaiser A, Vandenbroucke-Grauls C. PMID: PMCID: PMC Laboratorium voor Microbiologie en Infectiepreventie 189

191 Veenemans J, Overdevest IT, Snelders E, Willemsen I, Hendriks Y, Adesokan A, Doran G, Bruso S, Rolfe A, Pettersson A, Kluytmans JA. Next-generation sequencing for typing and detection of resistance genes: performance of a new commercial method during an outbreak of extendedspectrum-beta-lactamase-producing Escherichia coli. J Clin Microbiol Jul;52(7): Epub 2014 Apr 30. Next-generation sequencing (NGS) has the potential to provide typing results and detect resistance genes in a single assay, thus guiding timely treatment decisions and allowing rapid tracking of transmission of resistant clones. We evaluated the performance of a new NGS assay (Hospital Acquired Infection BioDetection System; Pathogenica) during an outbreak of sequence type 131 (ST131) Escherichia coli infections in a nursing home in The Netherlands. The assay was performed on 56 extended-spectrum-beta-lactamase (ESBL) E. coli isolates collected during 2 prevalence surveys (March and May 2013). Typing results were compared to those of amplified fragment length polymorphism (AFLP), whereby we visually assessed the agreement of the BioDetection phylogenetic tree with clusters defined by AFLP. A microarray was considered the gold standard for detection of resistance genes. AFLP identified a large cluster of 31 indistinguishable isolates on adjacent departments, indicating clonal spread. The BioDetection phylogenetic tree showed that all isolates of this outbreak cluster were strongly related, while the further arrangement of the tree also largely agreed with other clusters defined by AFLP. The BioDetection assay detected ESBL genes in all but 1 isolate (sensitivity, 98%) but was unable to discriminate between ESBL and non-esbl TEM and SHV beta-lactamases or to specify CTX-M genes by group. The performance of the hospital-acquired infection (HAI) BioDetection System for typing of E. coli isolates compared well with the results of AFLP. Its performance with larger collections from different locations, and for typing of other species, was not evaluated and needs further study. PMID: Veenemans J, Overdevest IT, Snelders E, Willemsen I, Hendriks Y, Adesokan A, Doran G, Bruso S, Rolfe A, Pettersson A, Kluytmans JA. Next-generation sequencing for typing and detection of resistance genes: performance of a new commercial method during an outbreak of extendedspectrum-beta-lactamase-producing Escherichia coli. J Clin Microbiol Jul;52(7): Epub 2014 Apr 30. Next-generation sequencing (NGS) has the potential to provide typing results and detect resistance genes in a single assay, thus guiding timely treatment decisions and allowing rapid tracking of transmission of resistant clones. We evaluated the performance of a new NGS assay (Hospital Acquired Infection BioDetection System; Pathogenica) during an outbreak of sequence type 131 (ST131) Escherichia coli infections in a nursing home in The Netherlands. The assay was performed on 56 extended-spectrum-beta-lactamase (ESBL) E. coli isolates collected during 2 prevalence surveys (March and May 2013). Typing results were compared to those of amplified fragment length polymorphism (AFLP), whereby we visually assessed the agreement of the BioDetection phylogenetic tree with clusters defined by AFLP. A microarray was considered the gold standard for detection of resistance genes. AFLP identified a large cluster of Publicaties arts-assistenten

192 indistinguishable isolates on adjacent departments, indicating clonal spread. The BioDetection phylogenetic tree showed that all isolates of this outbreak cluster were strongly related, while the further arrangement of the tree also largely agreed with other clusters defined by AFLP. The BioDetection assay detected ESBL genes in all but 1 isolate (sensitivity, 98%) but was unable to discriminate between ESBL and non-esbl TEM and SHV beta-lactamases or to specify CTX-M genes by group. The performance of the hospital-acquired infection (HAI) BioDetection System for typing of E. coli isolates compared well with the results of AFLP. Its performance with larger collections from different locations, and for typing of other species, was not evaluated and needs further study. PMID: Verkade E, Kluytmans-van den Bergh M, van Benthem B, van Cleef B, van Rijen M, Bosch T, Schouls L, Kluytmans J. Transmission of methicillin-resistant Staphylococcus aureus CC398 from livestock veterinarians to their household members. PLoS One Jul 25;9(7):e ecollection There are indications that livestock-associated MRSA CC398 has a reduced human-to-human transmissibility, limiting its impact on public health and justifying modified control measures. This study determined the transmissibility of MRSA CC398 from livestock veterinarians to their household members in the community as compared to MRSA non-cc398 strains. A oneyear prospective cohort study was performed to determine the presence of MRSA CC398 in four-monthly nasal and oropharyngeal samples of livestock veterinarians (n = 137) and their household members (n = 389). In addition, a cross-sectional survey was performed to detect the presence of MRSA non-cc398 in hospital derived control patients (n = 20) and their household members (n = 41). Staphylococcus aureus isolates were genotyped by staphylococcal protein A (spa) typing and multiple-locus variable-number tandem repeat analysis (MLVA). Mean MRSA CC398 prevalence over the study period was 44% (range %) in veterinarians and 4.0% (range %) in their household members. The MRSA CC398 prevalence in household members of veterinarians was significantly lower than the MRSA non-cc398 prevalence in household members of control patients (PRR 6.0; 95% CI ), indicating the reduced transmissibility of MRSA CC398. The impact of MRSA CC398 appears to be low at the moment. However, careful monitoring of the human-to-human transmissibility of MRSA CC398 remains important. PMID: PMCID: PMC Van Cleef BA, van Benthem BH, Verkade EJ, van Rijen M, Kluytmans-van den Bergh MF, Schouls LM, Duim B, Wagenaar JA, Graveland H, Bos ME, Heederik D, Kluytmans JA. Dynamics of methicillin-resistant Staphylococcus aureus and methicillin-susceptible Staphylococcus aureus carriage in pig farmers: a prospective cohort study. Clin Microbiol Infect Oct;20(10): Epub 2014 May 15. Laboratorium voor Microbiologie en Infectiepreventie 191

193 Our purpose was to determine the dynamics of livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) carriage and its determinants in persons working at pig farms, in order to identify targets for interventions. This prospective cohort study surveyed 49 pig farms in the Netherlands on six sampling dates in 1 year ( ). Nasal and oropharyngeal swabs were collected, as well as environmental surface samples from stables and house. Of 110 pig farmers, 38% were persistent MRSA nasal carriers. The average cross-sectional MRSA prevalence was 63%. Methicillin-susceptible S. aureus (MSSA) nasal carriage was associated with fewer MRSA acquisitions (prevalence rate (PR) = 0.47, p 0.02). In multivariate analysis, an age of years (PR = 2.13, p 0.01), a working week of 40 h (PR=1.89, p 0.01), giving birth assistance to sows (PR=2.26, p 0.03), removing manure of finisher pigs (PR=0.48, p 0.02), and wearing a facemask (PR = 0.13, p 0.02) were significantly related with persistent MRSA nasal carriage. A higher MRSA exposure in stables was associated with MRSA in pig farmers (p <0.0001). This study describes a very high prevalence of LA-MRSA carriage in pig farmers, reflecting extensive exposure during work. We identified the possible protective effects of MSSA carriage and of continuously wearing a facemask during work. PMID: Van Rijen MM, Bosch T, Verkade EJ, Schouls L, Kluytmans JA; CAM Study Group*. Livestock-associated MRSA carriage in patients without direct contact with livestock. PLoS One Jun 27;9(6):e BACKGROUND: Livestock-associated MRSA (MC398) has emerged and is related to an extensive reservoir in pigs and veal calves. Individuals with direct contact with these animals and their family members are known to have high MC398 carriage rates. Until now it was assumed that MC398 does not spread to individuals in the community without pig or veal calf exposure. To test this, we identified the proportion of MC398 in MRSA positive individuals without contact with pigs/veal calves or other known risk factors (MRSA of unknown origin; MUO). METHODS: In 17 participating hospitals, we determined during two years the occurrence of MC398 in individuals without direct contact with livestock and no other known risk factor (n = 271) and tested in a post analysis the hypothesis whether hospitals in pig-dense areas have higher proportions of MC398 of all MUO. RESULTS: Fifty-six individuals (20.7%) without animal contact carried MC398. In hospitals with high pig-densities in the adherence area, the proportion of MC398 of all MUO was higher than this proportion in hospitals without pigs in the surroundings. CONCLUSIONS: One fifth of the individuals carrying MUO carried MC398. So, MC398 is found in individuals without contact to pigs or veal calves. The way of transmission from the animal reservoir to these individuals is unclear, probably by human-to-human transmission or by exposure to the surroundings of the stables. Further research is needed to investigate the way of transmission. 192 Publicaties arts-assistenten

194 *Collaborators: van Cleef B, Hendriks Y, op den Kamp D, Kluytmans J, Kluytmans-van den Bergh M, Ladestein R, Punselie R, van Rijen M, Verkade E, Ernest M, Wulf M, Feingold B, Brekelmans M, Willemse P, ten Feld N, Wintermans R, Postma B, Terwee M, Thuy-Nga, de Ruiter T, van der Vorm E, Wijker A, Hamers H, Das P, Sanders E, Verduin K, van Dam D, Diederen J, ten Ham P, Nolles L, van der Vorm E, Smeulders A, Buiting A, Hörmann H, Nieuwkoop E, Muller Y, Haverkate D, Verweij P, Bonten M, van der Jagt-Zwetsloot M, Troelstra A, Berkhout H, van den Hout L, Kaiser A, Vandenbroucke-Grauls C. PMID: PMCID: PMC Bosch T, Verkade E, van Luit M, Landman F, Kluytmans J, Schouls LM. Transmission and Persistence of Livestock-Associated Methicillin-Resistant Staphylococcus aureus among Veterinarians and Their Household Members. Appl Environ Microbiol Jan 1;81(1): Epub After the first isolation of livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) in 2003, this MRSA variant quickly became the predominant MRSA obtained from humans as part of the Dutch national MRSA surveillance. Previous studies have suggested that human-to-human transmission of LA-MRSA, compared to that of other MRSA lineages, rarely occurs. However, these reports describe the transmission of LA-MRSA based on epidemiology and limited molecular characterization of isolates, making it difficult to assess whether transmission actually occurred. In this study, we used whole-genome maps (WGMs) to identify possible transmission of LA-MRSA between humans. For this, we used LA-MRSA isolates originating from a 2-year prospective longitudinal cohort study in which livestock veterinarians and their household members were repeatedly sampled for the presence of S. aureus. A considerable degree of genotypic variation among LA-MRSA strains was observed. However, there was very limited variability between the maps of the isolates originating from the same veterinarian, indicating that each of the veterinarians persistently carried or had reacquired the same LA-MRSA strain. Comparison of WGMs revealed that LA-MRSA transmission had likely occurred within virtually every veterinarian household. Yet only a single LA-MRSA strain per household appeared to be involved in transmission. The results corroborate our previous finding that LA-MRSA is genetically diverse. Furthermore, this study shows that transmission of LA-MRSA between humans occurs and that carriage of LA-MRSA can be persistent, thus posing a potential risk for spread of this highly resistant pathogen in the community. PMID: PMCID: PMC Laboratorium voor Microbiologie en Infectiepreventie 193

195 Longgeneeskunde Samenvattingen gepubliceerde artikelen Uzun S, Djamin RS, Kluytmans JA, Mulder PG, Van t Veer NE, Ermens AA, Pelle AJ, Hoogsteden HC, Aerts JG, van der Eerden MM. Azithromycin maintenance treatment in patients with frequent exacerbations of chronic obstructive pulmonary disease (COLUMBUS): a randomised, doubleblind, placebo-controlled trial. Lancet Respir Med May;2(5): Epub 2014 Apr 15. BACKGROUND: Macrolide resistance is an increasing problem; there is therefore debate about when to implement maintenance treatment with macrolides in patients with chronic obstructive pulmonary disease (COPD). We aimed to investigate whether patients with COPD who had received treatment for three or more exacerbations in the previous year would have a decrease in exacerbation rate when maintenance treatment with azithromycin was added to standard care. METHODS: We did a randomised, double-blind, placebo-controlled, single-centre trial in the Netherlands between May 19, 2010, and June 18, Patients ( 18 years) with a diagnosis of COPD who had received treatment for three or more exacerbations in the previous year were randomly assigned, via a computer-generated randomisation sequence with permuted block sizes of ten, to receive 500 mg azithromycin or placebo three times a week for 12 months. Randomisation was stratified by use of long-term, low-dose prednisolone ( 10 mg daily). Patients and investigators were masked to group allocation. The primary endpoint was rate of exacerbations of COPD in the year of treatment. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT FINDINGS: We randomly assigned 92 patients to the azithromycin group (n=47) or the placebo group (n=45), of whom 41 (87%) versus 36 (80%) completed the study. We recorded 84 exacerbations in patients in the azithromycin group compared with 129 in those in the placebo group. The unadjusted exacerbation rate per patient per year was 1 94 (95% CI ) for the azithromycin group and 3 22 ( ) for the placebo group. After adjustment, azithromycin resulted in a significant reduction in the exacerbation rate versus placebo (0 58, 95% CI ; p=0 001). Three (6%) patients in the azithromycin group reported serious adverse events compared with five (11%) in the placebo group. During follow-up, the most common adverse event was diarrhoea in the azithromycin group (nine [19%] patients vs one [2%] in the placebo group; p=0 015). INTERPRETATION: Maintenance treatment with azithromycin significantly decreased the exacerbation rate compared with placebo and should therefore be considered for use in patients with COPD who have the frequent exacerbator phenotype and are refractory to standard care. FUNDING: SoLong Trust. PMID: Publicaties arts-assistenten

196 Uzun S, Djamin RS, Veer NE van t, Kluytmans JAJW, Ermens AAM, Hoogsteden HC, Aerts JGJV, Eerden MM van der. Macrolides to prevent COPD exacerbations. Clin Pulm Med. 2014;21(2): Chronic obstructive pulmonary disease (COPD) is one of the major health problems in the world. Long-term treatment with macrolide antibiotics is a recent development that has been reported to have beneficial effects on exacerbation frequency. These effects are not only attributed to the antimicrobial effect but also to the immune modulatory effect. Six randomized trials and 1 retrospective study have been performed to investigate the efficacy of macrolides in the prevention of acute exacerbations of COPD. Besides the beneficial effects on the occurrence of exacerbations of COPD, this treatment also seems to improve quality of life and is well tolerated. Antimicrobial resistance is one of the future issues to consider before implementing this therapy. Djamin RS, Uzun S, Snelders E, Kluytmans JA, Hoogsteden HC, Aerts JG, van der Eerden MM. Occurrence of virus-induced COPD exacerbations during four seasons. Scand J Infect Dis Nov 26:1-5. [Epub ahead of print]. In this study, we investigated the occurrence of viral infections in acute exacerbations of chronic obstructive pulmonary disease (COPD) during four seasons. Viral infections were detected by the use of real-time reverse transcriptase polymerase chain reaction on pharyngeal swabs. During a 12-month period pharyngeal swabs were obtained in 136 exacerbations of 63 patients. In 35 exacerbations (25.7%) a viral infection was detected. Most viral infections occurred in the winter (n = 14, 40.0%), followed by summer (n = 9, 25.7%), autumn (n = 6, 17.1%), and spring (n = 6, 17.1%). Rhinovirus was the most frequently isolated virus (n = 19, 51.4%), followed by respiratory syncytial virus (n = 6, 16.2%), human metapneumovirus (n = 5, 13.5%), influenza A (n = 4, 10.8%), parainfluenza 4 (n = 2, 5.4%), and parainfluenza 3 (n = 1, 2.7%). This study showed that virus-induced COPD exacerbations occur in all four seasons with a peak in the winter months. However, the distribution of rhinovirus infections showed a different pattern, with most infections occurring in July. PMID: Longgeneeskunde 195

197 Orthopedie Samenvattingen gepubliceerde artikelen Ten Brinke B, de Haan LJ, Koenraadt KL, van Geenen RC. Medial femoral condyle fracture as an intraoperative complication of Oxford unicompartmental knee replacement. Knee Surg Sports Traumatol Arthrosc Dec 6. [Epub ahead of print]. Oxford unicompartmental knee replacement (OUKR) is associated with a low perioperative complication rate. This case report describes a periprosthetic fracture of the medial femoral condyle that occurred during an OUKR. The patient was treated with a non-weight-bearing long leg cast for 6 weeks. Afterwards, the fracture had healed, and 3 months postoperatively, there was a full range of motion. Factors leading to this complication could be the impaction force or direction, or a diminished load resistance of the distal femur. Minimally displaced coronal periprosthetic fractures after OUKR can be managed conservatively without residual functional impairment. LEVEL OF EVIDENCE: Case report, Level IV. PMID: Keijsers R, Eygendaal D, van den Bekerom MP. Should we really abandon PRP in the treatment of lateral epicondylar tendinopathy? BJSM Blog oct. In response to: Robert-Jan de Vos, Johann Windt, Adam Weir. Strong evidence against platelet-rich plasma injections for chronic lateral epicondylar tendinopathy: a systematic review. Br J Sports Med. 2014;48(12): Keijsers R, Eygendaal D, van den Bekerom MP. Letter to the editor in response to review by De Vos, Windt and Weir. BJSM Blog dec. Common ground and continued debate: further response to: Strong evidence against platelet-rich plasma injections for chronic lateral epicondylar tendinopathy: a systematic review De Vos RJ, Windt J, Weir A. Br J Sports Med. 2014;48(12): Publicaties arts-assistenten

198 Van den Bekerom MP, Kodde IF, Aster A, Bleys RL, Eygendaal D. Clinical relevance of distal biceps insertional and footprint anatomy. Knee Surg Sports Traumatol Arthrosc Sep 18. [Epub ahead of print]. PURPOSE: The aim of this review was to present an overview, based on a literature search, of surgical anatomy for distal biceps tendon repairs, based on the current literature. METHODS: A narrative review was performed using Pubmed/Medline using key words: Search terms were distal biceps, insertional, and anatomy. RESULTS: Last decade, the interest in both reconstruction techniques, as well as surgical anatomy of the distal biceps tendon, has increased. The insights into various aspects of distal biceps tendon anatomy (two tendons, bicipital tuberosity, lacertus fibrosis, bicipital-radial bursa, posterior interosseous nerve, and lateral antebrachial cutaneous nerve) have evolved significantly in the last years. CONCLUSION: Thorough knowledge of the anatomy is essential for the surgeon in order to understand the biomechanics of rupture and reconstruction of the distal biceps tendon and to avoid injuries of the nerves. Some tips and tricks are provided, and some pitfalls were described to avoid complications and optimize surgical outcome. LEVEL OF EVIDENCE: IV. PMID: Orthopedie 197

199 Publicaties medewerkers zorg- en kenniskernen en Directiecomité Klinisch Chemisch Hematologisch Laboratorium Samenvattingen gepubliceerde artikelen Van Gammeren AJ, Alcala LS, Smolders M, Boersma RS. Numerous Russell bodies and Dutcher bodies in multiple myeloma. Br J Haematol Oct 14. [Epub ahead of print]. No abstract available. PMID: Publicaties arts-assistenten

200 Laboratorium voor Microbiologie en Infectiepreventie Samenvattingen gepubliceerde artikelen Veenemans J, Overdevest IT, Snelders E, Willemsen I, Hendriks Y, Adesokan A, Doran G, Bruso S, Rolfe A, Pettersson A, Kluytmans JA. Next-generation sequencing for typing and detection of resistance genes: performance of a new commercial method during an outbreak of extendedspectrum-beta-lactamase-producing Escherichia coli. J Clin Microbiol Jul;52(7): Epub 2014 Apr 30. Next-generation sequencing (NGS) has the potential to provide typing results and detect resistance genes in a single assay, thus guiding timely treatment decisions and allowing rapid tracking of transmission of resistant clones. We evaluated the performance of a new NGS assay (Hospital Acquired Infection BioDetection System; Pathogenica) during an outbreak of sequence type 131 (ST131) Escherichia coli infections in a nursing home in The Netherlands. The assay was performed on 56 extended-spectrum-beta-lactamase (ESBL) E. coli isolates collected during 2 prevalence surveys (March and May 2013). Typing results were compared to those of amplified fragment length polymorphism (AFLP), whereby we visually assessed the agreement of the BioDetection phylogenetic tree with clusters defined by AFLP. A microarray was considered the gold standard for detection of resistance genes. AFLP identified a large cluster of 31 indistinguishable isolates on adjacent departments, indicating clonal spread. The BioDetection phylogenetic tree showed that all isolates of this outbreak cluster were strongly related, while the further arrangement of the tree also largely agreed with other clusters defined by AFLP. The BioDetection assay detected ESBL genes in all but 1 isolate (sensitivity, 98%) but was unable to discriminate between ESBL and non-esbl TEM and SHV beta-lactamases or to specify CTX-M genes by group. The performance of the hospital-acquired infection (HAI) BioDetection System for typing of E. coli isolates compared well with the results of AFLP. Its performance with larger collections from different locations, and for typing of other species, was not evaluated and needs further study. PMID: Van Rijen MM, Bosch T, Verkade EJ, Schouls L, Kluytmans JA; CAM Study Group* [Hendriks YJ et al...]. Livestock-associated MRSA carriage in patients without direct contact with livestock. PLoS One Jun 27;9(6):e BACKGROUND: Livestock-associated MRSA (MC398) has emerged and is related to an extensive reservoir in pigs and veal calves. Individuals with direct contact with these animals and their family members are known to have high MC398 carriage rates. Until now it was assumed that MC398 does not spread to individuals in the community without pig or veal calf exposure. To test this, we identified the proportion of MC398 in MRSA positive individuals without contact with pigs/veal calves or other known risk factors (MRSA of unknown origin; MUO). Laboratorium voor Microbiologie en Infectiepreventie 199

201 METHODS: In 17 participating hospitals, we determined during two years the occurrence of MC398 in individuals without direct contact with livestock and no other known risk factor (n = 271) and tested in a post analysis the hypothesis whether hospitals in pig-dense areas have higher proportions of MC398 of all MUO. RESULTS: Fifty-six individuals (20.7%) without animal contact carried MC398. In hospitals with high pig-densities in the adherence area, the proportion of MC398 of all MUO was higher than this proportion in hospitals without pigs in the surroundings. CONCLUSIONS: One fifth of the individuals carrying MUO carried MC398. So, MC398 is found in individuals without contact to pigs or veal calves. The way of transmission from the animal reservoir to these individuals is unclear, probably by human-to-human transmission or by exposure to the surroundings of the stables. Further research is needed to investigate the way of transmission. *Collaborators: van Cleef B, Hendriks Y, op den Kamp D, Kluytmans J, Kluytmans-van den Bergh M, Ladestein R, Punselie R, van Rijen M, Verkade E, Ernest M, Wulf M, Feingold B, Brekelmans M, Willemse P, ten Feld N, Wintermans R, Postma B, Terwee M, Thuy-Nga, de Ruiter T, van der Vorm E, Wijker A, Hamers H, Das P, Sanders E, Verduin K, van Dam D, Diederen J, ten Ham P, Nolles L, van der Vorm E, Smeulders A, Buiting A, Hörmann H, Nieuwkoop E, Muller Y, Haverkate D, Verweij P, Bonten M, van der Jagt-Zwetsloot M, Troelstra A, Berkhout H, van den Hout L, Kaiser A, Vandenbroucke-Grauls C. PMID: PMCID: PMC Willemsen I, Nelson-Melching J, Hendriks Y, Mulders A, Verhoeff S, Kluytmans-Vandenbergh M, Kluytmans J. Measuring the quality of infection control in Dutch nursing homes using a standardized method; the Infection prevention RIsk Scan (IRIS). Antimicrob Resist Infect Control Aug 18;3:26. BACKGROUND: We developed a standardised method to assess the quality of infection control in Dutch Nursing Home (NH), based on a cross-sectional survey that visualises the results. The method was called the Infection control RIsk Infection Scan (IRIS). We tested the applicability of this new tool in a multicentre surveillance executed June and July METHODS: The IRIS includes two patient outcome-variables, i.e. the prevalence of healthcare associated infections (HAI) and rectal carriage of Extended-Spectrum Beta-Lactamase (ESBL) producing Enterobacteriaceae (ESBL-E); two patient-related risk factors, i.e. use of medical devices, and antimicrobial therapy; and three ward-related risk factors, i.e. environmental contamination, availability of local guidelines, and shortcomings in infection prevention preconditions. Results were categorised as low-, intermediate- and high risk, presented in an easy-to-read graphic risk spider-plot. This plot was given as feedback to management and healthcare workers of the NH. 200 Publicaties medewerkers zorg- en kenniskernen en Directiecomité

202 RESULTS: Large differences were found among most the variables in the different NH. Common shortcomings were the availability of infection control guidelines and the level of environmental cleaning. Most striking differences were observed in the prevalence of ESBL carriage, ranged from zero to 20.6% (p < 0.001). CONCLUSIONS: The IRIS provided a rapid and easy to understand assessment of the infection control situation of the participating NH. The results can be used to improve the quality of infection control based on the specific needs of a NH but needs further validation in future studies. Repeated measurement can determine the effectiveness of the interventions. This makes the IRIS a useful tool for quality systems. PMID: PMCID: PMC Raven CF, van Wijngaarden P, Moen G, van Rijen MM. Clusteruitbraak MRSA buiten het ziekenhuis: Herkennen en aanpakken. [Cluster outbreak of MRSA in the community; recognition and approach]. Ned Tijdschr Geneeskd. 2014;158:A6812. BACKGROUND: Community-acquired infection with methicillin-resistant Staphylococcus aureus (CA-MRSA) mainly affects healthy young people, without health-care related risk factors for MRSA. Patients often present with skin and soft-tissue infections. CASE DESCRIPTION: An 18-year-old woman presented at the casualty department with recurrent purulent skin infections. She proved to be MRSA-positive. Within 6 months, 2 people around her also developed an MRSA infection. Culture showed CA-MRSA, with an identical strain (spa type: t008). Additional screening within her immediate circle identified 4 carriers, 2 of whom had corresponding skin infections. CONCLUSION: Cluster outbreaks of CA-MRSA require a coordinated approach from both the treating physician and the public health services. The choice of additional investigation among the circle of contacts was the determining factor in breaking the cycle of transmission and reinfection within this cluster. PMID: Van Rijen MM, Bosch T, Verkade EJ, Schouls L, Kluytmans JA; CAM Study Group*. Livestock-associated MRSA carriage in patients without direct contact with livestock. PLoS One Jun 27;9(6):e BACKGROUND: Livestock-associated MRSA (MC398) has emerged and is related to an extensive reservoir in pigs and veal calves. Individuals with direct contact with these animals and their family members are known to have high MC398 carriage rates. Until now it was assumed that MC398 does not spread to individuals in the community without pig or veal calf exposure. To test this, we identified the proportion of MC398 in MRSA positive individuals without contact with pigs/veal calves or other known risk factors (MRSA of unknown origin; MUO). Laboratorium voor Microbiologie en Infectiepreventie 201

203 METHODS: In 17 participating hospitals, we determined during two years the occurrence of MC398 in individuals without direct contact with livestock and no other known risk factor (n = 271) and tested in a post analysis the hypothesis whether hospitals in pig-dense areas have higher proportions of MC398 of all MUO. RESULTS: Fifty-six individuals (20.7%) without animal contact carried MC398. In hospitals with high pig-densities in the adherence area, the proportion of MC398 of all MUO was higher than this proportion in hospitals without pigs in the surroundings. CONCLUSIONS: One fifth of the individuals carrying MUO carried MC398. So, MC398 is found in individuals without contact to pigs or veal calves. The way of transmission from the animal reservoir to these individuals is unclear, probably by human-to-human transmission or by exposure to the surroundings of the stables. Further research is needed to investigate the way of transmission. *Collaborators: van Cleef B, Hendriks Y, op den Kamp D, Kluytmans J, Kluytmans-van den Bergh M, Ladestein R, Punselie R, van Rijen M, Verkade E, Ernest M, Wulf M, Feingold B, Brekelmans M, Willemse P, ten Feld N, Wintermans R, Postma B, Terwee M, Thuy-Nga, de Ruiter T, van der Vorm E, Wijker A, Hamers H, Das P, Sanders E, Verduin K, van Dam D, Diederen J, ten Ham P, Nolles L, van der Vorm E, Smeulders A, Buiting A, Hörmann H, Nieuwkoop E, Muller Y, Haverkate D, Verweij P, Bonten M, van der Jagt-Zwetsloot M, Troelstra A, Berkhout H, van den Hout L, Kaiser A, Vandenbroucke-Grauls C. PMID: PMCID: PMC Knox J, van Rijen M, Uhlemann AC, Miller M, Hafer C, Vavagiakis P, Shi Q, Johnson PD, Coombs G, Kluytmans-Van den Bergh M, Kluytmans J, Bennett CM, Lowy FD. Community-associated methicillin-resistant Staphylococcus aureus transmission in households of infected cases: a pooled analysis of primary data from three studies across international settings. Epidemiol Infect Apr 24:1-12. [Epub ahead of print] SUMMARY Diverse strain types of methicillin-resistant Staphylococcus aureus (MRSA) cause in fections in community settings worldwide. To examine heterogeneity of spread within households and to identify common risk factors for household transmission across settings, primary data from studies conducted in New York (USA), Breda (The Netherlands), and Melbourne (Australia) were pooled. Following MRSA infection of the index patient, household members completed questionnaires and provided nasal swabs. Swabs positive for S. aureus were genotyped by spa sequencing. Poisson regression with robust error variance was used to estimate prevalence odds ratios for transmission of the clinical isolate to non-index household members. Great diversity of strain types existed across studies. Despite differences between studies, the index patient being colonized with the clinical isolate at the home visit (P < 0 01) and the percent of household members aged <18 years (P < 0 01) were independently associated with transmission. Targeted decolonization strategies could be used across geographical settings to limit household MRSA transmission. PMID: Publicaties medewerkers zorg- en kenniskernen en Directiecomité

204 Van Rijen MM, Kluytmans JA. Adjustment of the MRSA Search and Destroy policy for outpatients in the Netherlands: a prospective cohort study with repeated prevalence measurements. Antimicrob Resist Infect Control Jan 15;3(1):3. BACKGROUND: In the Netherlands a successful MRSA Search and Destroy policy is applied in healthcare institutes. We determined the effect of an adjustment in the MRSA Search and Destroy policy for patients in the outpatient clinic on the MRSA transmission to health care workers (HCW). METHODS: In June 2008 an adjustment in the policy for outpatients was introduced in a large teaching hospital. Following this adjustment MRSA positive patients and patients at risk could be seen and treated applying general precautions, without additional protective measures. Also, disinfection of the room after the patient had left was abandoned. To monitor the effect of this policy on the transmission of MRSA all physicians and health care workers of the outpatient clinic were screened for MRSA carriage repeatedly. RESULTS: Before the introduction of the adjusted policy all physicians and HCW of the outpatient clinic were screened (=0-measurement, n = 1,073). None of them was found to be MRSA positive. After introduction of the policy in June 2008 the screening was repeated in October 2008 (n = 1,170) and April 2009 (n = 1,128). In April 2009 one health care worker was MRSA positive resulting in a mean prevalence of 0.09%. This is lower than the known prevalence in HCW. The health care worker was colonized with the livestock-related Spa type t011. As far as we could verify, no patients with this Spa-type had been cared for by the health care worker. CONCLUSIONS: The adjusted MRSA policy did not lead to detectable transmission of MRSA to HCW and was associated with less disturbances in the work flow. PMID: Verkade E, Kluytmans-van den Bergh M, van Benthem B, van Cleef B, van Rijen M, Bosch T, Schouls L, Kluytmans J. Transmission of methicillin-resistant Staphylococcus aureus CC398 from livestock veterinarians to their household members. PLoS One Jul 25;9(7):e ecollection There are indications that livestock-associated MRSA CC398 has a reduced human-to-human transmissibility, limiting its impact on public health and justifying modified control measures. This study determined the transmissibility of MRSA CC398 from livestock veterinarians to their household members in the community as compared to MRSA non-cc398 strains. A oneyear prospective cohort study was performed to determine the presence of MRSA CC398 in four-monthly nasal and oropharyngeal samples of livestock veterinarians (n = 137) and their household members (n = 389). In addition, a cross-sectional survey was performed to detect the presence of MRSA non-cc398 in hospital derived control patients (n = 20) and their household members (n = 41). Staphylococcus aureus isolates were genotyped by staphylococcal protein A (spa) typing and multiple-locus variable-number tandem repeat analysis (MLVA). Mean MRSA CC398 prevalence over the study period was 44% (range %) in veterinarians and Laboratorium voor Microbiologie en Infectiepreventie 203

205 4.0% (range %) in their household members. The MRSA CC398 prevalence in household members of veterinarians was significantly lower than the MRSA non-cc398 prevalence in household members of control patients (PRR 6.0; 95% CI ), indicating the reduced transmissibility of MRSA CC398. The impact of MRSA CC398 appears to be low at the moment. However, careful monitoring of the human-to-human transmissibility of MRSA CC398 remains important. PMID: PMCID: PMC Van Cleef BA, van Benthem BH, Verkade EJ, van Rijen M, Kluytmans-van den Bergh MF, Schouls LM, Duim B, Wagenaar JA, Graveland H, Bos ME, Heederik D, Kluytmans JA. Dynamics of methicillin-resistant Staphylococcus aureus and methicillin-susceptible Staphylococcus aureus carriage in pig farmers: a prospective cohort study. Clin Microbiol Infect Oct;20(10): Epub 2014 May 15. Our purpose was to determine the dynamics of livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) carriage and its determinants in persons working at pig farms, in order to identify targets for interventions. This prospective cohort study surveyed 49 pig farms in the Netherlands on six sampling dates in 1 year ( ). Nasal and oropharyngeal swabs were collected, as well as environmental surface samples from stables and house. Of 110 pig farmers, 38% were persistent MRSA nasal carriers. The average cross-sectional MRSA prevalence was 63%. Methicillin-susceptible S. aureus (MSSA) nasal carriage was associated with fewer MRSA acquisitions (prevalence rate (PR) = 0.47, p 0.02). In multivariate analysis, an age of years (PR = 2.13, p 0.01), a working week of 40 h (PR=1.89, p 0.01), giving birth assistance to sows (PR=2.26, p 0.03), removing manure of finisher pigs (PR=0.48, p 0.02), and wearing a facemask (PR = 0.13, p 0.02) were significantly related with persistent MRSA nasal carriage. A higher MRSA exposure in stables was associated with MRSA in pig farmers (p <0.0001). This study describes a very high prevalence of LA-MRSA carriage in pig farmers, reflecting extensive exposure during work. We identified the possible protective effects of MSSA carriage and of continuously wearing a facemask during work. PMID: Raven CF, van Wijngaarden P, Moen G, van Rijen MM. Clusteruitbraak MRSA buiten het ziekenhuis: Herkennen en aanpakken. [Cluster outbreak of MRSA in the community; recognition and approach]. Ned Tijdschr Geneeskd. 2014;158:A6812. BACKGROUND: Community-acquired infection with methicillin-resistant Staphylococcus aureus (CA-MRSA) mainly affects healthy young people, without health-care related risk factors for MRSA. Patients often present with skin and soft-tissue infections. CASE DESCRIPTION: An 18-year-old woman presented at the casualty department with recurrent purulent skin infections. She proved to be MRSA-positive. Within 6 months, 2 people around her 204 Publicaties medewerkers zorg- en kenniskernen en Directiecomité

206 also developed an MRSA infection. Culture showed CA-MRSA, with an identical strain (spa type: t008). Additional screening within her immediate circle identified 4 carriers, 2 of whom had corresponding skin infections. CONCLUSION: Cluster outbreaks of CA-MRSA require a coordinated approach from both the treating physician and the public health services. The choice of additional investigation among the circle of contacts was the determining factor in breaking the cycle of transmission and reinfection within this cluster. PMID: Willemsen I, Hille L, Vrolijk A, Bergmans A, Kluytmans J. Evaluation of a commercial real-time PCR for the detection of extended spectrum ß-lactamase genes. J Med Microbiol Apr;63 (Pt 4): Epub 2014 Jan 28. We investigated the performance of a real-time PCR for the detection of extended spectrum ß-lactamase genes in Enterobacteriaceae (Check-MDR ESBL PCR). Results from micro-arrays were considered as the gold standard. An analysis on 489 isolates resulted in a sensitivity of 98.9 % and a specificity of 100 % for the PCR. PMID: Reuland EA, Hays JP, de Jongh DM, Abdelrehim E, Willemsen I, Kluytmans JA, Savelkoul PH, Vandenbroucke-Grauls CM, al Naiemi N. Detection and occurrence of plasmid-mediated AmpC in highly resistant gram-negative rods. PLoS One Mar 18;9(3):e ecollection OBJECTIVES: The aim of this study was to compare the current screening methods and to evaluate confirmation tests for phenotypic plasmidal AmpC (pampc) detection. METHODS: For this evaluation we used 503 Enterobacteriaceae from 18 Dutch hospitals and 21 isolates previously confirmed to be pampc positive. All isolates were divided into three groups: isolates with 1) reduced susceptibility to ceftazidime and/or cefotaxime; 2) reduced susceptibility to cefoxitin; 3) reduced susceptibility to ceftazidime and/or cefotaxime combined with reduced susceptibility to cefoxitin. Two disk-based tests, with cloxacillin or boronic acid as inhibitor, and Etest with cefotetan-cefotetan/cloxacillin were used for phenotypic AmpC confirmation. Finally, presence of pampc genes was tested by multiplex and singleplex PCR. RESULTS: We identified 13 pampc producing Enterobacteriaceae isolates among the 503 isolates (2.6%): 9 CMY-2, 3 DHA-1 and 1 ACC-1 type in E. coli isolates. The sensitivity and specificity of reduced susceptibility to ceftazidime and/or cefotaxime in combination with cefoxitin was 97% (33/34) and 90% (289/322) respectively. The disk-based test with cloxacillin showed the best performance as phenotypic confirmation method for AmpC production. Laboratorium voor Microbiologie en Infectiepreventie 205

207 CONCLUSIONS: For routine phenotypic detection of pampc the screening for reduced susceptibility to third generation cephalosporins combined with reduced susceptibility to cefoxitin is recommended. Confirmation via a combination disk diffusion test using cloxacillin is the best phenotypic option. The prevalence found is worrisome, since, due to their plasmidal location, pampc genes may spread further and increase in prevalence. PMID: PMCID: PMC Veenemans J, Overdevest IT, Snelders E, Willemsen I, Hendriks Y, Adesokan A, Doran G, Bruso S, Rolfe A, Pettersson A, Kluytmans JA. Next-generation sequencing for typing and detection of resistance genes: performance of a new commercial method during an outbreak of extendedspectrum-beta-lactamase-producing Escherichia coli. J Clin Microbiol Jul;52(7): Epub 2014 Apr 30. Next-generation sequencing (NGS) has the potential to provide typing results and detect resistance genes in a single assay, thus guiding timely treatment decisions and allowing rapid tracking of transmission of resistant clones. We evaluated the performance of a new NGS assay (Hospital Acquired Infection BioDetection System; Pathogenica) during an outbreak of sequence type 131 (ST131) Escherichia coli infections in a nursing home in The Netherlands. The assay was performed on 56 extended-spectrum-beta-lactamase (ESBL) E. coli isolates collected during 2 prevalence surveys (March and May 2013). Typing results were compared to those of amplified fragment length polymorphism (AFLP), whereby we visually assessed the agreement of the BioDetection phylogenetic tree with clusters defined by AFLP. A microarray was considered the gold standard for detection of resistance genes. AFLP identified a large cluster of 31 indistinguishable isolates on adjacent departments, indicating clonal spread. The BioDetection phylogenetic tree showed that all isolates of this outbreak cluster were strongly related, while the further arrangement of the tree also largely agreed with other clusters defined by AFLP. The BioDetection assay detected ESBL genes in all but 1 isolate (sensitivity, 98%) but was unable to discriminate between ESBL and non-esbl TEM and SHV beta-lactamases or to specify CTX-M genes by group. The performance of the hospital-acquired infection (HAI) BioDetection System for typing of E. coli isolates compared well with the results of AFLP. Its performance with larger collections from different locations, and for typing of other species, was not evaluated and needs further study. PMID: Publicaties medewerkers zorg- en kenniskernen en Directiecomité

208 Willemsen I, Nelson-Melching J, Hendriks Y, Mulders A, Verhoeff S, Kluytmans-Vandenbergh M, Kluytmans J. Measuring the quality of infection control in Dutch nursing homes using a standardized method; the Infection prevention RIsk Scan (IRIS). Antimicrob Resist Infect Control Aug 18;3:26. BACKGROUND: We developed a standardised method to assess the quality of infection control in Dutch Nursing Home (NH), based on a cross-sectional survey that visualises the results. The method was called the Infection control RIsk Infection Scan (IRIS). We tested the applicability of this new tool in a multicentre surveillance executed June and July METHODS: The IRIS includes two patient outcome-variables, i.e. the prevalence of healthcare associated infections (HAI) and rectal carriage of Extended-Spectrum Beta-Lactamase (ESBL) producing Enterobacteriaceae (ESBL-E); two patient-related risk factors, i.e. use of medical devices, and antimicrobial therapy; and three ward-related risk factors, i.e. environmental contamination, availability of local guidelines, and shortcomings in infection prevention preconditions. Results were categorised as low-, intermediate- and high risk, presented in an easy-to-read graphic risk spider-plot. This plot was given as feedback to management and healthcare workers of the NH. RESULTS: Large differences were found among most the variables in the different NH. Common shortcomings were the availability of infection control guidelines and the level of environmental cleaning. Most striking differences were observed in the prevalence of ESBL carriage, ranged from zero to 20.6% (p < 0.001). CONCLUSIONS: The IRIS provided a rapid and easy to understand assessment of the infection control situation of the participating NH. The results can be used to improve the quality of infection control based on the specific needs of a NH but needs further validation in future studies. Repeated measurement can determine the effectiveness of the interventions. This makes the IRIS a useful tool for quality systems. PMID: PMCID: PMC Laboratorium voor Microbiologie en Infectiepreventie 207

209 Amphia Academy Infectious Disease Foundation Samenvattingen gepubliceerde artikelen Verkade E, Kluytmans-van den Bergh M, van Benthem B, van Cleef B, van Rijen M, Bosch T, Schouls L, Kluytmans J. Transmission of methicillin-resistant Staphylococcus aureus CC398 from livestock veterinarians to their household members. PLoS One Jul 25;9(7):e ecollection There are indications that livestock-associated MRSA CC398 has a reduced human-to-human transmissibility, limiting its impact on public health and justifying modified control measures. This study determined the transmissibility of MRSA CC398 from livestock veterinarians to their household members in the community as compared to MRSA non-cc398 strains. A oneyear prospective cohort study was performed to determine the presence of MRSA CC398 in four-monthly nasal and oropharyngeal samples of livestock veterinarians (n = 137) and their household members (n = 389). In addition, a cross-sectional survey was performed to detect the presence of MRSA non-cc398 in hospital derived control patients (n = 20) and their household members (n = 41). Staphylococcus aureus isolates were genotyped by staphylococcal protein A (spa) typing and multiple-locus variable-number tandem repeat analysis (MLVA). Mean MRSA CC398 prevalence over the study period was 44% (range %) in veterinarians and 4.0% (range %) in their household members. The MRSA CC398 prevalence in household members of veterinarians was significantly lower than the MRSA non-cc398 prevalence in household members of control patients (PRR 6.0; 95% CI ), indicating the reduced transmissibility of MRSA CC398. The impact of MRSA CC398 appears to be low at the moment. However, careful monitoring of the human-to-human transmissibility of MRSA CC398 remains important. PMID: PMCID: PMC Knox J, Van Rijen M, Uhlemann AC, Miller M, Hafer C, Vavagiakis P, Shi Q, Johnson PD, Coombs G, Kluytmans-Van den Bergh M, Kluytmans J, Bennett CM, Lowy FD. Community-associated methicillin-resistant Staphylococcus aureus transmission in households of infected cases: a pooled analysis of primary data from three studies across international settings. Epidemiol Infect Jan;143(2): Epub 2014 Apr 24. SUMMARY Diverse strain types of methicillin-resistant Staphylococcus aureus (MRSA) cause infections in community settings worldwide. To examine heterogeneity of spread within households and to identify common risk factors for household transmission across settings, primary data from studies conducted in New York (USA), Breda (The Netherlands), and Melbourne (Australia) were pooled. Following MRSA infection of the index patient, household members completed questionnaires and provided nasal swabs. Swabs positive for S. aureus were genotyped by spa sequencing. Poisson regression with robust error variance was used to estimate prevalence odds ratios for transmission of the clinical isolate to non-index household members. Great diversity of strain types existed across studies. 208 Publicaties medewerkers zorg- en kenniskernen en Directiecomité

210 Despite differences between studies, the index patient being colonized with the clinical isolate at the home visit (P < 0 01) and the percent of household members aged <18 years (P < 0 01) were independently associated with transmission. Targeted decolonization strategies could be used across geographical settings to limit household MRSA transmission. PMID: Van Cleef BA, van Benthem BH, Verkade EJ, van Rijen M, Kluytmans-van den Bergh MF, Schouls LM, Duim B, Wagenaar JA, Graveland H, Bos ME, Heederik D, Kluytmans JA. Dynamics of methicillinresistant Staphylococcus aureus and methicillin-susceptible Staphylococcus aureus carriage in pig farmers: a prospective cohort study. Clin Microbiol Infect Oct;20(10): Epub 2014 May 15. Our purpose was to determine the dynamics of livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) carriage and its determinants in persons working at pig farms, in order to identify targets for interventions. This prospective cohort study surveyed 49 pig farms in the Netherlands on six sampling dates in 1 year ( ). Nasal and oropharyngeal swabs were collected, as well as environmental surface samples from stables and house. Of 110 pig farmers, 38% were persistent MRSA nasal carriers. The average cross-sectional MRSA prevalence was 63%. Methicillin-susceptible S. aureus (MSSA) nasal carriage was associated with fewer MRSA acquisitions (prevalence rate (PR) = 0.47, p 0.02). In multivariate analysis, an age of years (PR = 2.13, p 0.01), a working week of 40 h (PR=1.89, p 0.01), giving birth assistance to sows (PR=2.26, p 0.03), removing manure of finisher pigs (PR=0.48, p 0.02), and wearing a facemask (PR = 0.13, p 0.02) were significantly related with persistent MRSA nasal carriage. A higher MRSA exposure in stables was associated with MRSA in pig farmers (p <0.0001). This study describes a very high prevalence of LA-MRSA carriage in pig farmers, reflecting extensive exposure during work. We identified the possible protective effects of MSSA carriage and of continuously wearing a facemask during work. PMID: Amphia Academy Infectious Disease Foundation 209

211 Van Rijen MM, Bosch T, Verkade EJ, Schouls L, Kluytmans JA; CAM Study Group* [Kluytmans-van den Bergh MF et al...]. Livestock-associated MRSA carriage in patients without direct contact with livestock. PLoS One Jun 27;9(6):e BACKGROUND: Livestock-associated MRSA (MC398) has emerged and is related to an extensive reservoir in pigs and veal calves. Individuals with direct contact with these animals and their family members are known to have high MC398 carriage rates. Until now it was assumed that MC398 does not spread to individuals in the community without pig or veal calf exposure. To test this, we identified the proportion of MC398 in MRSA positive individuals without contact with pigs/veal calves or other known risk factors (MRSA of unknown origin; MUO). METHODS: In 17 participating hospitals, we determined during two years the occurrence of MC398 in individuals without direct contact with livestock and no other known risk factor (n = 271) and tested in a post analysis the hypothesis whether hospitals in pig-dense areas have higher proportions of MC398 of all MUO. RESULTS: Fifty-six individuals (20.7%) without animal contact carried MC398. In hospitals with high pig-densities in the adherence area, the proportion of MC398 of all MUO was higher than this proportion in hospitals without pigs in the surroundings. CONCLUSIONS: One fifth of the individuals carrying MUO carried MC398. So, MC398 is found in individuals without contact to pigs or veal calves. The way of transmission from the animal reservoir to these individuals is unclear, probably by human-to-human transmission or by exposure to the surroundings of the stables. Further research is needed to investigate the way of transmission. *Collaborators: van Cleef B, Hendriks Y, op den Kamp D, Kluytmans J, Kluytmans-van den Bergh M, Ladestein R, Punselie R, van Rijen M, Verkade E, Ernest M, Wulf M, Feingold B, Brekelmans M, Willemse P, ten Feld N, Wintermans R, Postma B, Terwee M, Thuy-Nga, de Ruiter T, van der Vorm E, Wijker A, Hamers H, Das P, Sanders E, Verduin K, van Dam D, Diederen J, ten Ham P, Nolles L, van der Vorm E, Smeulders A, Buiting A, Hörmann H, Nieuwkoop E, Muller Y, Haverkate D, Verweij P, Bonten M, van der Jagt-Zwetsloot M, Troelstra A, Berkhout H, van den Hout L, Kaiser A, Vandenbroucke-Grauls C. PMID: PMCID: PMC Publicaties medewerkers zorg- en kenniskernen en Directiecomité

212 Willemsen I, Nelson-Melching J, Hendriks Y, Mulders A, Verhoeff S, Kluytmans-Vandenbergh M, Kluytmans J. Measuring the quality of infection control in Dutch nursing homes using a standardized method; the Infection prevention RIsk Scan (IRIS). Antimicrob Resist Infect Control Aug 18;3:26. BACKGROUND: We developed a standardised method to assess the quality of infection control in Dutch Nursing Home (NH), based on a cross-sectional survey that visualises the results. The method was called the Infection control RIsk Infection Scan (IRIS). We tested the applicability of this new tool in a multicentre surveillance executed June and July METHODS: The IRIS includes two patient outcome-variables, i.e. the prevalence of healthcare associated infections (HAI) and rectal carriage of Extended-Spectrum Beta-Lactamase (ESBL) producing Enterobacteriaceae (ESBL-E); two patient-related risk factors, i.e. use of medical devices, and antimicrobial therapy; and three ward-related risk factors, i.e. environmental contamination, availability of local guidelines, and shortcomings in infection prevention preconditions. Results were categorised as low-, intermediate- and high risk, presented in an easy-to-read graphic risk spider-plot. This plot was given as feedback to management and healthcare workers of the NH. RESULTS: Large differences were found among most the variables in the different NH. Common shortcomings were the availability of infection control guidelines and the level of environmental cleaning. Most striking differences were observed in the prevalence of ESBL carriage, ranged from zero to 20.6% (p < 0.001). CONCLUSIONS: The IRIS provided a rapid and easy to understand assessment of the infection control situation of the participating NH. The results can be used to improve the quality of infection control based on the specific needs of a NH but needs further validation in future studies. Repeated measurement can determine the effectiveness of the interventions. This makes the IRIS a useful tool for quality systems. PMID: PMCID: PMC Amphia Academy Infectious Disease Foundation 211

213 Orthopedie Samenvattingen gepubliceerde artikelen Ten Brinke B, de Haan LJ, Koenraadt KL, van Geenen RC. Medial femoral condyle fracture as an intraoperative complication of Oxford unicompartmental knee replacement. Knee Surg Sports Traumatol Arthrosc Dec 6. [Epub ahead of print]. Oxford unicompartmental knee replacement (OUKR) is associated with a low perioperative complication rate. This case report describes a periprosthetic fracture of the medial femoral condyle that occurred during an OUKR. The patient was treated with a non-weight-bearing long leg cast for 6 weeks. Afterwards, the fracture had healed, and 3 months postoperatively, there was a full range of motion. Factors leading to this complication could be the impaction force or direction, or a diminished load resistance of the distal femur. Minimally displaced coronal periprosthetic fractures after OUKR can be managed conservatively without residual functional impairment. LEVEL OF EVIDENCE: Case report, Level IV. PMID:

214 Directiecomité 1 voorzitter Directiecomité: O. (Olof) Suttorp, arts MBA 1 lid / vice-voorzitter Directiecomité: drs. E.A. (Ernst) Hoette 3 leden Directiecomité: dr. J.J. (Hans) Meij, MBA, L. (Elout) Vos, arts MBA, mr. M.J.R. (Mary) Groenewoud, MBA Samenvattingen gepubliceerde artikelen Beenakker KG, Koopman JJ, van Bodegom D, Kuningas M, Slagboom PE, Meij JJ, Maier AB, Westendorp RG. Variants of the IL-10 gene associate with muscle strength in elderly from rural Africa: a candidate gene study. Aging Cell Oct;13(5): Epub 2014 Jul 18. Recently, it has been shown that the capacity of the innate immune system to produce cytokines relates to skeletal muscle mass and strength in older persons. The interleukin-10 (IL-10) gene regulates the production capacities of IL-10 and tumour necrosis factor-a (TNF-a). In rural Ghana, IL-10 gene variants associated with different production capacities of IL-10 and TNF-a are enriched compared with Caucasian populations. In this setting, we explored the association between these gene variants and muscle strength. Among 554 Ghanaians aged 50 years and older, we determined 20 single nucleotide polymorphisms in the IL-10 gene, production capacities of IL-10 and TNF-a in whole blood upon stimulation with lipopolysaccharide (LPS) and handgrip strength as a proxy for skeletal muscle strength. We distinguished pro-inflammatory haplotypes associated with low IL-10 production capacity and anti-inflammatory haplotypes with high IL-10 production capacity. We found that distinct haplotypes of the IL-10 gene associated with handgrip strength. A pro-inflammatory haplotype with a population frequency of 43.2% was associated with higher handgrip strength (P = 0.015). An anti-inflammatory haplotype with a population frequency of 7.9% was associated with lower handgrip strength (P = 0.006). In conclusion, variants of the IL-10 gene contributing to a pro-inflammatory cytokine response associate with higher muscle strength, whereas those with anti-inflammatory response associate with lower muscle strength. Future research needs to elucidate whether these effects of variation in the IL-10 gene are exerted directly through its role in the repair of muscle tissue or indirectly through its role in the defence against infectious diseases. PMID: PMCID: PMC Directiecomité 213

215 Register Medische Staf Anesthesiologie Van Eerd M, Patijn J, Sieben JM, Sommer M, Van Zundert J, van Kleef M, Lataster A. Ultrasonography of the cervical spine: an in vitro anatomical validation model. Anesthesiology Jan;120(1): Tolsma M, Bentala M, Rosseel P, Gerritse BM, Dijkstra H, Mulder P, van der Meer N. The value of routine chest radiographs after minimally invasive cardiac surgery: an observational cohort study. J Cardiothorac Surg Nov 11;9(1):174. [Epub ahead of print]. Derikx HJ, Gerritse BM, Gans R, van der Meer NJ. A randomized trial comparing two intraosseous access devices in intrahospital healthcare providers with a focus on retention of knowledge, skill, and self-efficacy. Eur J Trauma Emerg Surg. 2014;40: Derikx HJ, Gerritse BM, Gans R, van der Meer NJ. A randomized trial comparing two intraosseous access devices in intrahospital healthcare providers with a focus on retention of knowledge, skill, and self-efficacy. Eur J Trauma Emerg Surg. 2014;40: Spoelstra-de Man AM, van der Heiden P, Spijkstra JJ, Verheijen AT, Kooter AJ. Treatment of hyperglycaemia in diabetic ketoacidosis: natura non facit saltus. Neth J Med Jan;72(1):54-8. Hulsman N, Hiddema PA, Veen EJ, van der Meer NJ. Traumatic cardiac injury by gun nails. Int J Crit Illn Inj Sci Apr;4(2): Tolsma M, Rijpstra TA, Schultz MJ, Mulder PG, van der Meer NJ. Significant changes in the practice of chest radiography in Dutch intensive care units: a web-based survey. Ann Intensive Care Apr 4;4(1):10. Tolsma M, Bentala M, Rosseel P, Gerritse BM, Dijkstra H, Mulder P, van der Meer N. The value of routine chest radiographs after minimally invasive cardiac surgery: an observational cohort study. J Cardiothorac Surg Nov 11;9(1):174. [Epub ahead of print]. Hogervorst E, Rosseel P, van der Bom J, Bentala M, Brand A, van der Meer N, van de Watering L. Tolerance of intraoperative hemoglobin decrease during cardiac surgery. Transfusion Oct;54(10 Pt 2): Epub 2014 Apr 14. Ottens TH, Dieleman JM, Sauër AM, Peelen LM, Nierich AP, de Groot WJ, Nathoe HM, Buijsrogge MP, Kalkman CJ, van Dijk D; Dexamethasone for Cardiac Surgery (DECS) Study Group [Van der Meer NJ et al...]. Effects of dexamethasone on cognitive decline after cardiac surgery: a randomized clinical trial. Anesthesiology Sep;121(3): Bunge JJ, van Osch D, Dieleman JM, Jacob KA, Kluin J, van Dijk D, Nathoe HM; Dexamethasone for Cardiac Surgery (DECS) Study Group* [Van der Meer NJ et al...]. Dexamethasone for the prevention of postpericardiotomy syndrome: A DExamethasone for Cardiac Surgery substudy. Am Heart J Jul;168(1): e1. Epub 2014 Apr

216 Tolsma M, Rijpstra TA, Schultz MJ, Mulder PG, van der Meer NJ. Significant changes in the practice of chest radiography in Dutch intensive care units: a web-based survey. Ann Intensive Care Apr 4;4(1):10. Tolsma M, Bentala M, Rosseel P, Gerritse BM, Dijkstra H, Mulder P, van der Meer N. The value of routine chest radiographs after minimally invasive cardiac surgery: an observational cohort study. J Cardiothorac Surg Nov 11;9(1):174. [Epub ahead of print]. Hogervorst E, Rosseel P, van der Bom J, Bentala M, Brand A, van der Meer N, van de Watering L. Tolerance of intraoperative hemoglobin decrease during cardiac surgery. Transfusion Oct;54(10 Pt 2): Epub 2014 Apr 14. Dietrich W, Faraoni D, von Heymann C, Bolliger D, Ranucci M, Sander M, Rosseel P. ESA guidelines on the management of severe perioperative bleeding: comments on behalf of the Subcommittee on Transfusion and Haemostasis of the European Association of Cardiothoracic Anaesthesiologists. Eur J Anaesthesiol Apr;31(4): No abstract available. Bunge JJ, van Osch D, Dieleman JM, Jacob KA, Kluin J, van Dijk D, Nathoe HM; Dexamethasone for Cardiac Surgery (DECS) Study Group* [Rosseel PM et al...]. Dexamethasone for the prevention of postpericardiotomy syndrome: A DExamethasone for Cardiac Surgery substudy. Am Heart J Jul;168(1): e1. Epub 2014 Apr 5. Joosen AM, Boonen K, Hulsman N, Schuitemaker FJ, Thelen MH. Hypernatraemia in disguise. Clin Chem Lab Med Nov;52(11):e Cardiologie Held C, Hylek EM, Alexander JH, Hanna M, Lopes RD, Wojdyla DM, Thomas L, Al-Khalidi H, Alings M, Xavier D, Ansell J, Goto S, Ruzyllo W, Rosenqvist M, Verheugt FW, Zhu J, Granger CB, Wallentin L. Clinical outcomes and management associated with major bleeding in patients with atrial fibrillation treated with apixaban or warfarin: insights from the ARISTOTLE trial. Eur Heart J Dec 12. [Epub ahead of print]. Habibovi M, Denollet J, Cuijpers P, Spek VR, van den Broek KC, Warmerdam L, van der Voort PH, Herrman JP, Bouwels L, Valk SS, Alings M, Theuns DA, Pedersen SS. E-health to manage distress in patients with an implantable cardioverter-defibrillator: primary results of the WEBCARE trial. Psychosom Med Oct;76(8): Vanassche T, Lauw MN, Eikelboom JW, Healey JS, Hart RG, Alings M, Avezum A, Díaz R, Hohnloser SH, Lewis BS, Shestakovska O, Wang J, Connolly SJ. Risk of ischaemic stroke according to pattern of atrial fibrillation: analysis of 6563 aspirin-treated patients in ACTIVE-A and AVERROES. Eur Heart J Feb 1;36(5): Epub 2014 Sep 3. Register Medische Staf 215

217 Mulder BA, Van Veldhuisen DJ, Crijns HJ, Tijssen JG, Hillege HL, Alings M, Rienstra M, Van den Berg MP, Van Gelder IC; RACE II Investigators. Digoxin in patients with permanent atrial fibrillation: data from the RACE II study. Heart Rhythm Sep;11(9): Epub 2014 Jun 9. Blankestijn PJ, Alings M, Voskuil M, Grobbee DE. The complexity after simplicity: How to proceed with renal denervation in hypertension? Eur J Prev Cardiol Jun 9. pii: [Epub ahead of print] PubMed PMID: Habibovi M, Cuijpers P, Alings M, van der Voort P, Theuns D, Bouwels L, Herrman JP, Valk S, Pedersen S. Attrition and adherence in a WEB-Based Distress Management Program for Implantable Cardioverter defibrillator Patients (WEBCARE): randomized controlled trial. J Med Internet Res Feb 28;16(2):e52. Whitlock R, Healey J, Vincent J, Brady K, Teoh K, Royse A, Shah P, Guo Y, Alings M, Folkeringa RJ, Paparella D, Colli A, Meyer SR, Legare JF, Lamontagne F, Reents W, Böning A, Connolly S. Rationale and design of the Left Atrial Appendage Occlusion Study (LAAOS) III. Ann Cardiothorac Surg Jan;3(1): Wallentin L, Lopes RD, Hanna M, Thomas L, Hellkamp A, Nepal S, Hylek EM, Al-Khatib SM, Alexander JH, Alings M, Amerena J, Ansell J, Aylward P, Bartunek J, Commerford P, De Caterina R, Erol C, Harjola VP, Held C, Horowitz J, Huber K, Husted S, Keltai M, Lanas F, Lisheng L, McMurray JJ, Oh BH, Rosenqvist M, Ruzyllo W, Steg PG, Vinereanu D, Xavier D, Granger CB. Response to letter regarding article, Efficacy and safety of apixaban compared with warfarin at different levels of predicted international normalized ratio control for stroke prevention in atrial fibrillation. Circulation Jan 14;129(2):e21-2. Dello SA, Alings M. Reply to letter from J. Finsterer and S. Zarrouk-Mahjoub. Neth Heart J Jun;22(6):306. Heidbuchel H; all the authors of the EHRA Practical Guide:, Verhamme P, Alings M, Antz M, Hacke W, Oldgren J, Sinnaeve P, John Camm A, Kirchhof P. Author reply on: European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace Jan;16(1): Alexander JH, Lopes RD, Thomas L, Alings M, Atar D, Aylward P, Goto S, Hanna M, Huber K, Husted S, Lewis BS, McMurray JJ, Pais P, Pouleur H, Steg PG, Verheugt FW, Wojdyla DM, Granger CB, Wallentin L. Apixaban vs. warfarin with concomitant aspirin in patients with atrial fibrillation: insights from the ARISTOTLE trial. Eur Heart J Jan;35(4): Epub 2013 Oct 20. Heidbuchel H; all authors of the EHRA Practical Guide:, Verhamme P, Alings M, Antz M, Hacke W, Oldgren J, Sinnaeve P, John Camm A, Kirchhof P. Authors response: from monitoring to vigilance about patient adherence to new oral anticoagulants. Europace Jan;16(1): Epub 2013 Sep

218 Van den Broek KC, Kupper N, van der Voort PH, Alings M, Denollet J, Nyklíček I. Trajectories of perceived emotional and physical distress in patients with an implantable cardioverter defibrillator. Int J Behav Med Feb;21(1): Vermond RA, Crijns HJ, Tijssen JG, Alings AM, Van den Berg MP, Hillege HL, Van Veldhuisen DJ, Van Gelder IC, Rienstra M; RACE II investigators. Symptom severity is associated with cardiovascular outcome in patients with permanent atrial fibrillation in the RACE II study. Europace Oct;16(10): Epub 2014 Jun 17. De Bree LC, Alings AM, van Wijngaarden P. Heparin-induced thrombocytopenia after ICD-lead flushing. Acta Cardiol Apr;69(2): Teeuwen K, Van den Branden BJ, Koolen JJ, van der Schaaf RJ, Henriques JP, Tijssen JG, Kelder JC, Vermeersch PH, Rensing BJ, Suttorp MJ. Three-year clinical outcome in the Primary Stenting of Totally Occluded Native Coronary Arteries III (PRISON III) trial: a randomised comparison between sirolimus-eluting stent implantation and zotarolimus-eluting stent implantation for the treatment of total coronary occlusions. EuroIntervention Aug 20. pii: [Epub ahead of print] Snijder RJ, Post MC, Mulder TB, Van den Branden BJ, Ten Berg JM, Suttorp MJ. Persistent high residual shunt rate 2 years after patent foramen ovale closure using a bioabsorbable device. JACC Cardiovasc Interv Jan;7(1): No abstract available. Bennaghmouch N, Dewilde WJ, Ten Berg JM. Dual antiplatelet therapy in the anticoagulated patient undergoing percutaneous coronary intervention risks, benefits, and unanswered questions. Curr Cardiol Rep Dec;16(12):548. Dewilde WJ, Janssen PW, Verheugt FW, Storey RF, Adriaenssens T, Hansen ML, Lamberts M, Ten Berg JM. Triple therapy for atrial fibrillation and percutaneous coronary intervention: a contemporary review. J Am Coll Cardiol Sep 23;64(12): Review. Lamberts M, Dewilde W, Hansen ML. Atrial fibrillation and coronary artery disease: which antithrombotic treatment strategy? Curr Opin Cardiol Nov;29(6): Dewilde WJ, Janssen PW, Kelder JC, Verheugt FW, De Smet BJ, Adriaenssens T, Vrolix M, Brueren GB, Vandendriessche T, Van Mieghem C, Cornelis K, Vos J, Breet NJ, Ten Berg JM. Uninterrupted oral anticoagulation versus bridging in patients with long-term oral anticoagulation during percutaneous coronary intervention: subgroup analysis from the WOEST trial. EuroIntervention Jun 28. pii: [Epub ahead of print] Bergmeijer TO, Janssen PW, Schipper JC, Qaderdan K, Ishak M, Ruitenbeek RS, Asselbergs FW, van t Hof AW, Dewilde WJ, Spanó F, Herrman JP, Kelder JC, Postma MJ, de Boer A, Deneer VH, ten Berg JM. CYP2C19 genotype-guided antiplatelet therapy in ST-segment elevation myocardial infarction patients-rationale and design of the Patient Outcome after primary PCI (POPular) Genetics study. Am Heart J Jul;168(1):16-22.e1. Epub 2014 Mar 21. Register Medische Staf 217

219 Valente MA, Hillege HL, Navis G, Voors AA, Dunselman PH, van Veldhuisen DJ, Damman K. The Chronic Kidney Disease Epidemiology Collaboration equation outperforms the Modification of Diet in Renal Disease equation for estimating glomerular filtration rate in chronic systolic heart failure. Eur J Heart Fail Jan;16(1): Epub 2013 Dec 3. McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau J, Shi VC, Solomon SD, Swedberg K, Zile MR; PARADIGM-HF Committees and Investigators* [Dunselman PH et al...]. Dual angiotensin receptor and neprilysin inhibition as an alternative to angiotensin-converting enzyme inhibition in patients with chronic systolic heart failure: rationale for and design of the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF). Eur J Heart Fail Sep;15(9): Epub 2013 Apr 5. Maggioni AP, Dahlström U, Filippatos G, Chioncel O, Crespo Leiro M, Drozdz J, Fruhwald F, Gullestad L, Logeart D, Fabbri G, Urso R, Metra M, Parissis J, Persson H, Ponikowski P, Rauchhaus M, Voors AA, Nielsen OW, Zannad F, Tavazzi L; Heart Failure Association of the European Society of Cardiology (HFA)* [Dunselman PH et al...]. EURObservational Research Programme: regional differences and 1-year follow-up results of the Heart Failure Pilot Survey (ESC-HF Pilot). Eur J Heart Fail Jul;15(7): Epub 2013 Mar 28. Daniels LB, Grady D, Mosca L, Collins P, Mitlak BH, Amewou-Atisso MG, Wenger NK, Barrett-Connor E; Raloxifene Use for the Heart (RUTH) Trial Investigators* [Dunselman PH et al...] Is diabetes mellitus a heart disease equivalent in women? Results from an international study of postmenopausal women in the Raloxifene Use for the Heart (RUTH) Trial. Circ Cardiovasc Qual Outcomes Mar 1;6(2): Epub 2013 Mar 12. Swedberg K, Young JB, Anand IS, Cheng S, Desai AS, Diaz R, Maggioni AP, McMurray JJ, O Connor C, Pfeffer MA, Solomon SD, Sun Y, Tendera M, van Veldhuisen DJ; RED-HF Committees; RED-HF Investigators* [Dunselman PH et al...]. Treatment of anemia with darbepoetin alfa in systolic heart failure. N Engl J Med Mar 28;368(13): Epub 2013 Mar 10. McMurray JJ, Anand IS, Diaz R, Maggioni AP, O Connor C, Pfeffer MA, Solomon SD, Tendera M, van Veldhuisen DJ, Albizem M, Cheng S, Scarlata D, Swedberg K, Young JB; RED-HF Committees Investigators* [Dunselman PH et al...]. Baseline characteristics of patients in the Reduction of Events with Darbepoetin alfa in Heart Failure trial (RED-HF). Eur J Heart Fail Mar;15(3): Epub 2013 Jan 17. Fernández-Rodríguez D, Regueiro A, Brugaletta S, Martín-Yuste V, Masotti M, Cequier A, Iñíguez A, Serra A, Hernández-Antolín R, Mainar V, Valgimigli M, Tespili M, den Heijer P, Bethencourt A, Vázquez N, Serruys PW, Sabaté M; EXAMINATION investigators. Optimization in stent implantation by manual thrombus aspiration in ST-segment-elevation myocardial infarction: findings from the EXAMINATION trial. Circ Cardiovasc Interv Jun;7(3): Epub 2014 May

220 Lenders GD, Collas V, Hernandez JM, Legrand V, Danenberg HD, den Heijer P, Rodrigus IE, Paelinck BP, Vrints CJ, Bosmans JM. Depth of valve implantation, conduction disturbances and pacemaker implantation with CoreValve and CoreValve Accutrak system for Transcatheter Aortic Valve Implantation, a multi-center study. Int J Cardiol Oct 20;176(3): Epub 2014 Aug 1. Nijenhuis VJ, Stella PR, Baan J, Brueren BR, de Jaegere PP, den Heijer P, Hofma SH, Kievit P, Slagboom T, van den Heuvel AF, van der Kley F, van Garsse L, van Houwelingen KG, Van t Hof AW, Ten Berg JM. Antithrombotic therapy in patients undergoing TAVI: an overview of Dutch hospitals. Neth Heart J Feb;22(2):64-9. Ielasi A, Brugaletta S, Silvestro A, Cequier A, Iñiguez A, Serra A, Hernandez-Antolin R, Mainar V, Valgimigli M, den Heijer P, Bethencourt A, Vazquez N, Serruys P, Sabate M, Tespili M. Everolimuseluting stent versus bare-metal stent in elderly ( 75years) versus non-elderly (<75years) patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention: Insights from the examination trial. Int J Cardiol Jan 20;179:73-8. Epub 2014 Oct 22. Den Dekker WK, Houtgraaf JH, Rowland SM, Ligtenberg E, de Boer SP, de Jong R, de Winter RJ, den Heijer P, Zijlstra F, Serruys PW, Cheng C, Duckers HJ. Efficiency of Statin Treatment on EPC Recruitment Depends on Baseline EPC Titer and Does Not Improve Angiographic Outcome in Coronary Artery Disease Patients Treated With the Genous Stent. Cell Transplantation 2014;23: Epub 2013 Apr 3. Petraco R, Al-Lamee R, Gotberg M, Sharp A, Hellig F, Nijjer SS, Echavarria-Pinto M, van de Hoef TP, Sen S, Tanaka N, Van Belle E, Bojara W, Sakoda K, Mates M, Indolfi C, De Rosa S, Vrints CJ, Haine S, Yokoi H, Ribichini FL, Meuwissen M, Matsuo H, Janssens L, Katsumi U, Di Mario C, Escaned J, Piek J, Davies JE. Real-time use of instantaneous wave-free ratio: results of the ADVISE in-practice: an international, multicenter evaluation of instantaneous wave-free ratio in clinical practice. Am Heart J Nov;168(5): Epub 2014 Jul 21. Verloop WL, Agema WR, Allaart CP, Blankestijn PJ, Khan M, Meuwissen M, Muijs van de Moer WM, Rensing BJ, Spiering W, Voskuil M, Doevendans PA; working group for renal denervation. Renal denervation for the treatment of hypertension: the Dutch consensus. Neth J Med Nov;72(9): Van de Hoef TP, Meuwissen M, Escaned J, Sen S, Petraco R, van Lavieren MA, Echavarria-Pinto M, Nolte F, Nijjer S, Chamuleau SA, Voskuil M, van Eck-Smit BL, Verberne HJ, Henriques JP, Koch KT, de Winter RJ, Spaan JA, Siebes M, Tijssen JG, Davies JE, Piek JJ. Head-to-head comparison of basal stenosis resistance index, instantaneous wave-free ratio, and fractional flow reserve: diagnostic accuracy for stenosis-specific myocardial ischaemia. EuroIntervention Aug 30. [Epub ahead of print]. Register Medische Staf 219

221 Petraco R, van de Hoef TP, Nijjer S, Sen S, van Lavieren MA, Foale RA, Meuwissen M, Broyd C, Echavarria-Pinto M, Foin N, Malik IS, Mikhail GW, Hughes AD, Francis DP, Mayet J, Di Mario C, Escaned J, Piek JJ, Davies JE. Baseline instantaneous wave-free ratio as a pressure-only estimation of underlying coronary flow reserve: results of the JUSTIFY-CFR Study (Joined Coronary Pressure and Flow Analysis to Determine Diagnostic Characteristics of Basal and Hyperemic Indices of Functional Lesion Severity-Coronary Flow Reserve). Circ Cardiovasc Interv Aug;7(4): Epub 2014 Jul 1. Nolte F, van de Hoef TP, Meuwissen M, Voskuil M, Chamuleau SA, Henriques JP, Verberne HJ, van Eck-Smit BL, Koch KT, de Winter RJ, Spaan JA, Tijssen JG, Siebes M, Piek JJ. Increased hyperaemic coronary microvascular resistance adds to the presence of myocardial ischaemia. EuroIntervention. 2014;9(12): Van de Hoef TP, Nolte F, EchavarrÍa-Pinto M, van Lavieren MA, Damman P, Chamuleau SA, Voskuil M, Verberne HJ, Henriques JP, van Eck-Smit BL, Koch KT, de Winter RJ, Spaan JA, Siebes M, Tijssen JG, Meuwissen M, Piek JJ. Impact of hyperaemic microvascular resistance on fractional flow reserve measurements in patients with stable coronary artery disease: insights from combined stenosis and microvascular resistance assessment. Heart Jun;100(12): Epub 2014 Apr 11. Van de Hoef TP, van Lavieren MA, Damman P, Delewi R, Piek MA, Chamuleau SA, Voskuil M, Henriques JP, Koch KT, de Winter RJ, Spaan JA, Siebes M, Tijssen JG, Meuwissen M, Piek JJ. Physiological basis and long-term clinical outcome of discordance between fractional flow reserve and coronary flow velocity reserve in coronary stenoses of intermediate severity. Circ Cardiovasc Interv Jun;7(3): Epub 2014 Apr 29. Schaap J, de Groot JA, Nieman K, Meijboom WB, Boekholdt SM, Kauling RM, Post MC, Van der Heyden JA, de Kroon TL, Rensing BJ, Moons KG, Verzijlbergen JF. Added value of hybrid myocardial perfusion SPECT and CT coronary angiography in the diagnosis of coronary artery disease. Eur Heart J Cardiovasc Imaging Nov;15(11): Epub 2014 Jul 29. Schaap J, de Groot JA, Nieman K, Meijboom WB, Boekholdt SM, Kauling RM, Post MC, Van der Heyden JA, de Kroon TL, Rensing BJ, Moons KG, Verzijlbergen JF. Added value of hybrid myocardial perfusion SPECT and CT coronary angiography in the diagnosis of coronary artery disease. Eur Heart J Cardiovasc Imaging Nov;15(11): Epub 2014 Jul 29. Schölzel BE, Snijder RJ, Mager JJ, van Es HW, Plokker HW, Reesink HJ, Morshuis WJ, Post MC. Chronic thromboembolic pulmonary hypertension. Neth Heart J Dec;22(12): Schölzel BE, Post MC, van de Bruaene A, Dymarkowski S, Wuyts W, Meyns B, Budts W, Delcroix M. Prediction of hemodynamic improvement after pulmonary endarterectomy in chronic thromboembolic pulmonary hypertension using non-invasive imaging. Int J Cardiovasc Imaging Jan;31(1): Epub 2014 Aug

222 Schölzel BE, Post MC, Dymarkowski S, Wuyts W, Meyns B, Budts W, Morshuis W, Snijder RJ, Delcroix M. Prediction of outcome after PEA in chronic thromboembolic pulmonary hypertension using indexed pulmonary artery diameter. Eur Respir J Mar;43(3): Dewilde WJ, Janssen PW, Kelder JC, Verheugt FW, De Smet BJ, Adriaenssens T, Vrolix M, Brueren GB, Vandendriessche T, Van Mieghem C, Cornelis K, Vos J, Breet NJ, Ten Berg JM. Uninterrupted oral anticoagulation versus bridging in patients with long-term oral anticoagulation during percutaneous coronary intervention: subgroup analysis from the WOEST trial. EuroIntervention Jun 28. pii: [Epub ahead of print]. Cardiothoracale Chirurgie Tolsma M, Bentala M, Rosseel P, Gerritse BM, Dijkstra H, Mulder P, van der Meer N. The value of routine chest radiographs after minimally invasive cardiac surgery: an observational cohort study. J Cardiothorac Surg Nov 11;9(1):174. [Epub ahead of print]. Hogervorst E, Rosseel P, van der Bom J, Bentala M, Brand A, van der Meer N, van de Watering L. Tolerance of intraoperative hemoglobin decrease during cardiac surgery. Transfusion Oct;54(10 Pt 2): Epub 2014 Apr 14. De Jonge M, van Boxtel A, Soliman Hamad M, Mokhles M, Bramer S, Osnabrugge R, van Straten A, Berreklouw E. Intermittent warm blood versus cold crystalloid cardioplegia for myocardial protection: a propensity score-matched analysis of 12-year single-center experience. Perfusion Jun 26. [Epub ahead of print]. Hulsman N, Hiddema PA, Veen EJ, van der Meer NJ. Traumatic cardiac injury by gun nails. Int J Crit Illn Inj Sci Apr;4(2): Chirurgie Van Erning FN, Crolla RM, Rutten HJ, Beerepoot LV, van Krieken JH, Lemmens VE. No change in lymph node positivity rate despite increased lymph node yield and improved survival in colon cancer. Eur J Cancer Dec;50(18): Van Baal MC, Bollen TL, Bakker OJ, van Goor H, Boermeester MA, Dejong CH, Gooszen HG, van der Harst E, van Eijck CH, van Santvoort HC, Besselink MG; Dutch Pancreatitis Study Group*. [Crolla R et al...]. The role of routine fine-needle aspiration in the diagnosis of infected necrotizing pancreatitis. Surgery Mar;155(3): Epub 2013 Oct 12. Register Medische Staf 221

223 Beek MA, Gobardhan PD, Klompenhouwer EG, Rutten HJ, Voogd AC, Luiten EJ. Axillary reverse mapping (ARM) in clinically node positive breast cancer patients. Eur J Surg Oncol Jan;41(1): Epub 2014 Oct 29. Barentsz MW, Postma EL, van Dalen T, van den Bosch MA, Miao H, Gobardhan PD, van den Hout LE, Pijnappel RM, Witkamp AJ, van Diest PJ, van Hillegersberg R, Verkooijen HM. Prediction of positive resection margins in patients with non-palpable breast cancer. Eur J Surg Oncol Jan;41(1): Epub 2014 Sep 2. Van der Slegt J, Steunenberg SL, Donker JM, Veen EJ, Ho GH, de Groot HG, van der Laan L. The current position of precuffed expanded polytetrafluoroethylene bypass grafts in peripheral vascular surgery. J Vasc Surg Jul;60(1): Epub 2014 Mar 12. Van der Slegt J, Flu HC, Veen EJ, Ho GH, de Groot HG, Vos LD, van der Laan L. Adverse events after treatment of patients with acute limb ischemia. Ann Vasc Surg Feb;29(2): Epub 2014 Nov 28. Van der Slegt J, Steunenberg SL, Donker JM, Veen EJ, Ho GH, de Groot HG, van der Laan L. The current position of precuffed expanded polytetrafluoroethylene bypass grafts in peripheral vascular surgery. J Vasc Surg Jul;60(1): Epub 2014 Mar 12. Te Slaa A, Dolmans D, Ho G, van der Laan L. Treatment strategies and clinical aspects of lower limb edema following peripheral bypass surgery. Phlebology May 19;29(1 suppl): [Epub ahead of print]. Van der Slegt J, Kluytmans JA, Mulder PG, Veen EJ, Ho GH, van der Laan L. Surgical site infection after multiple groin incisions in peripheral vascular surgery. Surg Infect (Larchmt) Dec;15(6): Raats JW, Flu HC, Ho GH, Veen EJ, Vos LD, Steyerberg EW, van der Laan L. Long-term outcome of ruptured abdominal aortic aneurysm: impact of treatment and age. Clin Interv Aging Oct 13;9: ecollection Van der Slegt J, Flu HC, Veen EJ, Ho GH, de Groot HG, Vos LD, van der Laan L. Adverse events after treatment of patients with acute limb ischemia. Ann Vasc Surg Feb;29(2): Epub 2014 Nov 28. De Kruijf M, Vroemen JP, de Leur K, van der Voort EA, Vos DI, van der Laan L. Proximal fractures of the humerus in patients older than 75 years of age: should we consider operative treatment? J Orthop Traumatol Jun;15(2): Van der Slegt J, Steunenberg SL, Donker JM, Veen EJ, Ho GH, de Groot HG, van der Laan L. The current position of precuffed expanded polytetrafluoroethylene bypass grafts in peripheral vascular surgery. J Vasc Surg Jul;60(1): Epub 2014 Mar

224 Hopmans CJ, den Hoed PT, van der Laan L, van der Harst E, van der Elst M, Mannaerts GH, Dawson I, Timman R, Wijnhoven BP, IJzermans JN. Assessment of surgery residents operative skills in the operating theater using a modified Objective Structured Assessment of Technical Skills (OSATS): A prospective multicenter study. Surgery Nov;156(5): Epub 2014 Sep 16. Te Slaa A, Dolmans D, Ho G, van der Laan L. Treatment strategies and clinical aspects of lower limb edema following peripheral bypass surgery. Phlebology May 19;29(1 suppl): [Epub ahead of print]. Raats JW, Donker JM, van der Laan L. Een jongen met pijn links onder in de buik. [A 15-year old boy with abdominal pain]. Ned Tijdschr Geneeskd. 2014;158:A6854. Van der Slegt J, Kluytmans JA, Mulder PG, Veen EJ, Ho GH, van der Laan L. Surgical site infection after multiple groin incisions in peripheral vascular surgery. Surg Infect (Larchmt) Dec;15(6): De Danschutter SJ, Schreinemakers JM, Smit LH, van der Laan L, Nuytinck HK. Thyroid surgery and the usefulness of intraoperative neuromonitoring, a single center study. J Invest Surg Nov 10. [Epub ahead of print] Raats JW, Flu HC, Ho GH, Veen EJ, Vos LD, Steyerberg EW, van der Laan L. Long-term outcome of ruptured abdominal aortic aneurysm: impact of treatment and age. Clin Interv Aging Oct 13;9: ecollection Van der Slegt J, Flu HC, Veen EJ, Ho GH, de Groot HG, Vos LD, van der Laan L. Adverse events after treatment of patients with acute limb ischemia. Ann Vasc Surg Feb;29(2): Epub 2014 Nov 28. Beek MA, Gobardhan PD, Klompenhouwer EG, Rutten HJ, Voogd AC, Luiten EJ. Axillary reverse mapping (ARM) in clinically node positive breast cancer patients. Eur J Surg Oncol Jan;41(1): Epub 2014 Oct 29. Van Verschuer VM, van Deurzen CH, Westenend PJ, Rothbarth J, Verhoef C, Luiten EJ, Menke-Pluijmers MB, Koppert LB. Prophylactic nipple-sparing mastectomy leaves more terminal duct lobular units in situ as compared with skin-sparing mastectomy. Am J Surg Pathol May;38(5): De Danschutter SJ, Schreinemakers JM, Smit LH, van der Laan L, Nuytinck HK. Thyroid surgery and the usefulness of intraoperative neuromonitoring, a single center study. J Invest Surg Nov 10. [Epub ahead of print] Sloothaak DA, van den Berg MW, Dijkgraaf MG, Fockens P, Tanis PJ, van Hooft JE, Bemelman WA; collaborative Dutch Stent-In study group [Rijken AM et al...]. Oncological outcome of malignant colonic obstruction in the Dutch Stent-In 2 trial. Br J Surg Dec;101(13): Register Medische Staf 223

225 Goos JA, Hiemstra AC, Coupé VM, Diosdado B, Kooijman W, Delis-Van Diemen PM, Karga C, Beliën JA, Menke-van der Houven van Oordt CW, Geldof AA, Meijer GA, Hoekstra OS, Fijneman RJ; DeCoDe PET group; DeCoDe PET group. [Rijken AM et al...]. Epidermal growth factor receptor (EGFR) and prostaglandin-endoperoxide synthase 2 (PTGS2) are prognostic biomarkers for patients with resected colorectal cancer liver metastases. Br J Cancer Aug 12;111(4): Epub 2014 Jul 1. Ruitenbeek K, Ayez N, Verhoef C, de Wilt JH, Bottema J, Rijken AM, van Rij M, Koopman J, Zuckerman LA, Frohna P, Porte RJ. Safety and efficacy of a novel, dry powder fibrin sealant for hemostasis in hepatic resection. Dig Surg. 2014;31(6): Epub 2015 Jan 14. De Rooij T, Jilesen AP, Boerma D, Bonsing BA, Bosscha K, van Dam RM, van Dieren S, Dijkgraaf MG, van Eijck CH, Gerhards MF, van Goor H, van der Harst E, de Hingh IH, Kazemier G, Klaase JM, Molenaar IQ, Nieveen van Dijkum EJ, Patijn GA, van Santvoort HC, Scheepers JJ, van der Schelling GP, Sieders E, Vogel JA, Busch OR, Besselink MG; Dutch Pancreatic Cancer Group. A nationwide comparison of laparoscopic and open distal pancreatectomy for benign and malignant disease. J Am Coll Surg Mar;220(3): e1. Epub 2014 Nov 20. Bakker OJ, van Brunschot S, van Santvoort HC, Besselink MG, Bollen TL, Boermeester MA, Dejong CH, van Goor H, Bosscha K, Ahmed Ali U, Bouwense S, van Grevenstein WM, Heisterkamp J, Houdijk AP, Jansen JM, Karsten TM, Manusama ER, Nieuwenhuijs VB, Schaapherder AF, van der Schelling GP, Schwartz MP, Spanier BW, Tan A, Vecht J, Weusten BL, Witteman BJ, Akkermans LM, Bruno MJ, Dijkgraaf MG, van Ramshorst B, Gooszen HG; Dutch Pancreatitis Study Group. Early versus on-demand nasoenteric tube feeding in acute pancreatitis. N Engl J Med Nov 20;371(21): Van Baal MC, Bollen TL, Bakker OJ, van Goor H, Boermeester MA, Dejong CH, Gooszen HG, van der Harst E, van Eijck CH, van Santvoort HC, Besselink MG; Dutch Pancreatitis Study Group*. [van der Schelling GP et al...]. The role of routine fine-needle aspiration in the diagnosis of infected necrotizing pancreatitis. Surgery Mar;155(3): Epub 2013 Oct 12. Van der Slegt J, Steunenberg SL, Donker JM, Veen EJ, Ho GH, de Groot HG, van der Laan L. The current position of precuffed expanded polytetrafluoroethylene bypass grafts in peripheral vascular surgery. J Vasc Surg Jul;60(1): Epub 2014 Mar 12. Van der Slegt J, Kluytmans JA, Mulder PG, Veen EJ, Ho GH, van der Laan L. Surgical site infection after multiple groin incisions in peripheral vascular surgery. Surg Infect (Larchmt) Dec;15(6): Raats JW, Flu HC, Ho GH, Veen EJ, Vos LD, Steyerberg EW, van der Laan L. Long-term outcome of ruptured abdominal aortic aneurysm: impact of treatment and age. Clin Interv Aging Oct 13;9: ecollection

226 Van der Slegt J, Flu HC, Veen EJ, Ho GH, de Groot HG, Vos LD, van der Laan L. Adverse events after treatment of patients with acute limb ischemia. Ann Vasc Surg Feb;29(2): Epub 2014 Nov 28. Hulsman N, Hiddema PA, Veen EJ, van der Meer NJ. Traumatic cardiac injury by gun nails. Int J Crit Illn Inj Sci Apr;4(2): De Kruijf M, Vroemen JP, de Leur K, van der Voort EA, Vos DI, Van der Laan L. Proximal fractures of the humerus in patients older than 75 years of age: should we consider operative treatment? J Orthop Traumatol Jun;15(2): Tiren D, Vos DI. Correction osteotomy of distal radius malunion stabilised with dorsal locking plates without grafting. Strategies Trauma Limb Reconstr Apr;9(1):53-8. Epub 2014 Mar 8. Schotanus M, van Hout N, Vos D. Pyoderma gangrenosum of the hand. Adv Skin Wound Care Feb;27(2):61-4. De Kruijf M, Vroemen JP, de Leur K, van der Voort EA, Vos DI, Van der Laan L. Proximal fractures of the humerus in patients older than 75 years of age: should we consider operative treatment? J Orthop Traumatol Jun;15(2): Bruinsma W, Kodde I, de Muinck Keizer RJ, Kloen P, Lindenhovius AL, Vroemen JP, Haverlag R, van den Bekerom MP, Bolhuis HW, Bullens PH, Meylaerts SA, van der Zwaal P, Steller PE, Hageman M, Ring DC, den Hartog D, Hammacher ER, King GJ, Athwal GS, Faber KJ, Drosdowech D, Grewal R, Goslings JC, Schep NW, Eygendaal D. A randomized controlled trial of nonoperative treatment versus open reduction and internal fixation for stable, displaced, partial articular fractures of the radial head: the RAMBO trial. BMC Musculoskelet Disord May 6;15:147. Mahabier KC, Van Lieshout EM, Bolhuis HW, Bos PK, Bronkhorst MW, Bruijninckx MM, De Haan J, Deenik AR, Dwars BJ, Eversdijk MG, Goslings JC, Haverlag R, Heetveld MJ, Kerver AJ, Kolkman KA, Leenhouts PA, Meylaerts SA, Onstenk R, Poeze M, Poolman RW, Punt BJ, Roerdink WH, Roukema GR, Sintenie JB, Soesman NM, Tanka AK, Ten Holder EJ, Van der Elst M, Van der Heijden FH, Van der Linden FM, Van der Zwaal P, Van Dijk JP, Van Jonbergen HP, Verleisdonk EJ, Vroemen JP, Waleboer M, Wittich P, Zuidema WP, Polinder S, Verhofstad MH, Den Hartog D. HUMeral shaft fractures: measuring recovery after operative versus non-operative treatment (HUMMER): a multicenter comparative observational study. BMC Musculoskelet Disord Feb 11;15:39. Van Gestel YR, de Hingh IH, van Herk-Sukel MP, van Erning FN, Beerepoot LV, Wijsman JH, Slooter GD, Rutten HJ, Creemers GJ, Lemmens VE. Patterns of metachronous metastases after curative treatment of colorectal cancer. Cancer Epidemiol. 2014;38(4): Epub 2014 May 16. Van Baal MC, Bollen TL, Bakker OJ, van Goor H, Boermeester MA, Dejong CH, Gooszen HG, van der Harst E, van Eijck CH, van Santvoort HC, Besselink MG; Dutch Pancreatitis Study Group*. [Wijsman J et al...]. The role of routine fine-needle aspiration in the diagnosis of infected necrotizing pancreatitis. Surgery Mar;155(3): Epub 2013 Oct 12. Register Medische Staf 225

227 Dermatologie Rozendaal AM, Erceg A, Kuijpers D. Een vergeten en ongewenste reisgezel. Ned Tijdschr Dermatol Veneorol okt. Rozendaal AM, Erceg A, Kuijpers D. Een vergeten en ongewenste reisgezel. Ned Tijdschr Dermatol Veneorol okt. De Kort WJ, El Seady-Rol M, Fisscher L. De visjestherapie bij psoriasis Ned Tijdschr Dermatol Venereol mrt;24(3): Gynaecologie / Verloskunde Jozwiak M, van de Lest HA, Burger NB, Dijksterhuis MG, De Leeuw JW. Cervical ripening with Foley catheter for induction of labor after cesarean section: a cohort study. Acta Obstet Gynecol Scand Mar;93(3): Epub 2014 Jan 13. Broekman EA, Versteeg H, Vos LD, Dijksterhuis MG, Papatsonis DN. Temporary balloon occlusion of the internal iliac arteries to prevent massive hemorrhage during cesarean delivery among patients with placenta previa. Int J Gynaecol Obstet Feb;128(2): Epub 2014 Nov 5. Dijksterhuis MG. De Nederlandse Voortgangstoets Obstetrie en Gynaecologie. Ned Tijdschr Obst Gyn Mar;127(3): Dijksterhuis MGK. Assessment to optimise postgraduate medical training [S.l.]: [s.n.], Proefschrift Vrije Universiteit Amsterdam. ISBN Van Doorn DE, van Leuken M, Rijnders RJ. Embolization of a left uterine artery mycotic aneurysm after a neglected, perforated appendicitis before delivery. Clin Case Rep Oct;2(5): Epub 2014 Jun 30. Monen L, van der Putten HW, van Hamont D. Een metastatisch proces na supra-cervicale laparoscopische hysterectomie. Ned Tijdschr Obst Gyn. 2014;127(3): Srebniak MI, Bos MJ, de Vries FA, Heydanus R, Wessels MW, Van Opstal D. SNP array detects chromosome aberrations that we thought do not exist: the first case of an isochromosome Xp (i(x)(p10)). Prenat Diagn Aug;34(8): Epub 2014 Apr 27. Nieuwenhuyzen-De Boer GM, Hoogeboom AJ, Smit LS, Heydanus R, Eggink AJ. Pfeiffer syndrome: the importance of prenatal diagnosis. Eur J Obstet Gynecol Reprod Biol Oct;181: Epub 2014 Aug

228 Hitzerd E, Jeurgens-Borst AJ, Pijnenborg JM. Peritoneal inclusion cysts in pregnancy, a diagnostic challenge. BMJ Case Rep Jun 13;2014. pii: bcr Ter Laak MA, Roos C, Touw DJ, van Hattum PR, Kwee A, Lotgering FK, J Mol BW, van Pampus MG, Porath MM, Spaanderman ME, van der Post JA, Papatsonis DN, van t Veer NE. Pharmacokinetics of nifedipine slow-release during sustained tocolysis. Int J Clin Pharmacol Ther Jan;53(1): Epub 2014 Nov 19. Broekman EA, Versteeg H, Vos LD, Dijksterhuis MG, Papatsonis DN. Temporary balloon occlusion of the internal iliac arteries to prevent massive hemorrhage during cesarean delivery among patients with placenta previa. Int J Gynaecol Obstet Feb;128(2): Epub 2014 Nov 5. Flenady V, Reinebrant HE, Liley HG, Tambimuttu EG, Papatsonis DN. Oxytocin receptor antagonists for inhibiting preterm labour. Cochrane Database Syst Rev Jun 6;6:CD Flenady V, Wojcieszek AM, Papatsonis DN, Stock OM, Murray L, Jardine LA, Carbonne B. Calcium channel blockers for inhibiting preterm labour and birth. Cochrane Database Syst Rev Jun 5;6:CD Wilmink FA, Hukkelhoven CW, van der Post JA, Steegers EA, Mol BW, Papatsonis DN. Timing van electieve keizersneden à terme: trends in Nederland. [Timing of elective term caesarean sections; trends in the Netherlands]. Ned Tijdschr Geneeskd. 2014;158:A6951. Van de Mheen L, Schuit E, Lim AC, Porath MM, Papatsonis D, Erwich JJ, van Eyck J, van Oirschot CM, Hummel P, Duvekot JJ, Hasaart TH, Groenwold RH, Moons KG, de Groot CJ, Bruinse HW, van Pampus MG, Mol BW. Prediction of preterm birth in multiple pregnancies: development of a multivariable model including cervical length measurement at 16 to 21 weeks gestation. J Obstet Gynaecol Can Apr;36(4): Quispel C, Bangma M, Kazemier BM, Steegers EA, Hoogendijk WJ, Papatsonis DN, Paarlberg KM, Lambregtse-Van Den Berg MP, Bonsel GJ. The role of depressive symptoms in the pathway of demographic and psychosocial risks to preterm birth and small for gestational age. Midwifery Aug;30(8): Epub 2014 Mar 19. Van der Ham DP, van Kuijk S, Opmeer BC, Willekes C, van Beek JJ, Mulder AL, van Loon AJ, Groenewout M, Mantel GD, Bloemenkamp KW, Porath M, Kwee A, Akerboom BM, Papatsonis DN, Metz GC, Nijhuis JG, Mol BW; PPROMEXIL trial group. Can neonatal sepsis be predicted in late preterm premature rupture of membranes? Development of a prediction model. Eur J Obstet Gynecol Reprod Biol May;176:90-5. Epub 2014 Feb 13. Register Medische Staf 227

229 Prick BW, Jansen AJ, Steegers EA, Hop WC, Essink-Bot ML, Uyl-de Groot CA, Akerboom BM, van Alphen M, Bloemenkamp KW, Boers KE, Bremer HA, Kwee A, van Loon AJ, Metz GC, Papatsonis DN, van der Post JA, Porath MM, Rijnders RJ, Roumen FJ, Scheepers HC, Schippers DH, Schuitemaker NW, Stigter RH, Woiski MD, Mol BW, van Rhenen DJ, Duvekot JJ. Transfusion policy after severe postpartum haemorrhage: a randomised non-inferiority trial. BJOG Jul;121(8): Epub 2014 Jan 10. Van Oostwaard MF, Langenveld J, Schuit E, Wigny K, Van Susante H, Beune I, Ramaekers R, Papatsonis DN, Mol BW, Ganzevoort W. Prediction of recurrence of hypertensive disorders of pregnancy in the term period, a retrospective cohort study. Pregnancy Hypertension 2014 apr 22;4(3): [E-pub]. Huisman C, Oude Rengerink K, Jozwiak M, Duvekot H, van Eyck J, Gaugler I, Franssen M, van Gemund N, Heres M, Langeveld J, de Leeuw JW, Oude Lohuis E, Oudijk M, Papatsonis D, van Pampus M, Porath M, van de Salm P, Scheepers L, Sikkema M, Sporken J, Stigter R, van Wijngaarden W, Woiski M, Mol BW, Bloemenkamp K. Effectiveness and safety of different methods for induction of labor in women with a previous cesarean section. [P682]. Am J Obstet Gynecol jan;210(suppl 1):S Van Oostwaard M, Langenveld J, Schuit E, Wigny K, van Susante H, Beune I, Ramaekers R, Papatsonis D, Mol BW, Ganzevoort W. Prediction of recurrence of hypertensive disorders of pregnancy in the term period, a retrospective cohort study.[p291]. Am J Obstet Gynecol jan;210 (suppl 1):S Broekhuijsen K, van Baaren GJ, van Pampus M, Sikkema M, Woiski M, Oudijk M, Bloemenkamp K, Scheepers H, Bremer H, Rijnders R, van Loon A, Perquin D, Sporken J, Papatsonis D, van Huizen M, Vredevoogd C, Brons J, van Kaam A, Groen H, Porath M, Mol B, Franssen M, Langenveld J. Delivery versus expectant monitoring for late preterm hypertensive disorders of pregnancy (HYPITAT-II): a multicenter, open label, randomized controlled trial. [P2]. Am J Obstet Gynecol jan;210(suppl 1): S2-3. Freeman L, Bloemenkamp K, Franssen M, Papatsonis D, Hollmann M, Woiski M, Porath, van den Berg H, van Beek E, Schuitemaker N, Sikkema M, Logtenberg S, Oudijk M, Bax C, van der Salm P, van den Akker-van Marle E, le Cessie S, van Lith J, Struys M, Dahan A, Mol BW, Middeldorp J. Remifentanil patient controlled analgesia versus epidural analgesia in labor; a randomized controlled equivalence trial. [P54]. Am J Obstet Gynecol jan;210(suppl 1):S36-7. Interne Geneeskunde en Maag-, Darm-, Levergeneeskunde Kant KM, Djamin RS, Belderbos HN, van den Berg B. Acute respiratoire insufficiëntie door COPD: Beslissen over wel of niet beademen. [Acute respiratory insufficiency due to COPD: invasive mechanical ventilation or not?]. Ned Tijdschr Geneeskd. 2014;158:A

230 Bodelier AG, Pierik MJ, van den Heuvel T, Bovee-Oudenhoven IM, de Boer E, Hameeteman W, Masclee AA, Jonkers D. Pancreatitis-associated protein has no additional value as a marker of disease activity in a real-life cohort of IBD patients. Eur J Gastroenterol Hepatol Aug;26(8): Boersma RS, Jie KS, Voogd AC, Hamulyak K, Verbon A, Schouten HC. Concentrated citrate locking in order to reduce the long-term complications of central venous catheters: a randomized controlled trial in patients with hematological malignancies. Support Care Cancer Jan;23(1): Epub 2014 Jun 20. Van Gammeren AJ, Alcala LS, Smolders M, Boersma RS. Numerous Russell bodies and Dutcher bodies in multiple myeloma. Br J Haematol Oct 14. [Epub ahead of print] Buiten MS, de Bie MK, Bouma-de Krijger A, van Dam B, Dekker FW, Jukema JW, Rabelink TJ, Rotmans JI. Soluble Klotho is not independently associated with cardiovascular disease in a population of dialysis patients. BMC Nephrol Dec 11;15:197. Van den Berg SA, Verwer PE, Idema RN, Van Guldener C. Transient cefuroxime/metronidazole treatment induced factor V antibodies. BMJ Case Rep Aug 19;2014. pii: bcr Van Heerde MJ, Buijs J, Rauws EA, de Buy Wenniger LJ, Hansen BE, Biermann K, Verheij J, Vleggaar FP, Brink MA, Beuers UH, Kuipers EJ, van Buuren HR, Bruno MJ. A comparative study of diagnostic scoring systems for autoimmune pancreatitis. Pancreas May;43(4): Buijs J, van Heerde MJ, Rauws EA, de Buy Wenniger LJ, Hansen BE, Biermann K, Verheij J, Vleggaar FP, Brink MA, Beuers UH, Kuipers EJ, Bruno MJ, van Buuren HR. Comparable efficacy of low- versus high-dose induction corticosteroid treatment in autoimmune pancreatitis. Pancreas Mar;43(2): Van Heerde MJ, Buijs J, Hansen BE, de Waart M, van Eijck CH, Kazemier G, Pek CJ, Poley JW, Bruno MJ, Kuipers EJ, van Buuren HR. Serum level of Ca 19-9 increases ability of IgG4 test to distinguish patients with autoimmune pancreatitis from those with pancreatic carcinoma. Dig Dis Sci Jun;59(6): Epub 2014 Jan 3. Boonstra K, Culver EL, de Buy Wenniger LM, van Heerde MJ, van Erpecum KJ, Poen AC, van Nieuwkerk KM, Spanier BW, Witteman BJ, Tuynman HA, van Geloven N, van Buuren H, Chapman RW, Barnes E, Beuers U, Ponsioen CY. Serum immunoglobulin G4 and immunoglobulin G1 for distinguishing immunoglobulin G4-associated cholangitis from primary sclerosing cholangitis. Hepatology May;59(5): Epub 2014 Apr 1. Register Medische Staf 229

231 Charehbili A, van de Ven S, Smit VT, Meershoek-Klein Kranenbarg E, Hamdy NA, Putter H, Heijns JB, van Warmerdam LJ, Kessels L, Dercksen M, Pepels MJ, Maartense E, van Laarhoven HW, Vriens B, Wasser MN, van Leeuwen-Stok AE, Liefers GJ, van de Velde CJ, Nortier JW, Kroep JR; Dutch Breast Cancer Research Group (BOOG). Addition of zoledronic acid to neoadjuvant chemotherapy does not enhance tumor response in patients with HER2-negative stage II/III breast cancer: the NEOZOTAC trial (BOOG ). Ann Oncol May;25(5): Epub 2014 Feb 27. Onstenk W, Kraan J, Mostert B, Timmermans MM, Charehbili A, Smit VT, Kroep JR, Nortier JW, van de Ven S, Heijns JB, Kessels LW, van Laarhoven HW, Bos MM, van de Velde CJ, Gratama JW, Sieuwerts AM, Martens JW, Foekens JA, Sleijfer S. Improved Circulating Tumor Cell Detection by a Combined EpCAM and MCAM CellSearch Enrichment Approach in Patients with Breast Cancer Undergoing Neoadjuvant Chemotherapy. Mol Cancer Ther Dec 31. [Epub ahead of print] Lankhorst S, Kappers MH, van Esch JH, Smedts FM, Sleijfer S, Mathijssen RH, Baelde HJ, Danser AH, van den Meiracker AH. Treatment of hypertension and renal injury induced by the angiogenesis inhibitor sunitinib: preclinical study. Hypertension Dec;64(6): Epub 2014 Sep 2. Krol CG, Klok FA, de Koning EJ. Diplopia as the presenting symptom of type 1 diabetes. Diabetes Care Mar;37(3):e45-6. Krol CG, Dekkers OM, Kroon HM, Rabelink TJ, van Hoek B, Hamdy NA. Longitudinal changes in BMD and fracture risk in orthotopic liver transplant recipients not using bone-modifying treatment. J Bone Miner Res Aug;29(8): Krol CG, Dekkers OM, Kroon HM, Rabelink TJ, van Hoek B, Hamdy NA. No association between BMD and prevalent vertebral fractures in liver transplant recipients at time of screening before transplantation. J Clin Endocrinol Metab Oct;99(10): Epub 2014 Jul 24. Sloothaak DA, van den Berg MW, Dijkgraaf MG, Fockens P, Tanis PJ, van Hooft JE, Bemelman WA; collaborative Dutch Stent-In study group [van Milligen de Wit M et al...]. Oncological outcome of malignant colonic obstruction in the Dutch Stent-In 2 trial. Br J Surg Dec;101(13): Van Baal MC, Bollen TL, Bakker OJ, van Goor H, Boermeester MA, Dejong CH, Gooszen HG, van der Harst E, van Eijck CH, van Santvoort HC, Besselink MG; Dutch Pancreatitis Study Group*. [van Milligen de Wit M et al...]. The role of routine fine-needle aspiration in the diagnosis of infected necrotizing pancreatitis. Surgery Mar;155(3): Epub 2013 Oct 12. De Boer YS, van Gerven NM, Zwiers A, Verwer BJ, van Hoek B, van Erpecum KJ, Beuers U, van Buuren HR, Drenth JP, den Ouden JW, Verdonk RC, Koek GH, Brouwer JT, Guichelaar MM, Vrolijk JM, Kraal G, Mulder CJ, van Nieuwkerk CM, Fischer J, Berg T, Stickel F, Sarrazin C, Schramm C, Lohse AW, Weiler-Normann C, Lerch MM, Nauck M, Völzke H, Homuth G, Bloemena E, Verspaget HW, Kumar V, Zhernakova A, Wijmenga C, Franke L, Bouma G; Dutch Autoimmune Hepatitis Study Group* [van Milligen de Wit M et al...].; LifeLines Cohort Study; Study of Health in Pomerania. Genome-wide association study identifies variants associated with autoimmune hepatitis type 1. Gastroenterology Aug;147(2): e5. Epub 2014 Apr

232 Van Gerven NM, Verwer BJ, Witte BI, van Erpecum KJ, van Buuren HR, Maijers I, Visscher AP, Verschuren EC, van Hoek B, Coenraad MJ, Beuers UH, de Man RA, Drenth JP, den Ouden JW, Verdonk RC, Koek GH, Brouwer JT, Guichelaar MM, Vrolijk JM, Mulder CJ, van Nieuwkerk CM, Bouma G; Dutch Autoimmune Hepatitis STUDY group [van Milligen de Wit AWM et al...]. Epidemiology and clinical characteristics of autoimmune hepatitis in the Netherlands. Scand J Gastroenterol Oct;49(10): Epub 2014 Aug 15. Barendse R, Musters G, Fockens P, Bemelman W, de Graaf E, van den Broek F, van der Linde K, Schwartz M, Houben M, van Milligen de Wit A, Witteman B, Winograd R, Dekker E; TREND study group. Endoscopic mucosal resection of large rectal adenomas in the era of centralization: Results of a multicenter collaboration. United European Gastroenterol J Dec;2(6): Van Baal MC, Bollen TL, Bakker OJ, van Goor H, Boermeester MA, Dejong CH, Gooszen HG, van der Harst E, van Eijck CH, van Santvoort HC, Besselink MG; Dutch Pancreatitis Study Group*. [Rijk M et al...]. The role of routine fine-needle aspiration in the diagnosis of infected necrotizing pancreatitis. Surgery Mar;155(3): Epub 2013 Oct 12. Ahmed Ali U, Issa Y, van Goor H, van Eijck CH, Nieuwenhuijs VB, Keulemans Y, Fockens P, Busch OR, Drenth JP, Dejong CH, van Dullemen HM, van Hooft JE, Siersema PD, Spanier BW, Poley JW, Poen AC, Timmer R, Seerden T, Tan AC, Thijs WJ, Witteman BJ, Romkens TE, Roeterdink AJ, Gooszen HG, van Santvoort HC, Bruno MJ, Boermeester MA; Dutch Pancreatitis Study Group. Dutch Chronic Pancreatitis Registry (CARE): Design and rationale of a nationwide prospective evaluation and follow-up. Pancreatology Jan-Feb;15(1): Epub 2014 Nov 29. Ruff P, Ferry DR, Lakom ỳ R, Prausová J, Van Hazel GA, Hoff PM, Cunningham D, Arnold D, Schmoll HJ, Moiseyenko VM, McKendrick JJ, Ten Tije AJ, Vishwanath RL, Bhargava P, Chevalier S, Macarulla T, Van Cutsem E. Time course of safety and efficacy of aflibercept in combination with FOLFIRI in patients with metastatic colorectal cancer who progressed on previous oxaliplatinbased therapy. Eur J Cancer Jan;51(1): Epub 2014 Nov 14. Lam SW, de Groot SM, Honkoop AH, Jager A, Ten Tije AJ, Bos MM, Linn SC, van den Bosch J, Kroep JR, Braun JJ, van Tinteren H, Boven E; Dutch Breast Cancer Research Group. Paclitaxel and bevacizumab with or without capecitabine as first-line treatment for HER2-negative locally recurrent or metastatic breast cancer: a multicentre, open-label, randomised phase 2 trial. Eur J Cancer Dec;50(18): Wissing MD, Coenen JL, van den Berg P, Westgeest HM, van den Eertwegh AJ, van Oort IM, Bos MM, Bergman AM, Hamberg P, Ten Tije AJ, Los M, Lolkema MP, de Wit R, Gelderblom H. CAST: A retrospective analysis of cabazitaxel and abiraterone acetate sequential treatment in patients with metastatic castrate-resistant prostate cancer previously treated with docetaxel. Int J Cancer Mar 15;136(6):E Epub 2014 Oct 3. Bosscher MR, Wentholt IM, Ackermans MT, Nieveen van Dijkum EJ. An adrenal mass and increased catecholamines: monoamine oxidase or pheochromocytoma effect? J Clin Med Res Mar;7(3): Epub 2014 Dec 29. Register Medische Staf 231

233 Wissing MD, Coenen JL, van den Berg P, Westgeest HM, van den Eertwegh AJ, van Oort IM, Bos MM, Bergman AM, Hamberg P, Ten Tije AJ, Los M, Lolkema MP, de Wit R, Gelderblom H. CAST: A retrospective analysis of cabazitaxel and abiraterone acetate sequential treatment in patients with metastatic castrate-resistant prostate cancer previously treated with docetaxel. Int J Cancer Mar 15;136(6):E Epub 2014 Oct 3. De Bree LC, Alings AM, van Wijngaarden P. Heparin-induced thrombocytopenia after ICD-lead flushing. Acta Cardiol Apr;69(2): Raven CF, van Wijngaarden P, Moen G, van Rijen MM. Clusteruitbraak MRSA buiten het ziekenhuis: Herkennen en aanpakken. [Cluster outbreak of MRSA in the community; recognition and approach]. Ned Tijdschr Geneeskd. 2014;158:A6812. Hendrikse WM, Grootenboers MJ, van Wijngaarden P. Type B lactic acidosis as initial presentation of acute myeloid leukaeemia. A case report. Neth J Crit Care apr;18(2):15-6. Keel-, Neus-, en Oorheelkunde Bruintjes TD, Companjen J, van der Zaag-Loonen HJ, van Benthem PP. A randomised shamcontrolled trial to assess the long-term effect of the Epley manoeuvre for treatment of posterior canal benign paroxysmal positional vertigo. Clin Otolaryngol Feb;39(1): De Ru JA, Van Benthem PP, van Wermeskerken GK. Injudicious use of EBM: one step forward, two steps back. B-ENT. 2014;10(4): Kindergeneeskunde De Man SA, Aarts-Tesselaar CD, Festen DA. Transitie van zorg bij jongeren met een verstandelijke beperking: van generalist naar generalist. [Health care transition in young people with intellectual disabilities: from generalist to generalist]. Ned Tijdschr Geneeskd. 2014;158:A8072. Hulsmann AR, Smid G, Landman JR, Schuur J, Langeveld-Wildschut EG. Van maat naar maatschap: Van IFMS naar GFMS. A & I jun;(2):53-8. Langeveld-Wildschut A, Joosten P, Nobruis O, Hulsmann A. Een goede maatschap, een goede specialist. Med Contact apr;69(15): De Wijs-Meijler DP, Jonkers MH, Ermens AA. Een neonaat met een navelstompbloeding. [A neonate with umbilical cord bleeding]. Ned Tijdschr Geneeskd. 2014;158:A7587. De Man SA, Aarts-Tesselaar CD, Festen DA. Transitie van zorg bij jongeren met een verstandelijke beperking: van generalist naar generalist. [Health care transition in young people with intellectual disabilities: from generalist to generalist]. Ned Tijdschr Geneeskd. 2014;158:A

234 Mergler S, de Man SA. Breekbaar vanaf jonge leeftijd: Osteoporose bij een kind met ernstige meervoudige beperkingen. [Fragile from an early age: osteoporosis in a child with multiple severe disabilities]. Ned Tijdschr Geneeskd. 2014;158:A8017. De Man SA, Merkus PJ. Aandoeningen van de luchtwegen. In: Medische zorg voor patiënten met een verstandelijke beperking / Braam W, van Duinen-Maas MJ, Festen DA, van Gelderen I, S.A. Huisman SA, M.A.M. Tonino MA. [red.]. Leerboek AVG. Houten: Prelum, ISBN pag Teunissen J, Hochs AH, Vaessen-Verberne A, Boehmer AL, Smeets CC, Brackel H, van Gent R, Wesseling J, Logtens-Stevens D, de Moor R, Rosias PP, Potgieter S, Faber MR, Hendriks HJ, Janssen- Heijnen ML, Loza BF. The effect of 3% and 6% hypertonic saline in viral bronchiolitis: a randomised controlled trial. Eur Respir J Oct;44(4): Epub 2014 Jun 25. Voorend-van Bergen S, Vaessen-Verberne AA, de Jongste JC, Pijnenburg MW. Asthma control questionnaires in the management of asthma in children: A review. Pediatr Pulmonol Feb;50(2): Epub 2014 Sep 3. Van de Griend EJ, Vaessen-Verberne A, de Jongste JC. Astma. In: Werkboek kinderallergologie / Dubois E. [...et al.][red.]. Amsterdam: VU University Press, ISBN: Korterink JJ, Benninga MA, van Wering HM, Deckers-Kocken JM. Glucose Hydrogen Breath Test for Small Intestinal Bacterial Overgrowth in Children with Abdominal Pain-Related Functional Gastrointestinal Disorders. J Pediatr Gastroenterol Nutr Nov 17. [Epub ahead of print] Rutten JM, Vlieger AM, Frankenhuis C, George EK, Groeneweg M, Norbruis OF, Tjon a Ten W, van Wering H, Dijkgraaf MG, Merkus MP, Benninga MA. Gut-directed hypnotherapy in children with irritable bowel syndrome or functional abdominal pain (syndrome): a randomized controlled trial on self exercises at home using CD versus individual therapy by qualified therapists. BMC Pediatr Jun 4;14:140. Klinisch Chemisch Hematologisch Laboratorium Joosen AM, Boonen K, Hulsman N, Schuitemaker FJ, Thelen MH. Hypernatraemia in disguise. Clin Chem Lab Med Nov;52(11):e Schmitz EM, Boonen K, van den Heuvel DJ, van Dongen JL, Schellings MW, Emmen JM, van der Graaf F, Brunsveld L, van de Kerkhof D. Determination of dabigatran, rivaroxaban and apixaban by ultra-performance liquid chromatography - tandem mass spectrometry (UPLC-MS/ MS) and coagulation assays for therapy monitoring of novel direct oral anticoagulants. J Thromb Haemost Oct;12(10): Register Medische Staf 233

235 Schmitz EM, Boonen K, van den Heuvel DJ, van Dongen JL, Schellings MW, Emmen JM, van der Graaf F, Brunsveld L, van de Kerkhof D. Determination of dabigatran, rivaroxaban and apixaban by ultra-performance liquid chromatography - tandem mass spectrometry (UPLC-MS/ MS) and coagulation assays for therapy monitoring of novel direct oral anticoagulants. J Thromb Haemost Oct;12(10): Emmen JM, Heijboer AC, de Jong SM, Endert E. Glucagon stability anno Clin Chim Acta Feb 2;440:1-2. Epub 2014 Nov 11. Uzun S, Djamin RS, Kluytmans JA, Mulder PG, Van t Veer NE, Ermens AA, Pelle AJ, Hoogsteden HC, Aerts JG, van der Eerden MM. Azithromycin maintenance treatment in patients with frequent exacerbations of chronic obstructive pulmonary disease (COLUMBUS): a randomised, doubleblind, placebo-controlled trial. Lancet Respir Med May;2(5): Epub 2014 Apr 15. Uzun S, Djamin RS, Veer NE van t, Kluytmans JA, Ermens AA, Hoogsteden HC, Aerts JG, Eerden MM van der. Macrolides to prevent COPD exacerbations. Clin Pulm Med. 2014;21(2): De Wijs-Meijler DP, Jonkers MH, Ermens AA. Een neonaat met een navelstompbloeding. [A neonate with umbilical cord bleeding]. Ned Tijdschr Geneeskd. 2014;158:A7587. Van Gammeren AJ, Alcala LS, Smolders M, Boersma RS. Numerous Russell bodies and Dutcher bodies in multiple myeloma. Br J Haematol Oct 14. [Epub ahead of print] Van den Berg SA, Verwer PE, Idema RN, Van Guldener C. Transient cefuroxime/metronidazole treatment induced factor V antibodies. BMJ Case Rep Aug 19;2014. pii: bcr Joosen AM, Boonen K, Hulsman N, Schuitemaker FJ, Thelen MH. Hypernatraemia in disguise. Clin Chem Lab Med Nov;52(11):e Klinische Farmacie Ter Laak MA, Roos C, Touw DJ, van Hattum PR, Kwee A, Lotgering FK, J Mol BW, van Pampus MG, Porath MM, Spaanderman ME, van der Post JA, Papatsonis DN, van t Veer NE. Pharmacokinetics of nifedipine slow-release during sustained tocolysis. Int J Clin Pharmacol Ther Jan;53(1): Epub 2014 Nov 19. Uzun S, Djamin RS, Kluytmans JA, Mulder PG, van t Veer NE, Ermens AA, Pelle AJ, Hoogsteden HC, Aerts JG, van der Eerden MM. Azithromycin maintenance treatment in patients with frequent exacerbations of chronic obstructive pulmonary disease (COLUMBUS): a randomised, doubleblind, placebo-controlled trial. Lancet Respir Med May;2(5): Epub 2014 Apr

236 Uzun S, Djamin RS, van t Veer NE, Kluytmans JA, Ermens AA, Hoogsteden HC, Aerts JG, Eerden MM van der. Macrolides to prevent COPD exacerbations. Clin Pulm Med. 2014;21(2): Ter Laak MA, Roos C, Touw DJ, van Hattum PR, Kwee A, Lotgering FK, J Mol BW, van Pampus MG, Porath MM, Spaanderman ME, van der Post JA, Papatsonis DN, van t Veer NE. Pharmacokinetics of nifedipine slow-release during sustained tocolysis. Int J Clin Pharmacol Ther Jan;53(1): Epub 2014 Nov 19. Klinische Geriatrie Jobse IC, de Jonckheere RA. Het effect van galantamine op de ecg- geleidingstijden [The effect of galantamine on cardiac conduction time] Tijdschr Gerontol Geriatr Dec;45(6): Jobse IC, de Jonckheere RA. Het effect van galantamine op de ecg- geleidingstijden [The effect of galantamine on cardiac conduction time] Tijdschr Gerontol Geriatr Dec;45(6): Laboratorium voor Microbiologie en Infectiepreventie Koningstein M, van der Bij AK, de Kraker ME, Monen JC, Muilwijk J, de Greeff SC, Geerlings SE, van Hall MA; ISIS-AR Study Group [Van Keulen PH et al.]. Recommendations for the empirical treatment of complicated urinary tract infections using surveillance data on antimicrobial resistance in the Netherlands. PLoS One Jan 28;9(1):e Kock R, Becker K, Cookson B, van Gemert-Pijnen JE, Harbarth S, Kluytmans J, Mielke M, Peters G, Skov RL, Struelens MJ, Tacconelli E, Witte W, Friedrich AW. Systematic literature analysis and review of targeted preventive measures to limit healthcare-associated infections by meticillinresistant Staphylococcus aureus. Euro Surveill Jul 24;19(29). pii: Verkade E, Kluytmans-van den Bergh M, van Benthem B, van Cleef B, van Rijen M, Bosch T, Schouls L, Kluytmans J. Transmission of methicillin-resistant Staphylococcus aureus CC398 from livestock veterinarians to their household members. PLoS One Jul 25;9(7):e ecollection Huijts SM, Boersma WG, Grobbee DE, Gruber WC, Jansen KU, Kluytmans JA, Kuipers BA, Palmen F, Pride MW, Webber C, Bonten MJ; The CAP Diagnostics investigators. Predicting Pneumococcal Community-Acquired Pneumonia in the Emergency Department Evaluation of clinical parameters. Clin Microbiol Infect Jun 30. [Epub ahead of print] Souverein D, Boers SA, Veenendaal D, Euser SM, Kluytmans J, Den Boer JW. Polyclonal spread and outbreaks with ESBL positive gentamicin resistant Klebsiella spp. in the region Kennemerland, The Netherlands. PLoS One Jun 27;9(6):e ecollection Register Medische Staf 235

237 Reuland EA, Al Naiemi N, Raadsen SA, Savelkoul PH, Kluytmans JA, Vandenbroucke-Grauls CM. Prevalence of ESBL-producing Enterobacteriaceae in raw vegetables. Eur J Clin Microbiol Infect Dis May 22. [Epub ahead of print] Perencevich EN, Skov R, Kluytmans J. Identifying livestock-associated methicillin-resistant Staphylococcus aureus in the United States. JAMA Intern Med May;174(5): Stewardson AJ, Renzi G, Maury N, Vaudaux C, Brossier C, Fritsch E, Pittet D, Heck M, van der Zwaluw K, Reuland EA, van de Laar T, Snelders E, Vandenbroucke-Grauls C, Kluytmans J, Edder P, Schrenzel J, Harbarth S. Extended-spectrum ß-lactamase-producing Enterobacteriaceae in hospital food: a risk assessment. Infect Control Hosp Epidemiol Apr;35(4): Bonten MJ, Friedrich A, Kluytmans JA, Vandenbroucke-Grauls CM, Voss A, Vos MC. Infectiepreventie in Nederlandse ziekenhuizen; resultaten zeggen meer dan procesindicatoren. [Infection prevention in Dutch hospitals; results say more than process indicators]. Ned Tijdschr Geneeskd. 2014;158:A7395. Willemsen I, Hille L, Vrolijk A, Bergmans A, Kluytmans J. Evaluation of a commercial real-time PCR for the detection of extended spectrum ß-lactamase genes. J Med Microbiol Apr;63 (Pt 4): Epub 2014 Jan 28. Halaby T, Al Naiemi N, Kluytmans J, van der Palen J, Vandenbroucke-Grauls CM. Reply to colistin resistance during selective digestive tract decontamination is uncommon. Antimicrob Agents Chemother. 2014;58(1):627. Van Zanten AR, Brinkman S, Arbous MS, Abu-Hanna A, Levy MM, de Keizer NF; Netherlands Patient Safety Agency Sepsis Expert Group* [Kluytmans JA et al...]. Guideline bundles adherence and mortality in severe sepsis and septic shock. Crit Care Med Aug;42(8): Uzun S, Djamin RS, Kluytmans JA, Mulder PG, Van t Veer NE, Ermens AA, Pelle AJ, Hoogsteden HC, Aerts JG, van der Eerden MM. Azithromycin maintenance treatment in patients with frequent exacerbations of chronic obstructive pulmonary disease (COLUMBUS): a randomised, doubleblind, placebo-controlled trial. Lancet Respir Med May;2(5): Epub 2014 Apr 15. Uzun S, Djamin RS, Veer NE van t, Kluytmans JA, Ermens AA, Hoogsteden HC, Aerts JG, Eerden MM van der. Macrolides to prevent COPD exacerbations. Clin Pulm Med. 2014;21(2): Van Rijen MM, Kluytmans JA. Adjustment of the MRSA Search and Destroy policy for outpatients in the Netherlands: a prospective cohort study with repeated prevalence measurements. Antimicrob Resist Infect Control Jan 15;3(1):3. 236

238 Veenemans J, Overdevest IT, Snelders E, Willemsen I, Hendriks Y, Adesokan A, Doran G, Bruso S, Rolfe A, Pettersson A, Kluytmans JA. Next-generation sequencing for typing and detection of resistance genes: performance of a new commercial method during an outbreak of extendedspectrum-beta-lactamase-producing Escherichia coli. J Clin Microbiol Jul;52(7): Epub 2014 Apr 30. Reuland EA, Hays JP, de Jongh DM, Abdelrehim E, Willemsen I, Kluytmans JA, Savelkoul PH, Vandenbroucke-Grauls CM, al Naiemi N. Detection and occurrence of plasmid-mediated AmpC in highly resistant gram-negative rods. PLoS One Mar 18;9(3):e ecollection Knox J, Van Rijen M, Uhlemann AC, Miller M, Hafer C, Vavagiakis P, Shi Q, Johnson PD, Coombs G, Kluytmans-Van den Bergh M, Kluytmans J, Bennett CM, Lowy FD. Community-associated methicillin-resistant Staphylococcus aureus transmission in households of infected cases: a pooled analysis of primary data from three studies across international settings. Epidemiol Infect Apr 24:1-12. [Epub ahead of print] Koningstein M, van der Bij AK, de Kraker ME, Monen JC, Muilwijk J, de Greeff SC, Geerlings SE, van Hall MA; ISIS-AR Study Group [Kluytmans JA et al.]. Recommendations for the empirical treatment of complicated urinary tract infections using surveillance data on antimicrobial resistance in the Netherlands. PLoS One Jan 28;9(1):e Van Cleef BA, van Benthem BH, Verkade EJ, van Rijen M, Kluytmans-van den Bergh MF, Schouls LM, Duim B, Wagenaar JA, Graveland H, Bos ME, Heederik D, Kluytmans JA. Dynamics of methicillinresistant Staphylococcus aureus and methicillin-susceptible Staphylococcus aureus carriage in pig farmers: a prospective cohort study. Clin Microbiol Infect Oct;20(10): Epub 2014 May 15. Van Rijen MM, Bosch T, Verkade EJ, Schouls L, Kluytmans JA; CAM Study Group*. Livestockassociated MRSA carriage in patients without direct contact with livestock. PLoS One Jun 27;9(6):e Van der Mee-Marquet NL, Corvaglia A, Haenni M, Bertrand X, Franck JB, Kluytmans J, Girard M, Quentin R, François P. Emergence of a novel subpopulation of CC398 Staphylococcus aureus infecting animals is a serious hazard for humans. Front Microbiol Dec 5;5:652. ecollection. Bos ME, Verstappen KM, van Cleef BA, Dohmen W, Dorado-García A, Graveland H, Duim B, Wagenaar JA, Kluytmans JA, Heederik DJ. Transmission through air as a possible route of exposure for MRSA. J Expo Sci Environ Epidemiol Dec 17. [Epub ahead of print]. Bosch T, Verkade E, van Luit M, Landman F, Kluytmans J, Schouls LM. Transmission and Persistence of Livestock-Associated Methicillin-Resistant Staphylococcus aureus among Veterinarians and Their Household Members. Appl Environ Microbiol Jan 1;81(1): Epub Register Medische Staf 237

239 Djamin RS, Uzun S, Snelders E, Kluytmans JA, Hoogsteden HC, Aerts JG, van der Eerden MM. Occurrence of virus-induced COPD exacerbations during four seasons. Scand J Infect Dis Nov 26:1-5. [Epub ahead of print]. Van der Slegt J, Kluytmans JA, Mulder PG, Veen EJ, Ho GH, van der Laan L. Surgical site infection after multiple groin incisions in peripheral vascular surgery. Surg Infect (Larchmt) Dec;15(6): Willemsen I, Nelson-Melching J, Hendriks Y, Mulders A, Verhoeff S, Kluytmans-Vandenbergh M, Kluytmans J. Measuring the quality of infection control in Dutch nursing homes using a standardized method; the Infection prevention RIsk Scan (IRIS). Antimicrob Resist Infect Control Aug 18;3:26. Van Rijen MM, Bosch T, Verkade EJ, Schouls L, Kluytmans JA; CAM Study Group* [Verduin K et al...]. Livestock-associated MRSA carriage in patients without direct contact with livestock. PLoS One Jun 27;9(6):e Longgeneeskunde Lievense LA, Hegmans JP, Aerts JG. Biomarkers for immune checkpoint inhibitors. Lancet Oncol Jan;15(1):e1. Stolz D, Boersma W, Blasi F, Louis R, Milenkovic B, Kostikas K, Aerts JG, Rohde G, Lacoma A, Rakic J, Boeck L, Castellotti P, Scherr A, Marin A, Hertel S, Giersdorf S, Torres A, Welte T, Tamm M. Exertional hypoxemia in stable COPD is common and predicted by circulating proadrenomedullin. Chest Apr 10. [Epub ahead of print]. Barlesi F, Scherpereel A, Gorbunova V, Gervais R, Vikström A, Chouaid C, Chella A, Kim JH, Ahn MJ, Reck M, Pazzola A, Kim HT, Aerts JG, Morando C, Loundou A, Groen HJ, Rittmeyer A. Maintenance bevacizumab-pemetrexed after first-line cisplatin-pemetrexed-bevacizumab for advanced nonsquamous nonsmall-cell lung cancer: updated survival analysis of the AVAPERL (MO22089) randomized phase III trial. Ann Oncol May;25(5): Epub 2014 Feb 27. Uzun S, Djamin RS, Kluytmans JA, Mulder PG, Van t Veer NE, Ermens AA, Pelle AJ, Hoogsteden HC, Aerts JG, van der Eerden MM. Azithromycin maintenance treatment in patients with frequent exacerbations of chronic obstructive pulmonary disease (COLUMBUS): a randomised, doubleblind, placebo-controlled trial. Lancet Respir Med May;2(5): Epub 2014 Apr 15. Uzun S, Djamin RS, Veer NE van t, Kluytmans JA, Ermens AA, Hoogsteden HC, Aerts JG, Eerden MM van der. Macrolides to prevent COPD exacerbations. Clin Pulm Med. 2014;21(2):

240 Mokhles S, Nuyttens JJ, Maat AP, Birim O, Aerts JG, Bogers AJ, Takkenberg JJ. Survival and Treatment of Non-small Cell Lung Cancer Stage I-II Treated Surgically or with Stereotactic Body Radiotherapy: Patient and Tumor-Specific Factors Affect the Prognosis. Ann Surg Oncol Jun 25. [Epub ahead of print]. Hegmans JP, Aerts JG. Immunomodulation in cancer. Curr Opin Pharmacol Aug;17C: Epub 2014 Jul 8. Cornelissen R, Lievense LA, Maat AP, Hendriks RW, Hoogsteden HC, Bogers AJ, Hegmans JP, Aerts JG. Ratio of intratumoral macrophage phenotypes is a prognostic factor in epithelioid malignant pleural mesothelioma. PLoS One Sep 5;9(9):e ecoll Aarts MJ, van den Borne BE, Biesma B, Kloover JS, Aerts JG, Lemmens VE. Improvement in population-based survival of stage IV NSCLC due to increased use of chemotherapy. Int J Cancer Sep 15. [Epub ahead of print].ecollection Aarts MJ, van den Borne BE, Biesma B, Kloover JS, Aerts JG, Lemmens VE. Improvement in population-based survival of stage IV NSCLC due to increased use of chemotherapy. Int J Cancer Sep 15. [Epub ahead of print]. Djamin RS, Uzun S, Snelders E, Kluytmans JA, Hoogsteden HC, Aerts JG, van der Eerden MM. Occurrence of virus-induced COPD exacerbations during four seasons. Scand J Infect Dis Nov 26:1-5. [Epub ahead of print]. Aarts MJ, Aerts JG, van den Borne BE, Biesma B, Lemmens VE, Kloover JS. Comorbidity in Patients With Small-Cell Lung Cancer: Trends and Prognostic Impact. Clin Lung Cancer Dec 11. pii: S (14) [Epub ahead of print] Struik FM, Sprooten RT, Kerstjens HA, Bladder G, Zijnen M, Asin J, Cobben NA, Vonk JM, Wijkstra PJ. Nocturnal non-invasive ventilation in COPD patients with prolonged hypercapnia after ventilatory support for acute respiratory failure: a randomised, controlled, parallel-group study. Thorax Sep;69(9): Epub 2014 Apr 29. Kant KM, Djamin RS, Belderbos HN, van den Berg B. Acute respiratoire insufficiëntie door COPD: Beslissen over wel of niet beademen. [Acute respiratory insufficiency due to COPD: invasive mechanical ventilation or not?]. Ned Tijdschr Geneeskd. 2014;158:A5276. Djamin RS, Uzun S, Snelders E, Kluytmans JA, Hoogsteden HC, Aerts JG, van der Eerden MM. Occurrence of virus-induced COPD exacerbations during four seasons. Scand J Infect Dis Nov 26:1-5. [Epub ahead of print]. Kant KM, Djamin RS, Belderbos HN, van den Berg B. Acute respiratoire insufficiëntie door COPD: Beslissen over wel of niet beademen. [Acute respiratory insufficiency due to COPD: invasive mechanical ventilation or not?]. Ned Tijdschr Geneeskd. 2014;158:A5276. Register Medische Staf 239

241 Uzun S, Djamin RS, Kluytmans JA, Mulder PG, Van t Veer NE, Ermens AA, Pelle AJ, Hoogsteden HC, Aerts JG, van der Eerden MM. Azithromycin maintenance treatment in patients with frequent exacerbations of chronic obstructive pulmonary disease (COLUMBUS): a randomised, doubleblind, placebo-controlled trial. Lancet Respir Med May;2(5): Epub 2014 Apr 15. Uzun S, Djamin RS, Veer NE van t, Kluytmans JAJW, Ermens AAM, Hoogsteden HC, Aerts JGJV, Eerden MM van der. Macrolides to prevent COPD exacerbations. Clin Pulm Med. 2014;21(2): Righini M, Van Es J, Den Exter PL, Roy PM, Verschuren F, Ghuysen A, Rutschmann OT, Sanchez O, Jaffrelot M, Trinh-Duc A, Le Gall C, Moustafa F, Principe A, Van Houten AA, Ten Wolde M, Douma RA, Hazelaar G, Erkens PM, Van Kralingen KW, Grootenboers MJ, Durian MF, Cheung YW, Meyer G, Bounameaux H, Huisman MV, Kamphuisen PW, Le Gal G. Age-adjusted D-dimer cutoff levels to rule out pulmonary embolism: the ADJUST-PE study. JAMA Mar 19;311(11): Erratum in: JAMA Apr 23-30;311(16):1694. Hendrikse WM, Grootenboers MJ, van Wijngaarden P. Type B lactic acidosis as initial presentation of acute myeloid leukaeemia. A case report. Neth J Crit Care apr;18(2):15-6. Kant KM, Djamin RS, Belderbos HN, van den Berg B. Acute respiratoire insufficiëntie door COPD: Beslissen over wel of niet beademen. [Acute respiratory insufficiency due to COPD: invasive mechanical ventilation or not?]. Ned Tijdschr Geneeskd. 2014;158:A5276. Van Ranst D, Stoop WA, Meijer JW, Otten HJ, van de Port IG. Reduction of exacerbation frequency in patients with COPD after participation in a comprehensive pulmonary rehabilitation program. Int J Chron Obstruct Pulmon Dis Oct 3;9: ecollection Mondziekten, Kaak- en Aangezichtschirurgie Mensink G, Gooris PJ, Bergsma JE, van Hooft E, van Merkesteyn JP. Influence of BSSO surgical technique on postoperative inferior alveolar nerve hypoesthesia: A systematic review of the literature. J Craniomaxillofac Surg Sep;42(6): Epub 2014 Jan 14. Gooris PJ, Zijlmans JC, Bergsma JE, Mensink G. A Case of Mental Nerve Paresthesia Due to Dynamic Compression of Alveolar Inferior Nerve Along an Elongated Styloid Process. J Oral Maxillofac Surg Jul;72(7):1267.e1-7. Epub 2014 Jan 16. Van Bakelen NB, Boermans BD, Buijs GJ, Jansma J, Pruim GJ, Hoppenreijs TJ, Bergsma JE, Stegenga B, Bos RR. Comparison of the long-term skeletal stability between a biodegradable and a titanium fixation system following BSSO advancement - a cohort study based on a multicenter randomised controlled trial. Br J Oral Maxillofac Surg Oct;52(8): Epub 2014 Aug 16. Gooris PJ, Zijlmans JC, Bergsma JE, Mensink G. A Case of Mental Nerve Paresthesia Due to Dynamic Compression of Alveolar Inferior Nerve Along an Elongated Styloid Process. J Oral Maxillofac Surg Jul;72(7):1267.e1-7. Epub 2014 Jan

242 Mensink G, Gooris PJ, Bergsma JE, van Hooft E, van Merkesteyn JP. Influence of BSSO surgical technique on postoperative inferior alveolar nerve hypoesthesia: A systematic review of the literature. J Craniomaxillofac Surg Sep;42(6): Epub 2014 Jan 14. Mensink G, Gooris P, Mulder F, Gooris-Kuipers C, van Merkesteyn R. Experiencing your own orthognathic surgery: A personal case report. Angle Orthod Nov 4. [Epub ahead of print] Mensink G, Gooris PJ, Bergsma JE, van Hooft E, van Merkesteyn JP. Influence of BSSO surgical technique on postoperative inferior alveolar nerve hypoesthesia: A systematic review of the literature. J Craniomaxillofac Surg Sep;42(6): Epub 2014 Jan 14. Mensink G, Gooris PJ, Bergsma JE, van Hooft E, van Merkesteyn JP. Influence of BSSO surgical technique on postoperative inferior alveolar nerve hypoesthesia: A systematic review of the literature. J Craniomaxillofac Surg Sep;42(6): Epub 2014 Jan 14. Gooris PJ, Zijlmans JC, Bergsma JE, Mensink G. A Case of Mental Nerve Paresthesia Due to Dynamic Compression of Alveolar Inferior Nerve Along an Elongated Styloid Process. J Oral Maxillofac Surg Jul;72(7):1267.e1-7. Epub 2014 Jan 16. Verweij JP, Houppermans PN, Mensink G, van Merkesteyn JP. Removal of bicortical screws and other osteosynthesis material that caused symptoms after bilateral sagittal split osteotomy: a retrospective study of 251 patients, and review of published papers. Br J Oral Maxillofac Surg Oct;52(8): Epub 2014 Jun 19. Mensink G, Gooris P, Mulder F, Gooris-Kuipers C, van Merkesteyn R. Experiencing your own orthognathic surgery: A personal case report. Angle Orthod Nov 4. [Epub ahead of print] Verweij JP, Mensink G, Fiocco M, van Merkesteyn JP. Presence of mandibular third molars during bilateral sagittal split osteotomy increases the possibility of bad split but not the risk of other post-operative complications. J Craniomaxillofac Surg Oct;42(7):e Epub 2014 Apr 4. Neurologie / Neurochirurgie Arntz RM, van Alebeek ME, Synhaeve NE, Brouwers PJ, van Dijk GW, Gons RA, den Heijer T, de Kort PL, de Laat KF, van Norden AG, Vermeer SE, van der Vlugt MJ, Kessels RP, van Dijk EJ, de Leeuw FE. Observational Dutch Young Symptomatic StrokE study (ODYSSEY): study rationale and protocol of a multicentre prospective cohort study. BMC Neurol Mar 22;14:55. Göttle M, Prudente CN, Fu R, Sutcliffe D, Pang H, Cooper D, Veledar E, Glass JD, Gearing M, Visser JE, Jinnah HA. Loss of dopamine phenotype among midbrain neurons in Lesch-Nyhan disease. Ann Neurol Jul;76(1): Epub 2014 Jun 20. Register Medische Staf 241

243 Gooris PJ, Zijlmans JC, Bergsma JE, Mensink G. A Case of Mental Nerve Paresthesia Due to Dynamic Compression of Alveolar Inferior Nerve Along an Elongated Styloid Process. J Oral Maxillofac Surg Jul;72(7):1267.e1-7. Epub 2014 Jan 16. Oogheelkunde Koenraads Y, van der Linden DC, van Schooneveld MM, Imhof SM, Gosselaar PH, Porro GL, Braun KP. Visual function and compensatory mechanisms for hemianopia after hemispherectomy in children. Epilepsia Jun;55(6): Epub 2014 Apr 22. Koenraads Y, Braun KP, van der Linden DC, Imhof SM, Porro GL. Perimetry in Young and Neurologically Impaired Children: The Behavioral Visual Field (BEFIE) Screening Test Revisited. JAMA Ophthalmol Dec 26. [Epub ahead of print] Orthopedie Walenkamp MM, Goslings JC, Beumer A, Haverlag R, Leenhouts PA, Verleisdonk EJ, Liem RS, Sintenie JB, Bronkhorst MW, Winkelhagen J, Schep NW. Surgery versus conservative treatment in patients with type A distal radius fractures, a randomized controlled trial. BMC Musculoskelet Disord Mar 19;15(1):90. Beumer A, Lindau TR. Grip strength ratio: a grip strength measurement that correlates well with DASH score in different hand/wrist conditions. BMC Musculoskelet Disord Oct 6;15:336. Spaans AJ, van Heeswijk EJ, Arnold DE, Beumer A. Foreign body reaction associated with polyethylene mesh interposition used for treatment of trapeziometacarpal osteoarthritis: report of 8 cases. J Hand Surg Am Oct;39(10): Epub 2014 Aug 27. Thoomes-de Graaf M, Scholten-Peeters GG, Duijn E, Karel YH, van den Borne MP, Beumer A, Ottenheijm RP, Dinant GJ, Tetteroo E, Lucas C, Koes BW, Verhagen AP. Inter-professional agreement of ultrasound-based diagnoses in patients with shoulder pain between physical therapists and radiologists in the Netherlands. Man Ther Oct;19(5): Epub 2014 May 14. Van Heeswijk EJ, Beumer A, Eygendaal D. Injuries of elbow and forearm. In: Nuclear Medicine and Radiologic Imaging in Sports Injuries / Glaudemans AW, Dierckx RA, Gielen J, Zwerver H. (Eds.). Berlin; Heidelberg: Springer, ISBN Thoomes-de Graaf M, Scholten-Peeters GG, Duijn E, Karel YH, van den Borne MP, Beumer A, Ottenheijm RP, Dinant GJ, Tetteroo E, Lucas C, Koes BW, Verhagen AP. Inter-professional agreement of ultrasound-based diagnoses in patients with shoulder pain between physical therapists and radiologists in the Netherlands. Man Ther Oct;19(5): Epub 2014 May

244 Ten Brinke B, de Haan LJ, Koenraadt KL, van Geenen RC. Medial femoral condyle fracture as an intraoperative complication of Oxford unicompartmental knee replacement. Knee Surg Sports Traumatol Arthrosc Dec 6. [Epub ahead of print] Kodde IF, Rahusen FT, Eygendaal D. Arthroscopic techniques in the elbow. In: Surgical Orthopaedics and Traumatology / George Bentley [ed.]. Berlin, Heidelberg: Springer-Verlag, ISBN: DeVos MJ, Verdonschot N, Luites JW, Anderson PG, Eygendaal D. Stable fixation of the IBP humeral component implanted without cement in total elbow replacement: a radiostereometric analysis study of 16 elbows at two-year follow-up. Bone Joint J Feb;96-B(2): De Vos MJ, Wagener ML, Verdonschot N, Eygendaal D. An extensive posterior approach of the elbow with osteotomy of the medial epicondyle. J Shoulder Elbow Surg Mar;23(3): Kaas L, Eygendaal D. Regarding Ligamentous repair of acute lateral collateral ligament rupture of the elbow. J Shoulder Elbow Surg Apr;23(4):e94. Bruinsma W, Kodde I, de Muinck Keizer RJ, Kloen P, Lindenhovius AL, Vroemen JP, Haverlag R, van den Bekerom MP, Bolhuis HW, Bullens PH, Meylaerts SA, van der Zwaal P, Steller PE, Hageman M, Ring DC, den Hartog D, Hammacher ER, King GJ, Athwal GS, Faber KJ, Drosdowech D, Grewal R, Goslings JC, Schep NW, Eygendaal D. A randomized controlled trial of nonoperative treatment versus open reduction and internal fixation for stable, displaced, partial articular fractures of the radial head: the RAMBO trial. BMC Musculoskelet Disord May 6;15:147. Luites JW, Wymenga AB, Blankevoort L, Eygendaal D, Verdonschot N. Accuracy of a computerassisted planning and placement system for anatomical femoral tunnel positioning in anterior cruciate ligament reconstruction. Int J Med Robot Dec;10(4): Epub 2013 Oct 24. Heijink A, Morrey BF, Eygendaal D. Radiocapitellar prosthetic arthroplasty: a report of 6 cases and review of the literature. J Shoulder Elbow Surg Jun;23(6): Epub 2014 Apr 13. Van den Bekerom MP, van Hooft MA, Eygendaal D. Osteoid osteoma of the elbow mimicking hemophilic arthropathy. World J Clin Cases Apr 16;2(4): Van den Bekerom MP, Eygendaal D. Posterior elbow problems in the overhead athlete. Sports Med Arthrosc Sep;22(3): Van den Bekerom MP, Doornberg JN, Eygendaal D. Letter to the editor: anconeus interposition arthroplasty: mid- to long-term results. Clin Orthop Relat Res Nov;472(11): Epub 2014 Aug 12. Register Medische Staf 243

245 Van den Bekerom MP, Kodde IF, Aster A, Bleys RL, Eygendaal D. Clinical relevance of distal biceps insertional and footprint anatomy. Knee Surg Sports Traumatol Arthrosc Sep 18. [Epub ahead of print] Arrigoni P, van Tongel A, Eygendaal D, Adamczyk G, Pederzini L. Elbow Arthroscopy: From Basic to Advance. In: ESSKA Instructional Course Lecture Book. Berlin; Heidelberg: Springer, Chapter 4: ISBN Tosti R, Ilyas AM, Mellema JJ, Guitton TG, Ring D; Science of Variation Group [Eygendaal D et al...]. Interobserver variability in the treatment of little finger metacarpal neck fractures. J Hand Surg Am Sep;39(9): Epub 2014 Jul 14. Bruinsma WE, Guitton T, Ring D; Science of Variation Group [Eygendaal D et al...]. Radiographic loss of contact between radial head fracture fragments is moderately reliable. Clin Orthop Relat Res Jul;472(7): Van Heeswijk EJ, Beumer A, Eygendaal D. Injuries of elbow and forearm. In: Nuclear Medicine and Radiologic Imaging in Sports Injuries / Glaudemans AW, Dierckx RA, Gielen J, Zwerver H. (Eds.). Berlin; Heidelberg: Springer, ISBN Keijsers R, Eygendaal D, van den Bekerom MP. Should we really abandon PRP in the treatment of lateral epicondylar tendinopathy? BJSM Blog oct. Keijsers R, Eygendaal D, van den Bekerom MP. Letter to the editor in response to review by De Vos, Windt and Weir. BJSM Blog dec. Kievit AJ, van Geenen RC, Kuijer PP, Pahlplatz TM, Blankevoort L, Schafroth MU. Total knee arthroplasty and the unforeseen impact on return to work: a cross-sectional multicenter survey. J Arthroplasty Jun;29(6): Epub 2014 Jan 10. Ten Brinke B, de Haan LJ, Koenraadt KL, van Geenen RC. Medial femoral condyle fracture as an intraoperative complication of Oxford unicompartmental knee replacement. Knee Surg Sports Traumatol Arthrosc Dec 6. [Epub ahead of print] Hoebink E, Journée H, Rácz I, Berends H, van Hal C. Evoked movements in transcranial electrical stimulation on 4 locations of the body at different stimulation electrode montages and stimulation paradigms. Clin Neurophysiol may;125(5):e16. Langeveld-Wildschut A, Joosten P, Nobruis O, Hulsmann A. Een goede maatschap, een goede specialist. Med Contact apr;69(15): The B, Brutty M, Wang A, Wambeek ND, Campbell P, Halliday MJ, Ackland TR. Biceps muscle fatty infiltration and atrophy. A midterm review after arthroscopic tenotomy of the long head of the biceps. Arthroscopy Oct 29. pii: S (14) [Epub ahead of print]. 244

246 The B, Brutty M, Wang A, Campbell PT, Halliday MJ, Ackland TR. Long-term functional results and isokinetic strength evaluation after arthroscopic tenotomy of the long head of biceps tendon. Int J Shoulder Surg Jul;8(3): Neuhaus V, Bot AG, Guitton TG, Ring DC; Science of Variation Group, Abdel-Ghany MI, Abrams J, Abzug JM, Adolfsson LE, Balfour GW, Bamberger HB, Barquet A, Baskies M, Batson WA, Baxamusa T, Bayne GJ, Begue T, Behrman M, Beingessner D, Biert J, Bishop J, Alves MB, Boyer M, Brilej D, Brink PR, Brunton LM, Buckley R, Cagnone JC, Calfee RP, Campinhos LA, Cassidy C, Catalano L 3rd, Chivers K, Choudhari P, Cimerman M, Conflitti JM, Costanzo RM, Crist BD, Cross BJ, Dantuluri P, Darowish M, de Bedout R, DeCoster T, Dennison DG, DeNoble PH, DeSilva G, Dienstknecht T, Duncan SF, Duralde XA, Durchholz H, Egol K, Ekholm C, Elias N, Erickson JM, Esparza JD, Fernandes CH, Fischer TJ, Fischmeister M, Forigua Jaime E, Getz CL, Gilbert RS, Giordano V, Glaser DL, Gosens T, Grafe MW, Filho JE, Gray RR, Gulotta LV, Gummerson NW, Hammerberg EM, Harvey E, Haverlag R, Henry PD, Hobby JL, Hofmeister EP, Hughes T, Itamura J, Jebson P, Jenkinson R, Jeray K, Jones CM, Jones J, Jubel A, Kaar SG, Kabir K, Kaplan FT, Kennedy SA, Kessler MW, Kimball HL, Kloen P, Klostermann C, Kohut G, Kraan GA, Kristan A, Loebenberg MI, Malone KJ, Marsh L, Martineau PA, McAuliffe J, McGraw I, Mehta S, Merchant M, Metzger C, Meylaerts SA, Miller AN, Wolf JM, Murachovsky J, Murthi A, Nancollas M, Nolan BM, Omara T, Omid R, Ortiz JA, Overbeck JP, Castillo AP, Pesantez R, Polatsch D, Porcellini G, Prayson M, Quell M, Ragsdell MM, Reid JG, Reuver JM, Richard MJ, Richardson M, Rizzo M, Rowinski S, Rubio J, Guerrero CG, Satora W, Schandelmaier P, Scheer JH, Schmidt A, Schubkegel TA, Schulte LM, Schumer ED, Sears BW, Shafritz AB, Shortt NL, Siff T, Silva DM, Smith RM, Spruijt S, Stein JA, Pemovska ES, Streubel PN, Swigart C, Swiontkowski M, Thomas G, Tolo ET, Turina M, Tyllianakis M, van den Bekerom MP, van der Heide H, van de Sande MA, van Eerten PV, Verbeek DO, Hoffmann DV, Vochteloo AJ, Wagenmakers R, Wall CJ, Wallensten R, Wascher DC, Weiss L, Wiater JM, Wills BP, Wint J, Wright T, Young JP, Zalavras C, Zura RD, Zyto K. Scapula fractures: interobserver reliability of classification and treatment. J Orthop Trauma Mar;28(3): Mellema JJ, Doornberg JN, Guitton TG, Ring D; Science of Variation Group [R. Wagenmakers et al...]. Biomechanical studies: science (f)or common sense? Injury Dec;45(12): Epub 2014 Sep 28. Pathologisch Anatomisch Laboratorium Van Gammeren AJ, Alcala LS, Smolders M, Boersma RS. Numerous Russell bodies and Dutcher bodies in multiple myeloma. Br J Haematol Oct 14. [Epub ahead of print] Radiologie Tolsma M, Bentala M, Rosseel P, Gerritse BM, Dijkstra H, Mulder P, van der Meer N. The value of routine chest radiographs after minimally invasive cardiac surgery: an observational cohort study. J Cardiothorac Surg Nov 11;9(1):174. [Epub ahead of print]. Register Medische Staf 245

247 Thoomes-de Graaf M, Scholten-Peeters GG, Duijn E, Karel YH, van den Borne MP, Beumer A, Ottenheijm RP, Dinant GJ, Tetteroo E, Lucas C, Koes BW, Verhagen AP. Inter-professional agreement of ultrasound-based diagnoses in patients with shoulder pain between physical therapists and radiologists in the Netherlands. Man Ther Oct;19(5): Epub 2014 May 14. Raats JW, Flu HC, Ho GH, Veen EJ, Vos LD, Steyerberg EW, van der Laan L. Long-term outcome of ruptured abdominal aortic aneurysm: impact of treatment and age. Clin Interv Aging Oct 13;9: ecollection Van der Slegt J, Flu HC, Veen EJ, Ho GH, de Groot HG, Vos LD, van der Laan L. Adverse events after treatment of patients with acute limb ischemia. Ann Vasc Surg Feb;29(2): Epub 2014 Nov 28. Broekman EA, Versteeg H, Vos LD, Dijksterhuis MG, Papatsonis DN. Temporary balloon occlusion of the internal iliac arteries to prevent massive hemorrhage during cesarean delivery among patients with placenta previa. Int J Gynaecol Obstet Feb;128(2): Epub 2014 Nov 5. Urologie Buijs J, Maillette de Buy Wenniger L, van Leenders G, Verheij J, van Onna I, Hansen B, van Heerde M, Krak N, Beuers U, Bruno M, van Buuren H. Immunoglobulin G4-related prostatitis: a case-control study focusing on clinical and pathologic characteristics. Urology Mar;83(3): Richters A, Derks J, Husson O, Van Onna IE, Fossion LM, Kil PJ, Verhoeven RH, Aarts MJ. Effect of surgical margin status after radical prostatectomy on health-related quality of life and illness perception in patients with prostate cancer. Urol Oncol Jan;33(1):16.e9-15. Epub 2014 Nov 14. Van der Schoot DKE. Van eunuch tot ageing male. in: Canon van de Urologie / Fons Ypma [red.]. Haarlem: DCHG Medische Communicatie, Hfdst 27. ISBN:

248 Register arts-assistenten Anesthesiologie Joosen AM, Boonen K, Hulsman N, Schuitemaker FJ, Thelen MH. Hypernatraemia in disguise. Clin Chem Lab Med Nov;52(11):e Chirurgie Beek MA, Gobardhan PD, Klompenhouwer EG, Rutten HJ, Voogd AC, Luiten EJ. Axillary reverse mapping (ARM) in clinically node positive breast cancer patients. Eur J Surg Oncol Jan;41(1): Epub 2014 Oct 29. Van der Slegt J, Steunenberg SL, Donker JM, Veen EJ, Ho GH, de Groot HG, van der Laan L. The current position of precuffed expanded polytetrafluoroethylene bypass grafts in peripheral vascular surgery. J Vasc Surg Jul;60(1): Epub 2014 Mar 12. Raats JW, Donker JM, van der Laan L. Een jongen met pijn links onder in de buik. [A 15-year old boy with abdominal pain]. Ned Tijdschr Geneeskd. 2014;158:A6854. Hopmans CJ, den Hoed PT, van der Laan L, van der Harst E, van der Elst M, Mannaerts GH, Dawson I, Timman R, Wijnhoven BP, IJzermans JN. Assessment of surgery residents operative skills in the operating theater using a modified Objective Structured Assessment of Technical Skills (OSATS): A prospective multicenter study. Surgery Nov;156(5): Epub 2014 Sep 16. De Kruijf M, Vroemen JP, de Leur K, van der Voort EA, Vos DI, Van der Laan L. Proximal fractures of the humerus in patients older than 75 years of age: should we consider operative treatment? J Orthop Traumatol Jun;15(2): De Kruijf M, Vroemen JP, de Leur K, van der Voort EA, Vos DI, Van der Laan L. Proximal fractures of the humerus in patients older than 75 years of age: should we consider operative treatment? J Orthop Traumatol Jun;15(2): Nanninga GL, de Leur K, Panneman MJ, van der Elst M, Hartholt KA. Increasing rates of pelvic fractures among older adults: The Netherlands, Age Ageing Jan 12. [Epub ahead of print] Raats JW, Donker JM, van der Laan L. Een jongen met pijn links onder in de buik. [A 15-year old boy with abdominal pain]. Ned Tijdschr Geneeskd. 2014;158:A6854. Raats JW, Flu HC, Ho GH, Veen EJ, Vos LD, Steyerberg EW, van der Laan L. Long-term outcome of ruptured abdominal aortic aneurysm: impact of treatment and age. Clin Interv Aging Oct 13;9: ecollection Register arts-assistenten 247

249 Van der Slegt J, Steunenberg SL, Donker JM, Veen EJ, Ho GH, de Groot HG, van der Laan L. The current position of precuffed expanded polytetrafluoroethylene bypass grafts in peripheral vascular surgery. J Vasc Surg Jul;60(1): Epub 2014 Mar 12. Te Slaa A, Dolmans D, Ho G, van der Laan L. Treatment strategies and clinical aspects of lower limb edema following peripheral bypass surgery. Phlebology May 19;29(1 suppl): [Epub ahead of print]. Van der Slegt J, Steunenberg SL, Donker JM, Veen EJ, Ho GH, de Groot HG, van der Laan L. The current position of precuffed expanded polytetrafluoroethylene bypass grafts in peripheral vascular surgery. J Vasc Surg Jul;60(1): Epub 2014 Mar 12. Van der Slegt J, Kluytmans JA, Mulder PG, Veen EJ, Ho GH, van der Laan L. Surgical site infection after multiple groin incisions in peripheral vascular surgery. Surg Infect (Larchmt) Dec;15(6): Van der Slegt J, Flu HC, Veen EJ, Ho GH, de Groot HG, Vos LD, van der Laan L. Adverse events after treatment of patients with acute limb ischemia. Ann Vasc Surg Feb;29(2): Epub 2014 Nov 28. Interne Geneeskunde en Maag-, Darm-, Levergeneeskunde De Bree LC, Alings AM, van Wijngaarden P. Heparin-induced thrombocytopenia after ICD-lead flushing. Acta Cardiol Apr;69(2): Hendrikse WM, Grootenboers MJ, van Wijngaarden P. Type B lactic acidosis as initial presentation of acute myeloid leukaeemia. A case report. Neth J Crit Care apr;18(2):15-6. Van den Berg SA, Verwer PE, Idema RN, Van Guldener C. Transient cefuroxime/metronidazole treatment induced factor V antibodies. BMJ Case Rep Aug 19;2014. pii: bcr Klinisch Chemisch Hematologisch Laboratorium Van den Berg SA, Verwer PE, Idema RN, Van Guldener C. Transient cefuroxime/metronidazole treatment induced factor V antibodies. BMJ Case Rep Aug 19;2014. pii: bcr Joosen AM, Boonen K, Hulsman N, Schuitemaker FJ, Thelen MH. Hypernatraemia in disguise. Clin Chem Lab Med Nov;52(11):e

250 Laboratorium voor Microbiologie en Infectiepreventie Van Cleef BA, van Benthem BH, Verkade EJ, van Rijen M, Kluytmans-van den Bergh MF, Schouls LM, Duim B, Wagenaar JA, Graveland H, Bos ME, Heederik D, Kluytmans JA. Dynamics of methicillin-resistant Staphylococcus aureus and methicillin-susceptible Staphylococcus aureus carriage in pig farmers: a prospective cohort study. Clin Microbiol Infect Oct;20(10):O Epub 2014 May 15. Verkade E, Kluytmans-van den Bergh M, van Benthem B, van Cleef B, van Rijen M, Bosch T, Schouls L, Kluytmans J. Transmission of methicillin-resistant Staphylococcus aureus CC398 from livestock veterinarians to their household members. PLoS One Jul 25;9(7):e ecollection Van Rijen MM, Bosch T, Verkade EJ, Schouls L, Kluytmans JA; CAM Study Group* [van Cleef BA et al...]. Livestock-associated MRSA carriage in patients without direct contact with livestock. PLoS One Jun 27;9(6):e Veenemans J, Overdevest IT, Snelders E, Willemsen I, Hendriks Y, Adesokan A, Doran G, Bruso S, Rolfe A, Pettersson A, Kluytmans JA. Next-generation sequencing for typing and detection of resistance genes: performance of a new commercial method during an outbreak of extendedspectrum-beta-lactamase-producing Escherichia coli. J Clin Microbiol Jul;52(7): Epub 2014 Apr 30. Veenemans J, Overdevest IT, Snelders E, Willemsen I, Hendriks Y, Adesokan A, Doran G, Bruso S, Rolfe A, Pettersson A, Kluytmans JA. Next-generation sequencing for typing and detection of resistance genes: performance of a new commercial method during an outbreak of extendedspectrum-beta-lactamase-producing Escherichia coli. J Clin Microbiol Jul;52(7): Epub 2014 Apr 30. Verkade E, Kluytmans-van den Bergh M, van Benthem B, van Cleef B, van Rijen M, Bosch T, Schouls L, Kluytmans J. Transmission of methicillin-resistant Staphylococcus aureus CC398 from livestock veterinarians to their household members. PLoS One Jul 25;9(7):e ecollection Van Cleef BA, van Benthem BH, Verkade EJ, van Rijen M, Kluytmans-van den Bergh MF, Schouls LM, Duim B, Wagenaar JA, Graveland H, Bos ME, Heederik D, Kluytmans JA. Dynamics of methicillinresistant Staphylococcus aureus and methicillin-susceptible Staphylococcus aureus carriage in pig farmers: a prospective cohort study. Clin Microbiol Infect Oct;20(10): Epub 2014 May 15. Van Rijen MM, Bosch T, Verkade EJ, Schouls L, Kluytmans JA; CAM Study Group*. Livestockassociated MRSA carriage in patients without direct contact with livestock. PLoS One Jun 27;9(6):e Register arts-assistenten 249

251 Bosch T, Verkade E, van Luit M, Landman F, Kluytmans J, Schouls LM. Transmission and Persistence of Livestock-Associated Methicillin-Resistant Staphylococcus aureus among Veterinarians and Their Household Members. Appl Environ Microbiol Jan 1;81(1): Epub Longgeneeskunde Uzun S, Djamin RS, Kluytmans JA, Mulder PG, Van t Veer NE, Ermens AA, Pelle AJ, Hoogsteden HC, Aerts JG, van der Eerden MM. Azithromycin maintenance treatment in patients with frequent exacerbations of chronic obstructive pulmonary disease (COLUMBUS): a randomised, doubleblind, placebo-controlled trial. Lancet Respir Med May;2(5): Epub 2014 Apr 15. Uzun S, Djamin RS, Veer NE van t, Kluytmans JAJW, Ermens AAM, Hoogsteden HC, Aerts JGJV, Eerden MM van der. Macrolides to prevent COPD exacerbations. Clin Pulm Med. 2014;21(2): Djamin RS, Uzun S, Snelders E, Kluytmans JA, Hoogsteden HC, Aerts JG, van der Eerden MM. Occurrence of virus-induced COPD exacerbations during four seasons. Scand J Infect Dis Nov 26:1-5. [Epub ahead of print]. Orthopedie Ten Brinke B, de Haan LJ, Koenraadt KL, van Geenen RC. Medial femoral condyle fracture as an intraoperative complication of Oxford unicompartmental knee replacement. Knee Surg Sports Traumatol Arthrosc Dec 6. [Epub ahead of print]. Keijsers R, Eygendaal D, van den Bekerom MP. Should we really abandon PRP in the treatment of lateral epicondylar tendinopathy? BJSM Blog oct. Keijsers R, Eygendaal D, van den Bekerom MP. Letter to the editor in response to review by De Vos, Windt and Weir. BJSM Blog dec. Van den Bekerom MP, Kodde IF, Aster A, Bleys RL, Eygendaal D. Clinical relevance of distal biceps insertional and footprint anatomy. Knee Surg Sports Traumatol Arthrosc Sep 18. [Epub ahead of print]. 250

252 Register medewerkers zorg- en kenniskernen en Directiecomité Klinisch Chemisch Hematologisch Laboratorium Van Gammeren AJ, Alcala LS, Smolders M, Boersma RS. Numerous Russell bodies and Dutcher bodies in multiple myeloma. Br J Haematol Oct 14. [Epub ahead of print]. Laboratorium voor Microbiologie en Infectiepreventie Veenemans J, Overdevest IT, Snelders E, Willemsen I, Hendriks Y, Adesokan A, Doran G, Bruso S, Rolfe A, Pettersson A, Kluytmans JA. Next-generation sequencing for typing and detection of resistance genes: performance of a new commercial method during an outbreak of extendedspectrum-beta-lactamase-producing Escherichia coli. J Clin Microbiol Jul;52(7): Epub 2014 Apr 30. Van Rijen MM, Bosch T, Verkade EJ, Schouls L, Kluytmans JA; CAM Study Group* [Hendriks YJ et al...]. Livestock-associated MRSA carriage in patients without direct contact with livestock. PLoS One Jun 27;9(6):e Willemsen I, Nelson-Melching J, Hendriks Y, Mulders A, Verhoeff S, Kluytmans-Vandenbergh M, Kluytmans J. Measuring the quality of infection control in Dutch nursing homes using a standardized method; the Infection prevention RIsk Scan (IRIS). Antimicrob Resist Infect Control Aug 18;3:26. Raven CF, van Wijngaarden P, Moen G, van Rijen MM. Clusteruitbraak MRSA buiten het ziekenhuis: Herkennen en aanpakken. [Cluster outbreak of MRSA in the community; recognition and approach]. Ned Tijdschr Geneeskd. 2014;158:A6812. Van Rijen MM, Bosch T, Verkade EJ, Schouls L, Kluytmans JA; CAM Study Group*. Livestockassociated MRSA carriage in patients without direct contact with livestock. PLoS One Jun 27;9(6):e Knox J, van Rijen M, Uhlemann AC, Miller M, Hafer C, Vavagiakis P, Shi Q, Johnson PD, Coombs G, Kluytmans-Van den Bergh M, Kluytmans J, Bennett CM, Lowy FD. Community-associated methicillin-resistant Staphylococcus aureus transmission in households of infected cases: a pooled analysis of primary data from three studies across international settings. Epidemiol Infect Apr 24:1-12. [Epub ahead of print] Van Rijen MM, Kluytmans JA. Adjustment of the MRSA Search and Destroy policy for outpatients in the Netherlands: a prospective cohort study with repeated prevalence measurements. Antimicrob Resist Infect Control Jan 15;3(1):3. Verkade E, Kluytmans-van den Bergh M, van Benthem B, van Cleef B, van Rijen M, Bosch T, Schouls L, Kluytmans J. Transmission of methicillin-resistant Staphylococcus aureus CC398 from livestock veterinarians to their household members. PLoS One Jul 25;9(7):e ecollection 2014 Register medewerkers zorg- en kenniskernen en Directiecomité 251

253 Van Cleef BA, van Benthem BH, Verkade EJ, van Rijen M, Kluytmans-van den Bergh MF, Schouls LM, Duim B, Wagenaar JA, Graveland H, Bos ME, Heederik D, Kluytmans JA. Dynamics of methicillinresistant Staphylococcus aureus and methicillin-susceptible Staphylococcus aureus carriage in pig farmers: a prospective cohort study. Clin Microbiol Infect Oct;20(10): Epub 2014 May 15. Raven CF, van Wijngaarden P, Moen G, van Rijen MM. Clusteruitbraak MRSA buiten het ziekenhuis: Herkennen en aanpakken. [Cluster outbreak of MRSA in the community; recognition and approach]. Ned Tijdschr Geneeskd. 2014;158:A6812. Willemsen I, Hille L, Vrolijk A, Bergmans A, Kluytmans J. Evaluation of a commercial real-time PCR for the detection of extended spectrum ß-lactamase genes. J Med Microbiol Apr;63 (Pt 4): Epub 2014 Jan 28. Reuland EA, Hays JP, de Jongh DM, Abdelrehim E, Willemsen I, Kluytmans JA, Savelkoul PH, Vandenbroucke-Grauls CM, al Naiemi N. Detection and occurrence of plasmid-mediated AmpC in highly resistant gram-negative rods. PLoS One Mar 18;9(3):e ecollection Veenemans J, Overdevest IT, Snelders E, Willemsen I, Hendriks Y, Adesokan A, Doran G, Bruso S, Rolfe A, Pettersson A, Kluytmans JA. Next-generation sequencing for typing and detection of resistance genes: performance of a new commercial method during an outbreak of extendedspectrum-beta-lactamase-producing Escherichia coli. J Clin Microbiol Jul;52(7): Epub 2014 Apr 30. Willemsen I, Nelson-Melching J, Hendriks Y, Mulders A, Verhoeff S, Kluytmans-Vandenbergh M, Kluytmans J. Measuring the quality of infection control in Dutch nursing homes using a standardized method; the Infection prevention RIsk Scan (IRIS). Antimicrob Resist Infect Control Aug 18;3:26. Amphia Academy Infectious Disease Foundation Verkade E, Kluytmans-van den Bergh M, van Benthem B, van Cleef B, van Rijen M, Bosch T, Schouls L, Kluytmans J. Transmission of methicillin-resistant Staphylococcus aureus CC398 from livestock veterinarians to their household members. PLoS One Jul 25;9(7):e ecollection Knox J, Van Rijen M, Uhlemann AC, Miller M, Hafer C, Vavagiakis P, Shi Q, Johnson PD, Coombs G, Kluytmans-Van den Bergh M, Kluytmans J, Bennett CM, Lowy FD. Community-associated methicillin-resistant Staphylococcus aureus transmission in households of infected cases: a pooled analysis of primary data from three studies across international settings. Epidemiol Infect Jan;143(2): Epub 2014 Apr

254 Van Cleef BA, van Benthem BH, Verkade EJ, van Rijen M, Kluytmans-van den Bergh MF, Schouls LM, Duim B, Wagenaar JA, Graveland H, Bos ME, Heederik D, Kluytmans JA. Dynamics of methicillin-resistant Staphylococcus aureus and methicillin-susceptible Staphylococcus aureus carriage in pig farmers: a prospective cohort study. Clin Microbiol Infect Oct;20(10): Epub 2014 May 15. Van Rijen MM, Bosch T, Verkade EJ, Schouls L, Kluytmans JA; CAM Study Group* [Kluytmans-van den Bergh MF et al...]. Livestock-associated MRSA carriage in patients without direct contact with livestock. PLoS One Jun 27;9(6):e Willemsen I, Nelson-Melching J, Hendriks Y, Mulders A, Verhoeff S, Kluytmans-Vandenbergh M, Kluytmans J. Measuring the quality of infection control in Dutch nursing homes using a standardized method; the Infection prevention RIsk Scan (IRIS). Antimicrob Resist Infect Control Aug 18;3:26. Orthopedie Ten Brinke B, de Haan LJ, Koenraadt KL, van Geenen RC. Medial femoral condyle fracture as an intraoperative complication of Oxford unicompartmental knee replacement. Knee Surg Sports Traumatol Arthrosc Dec 6. [Epub ahead of print] Directiecomité Beenakker KG, Koopman JJ, van Bodegom D, Kuningas M, Slagboom PE, Meij JJ, Maier AB, Westendorp RG. Variants of the IL-10 gene associate with muscle strength in elderly from rural Africa: a candidate gene study. Aging Cell Oct;13(5): Epub 2014 Jul 18. Register medewerkers zorg- en kenniskernen en Directiecomité 253

255 254

256 255

257 Colofon Vormgeving Commond Content for Brands, Breda Fotografie Joris Buijs, Persbureau Van Eijndhoven, Tilburg Overzicht publicaties Jan van Trier Eindredactie Attie Tuinenburg, Judith Jansen Verspreiding Kenniskern Amphia Academie 256

258 Locatie Langendijk Langendijk EV Breda Locatie Molengracht Molengracht CK Breda Locatie Pasteurlaan Pasteurlaan DH Oosterhout Locatie Trivium Trivium LP Etten-Leur T I