Wetenschappelijk onderzoek in Medisch Spectrum Twente 2012
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Inhoudsopgave Inhoudsopgave ........................................................................................................... 3 Voorwoord .................................................................................................................. 5 Overzicht publicaties en de Top 3 .............................................................................. 7 Overzicht aantal publicaties per vakgroep: ................................................................ 9 Promoties in MST in 2012 ........................................................................................ 11 Financien en Informatiezaken .............................................................................. 11 Intensive Care ...................................................................................................... 15 Interne Geneeskunde ........................................................................................... 25 Interne Geneeskunde ........................................................................................... 33 Neurologie ............................................................................................................ 37 Reumatologie ....................................................................................................... 45 Reumatologie ....................................................................................................... 51 Reumatologie ....................................................................................................... 57 Reumatologie ....................................................................................................... 63 PubMed publicaties per vakgroep ............................................................................ 69 Anesthesiologie .................................................................................................... 69 Cardiologie ........................................................................................................... 70 Gynaecologie ....................................................................................................... 89 Heelkunde ............................................................................................................ 93 Intensive Care .................................................................................................... 108 Interne Geneeskunde ......................................................................................... 119 Kindergeneeskunde ........................................................................................... 129 Klinische Chemie................................................................................................ 133 Klinische Farmacie ............................................................................................. 137 Klinische Psychologie......................................................................................... 140 Laboratorium voor Microbiologie ........................................................................ 143 Longziekten ........................................................................................................ 146 MDL .................................................................................................................... 152 Medical School Twente ...................................................................................... 160 Mond- kaak- en aangezichtschirurgie ................................................................ 177 Neurochirurgie .................................................................................................... 178 Neurologie .......................................................................................................... 180 Nucleaire Geneeskunde ..................................................................................... 192 Orthopedie .......................................................................................................... 193 Pathologie .......................................................................................................... 195 Radiologie .......................................................................................................... 202 Radiotherapie ..................................................................................................... 207 Reumatologie ..................................................................................................... 215 Revalidatiegeneeskunde .................................................................................... 230 Thoraxchirurgie .................................................................................................. 237
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Voorwoord Voor u ligt de vierde editie van het jaarlijkse overzicht van het wetenschappelijk overzicht wat door medewerkers van Medisch Spectrum Twente in 2012 is gepubliceerd. Zoals u zult zien is de grote stijging van de afgelopen jaren afgevlakt maar we publiceren nog steeds een groot aantal artikelen. Dit jaaroverzicht wordt ook buiten MST verspreid onder huisartsen, apothekers, fysiotherapeuten en andere wetenschappelijke instellingen in de regio. De publicaties zijn gegroepeerd op vakgroep of maatschap. Niet op volgorde van belangrijkheid maar alfabetisch. Hierbij is als criterium genomen dat de publicatie terug te vinden moet zijn op PubMed en de publicatiedatum moet ook in 2012 zijn. De zogenaamde “Epub Ahead of Print” artikelen komen in de volgende uitgave. Daarnaast worden ook peer-reviewed artikelen uit Nederlandstalige tijdschriften opgenomen. In 2012 zijn 213 unieke publicaties verschenen in peer-reviewed tijdschriften. Dit is weer behoorlijk meer dan voorgaande jaren, en we hebben de grens van 200 peer reviewed publicaties inmiddels doorbroken. De gemiddelde impact score van alle artikelen is 3,97. Dat is iets hoger dan 2011 maar nog steeds lager dan het topjaar 2010. Er waren in 2012 9 promoties in MST. Dat is een record! Een van de redenen voor het grote aantal publicaties en de hoge gemiddelde impact factor lijkt gelegen in een aantal nieuwe onderzoekers in MST. Blijkbaar slagen we er in om goede en veel publicerende onderzoekers naar “het Oosten” te lokken! Dit zal zeker bijdragen aan een nog vruchtbaarder onderzoeksklimaat. Naast de Elsevier lijstjes en AD ranglijsten staan ook in deze uitgave lijstjes in de vorm van een Top 3. U vindt per gepubliceerd artikel de impact factor van het tijdschrift en per vakgroep of maatschap de totale en gemiddelde impact factor score van alle gepubliceerde artikelen. Om een indruk te krijgen van de bijdrage van eigen onderzoek is ook een overzicht gegeven van het aantal artikelen waarbij een onderzoeker uit MST 1e, 2e, of laatste auteur is. Daarvan wordt ook apart de totale en gemiddelde impact score weergegeven. Om de ontwikkeling te kunnen volgen zijn de ranglijsten van 2012 naast die van 2009, 2010 en 2011 weergegeven. Ik wens u veel leesplezier toe, Prof. dr. Job van der Palen Coördinator Wetenschappelijk Onderzoek Medical School Twente Medisch Spectrum Twente E-mail:
[email protected]
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Overzicht publicaties en de Top 3 Aantal unieke publicaties Gemiddelde impact factor score
2009
2009 109 3,16
2010
2010 177 5,12
2011 190 3,63
2011
2012 213 3,97
2012
Top 3: Aantal publicaties: 1 Heelkunde
16 1 Heelkunde
38 1 Heelkunde
26 1 Cardiologie
33
2 Cardiologie
14 2 Neurologie
23 2 Reumatologie
25 2 Medical School 27
2 Reumatologie
14 3 Reumatologie
17 3 Cardiologie
23 3 Heelkunde
24
152 1 Cardiologie
148
Top 3: Totale impact factor score: 1 Interne
59 1 Heelkunde
214 1 Interne
2 Reumatologie
54 2 Gynaecologie
140 2 Reumatologie
94 2 Iinterne
3 Neurologie
41 3 Interne
110 3 Heelkunde
69 3 Intensive Care
107 80
Top 3: Gemiddelde impact factor score: 1 Radiotherapie
11 1 Radiotherapie
10 1 Interne
9 1 Anesthesie
30
2 Interne
5 2 Gynaecologie
9 2 Radiotherapie
7 2 Interne
7
3 MDL
5 3 Interne
9 3 MDL
7 3 Radiotherapie
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Top 3: Aantal publicaties als 1e, 2e of laatste auteur: 1 Cardiologie
12 1 Heelkunde
20 1 Heelkunde
18 1 Cardiologie
21
2 Heelkunde
7 2 Cardiologie
12 2 Cardiologie
17 2 Reumatologie
18
3 Interne
5 2 Reumatologie
12 3 Reumatologie
15 3 MDL
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3 Longziekten
5
3 Medical School
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Top 3: Totale impact factor score als 1e, 2e of laatste auteur: 1 Longziekten
28 1 Radiologie
54 1 Reumatologie
48 1 Cardiologie
126
2 Medical School
21 2 Klin. Chemie
45 2 Longziekten
33 2 Reumatologie
55
3 Neurologie
16 3 Neurologie
43 3 Cardiologie
32 3 Neurologie
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Top 3: Gemiddelde impact factor score als 1e, 2e of laatste auteur: 1 Neurologie
8 1 Interne
2 Longziekten
6 2 Klin. Farmacie
18 1 MDL 7 2 Radiotherapie
3 MDL
5 3 Klin. Chemie
6 3 Intensive Care
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18 1 Interne 4 2 Cardiologie 48 3 Intensive Care
6 6 5
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Overzicht aantal publicaties per vakgroep: 2009
2010
2011
2012
1
2
1
1
14
14
23
33
Anesthesiologie Cardiologie Gynaecologie
2
15
7
5
16
38
26
24
1
2
12
16
12
13
17
15
Kindergeneeskunde
5
4
7
6
Klinische Chemie
4
14
10
6
Klinische Farmacie
4
3
4
4
Klinische Fysica
0
1
0
0
Klinische Psychologie
0
0
1
4
KNO
0
1
1
0
Laboratorium voor Microbiologie
4
6
8
5
Longziekten
8
5
17
10
MDL
4
5
4
13
12
13
13
27
Mond- kaak- en aangezichtschirurgie
0
1
0
1
Neurochirurgie
3
0
0
2
Heelkunde Intensive Care Interne Geneeskunde
Medical School Twente
Neurologie
11
23
21
19
Nucleaire Geneeskunde
1
1
0
1
Orthopedie
1
2
3
3
Pathologie
1
6
9
12
Plastische Chirurgie
4
1
1
0
Psychiatrie
1
0
0
0
Radiologie
2
11
6
7
Radiotherapie
2
4
5
10
Reumatologie
14
17
25
21
Revalidatiegeneeskunde
2
5
4
11
Spoedeisende Hulp
0
2
1
0
Tandheelkunde
0
0
1
0
Thoraxchirurgie
4
2
5
3
9
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Promoties in MST in 2012 Financien en Informatiezaken Be Patient A longitudinal Study On Adoption And Diffusion Of Information Technology Innovation In Dutch Healthcare
Proefschrift ter verkrijging van de graad van doctor aan Tilburg University, op gezag van de rector magnificus, prof.dr. Ph. Eijlander, in het openbaar te verdedigen ten overstaan van een door het college voor promoties aangewezen commissie in de aula van de Universiteit op vrijdag 7 september 2012 om 10.15 uur door Ronald Wilhelmus Lambertus Spanjers, geboren op 9 april 1969 te Eindhoven
Promotor:
Prof. dr. P.M.A. Ribbers
Copromotor:
Dr. A.F. Rutkowski
Overige leden:
Prof.dr.ing. W.J.H. van Groenendaal Prof.dr. D. Vogel Prof.dr. N. Wickramasinghe
Opponent:
Prof.dr. J.H. Kingma
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Samenvatting Healthcare spending is increasing, and with 9% of the Gross Domestic Product (GDP), has become a factor of economic and political importance in Europe. Healthcare organisations have to modify their business to remain competitive. The author has the vision that information technology (IT) innovations have the potential to revolutionise healthcare and to contribute to its future sustainability. The emerging field in the intersection of medical informatics, public health, and business, referring to healthcare services and information delivered or enhanced through the Internet and related technologies, became known under the term ‘ehealth’. The World Health Organisation (2006) proposed a compact definition of ehealth: “the use of information and communication technologies for health”. Even with its potential to lower costs and transform healthcare; economy, policy and technology barriers seem to hinder the adoption and diffusion of IT innovations. One of the challenges in adoption and diffusion research is to study innovations that contribute to the public good, but diffuse slowly. This research generates insight into the adoption and diffusion of an IT innovation in healthcare presented in a longitudinal case study and market analysis in hospitals in the Netherlands. The IT innovation, Virtual Baby Visit System (VBVS), is an Internet based facility providing a live video stream that connects parents to their hospitalised new-born. The case study is analysed along the stages of the innovation-decision process: the first knowledge (initiation) of an innovation, towards forming an attitude toward the innovation, the decision to adopt or reject, the implementation of the innovation, and the confirmation of the decision. An in-depth investigation of the adoption and diffusion of IT innovation with a focus group of IT management in hospitals demonstrates that financial resources, alignment and perceived IT innovativeness do not play a significant role the adoption and diffusion of IT innovations such as the VBVS. A positive relation is suggested between perceived personal IT innovativeness and the adoption and diffusion of IT innovations such as the VBVS. This research combines 10 years of research with 20 years of field experience, with contributions of over 150 participants from healthcare, from IT managers to patients. Three factors played an important role in the IT innovation alignment for the VBVS: economy, policy and technology. The results of this research lead to the following conclusions: Economy - The VBVS in the Netherlands represent an potential economic value of 1.9 million Euro; less than 0.7% of the average hospital annual budget for IT and almost 0.002% of the average hospital annual budget. The relative negligible economic effect of this investment far outweighs the intangible effects in the innovation-decision process. Support of the policy, high promotional value, and identification with the innovation are examples of these intangible effects that supported the adoption and diffusion of the VBVS technology.
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Policy - New and unfamiliar technologies can generate ethical concerns, and issues such as trust and confidence, that must be addressed. Hospital policy and legislation in the Netherlands was not a barrier in the adoption and diffusion of the VBVS. Key element in the adoption of the VBVS is the policy commitment of the perinatal centres to provide family centred care, in a healing environment; supporting the development of the new-born beyond the boundaries of the hospital. This policy stimulated the healthcare professionals in the adoption and diffusion of the VBVS technology. Technology - Over time the technology evolved and supported the sustainability of VBVS. The increasing quality and availability of bandwidth supported higher image quality and accessibility, stimulating the VBVS through the phases of adoption and diffusion. Patient - IT management played a crucial role in the IT alignment process of the VBVS, their patient centred approach was favourable in the decision-making process, stimulating the nationwide adoption and diffusion of the VBVS. However, IT management in healthcare organisations still has an internal focus when it comes to IT innovations; at best, healthcare professionals are treated as customers, instead of the patients. When IT management realises that the actual adoption and diffusion of an IT innovation in healthcare is an expression of the intangible benefit it brings the patients... ... IT management can consider stimulating the adoption and diffusion of IT innovations by aligning the decision making process around the patients’ needs, and literally ‘be patient.’
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Intensive Care Optimizing fluid management in critically ill patients
Proefschrift ter verkrijging van de graad van doctor aan de Vrije Universiteit Amsterdam, op gezag van de Rector Magnificus prof.dr. L.M. Bouter, in het openbaar te verdedigen ten overstaan van de promotiecommissie van de Faculteit der Geneeskunde op maandag 26 november 2012 om 15.45 uur in de aula van de universiteit, De Boelelaan 1105 door Ronald Jan Trof geboren te Veendam
Promotores: Prof. dr. A.B.J. Groeneveld Prof. dr. A.R.J. Girbes Co-promotor: Dr. A. Beishuizen
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Samenvatting Inleiding Het doel van deze samenvatting is om niet-ingewijden in kennis te stellen van de inhoud van dit proefschrift. De titel van het proefschrift is “optimizing fluid management in critically ill patients”, ofwel vrij vertaald “Het optimaliseren van vloeistof therapie bij ernstig zieke patiënten”. Ernstig zieke patiënten worden doorgaans op de Intensive Care (IC) opgenomen omdat er sprake is van een bedreiging van een of meerdere vitale functies zoals de bloedsomloop, ademhaling en/of bewustzijn, ten gevolge van een onderliggende ziekte, zoals een ernstige infectie (sepsis), of na een ingrijpende operatie zoals na hartchirurgie. De meeste patiënten die opgenomen worden op de Intensive Care hebben veelal te maken met een bedreiging van het in standhouden van de bloedsomloop, dit meestal ten gevolge van een absoluut of relatief vochttekort (hypovolemie). Dit uit zich meestal in een verlaagde bloeddruk waarbij de afgifte van zuurstof aan de weefsels en cellen tekort kan schieten, dit wordt circulatoire shock genoemd. Indien er binnen afzienbare tijd geen herstel optreedt dan zal de kans op progressief orgaanfalen en daarmee de sterftekans aanzienlijk toenemen. Het herstellen en het behouden van een effectief circulerend volume is dan ook één van de belangrijkste initiële doelen in de Intensive Care geneeskunde. Het toedienen van artificiële vloeistoffen vormt de hoeksteen van de behandeling van circulatoire shock. Het doel van het toedienen van vloeistoffen is dat door een toegenomen voorbelasting van het hart (preload) en hartminuutvolume (cardiac output) de bloeddruk zal stijgen waardoor getracht wordt de doorbloeding (perfusie) van de organen en daarmee het zuurstoftransport te waarborgen. Indien namelijk te weinig vloeistof wordt gegeven bestaat er een risico op een aanhoudend perfusietekort van de organen, leidende tot orgaandysfunctie en uiteindelijk orgaanfalen. Echter, indien teveel vloeistof wordt toegediend neemt het risico op overvulling toe met als gevolg het ontstaan van vocht in de longen (longoedeem) en in andere organen; hierdoor kan de toestand van de patiënt verslechteren waardoor de beademingsduur en de kans op gerelateerde complicaties kan toenemen. Om te voorkomen dat een perfusietekort persisteert of juist overvulling kan ontstaan, zou het bewaken (monitoren) van vloeistoftherapie uitkomst kunnen bieden. In dit proefschrift staan twee aspecten van het “optimaliseren van vloeistoftherapie” centraal. Ten eerste het soort vloeistof en ten tweede de wijze waarop de effectiviteit van vloeistoftherapie bewaakt zou kunnen worden (hemodynamisch monitoren). In het eerste gedeelte van het proefschrift wordt nader ingegaan op het soort vloeistof waarbij zogenaamde colloïdale vloeistoffen en kristalloïde vloeistoffen met elkaar vergeleken worden met betrekking tot enerzijds de effecten op het hartminuutvolume (hemodynamische effecten) en anderzijds eventueel nadelige bijwerkingen. In het tweede gedeelte van het proefschrift zal nader worden ingegaan op het monitoren van vloeistoftherapie, waarbij twee monitoringtechnieken centraal staan en met elkaar vergeleken worden; enerzijds de arteria pulmonalis katheter (PAC) en anderzijds de transpulmonale (thermo)dilutie techniek (TPTD). Beide technieken zullen bestudeerd worden met betrekking tot de behandeling van hypovolemie bij patiënten met verschillende ziektebeelden (sepsis en non-sepsis).
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In een aantal studies zal tevens onderzocht worden of de (ziekte gerelateerde) hartfunctie van invloed is op de toepasbaarheid van vullingsdrukken versus vullingsvolumina. DEEL I
Vloeistoffen
Er zijn verschillende soorten artificiële vloeistoffen beschikbaar om het bloedplasmavolume te doen toenemen. Deze soorten kunnen grofweg worden ingedeeld in kristalloïde en colloïdale vloeistoffen. De meest gebruikte kristalloïde vloeistoffen zijn isotoon zout (NaCl 0,9%) en Ringer’s Lactaat. Een nadeel van kristalloïde vloeistoffen is dat het volume expanderend effect (toename van het bloedplasmavolume) van betrekkelijk korte duur is door snelle diffusie vanuit de bloedbaan via de celmembraan naar de weefsels. Slechts 20-25% van de toegediende hoeveelheid kristalloïde vloeistoffen blijft behouden voor (tijdelijke) volume expansie. Colloïdale vloeistoffen bevatten grote moleculen die minder snel door semipermeabele membranen kunnen diffunderen dan kristalloïden. Een theoretisch voordeel is dan ook dat colloïdale vloeistoffen langer in de bloedbaan blijven waardoor het volume expanderend effect mogelijk langer aanhoudt. Colloïdale vloeistoffen zijn in te delen in natuurlijke colloïden (humaan albumine) en synthetische colloïden (hydroxyethyl zetmeel, gelatine). In hoofdstuk 2 hebben we onderzocht of het toedienen van colloïdale vloeistoffen tot een grotere toename van hartminuutvolume leidt in vergelijking met kristalloïde vloeistoffen. In zowel septische als niet-septische patiënten met klinische tekenen van hypovolemie werd gedurende 90 minuten, volgens randomisatie, colloïdale of kristalloïde vloeistoffen toegediend op geleide van een vooraf vastgesteld vloeistof toedieningsprotocol. Na toediening van vloeistof werden elke 30 minuten hemodynamische parameters gemeten. Uit onze observatie bleek dat onafhankelijk van onderliggende ziekte het hartminuutvolume een grotere stijging liet zien na toediening van een zelfde hoeveelheid colloïdale vloeistoffen vergeleken met kristalloïde vloeistoffen (12% versus 2%). De verklaring hiervoor is een grotere toename van cardiale preload na toediening van colloïdale vloeistoffen met als gevolg een sterkere toename van cardiaal slagvolume. De groter toename van cardiale preload kan verklaard worden door een sterkere toename van de colloïd osmotische druk1 na colloïdale vloeistoftoediening, in tegenstelling tot kristalloïde vloeistoffen, waardoor waarschijnlijk een grotere toename van het plasmavolume en dus cardiale preload. Dat na toediening van colloïdale vloeistoffen de toename van de colloïd osmotische druk, cardiale preload en het hartminuutvolume even groot was onder septische als niet-septische omstandigheden - althans binnen het gemeten tijdstraject van 90 minuten - is verassend aangezien de veronderstelde toename van vaatwandlekkage (permeabiliteit) tijdens sepsis aanleiding geeft tot snellere equilibratie van geïnfundeerde vloeistoffen met het compartiment buiten de vaatwand (extravasculaire compartiment). Klaarblijkelijk is de toename van permeabiliteit hiervoor onvoldoende hoewel een tragere equilibratie niet uitgesloten is. Onze 1
colloïd osmotische druk = het drukverschil dat tussen twee eiwitoplossingen (binnen- en buiten het bloedvat) van verschillende concentraties ontstaat ten gevolge van osmose.
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resultaten laten zien dat vergeleken met colloïdale vloeistoffen, 2-3 maal de hoeveelheid kristalloïde vloeistoffen toegediend moeten worden voor het bereiken van een zelfde toename van hartminuutvolume. In hoofdstuk 3 hebben we uitgezocht wat er in de bestaande literatuur bekend is over het volume verschil (volumeratio) tussen colloïdale en kristalloïde vloeistoffen. In hoofdstuk 2 is aangetoond dat vergeleken met colloïdale vloeistoffen er 2 tot 3 keer meer kristalloïde vloeistoffen toegediend moeten worden om hetzelfde hemodynamische eindpunt te bereiken, echter hierover bestaat controverse, waarbij gesuggereerd wordt dat deze volumeratio hooguit 1:1.5 is. Wij beoordeelden alle studies waarbij colloïdale vloeistoffen vergeleken zijn met kristalloïde vloeistoffen. Het resultaat hiervan was dat de volumeratio inderdaad 1:2-3 is, echter vooropgesteld dat dezelfde hemodynamische effecten zijn bereikt. Het verschil tussen onze observatie (1:2-3) en andere studies (1:1.5) lijkt derhalve gebaseerd te zijn op de variatie in hemodynamische eindpunten van de onderzochte studies. In hoofdstuk 4 zijn we ingegaan op de controverse die bestaat met betrekking tot vloeistof therapie bij patiënten met acute longbeschadiging (ALI)/ acuut respiratoir distress syndroom (ARDS). ALI/ARDS kant ontstaan bij patiënten met sepsis, na ernstig trauma of grote chirurgie. Deze ziektebeelden worden gekenmerkt door ontsteking (inflammatie) en een toegenomen lekkage/doorlaatbaarheid (permeabiliteit) van de longvaten. Deze toegenomen permeabiliteit kan leiden tot longoedeem. Het longoedeem belemmert de gaswisseling in de long waardoor zuurstoftekort en stapeling van koolzuur kan ontstaan. Toediening van vloeistof kan het longoedeem doen verergeren door lekkage vanuit de bloedvaten (extravasatie) naar het longweefsel met als gevolg dat de patiënt zijn conditie kan verslechteren. De mate van extravasatie wordt bepaald door de hydrostatische druk in de longhaarvaten (capillairen), de colloïd osmotische druk en de mate van permeabiliteit van de longcapillairen. Indien de druk in de capillairen de druk buiten de capillairen overschrijdt neemt de filtratiedruk toe waardoor toename van longoedeem kan ontstaan. Echter toediening van vloeistof bij ALI/ARDS leidt niet tot toename van oedeem indien de filtratiedruk lager is dan de druk in het longweefsel (interstitiële druk). Indien vloeistoftoediening plaats vindt tijdens hypovolemie waardoor het hartminuutvolume significant zal toenemen (vloeistofresponsiviteit), zal door een relatief lage filtratiedruk geen toename van longoedeem ontstaan, ongeacht het soort vloeistof (kristalloïden of colloïden) en ondanks een toegenomen permeabiliteit. Indien het hartminuutvolume echter niet meer toeneemt na toediening van vloeistof neemt het risico op de vorming van longoedeem belangrijk toe. Toediening van vloeistof tijdens ALI/ARDS is geïndiceerd zolang er sprake is van orgaan hypoperfusie waarbij verondersteld wordt dat toediening van vloeistof de mate van hypoperfusie zal verminderen, echter vooropgesteld dat de patiënt vloeistofresponsief is en de pulmonale filtratiedruk de interstitiële druk in de long niet zal overschrijden tijdens vloeistoftoediening. Indien er geen sprake meer is van hypoperfusie dan zou vloeistof beperking kunnen bijdragen aan het terugdringen van longoedeem waardoor de beademingsduur verkort zou kunnen worden.
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In hoofdstuk 5 hebben we gekeken naar de veiligheid van synthetische colloïden, in het bijzonder hydroxyethyl zetmeel oplossingen (HES) bij patiënten met sepsis. We hebben ons enerzijds gefocust op data inzake de relatie tussen het gebruik van colloïden en sterfte (mortaliteit), en anderzijds op het risico op HES geïnduceerd nierfalen. Onze resultaten lieten zien dat op basis van de beschikbare literatuur niet kan worden gesteld dat het gebruik van colloïden (versus kristalloïden) de mortaliteit negatief of positief beïnvloedt. Echter de meeste studies die zijn onderzocht waren niet gepowered op sterfte noch was mortaliteit gedefinieerd als primaire uitkomstmaat. Het gebruik van HES oplossingen lijkt geassocieerd te zijn met een toegenomen risico op hete ontstaan van acuut nierfalen. De oorzaak hiervan is niet geheel opgehelderd, mogelijk dat grote moleculen in HES oplossingen de niertubuli doen verstoppen waardoor nierfalen kan ontstaan. Dit verklaart wellicht waarom vooral oudere generatie HES oplossingen geassocieerd zijn met acuut nierfalen; oudere generaties HES oplossingen bevatten grotere moleculen dan de huidige HES oplossingen. Het gebruik van groot moleculaire HES oplossingen dient dan ook ontmoedigd te worden. Huidige generatie HES oplossingen lijken vooralsnog niet geassocieerd te zijn met een toegenomen risico op acuut nierfalen, ook niet bij patiënten met sepsis, hoewel er wel een dosisafhankelijk effect lijkt te bestaan. Conclusie Gesteld kan worden dat toediening van colloïdale vloeistoffen (versus kristalloïden) leidt tot een grotere expansie van het plasmavolume en dientengevolge tot snellere hemodynamische optimalisatie in zowel septische als niet-septische condities. In tegenstelling tot oudere generaties HES oplossingen lijkt het gebruik van de huidige generatie HES oplossingen vooralsnog niet geassocieerd te zijn met een toegenomen risico op acuut nierfalen, vooropgesteld dat de maximaal aanbevolen dosering niet wordt overschreden. DEEL II
Hemodynamische monitoring van vloeistoftherapie
Het is aannemelijk dat toediening van vloeistof ten behoeve van het optimaliseren van de bloedsomloop tijdens ernstige ziekte maatwerk is. Enerzijds, toediening van te weinig vloeistof kan leiden tot een insufficiënt hartminuutvolume leidende tot een verminderd aanbod van zuurstof aan de organen (hypoperfusie). Anderzijds, toediening van teveel vloeistof kan juist leiden tot overvulling (oedeem), bijvoorbeeld in de longen, met als gevolg verdere verslechtering van orgaanfunctie, toename van beademingsduur en Intensive Care opname. Het bewaken van vloeistof therapie gebeurt door middel van hemodynamische monitoring. In dit proefschrift zijn twee hemodynamische monitoringstechnieken nader onderzocht, te weten de arteria pulmonalis katheter (PAC) en de transpulmonale (thermo)dilutie techniek (TPTD). De PAC techniek bestaat reeds enkele decennia en maakt gebruik van een katheter die wordt ingebracht in een grote ader (meestal in de hals of onder het sleutelbeen) en via de rechter harthelft wordt opgevoerd tot in de longslagader (figuur 1). Met deze techniek kan de druk worden bepaald in de bovenste holle ader (centraal veneuze druk, CVD), rechter hartboezem, rechter hartkamer en in de
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longslagader. Deze drukken worden de zogenaamde vullingdrukken genoemd. Daarnaast kan door het inspuiten van (koude) vloeistof een schatting worden gemaakt van het hartminuutvolume van de rechter harthelft. Door middel van het opblazen van een ballonnetje aan het uiteinde van de katheter stopt de flow distaal van de katheter waardoor de zogenaamde occlusie druk (PAOP) in de longslagader kan worden gemeten. Deze occlusie druk is een surrogaat voor preload van de linker harthelft, terwijl de CVD een surrogaat is voor preload van de rechter harthelft. Een lage CVD en PAOP suggereren de mogelijkheid van preload toename en dus toename van hartminuutvolume na vloeistoftoediening, terwijl een hoge CVD en PAOP vloeistofresponsiviteit wellicht uitsluit. Deze drukken worden echter beïnvloed door de drukken die ontstaan tijdens mechanische beademing waardoor interpretatie kan worden bemoeilijkt.
Figuur 1. Arteria Pulmonalis Katheter. De katheter wordt ingebracht via een centrale grote ader (catheter entrance) en via de bovenste holle ader (superior vena cava) door de rechter boezem (right atrium) door de tricuspidalis hartklep (tricuspid valve), via de rechter hartkamer (right ventricle) door de pulmonalis hartklep (pulmonary valve) in de longslagader opgevoerd (pulmonary artery).
De TPTD techniek is in de jaren 90 van de vorige eeuw ontwikkeld. Deze techniek vereist de aanwezigheid van een centraal veneuze katheter en een speciale katheter in de liesslagader. Door toediening van een zogenaamde indicator wordt door middel van subtractie (vullings)volumina berekend. Omdat geen gebruik gemaakt wordt van een katheter die door het hart opgevoerd dient te worden, wordt deze techniek als minder invasief beschouwd. Initieel werd gebruik gemaakt van een dubbele indicator: een kleurstof indicator (indocyanine groen) en thermale indicator (koude vloeistof). Inmiddels is de dubbele indicator techniek vervangen door gebruik van alleen een thermale indicator. De thermale indicator wordt toegediend via de centraal veneuze katheter. Na toediening detecteert de katheter
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in de liesslagader de temperatuursverandering in de tijd (figuur 2). Een computer berekent onder andere het hartminuutvolume, het (virtuele) volume van de hartkamers als maat voor cardiale preload (globaal einddiastolisch volume, GEDV) en de mate van longoedeem (extravasculair longwater, EVLW). Door het monitoren van het EVLW kan in theorie vloeistof overbelasting worden voorkomen, een extra voordeel van deze techniek. Een ander voordeel van deze techniek is dat de gegenereerde parameters niet beïnvloed worden door mechanische beademing. In dit gedeelte van dit proefschrift hebben we bovengenoemde monitoringstechnieken met elkaar vergeleken en onderzocht of de klinische toepasbaarheid beïnvloed wordt door onderliggende ziekte (sepsis of non-sepsis) en/of (gerelateerde) hartfunctie.
Figuur 2. Transpulmonale thermodilutie techniek (PiCCO™). Benodigd zijn een katheter in een centrale grote ader (standard CVC) en een katheter in de liesslagader (PiCCO® Catheter) die tevens fungeert als invasieve bloeddruk meter (pressure connection cable). Via een injectie met koude vloeistof in de centrale grote ader wordt in de katheter in de liesslagader gedetecteerd hoelang het duurt voordat de koude bolus hier arriveert. Een computer die aangesloten is op beide katheters (injectate sensor cable, arterial connection cable) berekent vervolgens het hartminuutvolume, het globaal einddiastolisch volume (GEDV) en het extravasculair longwater (EVLW).
In hoofdstuk 6 hebben we verondersteld dat bij patiënten met een verminderde hartfunctie (systolische dysfunctie) na hart- en vaatchirurgie, vullingsdrukken (CVD en PAOP) superieur zijn aan vullingsvolumina (GEDV) voor het voorspellen van vloeistofresponsiviteit. Hiertoe hebben we 32 patiënten onderzocht (18 na hartchirurgie, 14 na vaatchirurgie) op de Intensive Care. Deze patiënten hadden allemaal klinisch tekenen van hypovolemie. Colloïdale vloeistof werd gegeven gedurende 3 achtereenvolgende intervallen van 30 minuten op geleide van een vooraf vastgesteld algoritme gebaseerd op verandering van centraal veneuze druk. Patiënten werden onderverdeeld in twee groepen; verminderde systolische
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hartfunctie en normale systolisch hartfunctie. In totaal werden 32 maal 3 = 96 vloeistofstappen geëvalueerd, waarbij onderscheid werd gemaakt tussen responders (toename van hartminuutvolume na toediening van vloeistof) en nonresponders. Uit de resultaten bleek dat de CVD voorspellende waarde had in beide groepen. Echter PAOP bleek superieur aan GEDV inzake het voorspellen van vloeistofresponsiviteit bij patiënten met systolische dysfunctie, terwijl bij patiënten met een normale systolisch functie dit juist andersom was. Het lijkt erop dat in patiënten met systolisch dysfunctie, preload toename meer afhankelijk is van drukken dan van volumes. Derhalve kan worden gesuggereerd dat bij patiënten na hart- of vaatchirurgie met een verminderde systolische hartfunctie, het gebruik van vullingsdrukken gegenereerd door de arteria pulmonalis katheter wellicht de voorkeur heeft boven het gebruik van volume parameters zoals de TPTD techniek. In hoofdstuk 7 hebben we ons gericht op patiënten met ernstige sepsis / septische shock2. Een deel van de patiënten met ernstige sepsis / septische shock ontwikkelt cardiale dysfunctie zich uitend in systolisch falen en dientengevolge verwijding (dilatatie) van de hartkamers. Gesuggereerd wordt dat deze dilatatie een adaptief mechanisme is ten behoeve van het in stand houden een hoog hartminuutvolume, hetgeen geassocieerd is met overleving. Door toepassing van de TPTD techniek kan deze cardiale dilatatie worden gereflecteerd door een verhoogd GEDV. Wij onderzochten of een verhoogd GEDV als uiting van cardiale dilatatie ten gevolge van systolisch dysfunctie inderdaad geassocieerd is met het in stand houden van vloeistofresponsiviteit. Hiertoe bestudeerden we 16 patiënten met ernstige sepsis/septisch shock op de Intensive Care. Colloïdale vloeistof werd gegeven gedurende 3 achtereenvolgende intervallen van 30 minuten op geleide van een vooraf vastgesteld algoritme gebaseerd op verandering van centraal veneuze druk. Patiënten werden onderverdeeld in twee groepen; verminderde systolische hartfunctie ( 9 patiënten) en normale systolisch hartfunctie (7 patiënten). In totaal werden 16 maal 3 = 48 vloeistofstappen geëvalueerd, waarbij onderscheid werd gemaakt tussen responders (toename van hartminuutvolume na toediening van vloeistof) en non-responders. Uit de resultaten bleek dat in de groep van patiënten met een verminderde systolisch functie basaal GEDV hoger was in de responders dan in de nonresponders. Echter in de groep patiënten met een normale systolische functie was er geen verschil in basaal GEDV tussen responders en non-responders. Onze bevinding bevestigt de resultaten van ander onderzoek dat de voorspellende waarde van basaal GEDV voor vloeistofresponsiviteit imperfect is omdat deze waarde afhangt van systolisch functie. Geconcludeerd kan worden dat bij patiënten met een sepsis geïnduceerde systolische dysfunctie en dilatatie een hoog GEDV vloeistofresponsiviteit niet uitsluit,
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Septische shock is de ernstigste manifestatie van sepsis. Hierbij is er meestal sprake van aanhoudend lage bloeddrukken ondanks het toedienen van adequate hoeveelheden vloeistoffen waarbij het functioneren van organen ernstig bedreigd is. 22
en GEDV dus nog verder kan toenemen. Dit is belangrijk gegeven omdat in de literatuur lagere normaalwaarden of streefwaarden worden gesuggereerd. In hoofdstuk 8 hebben we het principe en de toepasbaarheid van door de TPTD techniek verkregen extravasculaire longwater nader beschreven. Er is aangetoond dat EVLW metingen zeer goed correleren met de goudstandaard via post mortem gravimetry in proefdieren. Klinische studies bij patiënten toont aan dat aanhoudend verhoogd EVLW sterk gecorreleerd is met sterfte. Het is derhalve aannemelijk dat EVLW-geleide (vloeistof) therapie van invloed zou kunnen zijn op beademingsduur en wellicht opnameduur op de IC. In hoofdstuk 9 hebben we onderzocht of het risico op vloeistof overbelasting minder groot is wanneer vloeistof management wordt bepaald aan de hand van GEDV en EVLW metingen in vergelijking met PAOP metingen met de PAC. 120 patiënten opgenomen op de Intensive Care werden gerandomiseerd en geïncludeerd waarvan 60 patiënten werden voorzien van een PAC en 60 patiënten van de TPTD techniek. Patiënten werden gestratificeerd naar onderliggende ziekte: septische shock versus non-septische shock. Gedurende een periode van 72 uur werd op basis van vooraf gedefinieerde algoritmes vloeistof toegediend. Vloeistoftoediening was toegestaan zolang bovenste limieten van PAOP, GEDV of EVLW niet waren bereikt. Primaire uitkomstmaat was beademingsvrije dagen, secondaire uitkomstmaten waren orgaanfalen en sterfte. Uit de studie kwam naar voren dat zowel primaire als secundaire uitkomstmaten in beide groepen (PAC versus TPTD) vergelijkbaar was, maar dat TPTD monitoring geassocieerd was met langere beademingsduur en een langer verblijf op de Intensive Care een ziekenhuis in de niet-septische shock groep, doch niet in de septische shock groep. De verklaring hiervoor zou kunnen zijn dat in de non-septische groep er meer patiënten zaten met bijkomende hartziekten. Toepassing van een maximale limiet van 10 ml/kg EVLW zou in deze groep wellicht te hoog kunnen zijn waardoor er een grotere kans bestaat op het ontstaan van longoedeem, met als gevolg een langere beademingsduur. Onze resultaten lijken te bevestigen dat patiënten met septische shock een anders reageren met betrekking tot cardiorespiratoire fysiologie dan patiënten met niet-septische shock. Conclusie We mogen stellen dat de interpretatie van parameters verkregen door hemodynamische monitoring met de PAC of TPTD techniek gerelateerd dient te worden aan onderliggende ziekte en (gerelateerde) hartfunctie. De PAC faciliteert het inzichtelijk maken van de cardiale dynamiek tijdens vloeistoftherapie, met name bij patiënten met een verminderde systolische functie. De TPTD techniek daarentegen kan door de mogelijkheid van het relatief betrouwbaar schatten van de mate van het extravasculaire longwater behulpzaam zijn tijdens vloeistoftherapie bij patiënten die een verhoogd risico hebben op (toename van) longoedeem, zoals patiënten met ARDS, om schadelijke overvulling te voorkomen.
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Interne Geneeskunde Immune control by the autonomic nervous system towards clinical implementation of enriched enteral nutrition
Proefschrift ter verkrijging van de graad van doctor aan de Universiteit Maastricht, op gezag van de Rector Magnificus, Prof. dr. L.L.G. Soete, volgens het besluit van het College van Decanen, in het openbaar te verdedigen op donderdag 22 november 2012 om 14.00 uur door Jacco Juri de Haan
Promotoren: Prof. dr. W.A. Buurman Prof. dr. J.W.M. Greve Beoordelingscommissie: Prof. dr. H. ten Cate (voorzitter) Prof. dr. L.M.A. Akkermans (UMC Utrecht) Prof. dr. G.E. Boeckxstaens (Katholieke Universiteit Leuven) Prof. dr. A.M.W.J. Schols Prof. dr. P.B. Soeters
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Samenvatting Verschillende barrières beschermen het lichaam tegen het binnendringen van pathogenen. Een beschadiging van deze barrières leidt tot een reactie van het immuunsysteem. Deze reactie wordt niet alleen worden veroorzaakt door binnendringende pathogenen, maar kan ook worden opgeroepen door lichaamseigen stoffen die bijvoorbeeld vrijkomen bij weefselschade. Een adequate en proportionele immuunrespons leidt tot neutralisatie van ziekteverwekkers en herstel van de geleden schade. Echter, vooral traumapatiënten, patiënten die een grote operatie krijgen of patiënten die een zware chemokuur ondergaan lopen risico op het ontwikkelen van excessieve ontstekingsreacties. Dergelijke buitensporige reacties van het immuunsysteem worden gedefinieerd als sepsis en sepsis‐achtige syndromen. Hoewel de behandeling van sepsis in de laatste jaren is verbeterd, blijven de morbiditeit en mortaliteit van patiënten met deze ziektebeelden zeer hoog. Er bestaat daarom een grote behoefte aan nieuwe methoden om de immuunreactie onder controle te houden, zodat sepsis kan worden voorkomen of beter kan worden behandeld. Een veelbelovende manier om de ontstekingsreactie te beïnvloeden is stimulering van het autonome zenuwstelsel, en in het bijzonder het parasympatisch zenuwstelsel. De ontstekingsremmende impulsen van het parasympatisch zenuwstelsel, die vooral via de nervus vagus worden voortgeleid, werden voor het eerst door dr. Tracey en collega’s beschreven. In septische proefdieren toonden zij aan dat zowel elektrische prikkeling van de nervus vagus als farmacologische stimulering van nicotinerge acetylcholine (nACh) receptoren de afgifte van ontstekingsstoffen (bijvoorbeeld cytokines) remt. Ook leiden deze interventies tot minder orgaanschade en minder sterfte. Onze onderzoeksgroep liet eerder in een diermodel zien dat lipiderijke voeding via stimulatie van de nervus vagus de ontstekingsreactie remt en schade aan de darm en lever vermindert. Bij gezonde mensen zouden deze dempende effecten van enterale voeding een onnodige ontstekingsreactie kunnen voorkomen. Inname van voeding leidt namelijk tot een beperkte blootstelling van de darmwand aan microorganismen en antigenen die doorgaans geen sterke afweerreactie vereist. Bij patiënten bij wie de ontstekingsreactie te hevig is, zou activatie van deze ontstekingsremmende neuro‐immuun‐as door specifieke voeding kunnen bijdragen aan de behandeling. De in dit proefschrift beschreven studies kunnen worden beschouwd als stappen op de weg naar klinische toepassing van stimulering van het parasympatische zenuwstelsel door middel van enterale voeding. Het eerste doel van dit proefschrift is het verder ontrafelen van het mechanisme dat aan de ontstekingsremmende werking van lipiderijke voeding ten grondslag ligt. Het tweede doel is de werkzaamheid van stimulatie van het autonome zenuwstelsel door voeding te onderzoeken. Hiervoor gebruiken we verschillende diermodellen voor belangrijke ziektebeelden in chirurgische en intensive care patiënten. Het derde doel is het vertalen van deze experimentele bevindingen naar de mens. Voor het eerst wordt aangetoond dat kortdurende interventie met verrijkte enterale voeding een acute ontstekingsrespons bij de mens remt. Kennis van de mechanismen die de ontstekingsremmende werking van lipiderijke voeding verklaren is noodzakelijk om een optimale klinische behandeling te ontwikkelen en gezondheidsrisico’s te beperken. In het eerste deel van dit
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proefschrift wordt onderzocht op welke manier voeding het centraal zenuwstelsel aanzet tot remming van de ontstekingsreactie. In eerdere studies bleek de communicatie tussen enterale voedingsstoffen en het brein te verlopen zowel via sensorische zenuwen als via de bloedbaan. Om de route te achterhalen waarlangs het ontstekingsremmende signaal wordt overgebracht, worden de sensorische zenuwen op cervicaal niveau uitgeschakeld door middel van capsaicine. Wanneer de signaaloverdracht via afferente vagusbundels op deze wijze wordt onderbroken, is lipiderijke voeding niet langer in staat om de ontstekingsreactie te dempen (hoofdstuk 2). Vervolgens wordt ingegaan op de activatie van de zenuwuiteinden in de darmwand. In eerdere studies werd aangetoond dat cholecystokinine (CCK) receptoren een essentiële schakel vormen in de ontstekingsremmende werking van lipiderijke voeding. CCK‐receptoren komen onder meer voor op de perifere uiteinden van de afferente nervus vagus. Met behulp van specifieke antagonisten stellen we vast dat perifeer gelegen CCK‐1 receptoren een cruciale schakel vormen in de gunstige effecten van lipiderijke voeding. In overeenstemming hiermee leidt toediening van een vorm van CCK die specifiek aan perifeer gelegen CCK‐1 receptoren bindt, in gevaste dieren tot een zelfde mate van ontstekingsremming als lipiderijke voeding. Concluderend toont deze studie een voorheen onbekende darm‐hersen‐immuun reflex aan, berustend op activatie van perifeer gelegen CCK‐1 receptoren en aanvoerende takken van de nervus vagus door nutriënten in het darmlumen. In het tweede deel van dit proefschrift wordt de aantasting van de darmwand in de vroege fase van een systemische ontstekingsrespons bestudeerd, en de effecten van lipiderijke voeding hierop. Verschillende experimentele en klinische studies wijzen op een belangrijke rol van de darm in de ontwikkeling en ontsporing van de systemische ontstekingsreactie. Met behulp van de in het bloed gemeten biomarker I‐FABP werd door dr. Derikx en collega’s aangetoond dat schade aan enterocyten (darmepitheelcellen) plaatsvindt zowel in een vroeg stadium van sepsis als kort na niet‐abdominale chirurgie. De mate van enterocytschade bleek samen te hangen met de prognose van deze patiënten en het ontstaan van complicaties. Een belangrijke patiëntengroep met een sterk verhoogd risico op het ontstaan van sepsis zijn mensen met een groot fysiek trauma. In hoofdstuk 3 wordt beschreven hoe met behulp van IFABP is vastgesteld dat enterocytschade na trauma al detecteerbaar is op het moment dat patiënten arriveren op de spoedeisende hulp. De mate van vroege enterocytschade is gerelateerd aan de omvang van het trauma, alsook aan de hoogte van ontstekingsparameters IL‐6, CRP en procalcitonine, gemeten in de dagen na het trauma. Deze bevindingen impliceren dat vroege aantasting van de darmwand als een aangrijpingspunt kan worden beschouwd voor ontstekingsremmende interventies in traumapatiënten. De veranderingen in de darmwand kort na activatie van het afweersysteem worden nader bestudeerd in een diermodel van hemorragische shock. In hoofdstuk 4 wordt beschreven dat afbraak van de actinefilamenten die de enterocyt structuur geven al een kwartier na shock plaatsvindt. De verstoring van de celstructuur wordt gevolgd door afbraak van de ‘tight junctions’ die de enterocyten onderling verbinden. Deze structurele veranderingen gaan gepaard met een toename van de permeabiliteit van de darmwand en het ontstaan van een lokale ontstekingsrespons. Deze processen in de darmwand gaan vooraf aan het verschijnen van ontstekingsstoffen in de
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circulatie. Vervolgens worden de effecten van lipiderijke voeding op de vroege aantasting van de darmwand bestudeerd. In hoofdstuk 5 wordt beschreven dat toediening van lipiderijke voeding de doorlaatbaarheid van de darmwand beperkt. Verder leidt voedingsinterventie tot een afname van enterocytschade en minder ontsteking van de darmwand. Blokkade van de CCK‐receptoren, die een cruciale rol spelen in de activatie van de nervus vagus, neemt de effecten van voeding weg. Concluderend tonen deze data aan dat lipiderijke voeding vroege aantasting van de darmwand voorkomt via activatie van de vagale reflex. Wanneer de darmbarrière wordt aangetast, behoren mestcellen tot de eerste cellen van het afweersysteem die immuno‐actieve mediatoren uitscheiden. Verschillende recente studies tonen aan dat mestcellen een belangrijk onderdeel vormen van de immunologische barrière tussen de darminhoud en het lichaam. De reactiviteit van mucosale mestcellen wordt nader bestudeerd in het endotoxinemodel, een veel gebruikt model voor de systemische ontstekingsreactie die tijdens de vroege fase van sepsis optreedt (hoofdstuk 6). Toediening van een bolus endotoxine, een component van de celwand van Gramnegatieve bacteriën, roept een respons van het afweersysteem op. Behandeling met histamine receptor‐1 blokker en mestcelstabilisator ketotifen leidt tot lagere concentraties ontstekingsstoffen in de circulatie en behoud van de darmbarrière. Hiermee wordt het belang van mestcelactivatie in het ontstaan van ontsteking en aantasting van darmintegriteit bevestigd. Lipiderijke voeding voorafgaand aan de gift endotoxine remt de mestcelactivatie. Blokkade van zowel CCK‐1 receptoren als nACh receptoren neemt de remmende effecten van voeding op mestcelactivatie weg, wat een cruciale rol van de CCK‐1 receptorafhankelijke vagale reflex aantoont. Deze bevindingen worden ondersteund door in vitro experimenten waarin een dosisafhankelijke mestcelremming wordt aangetoond door nicotine en acetylcholine (agonisten van de nACh receptor). Concluderend blijkt uit deze experimenten dat remming van mucosale mestcellen een aangrijpingspunt is voor de door enterale voeding geactiveerde vagale reflex. In het derde deel van dit proefschrift wordt de werkzaamheid van verrijkte voeding onderzocht in verschillende situaties waarin een ontregelde afweerreactie centraal staat. Al eerder werden patiënten met een ernstig trauma genoemd als een patiëntengroep bij wie een sterke activatie van het immuunsysteem optreedt. Logischerwijs kan bij deze patiënten de behandeling pas worden gestart op het moment dat er al weefselschade is en de ontstekingsrespons zich reeds ontwikkelt. Om deze situatie na te bootsen wordt in het hemorragische shockmodel pas gestart met voeding op het moment dat shock‐gerelateerde ontsteking en weefselschade al aanwezig zijn (hoofdstuk 7). Lipiderijke voeding toegediend na shock resulteert in een vermindering van de ontstekingsrespons en behoud van de darmwand in vergelijking met gevaste dieren. Het feit dat blokkers van de CCK‐receptor het beschermende effect van voeding na shock wegnemen wijst erop dat stimulatie van de CCK receptor afhankelijke vagale reflex ook in deze situatie cruciaal is. Afbraak van erytrocyten, oftewel hemolyse, is een fenomeen dat frequent wordt waargenomen bij verschillende groepen (cardio)chirurgische patiënten en patiënten op de intensive care. Recente studies leggen een verband tussen massale hemolyse, het optreden van circulatieproblemen en een verslechterde orgaanfunctie. Tijdens hemolyse komen grote hoeveelheden hemoglobine vrij, dat
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een onomkeerbare reactie met stikstofmonoxide aangaat. De tekorten aan stikstofmonoxide die vervolgens ontstaan worden verondersteld een belangrijk deel van de circulatieproblemen te verklaren. Stikstofmonoxide zorgt namelijk voor relaxatie van glad spierweefsel. Het is bekend dat de gevoeligheid voor stikstofmonoxide‐onafhankelijke vaatverwijders tijdens hemolyse juist toeneemt. Aangezien acetylcholine, een neurotransmitter die vrijkomt door stimulatie van de nervus vagus, als een krachtige en stikstofmonoxideonafhankelijke vaatverwijder functioneert, veronderstelden wij dat lipiderijke voeding via het vrijkomen van acetylcholine de schadelijke gevolgen van acute hemolyse zou kunnen beperken. Het effect van lipiderijke voeding wordt onderzocht in een diermodel waarin hemolyse wordt nagebootst door infusie van gelyseerde erythrocyten (hoofdstuk 8). Conform de hypothese leidt interventie met enterale voeding via activatie van CCK‐1 receptoren en nACh receptoren tot een sterke vermindering van orgaanschade en afname van de systemische ontstekingsreactie. Bovendien wordt met behulp van microsferen (fluorescente bolletjes) aangetoond dat lipiderijke voeding de microcirculatie in de nier, darm en lever verbetert. Deze data impliceren dat stimulatie van de vagale reflex door middel van voeding kan bijdragen aan het voorkomen van complicaties van acute hemolyse. Sepsis is een veel voorkomende excessieve reactie van het lichaam op een bacteriële infectie. In hoofdstuk 9 worden de effecten van nervus vagusstimulatie met enterale voeding in het endotoxinemodel beschreven. Zowel lipiderijke voeding als controlevoeding remmen dosisafhankelijk de afgifte van cytokines. Lipiderijke voeding vermindert de ontstekingsreactie in lagere doseringen dan de controlevoeding, wat aangeeft dat het ontstekingsremmende effect van voeding kan worden vergroot door toevoeging van specifieke voedingsstoffen. Ook de mate van enterocytschade en ontsteking in de lever en milt zijn verminderd in dieren die lipiderijke voeding krijgen. De betrokkenheid van de nervus vagus wordt aangetoond door middel van blokkers van CCK receptoren en nACh receptoren. Bovendien leidt lipiderijke voeding tot een toegenomen activiteit van mechanosensitieve zenuwen na rek van de darmwand. Overigens resulteert het oprekken van de maag op zichzelf niet in een significante remming van de ontstekingsrespons, wat er op wijst dat de aanwezigheid van voedingsstoffen essentieel is. De effecten van lipiderijke voeding op sepsis worden verder onderzocht in een model voor polymicrobiële sepsis waarbij de blinde darm wordt afgebonden en geperforeerd (CLP; cecal ligation and puncture). Ook in dit sepsismodel leidt voedingsinterventie tot een afname van de acute ontstekingsrespons (hoofdstuk 10). Een belangrijk kenmerk van het CLP‐model is de ontwikkeling van een immuunsuppressieve periode na de initiële hyperinflammatoire fase. In de kliniek wordt de periode waarin het afweersysteem minder responsief is gekenmerkt door het optreden van opportunistische infecties die moeilijk te behandelen zijn. De verminderde reactiviteit van het immuunsysteem op deze secundaire infecties is gecorreleerd met de mate van ontsteking in de vroege fase van sepsis. Daarom wordt vermindering van de acute ontstekingsrespons als een potentieel aangrijpingspunt beschouwd om de daarop volgende non‐responsiviteit van het immuunsysteem te verminderen. Na het induceren van een secundaire luchtweginfectie met Pseudomonas aeruginosa vier dagen na CLP is de hoeveelheid bacteriën in de long hoger in vergelijking met een controle operatie (niet
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leidend tot sepsis). Dit geeft een toestand van immunosuppressie tijdens sepsis weer. In dieren die lipiderijke voeding krijgen toegediend, is de kolonisatie in de long echter niet verschillend tussen septische en niet‐septische dieren. Het behoud van de afweerrespons gaat gepaard met een toename van de inflammatoire markers IL‐12 en IFN‐γ en een afname van immunosuppressor IL‐10. Hiermee wordt aangetoond dat lipiderijke voeding niet alleen de acute ontstekingsrespons remt, maar ook een verzachtende werking uitoefent op de daarop volgende immunosuppressieve fase. De dierexperimentele studies laten samen een breed beschermend effect van lipiderijke voeding zien en verschaffen bovendien inzicht in de onderliggende vagale reflex. Op grond van deze kennis zijn de eerste humane studies met verrijkte voeding uitgevoerd. Eerst wordt gezocht naar een optimale voedingscompositie (hoofdstuk 11). Een veelgebruikte klinische voeding met een hoge lipidenfractie (Diasip) wordt vergeleken met een klinische voeding met een laag lipidengehalte (Respifor). Omdat CCK concentraties in de darmwand niet op een non‐invasieve manier gemeten kunnen worden in de mens, worden de CCK spiegels in het bloed bepaald voor en na voeding. Hieruit blijken geen verschillen tussen beide voedingen. Dit is een opvallende bevinding, aangezien de samenstelling van deze klinische voedingen vergelijkbaar is met de lipiderijke en controlevoeding die in de dierexperimentele studies werden toegepast. Uit de literatuur blijkt dat vooral vetzuren met koolstofketens van meer dan twaalf koolstofatomen en gehydrolyseerde eiwitten leiden tot afgifte van CCK. Op basis van deze gegevens werd een speciale eiwit‐ en lipiderijke voeding ontwikkeld gericht op maximale CCK afgifte. Echter ook deze voeding resulteert niet in hogere CCK‐spiegels in het bloed in vergelijking met isocalorische controlevoeding. Deze gegevens wijzen erop dat de serumconcentraties van CCK geen goede maat zijn om een voeding gericht op optimale nervus vagusstimulatie te selecteren. Het gebrek aan onderscheidingsvermogen tussen beide voedingen kan liggen in het feit dat systemische spiegels een overmaat betekenen van lokaal CCK in de darmwand en de mate van nervus vagus‐activatie dus niet goed representeren. Nadere experimenten tonen aan dat ophoging van de voedingsdoseringen niet tot hogere CCK‐pieken in het plasma leidt, maar wel tot een langer aanhoudende stijging van de CCK‐waarden. Dit fenomeen kan worden verklaard door de vertraagde maaglediging na een grotere hoeveelheid voeding, wat resulteert in verlengde blootstelling van de darmwand aan de voedingsstoffen. Met het oog op klinische toepassing zou voeding, om een aanhoudende afgifte van CCK te bewerkstelligen, ofwel als een bolus in de maag, ofwel continu voorbij de pylorus toegediend moeten worden. Een tweede marker die wordt verondersteld het ontstekingsremmende effect van voeding weer te geven is de variabiliteit van de hartslag (heart rate variability). Uit verschillen tussen de hartslag‐intervallen kan de mate van sympatische en parasympatische activiteit worden afgeleid. Echter de variabiliteit van de hartslag blijkt niet te verschillen tussen vrijwilligers die 200 ml Diasip of Respifor drinken (hoofdstuk 12). Mogelijk komen de zenuwbanen die het hart beïnvloeden niet overeen met de nervus vagus‐vezels die de ontstekingsrespons remmen. Deze gedachte wordt ook verwoord in een reactie van onze onderzoeksgroep op een studie van dr. Thayer, die een verband aantoonde
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tussen de hoogte van ontstekingsmarkers en de variabiliteit van de hartslag in een cohort met overwegend gezonde mensen (hoofdstuk 13). Eerder werd in muizen aangetoond dat lipiderijke voeding een endotoxinegemedieerde ontstekingsrespons remt (hoofdstuk 9). Wij beschrijven in hoofdstuk 14 een proof‐of‐principle studie naar het effect van eiwit‐ en lipiderijke voeding op een endotoxine‐gemedieerde ontstekingsrespons in de mens. Bij gezonde vrijwilligers resulteert een bolus endotoxine in ziekteverschijnselen en stijging van ontstekingswaarden in het bloed. Om aspiratie te voorkomen wordt de voeding via een nasojejunale sonde toegediend. Verrijkte voeding leidt tot een significante afname van pro‐inflammatoire markers TNFα, IL‐6 en IL‐1RA en een toename van antiinflammatoire marker IL‐10 in vergelijking met zowel controlepersonen die geen voeding krijgen als personen die de controlevoeding ontvangen. Daarmee is dit de eerste studie die een beschermend effect van kortdurende toediening van eiwit‐ en lipiderijke voeding laat zien tijdens een acute ontsteking in de mens. Toekomstige studies dienen vast te stellen in hoeverre de vagale ontstekingsremmende reflex deze effecten verklaart. Samenvattend verschaft dit proefschrift inzicht in het mechanisme dat aan de ontstekingsremmende werking van lipiderijke voeding ten grondslag ligt, wordt een breed beschermend effect aangetoond in verschillende modellen voor belangrijke ziektebeelden in chirurgische en intensive care patiënten en wordt tenslotte een vertaalslag van deze bevindingen naar de mens gemaakt. Stimulatie van het autonome zenuwstelsel door enterale voeding sluit goed aan bij de recent aangepaste richtlijnen rondom het voeden van patiënten perioperatief en op de intensive care. In deze richtlijnen wordt aanbevolen om periodes van vasten te reduceren en voeding zo mogelijk enteraal toe te dienen. Wat toekomstige humane studies betreft die zich richten op stimulatie van de vagale reflex, is het van groot belang om te vermelden dat er tot dusver geen bijwerkingen of gezondheidsrisico’s naar voren zijn gekomen. Het voeden per duodenumsonde, zoals in deze studie werd uitgevoerd, wordt wereldwijd als een veilige wijze van voedseltoediening beschouwd, ook in hemodynamisch instabiele patiënten. Complicaties van duodenaal voeden worden alleen beschreven in patiënten met een pre‐existent aangetaste darm die langdurig werden gevoed. De volgende stap richting klinische toepassing van stimulatie van het autonoom zenuwstelsel door middel van voeding is een studie waarin de specifiek de veiligheid van voedingsinterventie wordt onderzocht en de mate waarin voeding wordt verdragen. Hieruit zal blijken of vervolgstudies uitgevoerd kunnen worden naar de effectiviteit van voedingsinterventies die door modulatie van de ontstekingsrespons het klinisch herstel gunstig beïnvloeden. Aangezien voeding voorafgaand aan de ontsteking tot sterkere bescherming leidt ten opzichte van voeding gestart tijdens een al bestaande ontsteking, vormen patiënten die electieve chirurgie ondergaan een geschikte populatie voor verdere studies.
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Interne Geneeskunde Infections, inflammation and venous thrombosis An epidemiological perspective
Proefschrift ter verkrijging van het doctoraat in de Medische Wetenschappen aan de Rijksuniversiteit Groningen op gezag van de Rector Magnificus, dr. E. Sterken, in het openbaar te verdedigen op woensdag 28 maart 2012 om 12.45 uur door Ynse Ieuwe Gerardus Vladimir Tichelaar geboren op 10 november 1979 te Harlingen
Promotoren: Prof. dr. J.C. Kluin-Nelemans Copromotores: Dr. K. Meijer Dr. W.M. Lijfering Beoordelingscommissie: Prof. dr. H. ten Cate Prof. dr. F.W.G. Leebeek Prof. dr. F.R. Rosendaal
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Samenvatting Ontsteking, infecties en stolling hebben een aantal pathofysiologische processen en stoffen, welke deze processen kenmerken, gemeenschappelijk. In het begin droegen vooral de basale wetenschappen bij aan het bevestigen van deze hypothese, later kwam er ook bewijs van klinisch epidemiologische studies. In hoofdstuk 2 werd een systematisch overzicht gegeven van onderzoeken van de afgelopen 15 jaar, waarin de relatie tussen infecties of ontstekingsziekten en veneuze trombose werd onderzocht en uitgedrukt in een relatief of absoluut risico. Longontsteking, urineweginfecties en het HIV-virus vergroten de kans op een veneuze trombose ongeveer twee keer. Dat lijkt ook te gelden voor infecties niet nader omschreven, waaronder normale, banale (veel voorkomende en relatief onschuldige) virus-infecties. Het risico op veneuze trombose is mogelijk nog groter wanneer mensen hierbij erger ziek zijn. Patiënten met een systeemziekte, zoals ANCA-associated vasculitis, een ziekte waarbij de bloedvaten chronisch ontstoken zijn, en mensen met een chronische darmziekte (colitis ulcerosa en de ziekte van Crohn), hebben ook een twee tot vier keer verhoogde kans op veneuze trombose. Wanneer deze ziekten erg actief zijn of de patient is ziek, dan is het risico op veneuze trombose zelfs acht keer zo hoog. Wij hebben de BEAST studie uitgevoerd, om te onderzoeken of er een relatie bestaat tussen milde symptomen van ontsteking of infectie, door patiënten zelf gerapporteerd, en waarschijnlijk van virale oorsprong, én veneuze trombose. Het gaat dan om de symptomen zoals verkoudheid, een luchtweginfectie, grieperig of “ niet lekker “ gevoel, diarree of koorts. In deze case-control studie vonden wij dat patiënten met dergelijke symptomen een 2.5 keer zo hoge kans hebben op veneuze trombose, vergeleken met de mensen die deze symptomen niet hebben ervaren. Deze relatie lijkt te gelden voor alle symptomen van ontsteking en infectie die men vier weken vóór de klachten van het been heeft gehad. Ook vonden we, zoals beschreven in hoofdstuk 3, dat één van de waarden van ontsteking in het bloed, het zogenaamde CRP, ook gerelateerd was aan veneuze trombose. Het risico op veneuze trombose was het hoogst wanneer mensen een hoge ontstekingwaarde in het bloed hadden en ook nog symptomen van infectie of ontsteking gehad hadden in de afgelopen vier weken. In hoofdstuk 4 hebben we gekeken of we deze symptomen van ontsteking en infectie, zoals hierboven beschreven, nader kunnen duiden of herleiden tot een bepaalde bacterie of virus infectie. Het cytomegalovirus zou hierbij misschien een rol kunnen spelen. In de BEAST studie waren 5 vrouwen met veneuze trombose en een actieve cytomegalovirus infectie. Daarnaast hadden ze ook nog een andere milde risicofactor, zoals bijvoorbeeld de anticonceptie pil. In de groep mensen zonder trombose, kwamen geen actieve cytomegalovirus infecties voor. Een andere infectie, die veel voorkomt en gerelateerd is aan stolling, is het HIV-virus. In hoofdstuk 5 beschrijven we een aantal studies waarin men laat zien dat HIV en de behandeling daartegen, beide gerelateerd zijn aan een verhoogd risico op veneuze en arteriele trombose. Dit kan zelfs wel vier tot zes keer zo hoog zijn. Dit is echter geen reden om te stoppen met de anti-HIV medicatie, omdat de sterfte van deze groep patiënten toch forst is terug gedrongen in de laatste 15 jaar. Dokters moeten dit verhoogde risico wel meenemen in hun risicoinschatting van individuele patienten.
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In een andere groep patienten, namelijk patiënten met een actieve HIVinfectie, hebben we gekeken naar de stollingsfactoren in het bloed, en de invloed van een extra infectie, namelijk een cytomegalovirus infectie, hierop. Mensen met HIV hebben er vaak ook andere infecties bij. In hoofdstuk 6 laten wij zien dat niet alleen HIV zelf, maar ook de extra infectie met het cytomegalovirus de stollingsfactoren activeert en hiermee de neiging tot stollen van het bloed vergroot. Een verhoogde suiker (glucose) waarde in het bloed, wordt vaak gezien bij mensen die erg ziek zijn, of veel pijn hebben. Er zijn aanwijzingen dat dit ook kan samenhangen met de stolling. In hoofdstuk 7 laten wij zien dat zo’n verhoogde glucose waarde ook bij mensen met een trombosebeen voorkomt, maar dat het niet alleen met de trombose lijkt samen te hangen, maar inderdaad ook met het feit dat iemand pijn en stress heeft of dat de trombose (lokaal) ontsteking veroorzaakt (dat noemen we de acute fase reactie). Ook laten we in hoofdstuk 8 zien, weer door middel van de BEAST studie, dat mensen met een trombose een stollingsafwijking kunnen hebben, namelijk een proteine S type III tekort. Of dit dan een erfelijke variant is of niet, konden we niet met deze studie aantonen. Wel vonden we dat de stress, pijn en algehele ontsteking (de acute fase reactie) die een patiënt met trombose kan ervaren, invloed heeft op deze proteine S waarde. Ook vonden wij dat het veronderstelde mechanisme wat hieraan ten grondslag zou liggen, niet klopt. De hypothese was dat een ander eiwit, genaamd C4BP, dit proteine S méér zou gaan binden wanneer een patiënt net een trombose heeft gekregen en daarbij pijn, stress of ontsteking ervaart. Dat dit dus niet op deze manier gebeurd, was al eerder maar op een andere manier aangetoond. Een andere stollingsafwijking is het verhoogd factor VIII (acht). Er is in de literatuur veel discussie of dit een erfelijke of een meer tijdelijke risicofactor is voor het ontwikkelen van een trombosebeen of longembolie. In het verleden zijn er een aantal studies uitgevoerd, die aantoonden dat het factor VIII toch voornamelijk een stabiele, mogelijk erfelijke, factor is, die niet beïnvloed wordt door bijvoorbeeld ontsteking, stress of pijn. In hoofdstuk 9 laten wij zien dat het factor VIII toch een beetje beïnvloed wordt door (lokale) ontsteking, pijn of stress (de acute fase reactie). Maar, het grootste deel van de patiënten die een verhoogd factor VIII in hun bloed hadden bij aanvang van de klachten van de trombose, hield dat ook na afloop van de behandeling van de trombose, hoewel de waarden wel iets gedaald waren. Dit kwam waarschijnlijk doordat de acute fase reactie voorbij was (dus geen stress, pijn en [lokale] ontsteking meer). Het lijkt dus mogelijk om mensen een verhoogde kans op nog een trombose (een recidief trombose) in een vroege fase te identificeren, dus wanneer zij zich presenteren met klachten van hun eerste trombose. Of deze patiënten extra lang behandeld moeten worden is nog niet helemaal duidelijk. Tenslotte, in hoofdstuk 10, laten wij zien dat een nieuw antistollingsmiddel, genaamd Rivaroxaban of Xarelto, het meten van het factor VIII gehalte kan verstoren. Dit geldt voor meerdere soorten factor VIII testen, en er zijn (nog) geen goede methoden om de invloed van Rivaroxaban te verminderen of te blokkeren. Dokters die factor VIII willen meten, zoals bij patiënten genoemd in hoofdstuk 9, moeten daar dus rekening meehouden en patiënten vragen of zij dit middel gebruiken. Als dit vergeten wordt, kan het factor VIII gehalte lager lijken is dan het in werkelijkheid is.
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Neurologie Vascular endothelial function and genetic epidemiology in lacunar stroke subtypes
Proefschrift ter verkrijging van de graad van doctor aan de Universiteit Maastricht, op gezag van de Rector Magnificus, Prof. Mr. G.P.M.F. Mols, volgens het besluit van het College van Decanen, in het openbaar te verdedigen op vrijdag 2 maart 2012 om 12.00 uur door Iris Lodewina Hubertina Knottnerus geboren te Heerlen op 20 juli 1977
Promotor: Prof.dr. R.J. van Oostenbrugge Prof.dr. J. Lodder Prof.dr. H. ten Cate Beoordelingscommissie: Prof.dr. H.J.M. Smeets Prof.dr. J.W. Cohen Tervaert Prof.dr. J.W.M. Heemskerk Prof.dr. J. Stam Prof.dr. J.M. Wardlaw
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Samenvatting Ongeveer een kwart van alle ischemische beroertes wordt veroorzaakt door een zogenaamd lacunair herseninfarct. Dit type herseninfarct is het gevolg van een afsluiting van een perforerend bloedvat, is meestal klein (<15‐20 mm) en is gelokaliseerd in de basale kernen, diepe cerebrale witte stof of hersenstam. Klinisch kenmerkt een lacunair herseninfarct zich door één van de klassieke lacunaire syndromen zoals éénzijdige motorische uitval, éénzijdige sensibele uitval of een combinatie van beide. Hierbij zijn tenminste 2 van de 3 lichaamsdelen (gelaat, arm en/of been) betrokken en er mag geen sprake zijn van een bewustzijnsstoornis of een hogere corticale functiestoornis. Ongeveer een halve eeuw geleden verrichtte Fisher pathologisch‐anatomisch onderzoek op hersenen van patiënten met een lacunair herseninfarct. Hij onderscheidde een tweetal aandoeningen van de kleine hersenvaten die ten grondslag kunnen liggen aan deze lacunaire herseninfarcten. Enerzijds beschreef hij als oorzaak een kleine atherosclerotische plaque gelokaliseerd aan de origo van één van de perforerende vaten (micro‐atheromatose). Deze variant veroorzaakt veelal het geïsoleerde lacunaire infarct. Anderzijds definieerde hij het type dat wordt veroorzaakt door een diffuse aandoening van de kleine hersenvaten (lipohyalinosis). Dit type wordt gekenmerkt door bijkomende stille afwijkingen, namelijk asymptomatische lacunaire infarcten. Onderzoek bij klinisch en radiologisch getypeerde patiënten met een lacunair herseninfarct, toonde aan dat deze asymptomatische lacunaire infarcten gerelateerd zijn aan een tweetal afwijkingen; ischemische witte stofafwijkingen en micro‐ of puntbloedingen (<5‐10mm). Deze puntbloedingen worden gezien op gradient echo Magnetische Resonantie‐opnamen en bestaan uit hemosiderine‐deposities. In het voorgaande decennium ontwikkelden Boiten en Lodder de hypothese dat beide typen gedurende het leven van elkaar onderscheiden kunnen worden op basis van verschillen bij beeldvormend onderzoek. Door het aantonen van klinische verschillen, onder andere in lange termijnprognose tussen de beide typen, werd deze hypothese door anderen bevestigd. Op basis van gegevens uit pathologie‐ en beeldvormingstudies vormden Wardlaw en anderen de hypothese dat endotheliale activatie leidt tot het ontstaan van de cerebrale kleine hersenvaten aandoening welke gepaard gaat met bijkomende stille afwijkingen. Endotheliale activatie, en uiteindelijk dysfunctie, leidt tot een toegenomen doorlaatbaarheid van de bloed‐hersen‐barrière. Hierdoor ontstaat er lekkage van plasma‐eiwitten naar de vaatwand en de perivasculaire ruimte. Dit proces leidt uiteindelijk tot het ontstaan van lacunaire infarcten, witte stofafwijkingen en puntbloedingen. Het doel van de studies in dit proefschrift was de verdere evaluatie van de pathologische processen die ten grondslag liggen aan de verschillende typen aandoeningen van de cerebrale kleine vaten leidend tot het lacunaire herseninfarct. Het proefschrift focust op een tweetal thema’s. Ten eerste onderzochten we de aanwezigheid van endotheliale activatie bij patiënten met een lacunair herseninfarct. We bepaalden hiervoor bloedspiegels van enkele hemostase gerelateerde endotheliale markers en keken naar verschillen tussen beide typen (hoofdstuk 4 en 5). Ten tweede bekeken we genetisch‐epidemiologisch de rol van genetische factoren ten aanzien van het lacunaire herseninfarct en zijn subtypen. Gezien de verschillende pathofysiologische mechanismen in de subtypen, verwachtten wij
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verschillen in de bijdrage van genetische factoren. Hiervoor onderzochten we de clustering van beroertes in eerstegraads familieleden van patiënten met lacunaire herseninfarcten (hoofdstuk 6 en 7). In hoofdstuk 1, de algemene introductie, worden de bovenbeschreven achtergronden besproken en wordt tevens een overzicht van de studies behorende bij dit proefschrift gegeven. In hoofdstuk 2 beschrijven wij een tweetal patiënten met een lacunair herseninfarct en bijkomende asymptomatische lacunaire infarcten, witte stofafwijkingen en puntbloedingen. Beide patiënten ontwikkelden een bloeding op de plaats van een eerder gedocumenteerde puntbloeding. Wij concluderen dat puntbloedingen niet alleen een verhoogd risico geven op een intracerebrale bloeding, maar dat zij ook de bron van de bloeding kunnen zijn. Derhalve zijn deze puntbloedingen op Magnetische Resonantie Imaging (MRI) mogelijk een sterke voorspeller van het bloedingsrisico bij de individuele patiënt. Een grote prospectieve studie om dit risico te evalueren lijkt relevant omdat daardoor de voordelen en de risico’s van anti‐thrombotische therapie bij deze patiënten beter afgewogen kunnen worden. Hoofdstuk 3 bevat een systematische review van de literatuur naar bewijs voor endotheliale activatie en dysfunctie bij patiënten met een lacunair herseninfarct. Onze zoekstrategie (Appendix 1) leverde 29 artikelen op die bruikbaar waren voor verdere evaluatie. De verdere evaluatie vond plaats door middel van een checklist met items betreffende methodologische en informatieve kwaliteit (Appendix 2). De artikelen werden gesorteerd naar de verschillende fysiologische functies van het endotheel en een categorie betreffende toxische stoffen voor het endotheel. Publicaties over de regulatie van de vaattonus door het endotheel toonden een gestoorde endotheelfunctie op verschillende meetmomenten na de beroerte. Spiegels van hemostase gerelateerde markers van het endotheel waren verhoogd in de acute en subacute fase. Daarentegen bleken spiegels van adhesiemoleculen alleen verhoogd gedurende de acute fase. Tenslotte was homocysteïne, hetgeen in hoge concentraties toxisch voor het endotheel is, verhoogd bij patiënten met een lacunair herseninfarct. Wij concluderen dat, op basis van de huidige literatuur, endotheeldysfunctie waarschijnlijk een rol speelt in de pathogenese van het lacunaire herseninfarct. Deze endotheeldysfunctie speelt met name een rol bij patiënten met bijkomende stille afwijkingen. Overigens lijkt het nog te vroeg voor robuuste conclusies. Ten eerste wordt beroerte in veel studies als een homogene ziekte beschreven, terwijl andere studies verschillende classificatiesystemen voor beroertes gebruiken. Het gevolg is dat een patiënt in verschillende categorieën terecht kan komen. Wij adviseren dat toekomstige studies het begrip lacunair herseninfarct duidelijk definiëren waarbij klinische criteria voor lacunaire syndromen gecombineerd worden met MRIbevindingen zonder dat er risicofactoren in de definitie meegenomen worden. Ten tweede bepaalden veel studies alleen plasmaconcentraties in de acute fase, waardoor de invloed van de acute fase respons, met andere woorden de acute ontstekingsreactie, niet uitgesloten is. Met deze gegevens in het achterhoofd ontwierpen wij onze studies betreffende hemostase gerelateerde endotheliale markers bij patiënten met een eerste lacunair herseninfarct.
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Circulerende hemostase gerelateerde markers van endotheel functie Het vasculaire endotheel speelt een belangrijke rol in de hemostase. Dit blijkt onder andere uit de aanwezigheid van een aantal hemostase‐ en stollingsgerelateerde eiwitten in het bloed, die afkomstig zijn van het endotheel. In hoofdstuk 4 bepaalden we spiegels van dergelijke eiwitten (tissue plasminogeen activator [tPA], plasminogeen activator inhibitor type 1 [PAI‐1], tPA‐PAI‐1‐complex, Von Willebrand factor [vWF], tissue factor, trombomoduline en stollingsfactor VIII) in patiënten met een eerste lacunair herseninfarct. We verwachtten de hoogste spiegels bij patiënten met bijkomende witte stofafwijkingen en/of asymptomatische lacunaire infarcten. tPA‐activiteit bleek verhoogd bij patiënten met bijkomende witte stofafwijkingen (0.79 IU/mL versus 0.44 IU/mL voor het geïsoleerde lacunaire infarct, P=0.02) en spiegels van PAI‐1 bleken het laagst in deze groep (27.5 ng/mL versus 44.0 ng/mL voor het geïsoleerde lacunaire infarct, P=0.02). Deze laatste associatie bleef overeind in de multivariate analyse (OR 0.99; 95%CI 0.98‐1.00 per ng/mL verandering van PAI‐1, P=0.04). De hoogste spiegels van vWF‐antigeen werden gevonden bij patiënten met bijkomende asymptomatische lacunaire infarcten, gevolgd door patiënten met witte stofafwijkingen en het laagst bij diegenen met het geïsoleerde lacunaire infarct, echter deze verschillen waren niet significant. De concentraties van de andere eiwitten verschilden niet tussen de subtypen van het lacunaire herseninfarct. Wij concluderen dat de hogere spiegels van tPA bij patiënten met bijkomende witte stofafwijkingen een argument vormen voor endotheliale activatie in het subtype van het lacunaire herseninfarct veroorzaakt door de diffuse vasculopathie. Ten tweede concluderen wij dat de combinatie van lage spiegels van PAI‐1 en hoge spiegels van tPA in patiënten met bijkomende witte stofafwijkingen, suggereren dat verschillen in activiteit van het fibrinolytische systeem bijdragen aan de ontwikkeling van witte stofafwijkingen. Tenslotte onderkennen wij dat spiegels van diverse endotheliale markers gelijk zijn tussen de subtypen van het lacunaire herseninfarct. Dit zou verklaard kunnen worden door het gebruik van medicatie. Zo kunnen zogenaamde statines (cholesterolverlagers) de bloedspiegel van tissue factor verlagen. Daarnaast wordt de aanwezigheid van enkele endotheliale markers, bijvoorbeeld trombomoduline, in de cerebrale kleine bloedvaten in een aantal studies betwijfeld. In hoofdstuk 5 hebben we spiegels van de verschillende vormen van tissue factor pathway inhibitor (TFPI) gemeten en verwachtten wij de hoogste spiegels bij patiënten met bijkomende stille afwijkingen. TFPI bevindt zich op verschillende plaatsen in het menselijk lichaam. TPFI wordt geproduceerd en opgeslagen in de vasculaire endotheelcel. Bij uitscheiding wordt een gedeelte gebonden aan celwand proteoglycanen. In plasma is het grootste gedeelte van TFPI gebonden aan lipoproteinen, voornamelijk LDL, en bestaat uit verschillende incomplete (truncated) vormen. Slechts 10% van het plasma TFPI bestaat uit de vrije volledige (full‐length) vorm. Antigeen spiegels van het totale TFPI (vrij en lipoproteïne gebonden vormen) en het vrije volledige (full‐length) TFPI werden bepaald door middel van ELISA in 149 patiënten en 42 controles. Na toediening van heparine komt TFPI vrij uit het endotheel. Spiegels van door heparine vrijgemaakt TFPI werden gemeten in een subgroep van 17 patiënten en 15 controles. Op basis van MRI‐kenmerken werden
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patiënten met een lacunair herseninfarct geclassificeerd als geïsoleerd lacunair infarct of met tevens bijkomende stille afwijkingen. Alhoewel spiegels van het totale TFPI lager bleken bij patiënten (mediaan 69.5 [IQR 60.5‐83.9] ng/mL) dan controles (80.3 [68.1‐91.9] ng/mL, P<0.01), en spiegels van totale TFPI hoger waren in patiënten met bijkomende stille schade (71.0 [62.8‐86.0] ng/mL) dan diegenen met het geïsoleerde lacunaire infarct (61.3 [54.1‐77.7] ng/mL, P<0.01), verdwenen beide associaties na correctie voor leeftijd en de hoogte van cholesterolspiegel. Opnieuw zou het gebruik van medicatie een verklaring kunnen zijn voor het ontbreken van een verschil in spiegels van totaal TFPI. Het overgrote deel van plasma TFPI bestaat uit enkele incomplete vormen gebonden aan LDL‐cholesterol. Omdat statines LDL‐cholesterol in het bloed verlagen, dalen ook de spiegels van TFPI. Spiegels van het vrije volledige (full‐length) TFPI verschilden niet tussen patiënten en controles en tussen subtypen van het lacunaire herseninfarct. Tenslotte, aangezien het totale TFPI en het vrije volledige (full‐length) TFPI slechts een klein gedeelte vormen van de totale hoeveelheid TFPI aanwezig in het lichaam, bepaalden wij de grotere (endotheel‐geassocieerde) TFPI‐voorraad door intraveneuze toediening van heparine. Het toedienen van heparine leidde tot een 9‐voudige stijging in de concentratie van het vrije volledige (full‐length) TFPI en de spiegels bleken hoger bij patiënten dan bij controles (1297 ± 246 %d.N. [percentage van normaal] versus 1039 ± 302 %d.N., P=0.01). Het TFPI dat vrijkomt na toediening van heparine komt van de celwandproteoglycanen en vanuit de endotheelcel zelf. Het feit dat er meer TFPI vrijkomt na toediening van heparine bij patiënten, dan bij controles, zou een argument kunnen zijn voor endotheelactivatie bij patiënten met een lacunair herseninfarct. Genetische epidemiologische studies en het lacunaire herseninfarct Gegevens uit case‐control studies laten zien dat een positieve familie‐anamnese voor een beroerte een onafhankelijke risicofactor is voor het optreden van een lacunair herseninfarct. Verder tonen een beperkt aantal tweelingstudies, dat monozygote tweelingen vaker beide een beroerte doormaakten dan dizygote tweelingen. Dit past bij een rol voor genetische factoren in het ontstaan van een beroerte. In hoofdstuk 6 onderzochten wij of clustering van beroertes in families van patiënten met een lacunair herseninfarct verschilt tussen de verschillende fenotypen van het lacunaire herseninfarct. Met behulp van de gestandaardiseerde vragenlijst, aangevuld met een interview tijdens polikliniekbezoek, onderzochten wij de familie‐anamnese voor een beroerte bij 157 patiënten met een lacunair herseninfarct, die gefenotypeerd werden door middel van MRI. 52% van de patiënten rapporteerde een positieve familie‐anamnese voor een beroerte bij één of meerdere eerstegraad familieleden. Jonge (<65 jaar) indexpatiënten met bijkomende asymptomatische lacunaire infarcten bleken vaker een aangedane ouder te hebben dan jonge indexpatiënten zonder asymptomatische lacunaire infarcten (59% versus 20%, P<0.01). In de multivariate analyse vonden wij de sterkste verbanden tussen bijkomende asymptomatische lacunaire infarcten en een positieve familie‐anamnese bij ouders (OR 6.46 [95%CI 1.96‐ 21.33]), moeders (OR 4.00 [95%CI 1.18‐13.56]) en vaders (OR 5.40 [95%CI 1.14‐25.61]). Wij concluderen dat de clustering van beroertes in families van patiënten met bijkomende
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asymptomatische lacunaire infarcten een argument is voor een genetische component. Het feit dat de familiare aggregatie zich voordoet in dit subtype, wijst op een rol voor genetische factoren in de onderliggende pathofysiologie van endotheelactivatie. In deze studie vonden we geen verband tussen positieve familie‐anamnese en witte stofafwijkingen. Mogelijk hebben we een verband gemist omdat we de mate van witte stof afwijkingen beoordeelden met een visuele scoringsschaal, te weten de Fazekasschaal. Deze schaal correleert op zich goed met kwantitatieve scoringsmethoden, hij bezit echter wel een zogenaamd plafond‐fenomeen. Dit laatste betekent dat de variabiliteit in volumes van witte stofafwijkingen groot is bij patiënten met eenzelfde hoge score op de visuele schalen. In hoofdstuk 7 berekenden we het genetisch relatief risico voor beroertes bij patiënten met een lacunair herseninfarct. Daarvoor vergeleken we de prevalentie van beroertes bij familieleden van patiënten met een lacunair herseninfarct met de prevalentie van beroertes in een Nederlands cohort van oudere vrijwilligers. 144 van de 1066 eerstegraads familieleden (13.5%) maakten een beroerte door. Het genetisch relatief risico was daarmee 2.94 (95%CI 2.45‐3.53) voor alle eerstegraads familieleden, 4.52 (95%CI 3.61‐5.65) voor ouders van patiënten en 2.10 (95%CI 1.63‐ 2.69) voor broers en zussen van patiënten. De getallen zijn hoger dan het gemiddelde relatieve risico voor een multifactoriële aandoening en voor beroerte in het algemeen. De clustering van beroertes in families van patiënten met een lacunair herseninfarct is op zich niet nieuw. Echter, de meeste studies definieerden een positieve familieanamnese als minimaal één aangedaan eerstegraads familielid. De toegevoegde waarde van het genetisch relatief risico is gelegen in het feit dat het aantal aangedane en bekende familieleden wordt meegenomen in de berekening, waardoor er iets gezegd kan worden over de mate van clustering van beroertes. In hoofdstuk 8, de algemene discussie, bespreken wij de implicaties van de bevindingen in dit proefschrift voor toekomstig onderzoek. Het eerste thema betreft het ontbreken van verschillen in plasmaspiegels van enkele endotheliale markers tussen patiënten en controles en tussen de subtypen van het lacunaire herseninfarct. De aanwezigheid van de bepaalde markers in de cerebrale kleine vaten wordt in enkele pathologisch‐anatomische studies betwijfeld. De vraag is of dit relevant is aangezien nieuwe informatie laat zien dat de ziekte niet beperkt is tot de kleine vaten van de hersenen, maar dat er sprake is van een systeemaandoening. Functionele testen van het vasculaire endotheel in verschillende vaatgebieden in combinatie met meting van endotheliale plasma markers zou meer duidelijkheid kunnen bieden. Daarnaast heeft het gebruik van statines door onze patiënten met een lacunair herseninfarct mogelijke verschillen in spiegels van endotheliale markers waarschijnlijk gereduceerd. Een studie waarbij endotheelfunctie wordt vergeleken tussen een laag en een hoog doseringsregime van statines zou nieuwe inzichten in pathofysiologie kunnen genereren, ook lijken therapeutische mogelijkheden binnen handbereik. Het tweede thema omvat de tekortkomingen van de voorgaande moleculair genetische studies, zoals de beperkte toepassingsmogelijkheden van zogenaamde linkage studies en conflicterende resultaten van kandidaat‐genen studies. “Genome wide association studies” lijken op het eerste gezicht een veelbelovende methode
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omdat er geen hypothese betreffende interessante genetische loci nodig is, waardoor nieuwe risico‐allelen voor herseninfarcten ontdekt kunnen worden. Echter de grote patiënten aantallen, kleine effecten van veel voorkomende varianten en het feit dat vaak alleen interessante regio’s gevonden worden, leidt tot de conclusie dat deze methode minder geschikt is bij het lacunaire herseninfarct. Zeer recent is het zoeken naar zeldzame varianten in veel voorkomende ziekten als methode ontwikkeld. Hierbij worden interessante regio’s van het genoom volledig in kaart gebracht. Deze interessante regio’s worden geselecteerd op grond van pathofysiologische overwegingen, zoals genen gerelateerd aan endotheel functie. Eén van de voorwaarden voor dit type onderzoek, is een goed gedefinieerd fenotype, zoals onze patiënten met een lacunair herseninfarct. Mogelijk is dit een goede methode voor verder onderzoek naar genetische factoren en daarmee de verdere ontrafeling van de pathofysiologie van het lacunaire herseninfarct.
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Reumatologie Towards a better understanding of foot and ankle kinematics in rheumatoid arthritis The effects of walking speed and structural impairments Proefschrift ter verkrijging van de graad van doctor aan de Universiteit Twente, op gezag van de rector magnificus, prof. dr. H. Brinksma, volgens besluit van het College voor Promoties in het openbaar te verdedigen op vrijdag 19 oktober 2012 om 16.45 uur door Rosemary Dubbeldam geboren op 9 juli 1972 te Den Helder
Promotor: Prof. dr. ir. H.J. Hermens Prof. dr. M.A.F.J. van de Laar Assistent-promotor: Dr. J.H. Buurke
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Samenvatting Achtergrond Al in een vroeg stadium van de ziekte lijdt 40% tot 60% van de reumatoïde artritis (RA) patiënten aan loopstoornissen zoals pijn, verminderde mobiliteit en problemen met de dagelijkse activiteiten. Deze loopstoornissen zijn gerelateerd aan pathologische veranderingen van voet- en enkelstructuren, die ook al in een vroeg stadium van de ziekte voorkomen. Lopen wordt gekenmerkt door plantaire druk, ruimte-tijd en kinematische parameters. De plantaire druk en ruimte-tijd parameters en hun relatie met loopstoornissen en pathologische veranderingen van de voet en enkel zijn reeds uitvoerig bestudeerd bij patiënten met RA. Deze parameters worden samen met de scores van ervaren dagelijkse functionele beperking en pathologische veranderingen gebruikt bij de keuze voor en het evaluatie proces van chirurgische en conventionele ingrepen. Met behulp van recente ontwikkelingen in de gangbeeldanalyse van optische meettechnieken en gedetailleerde voet en enkel computermodellen, zijn de typische gewrichtsbewegingen van de RA voet en enkel tijdens lopen geanalyseerd en beschreven. Deze techniek wordt echter nog niet regelmatig gebruikt in de kliniek. Gangbeeldanalyse van gewrichtsbewegingen van de heup, knie en enkel dragen in belangrijke mate en met succes bij aan de diagnose en evaluatie van patiënten met een beroerte of cerebrale parese. Voor patiënten met RA zijn de relaties tussen gewrichtsbewegingen en loopstoornissen of pathologische veranderingen van de voet en enkel nog niet voldoende bestudeerd. Deze fundamentele kennis is nodig ter ondersteuning van de ontwikkeling en evaluatie van meer effectieve interventies, die gericht zijn op verbetering of herstel van een normale dynamische functie van de voet en enkel. Het doel van dit proefschrift was om meer inzicht te krijgen in de oorzaken van de veranderingen in de voet en enkel gewrichtsbewegingen van RA patiënten ten opzichte van gezonde proefpersonen. Methodologie Een literatuuronderzoek naar bestaande gangbeeld studies van patiënten met RA werd uitgevoerd. De kwaliteit van deze studies en hun conclusies werden geanalyseerd en beschreven (HOOFDSTUK 2). De analyse van voet en enkel gewrichtsbewegingen vereist een goede reproduceerbaarheid van de parameters van de meting. Voor gezonde personen is reeds aangetoond dat de gangbeeldanalyse van de voet en enkel bewegingen herhaalbaar is. Echter, bij RA voeten kunnen misvormingen en zwellingen aanwezig zijn die de positie van de marker kunnen beïnvloeden. Tijdens eerste proefmetingen bij RA patiënten bleek dat de precieze positionering van markers ter hoogte van het distale os metatarsale I en het os naviculare discutabel was. Op het moment van deze metingen waren nog geen gangbeeld reproduceerbaarheid-studies uitgevoerd bij RA patiënten. Daarom werd het effect van variatie in herhaalde markerplaatsing op meer of minder ernstig misvormde voeten van 3 RA patiënten geanalyseerd (HOOFDSTUK 3). Aanvullend werd de variatie in markerpositie gesimuleerd door een computermodel. Door het beperkt aantal proefpersonen werd geen statistische analyse uitgevoerd. Met behulp van de resultaten werden keuzes gemaakt voor de in de vervolg studies te gebruiken kinematische parameters en werden conclusies getrokken over markerpositionering op ernstig misvormde voeten.
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Het gangbeeld werd geregistreerd van 23 RA patiënten met verschillende ziektestadia en van 14 gezonde proefpersonen van gelijke leeftijd. De voet en enkel gewrichtsbewegingen zijn berekend met behulp van een gedetailleerd voet en enkel computermodel bestaande uit 5 segmenten: onderbeen, achtervoet, middenvoet, voorvoet en hallux. In eerste instantie werden de effecten van loopsnelheid op de voet en enkel gewrichtsbewegingen bij gezonde proefpersonen geanalyseerd door middel van een herhaalde-metingen-ANOVA (HOOFDSTUK 4). De voet en enkel gewrichtsbewegingen van de gezonde proefpersonen werden geregistreerd en geanalyseerd bij drie loopsnelheid: comfortabele loopsnelheid en 70% en 50% van de comfortabele loopsnelheid. De betrouwbaarheid werd bepaald om de klinische betekenis van de bevindingen te toetsen. Dit is gedaan aan de hand van een lineairmixed-model. De ganganalyse van de RA patiënten is uitgevoerd bij een door henzelf gekozen comfortabele snelheid. De gewrichtsbewegingen van de RA voeten en enkels werden vergeleken met die van de gezonde proefpersonen bij de drie verschillende snelheden. Uit bestudering van de grafieken bleek dat de loopsnelheid alleen niet de waargenomen verschillen in gewrichtsbewegingen tussen de RA patiënten en gezonde proefpersonen kon verklaren. Daarom werd in een tweede stap een lineair-mixed-model gebruikt om de onafhankelijke bijdrage van de factor 'loopsnelheid' en de factor 'ziekte' op de voet en enkel gewrichtsbewegingen van RA patiënten te analyseren (HOOFDSTUK 5). De gewrichtsbewegingen die werden beïnvloed door de factor ‘ziekte’ werden geïdentificeerd en gebruikt om de relaties tussen gewrichtsbewegingen en klinische parameters te bestuderen (HOOFDSTUK 7). Als tussenstap werden de koppelingen tussen de bewegingen van aangrenzende en niet-aangrenzende voet- en enkelsegmenten onderzocht bij gezonde proefpersonen. Daarvoor is gebruik gemaakt van de Pearson correlatie-test (determinatiecoeficient R2) en de variatiecoëfficiënt (CV) (HOOFDSTUK 6). Verschillende actieve en passieve structuren zijn bevestigd aan (niet) aangrenzende voeten enkelsegmenten en beïnvloeden de relatieve bewegingen tussen deze segmenten. De bevindingen kunnen inzicht geven in de onderliggende mechanismen van de geobserveerde RA voet en enkel gewrichtsbewegingen. Aan de hand van koppeling tussen segmentbewegingen is het bijvoorbeeld mogelijk uit te leggen hoe een verandering in de beweging in één segment, die wordt beïnvloed door een lokale pathologie, beweging van een meer distaal of proximaal gelegen segment beïnvloedt. Als onderdeel van een andere studie heeft dr. Hetty Baan verschillende klinische scores van 25 RA patiënten gemeten en geanalyseerd. Van haar uitgebreide database zijn in dit proefschrift gebruikt: de erosie en synovitis scores van het eerste metatarsalephalange (MTP I) gewricht, de middenvoet en achtervoet gewrichten en ook de letsel scores van pezen van spieren van het onderbeen welke aanhechten op de voet (HOOFDSTUK 7). De pees- en gewrichtscores werden vastgesteld op basis van Magnetic Resonance Imaging (MRI). Verder werden sub-scores van de Joint Alignment en Motion (JAM) voor de achtervoet en MTP I inbegrepen. De klinische bevindingen die betrekking hebben op de MTP II-V en de kleinere tenen zijn niet meegenomen in deze studie omdat het computermodel deze gewrichtsbewegingen niet berekent. De klinische en kinematische scores werden getest op onderlinge afhankelijkheid door middel van Spearman correlatietests. De relaties tussen de kinematische en klinische parameters werd bestudeerd door middel van Spearman correlatietests. In deze explorerende studie zijn de laagste en hoogste waarde van
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de 95% betrouwbaarheidsintervallen (BI) van de correlatie-coëfficiënten geëvalueerd en beschreven. Relaties met een correlatie-coëfficiënt van meer dan 0.3 of 0.5 worden gedefinieerd als matig of sterk, respectievelijk. Resultaten Het literatuuronderzoek omvatte 78 studies. De kwaliteit van de studies werd voornamelijk als matig gescoord als gevolg van de relatief kleine steekproef in vergelijking met het hoog aantal proefpersonen (> 50 personen) welke vereist is voor een hoge kwaliteit klinische effect studie. Maar ook de gekozen methodologie en analyse beïnvloedden de kwaliteit: loopstoornissen werden niet vergeleken met klinisch relevante scores voor de functie en of pathologische veranderingen en de reproduceerbaarheid van de methodologie kwam niet aan de orde. Bovendien zou meer uniformiteit in methodologie, met name in de berekening en analyse van kinematische parameters, de vergelijking tussen studies verbeteren. De conclusies voor ruimte-tijd parameters kwamen overeen en er werd bij RA patiënten een vermindering van de loopsnelheid, verkleining van de paslengte en verkorting van de singlestance tijd waargenomen in vergelijking met gezonde proefpersonen. In vergelijking met gezonde personen die lopen bij een vergelijkbare snelheid, werd bij RA patienten een verhoogde cadans ter compensatie van een kleinere staplengte waargenomen. Hogere drukken werden waargenomen onder de kopjes van metatarsale II-V en een aantal druk parameters konden worden gerelateerd aan klinische scores, zoals pijn. Veranderingen in de bewegingen van de achtervoet, voorvoet en MTP I werden waargenomen bij RA patiënten in vergelijking met gezonde proefpersonen. De verschillende gangbeeld studies onderzochten verschillende kinematische parameters, maar over het algemeen werd het volgende waargenomen: een vermindering van de achtervoet plantarflexie en MTP I dorsaalflexie bij pre-swing, afname van de maximale voorvoet abductie en een abnormale verschuiving naar achtervoet eversie tijdens de standfase. Er werden geen studies gevonden die de relatie tussen de kinematische veranderingen en de klinsiche scores voor het dagelijkse functioneren of pathologische veranderingen bestudeerden. Slechts één studie evalueerde het effect van (voorvoet) operaties aan de voet op gewrichtbewegingen tijdens lopen en slechts één studie analyseerde het effect van orthesen op gewrichtsbewegingen van de voet. Variatie in markerpositie op de voet van 3 RA patiënten resulteerde in een offset (tot 10º) van de berekende gewrichtbewegingen en in een verandering in patroon (maximaal 5º) van de gewrichtbewegingen als functie van de standfase. De simulaties in markerpositie in het computermodel voorspelden soortgelijke bevindingen. De meest gevoelige gewrichtsbewegingen voor variatie in markerpositie waren de MTP I plantair/dorsaalflexie (5º) als gevolg van variatie in de proximaal-distaal positie van de distale metatarsale I marker en de middenvoet pro/supinatie (2°) als gevolg van variatie in de mediaal-lateraal positie van de naviculare marker. Door de aanwezigheid van eeltknobbels, zwellingen en of vervormingen was de plaatsing van de distale metatarsale I marker en navicular marker vaak niet in overeenkomst met de voorgeschreven positie in het markerplaatsing protocol. Het lopen van 14 gezonde proefpersonen werd opgenomen bij hun eigen comfortabele en twee langzamere loopsnelheden van gemiddeld 1.28 m/s, 0.97 m/s en 0.65 m/s, respectievelijk. Het effect van loopsnelheid was significant en klinisch relevant in het sagittale vlak voor de maximale enkel plantairflexie (3º-6º), minimale
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mediale boog (1º-2º) en een maximale MTP I dorsaalflexie (5º-9º). In het frontale vlak waren de verschillen in minimale middenvoet pronatie tussen loopsnelheid sessies klein (1º-2º), maar significant verschillend en uiterst betrouwbaar (0.94). De onafhankelijke bijdrage van de factoren ‘loopsnelheid’ en ‘ziekte’ werd onderzocht in een lineair-mixed-model. De input van het lineair-mixed-model omvatte de kinematische parameters van 21 RA patiënten die lopen op hun eigen comfortabele snelheid en de kinematische parameters van 14 gezonde proefpersonen die lopen op een comfortabele en twee langzamere snelheden. De resultaten toonden aan dat de factor ‘loopsnelheid’ alleen de achtervoet plantairflexie, de inzakking van de mediale boog, de onderbeen rotatie en de voorvoet abductiebeweging tijdens pre-swing beïnvloedde. De MTP I dorsaalflexie tijdens pre-swing en de middenvoet supinatiebeweging tijdens single-stance werden beïnvloed door zowel de factor ‘loopsnelheid’ als de factor ‘ziekte’. De factor ‘ziekte’ alleen beïnvloedde de achtervoet eversiebeweging tijdens single-stance. Bij gezonde personen werd een sterke en consistente quasi-lineaire koppeling waargenomen tussen de achtervoet eversiebeweging en de MTP I plantairflexiebeweging (gemiddelde determinatiecoëfficiënt R2 0.8). De individuele variatie in deze koppeling was klein (variatiecoëfficiënt CV 0,2). Koppeling tussen de onderbeen rotatie en de inzakking van de mediale boog was consistent, maar was minder sterk (R2 0,5) en toonde veel meer individuele verschillen (R2 0,1-0,8) en variabiliteit (CV 0,4). Koppeling tussen naast elkaar liggende segmenten was minder consistent, met grote individuele verschillen (R2 0,2-0,8) en meer individuele variatie (CV 0,4-0,5). De relaties tussen klinische en kinematische parameters zijn geanalyseerd. Een vermindering van de maximale MTP I dorsaalflexie op pre-swing was matig tot sterk gecorreleerd aan toegenomen erosie en synovitis van het MTP I gewricht (BI 0.3,0.8), erosie van de middenvoet gewrichten (BI 0.2,0.8) en achtervoet gewrichten (BI 0.0,0.7). Een toename van de middenvoet pronatie tijdens single-stance was gecorreleerd aan een pathologische veranderingen van de achillespees (BI 0.0,0.7). Afname van de eversiebeweging van de achtervoet tijdens single-stance was gecorreleerd aan pathologische veranderingen van de peroneus pees (BI 0.0,0.7). De sub-schalen van de JAM waren ook gecorreleerd aan veranderingen in gewrichtsbewegingen: een afname van de beweeglijkheid van het MTP I gewricht resulteerde in een afname van de MTP I dorsaalflexie tijdens pre-swing (BI 0.1,0.8) en een slechtere uitlijning van de achtervoet resulteerde in een afname van de middenvoet pronatiebeweging (BI 0.1,0.8) en achtervoet eversiebeweging (BI 0.2,0.8) tijdens single-stance. In deze studie waren de pathologische veranderingen van de tibialis posterior pees niet gecorreleerd aan veranderingen in middenvoet pronatiebeweging (BI -0.3,0.5) of achtervoet eversiebeweging (BI -0.5,0.4). Conclusies Er is slechts beperkte kennis beschikbaar over de onderliggende mechanismen voor de waargenomen veranderingen in de voet en enkel gewrichtbewegingen in RA en hoe chirurgische en conventionele interventies deze abnormale bewegingen beïnvloeden. Reproduceerbaarheid van de gemeten en berekende voet en enkel kinematische parameters is minder goed voor ernstig misvormde voeten dan voor normale voeten. Dit is een gevolg van, onder andere, een hogere variatie in de
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markerplaatsing op de voet. Vooral de kinematische parameters voor de middenvoet en MTP I dorsaalflexie zijn gevoelig voor variatie in markerpositie. De protocollen voor markerplaatsing moeten worden geoptimaliseerd voor meer of minder ernstig misvormde voeten. Zo kan bijvoorbeeld de reproduceerbaarheid van de MTP I dorsaalflexie worden geoptimaliseerd door het meer dorsaal plaatsen van de distale metatarsale I marker of door het aanbrengen van een extra marker distaal van het MTP I gewricht op de hallux. Loopsnelheid beïnvloedt de voet en enkel gewrichtbewegingen, maar kan niet alle waargenomen kinematische verschillen tussen RA en gezonde proefpersonen verklaren. Onafhankelijk van de factor ‘loopsnelheid’ beïnvloedt de factor ‘ziekte’ de maximale MTP I dorsaalflexie tijdens pre-swing en de middenvoet pronatiebeweging en achtervoet eversiebeweging tijdens single-stance. Een dergelijke verandering in gewrichtbewegingen werden niet waargenomen bij gezonde personen die bij eenzelfde snelheid lopen. Daarom wordt aangenomen dat deze veranderingen in gewrichtbewegingen van pathologische aard zijn en met prioriteit moeten worden behandeld door middel van conventionele of chirurgische interventies. De koppeling tussen de bewegingen van de achtervoet eversie en MTP I plantairflexie was sterk en consistent voor gezonde proefpersonen. Passieve structuren zoals de fasciaplantaris en de plantaire ligamenten verbinden deze twee voetsegmenten. Derhalve zal een pathologische verandering van een lokale structuur van één dezer segmenten niet alleen de beweging van dat ene segment beïnvloeden maar ook, door de koppelingsrelatie, indirect de beweging van het andere segment. Anderzijds zal een pathologische verandering van de plantaire structuren de koppeling tussen de MTP I en achtervoet beweging beïnvloeden en kunnen compensatoire bewegingen nodig zijn van een ander segment zoals de middenvoet. In de cross-sectionele observatiestudie met 25 RA patiënten konden enkele klinische bevindingen gerelateerd worden aan veranderingen in gewrichtbewegingen: pathologische veranderingen van het lokale gewricht en van de meer proximaal gelegen gewrichten werden gecorreleerd aan een afname van de MTP I dorsaalflexie tijdens pre-swing. De stand van de achtervoet en pathologische veranderingen van de achillespees werden gecorreleerd aan een afname van middenvoet pronatie. Alle 5 RA patiënten met pathologische veranderingen van de achillespees hadden ook pathologische veranderingen van plantaire structuren. Dergelijke pathologische veranderingen werden niet geobserveerd bij de andere RA patiënten. Naar aanleiding van deze bevindingen en de bevindingen uit het koppelingsonderzoek, wordt geconcludeerd dat in toekomstige studies de rol van plantaire structuren op de gewrichtbewegingen van RA patiënten moet worden onderzocht. Verder werden zowel de stand (uitlijning) van de achtervoet als pathologische veranderingen van de peroneus pees gerelateerd aan een afname van de achtervoet eversiebeweging. De twee klinische parameters waren ook onderling gecorreleerd. Er werden echter geen effecten op gewrichtsbewegingen gevonden voor pathologische veranderingen van de tibialis posterior pees. Toekomstige studies dienen verder in te gaan op de effecten van veranderde stand van de voet en enkel (uitlijning) en pathologische veranderingen van de pezen van het onderbeen op veranderingen in gewrichtbewegingen in een meer homogene RA populatie of tijdens longitudinale RA studies.
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Reumatologie Remission is the mission Proefschrift ter verkrijging van de graad van doctor aan de Universiteit Twente, op gezag van de rector magnificus, prof. dr. H. Brinksma, volgens besluit van het College voor Promoties in het openbaar te verdedigen op vrijdag 6 december 2012 om 16.45 uur door Marloes Vermeer geboren op 22 maart 1984 te Enschede
Promotor: Prof. dr. M.A.F.J. van de Laar Prof. dr. P.L.C.M. van Riel Assistent-promotor: Dr. H.H. Kuper
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Samenvatting In hoofdstuk 1 werd beschreven dat reumatoïde artritis (RA) een chronische ziekte is die wordt gekenmerkt door ontstekingen in de gewrichten en dat het snel tot rust brengen van de ontstekingen essentieel is voor een goede prognose. Daarom is het doel van de behandeling het bereiken van remissie in een zo vroeg mogelijk stadium van de ziekte. Meerdere klinische trials hebben laten zien dat het frequent meten van de ziekteactiviteit en het streven naar een van tevoren bepaalde mate van ziekteactiviteit (bijvoorbeeld remissie) een goede aanpak is om patiënten met recent gediagnosticeerde RA te behandelen. Indien de ziekteactiviteit op een bepaald meetmoment te hoog is moet vervolgens direct de medicatie worden aangepast, hierbij optimaal gebruik makend van de momenteel beschikbare medicamenten. Deze behandelwijze wordt ook wel treat-totarget (T2T) of tight control genoemd. De mate van ziekteactiviteit kan worden gemeten met de Disease Activity Score in 28 gewrichten (DAS28). Deze score wordt berekend met behulp van het aantal pijnlijke en gezwollen gewrichten, de bloedbezinking en de mate van algeheel welbevinden van de patiënt. Volgens onze werkdefinitie wordt remissie gedefinieerd als zijnde een DAS28 kleiner dan 2.6. Er bestaan echter ook andere definities van remissie, een eenduidige definitie ontbreekt tot op dit moment. Uit klinische trials is gebleken dat een T2T behandelstrategie effectief is in het verlagen van de ziekteactiviteit en uiteindelijk in het bereiken van remissie in de behandeling van recent gediagnosticeerde RA. T2T is echter nog niet geïmplementeerd. In de dagelijkse klinische praktijk wordt de ziekteactiviteit niet consistent gemeten met een valide meetinstrument en medicatie wordt vaak niet aangepast ondanks de aanwezigheid van actieve ziekte. Het is de vraag of de veelbelovende resultaten van klinische trials met betrekking tot T2T kunnen worden vertaald naar de dagelijkse klinische praktijk. Klinische trials en de dagelijkse praktijk verschillen in meerdere opzichten van elkaar. Er wordt verondersteld dat de werkzaamheid van therapeutische interventies zoals wordt waargenomen in klinische trials, niet vaak wordt bereikt in de dagelijkse klinische praktijk. Dit kan onder andere worden verklaard door de strenge inclusie criteria die worden gehanteerd bij klinische trials (bijvoorbeeld met betrekking tot leeftijd, ziekteactiviteit en comorbiditeiten), waardoor de generaliseerbaarheid van de resultaten naar de praktijk wordt beperkt. In het kader van het Dutch Rheumatoid Arthritis Monitoring (DREAM) remissie inductie cohortonderzoek is een T2T behandelstrategie, waarbij werd gestreefd naar het bereiken van DAS28-remissie, geïmplementeerd in verschillende ziekenhuizen in Nederland. In dit onderzoek worden patiënten waarbij onlangs de diagnose RA is gesteld op vaste momenten onderzocht en behandeld volgens een vast behandelschema met van tevoren vastgestelde beslismomenten over het aanpassen van de medicatie gericht op het zo snel mogelijk bereiken van remissie in de dagelijkse klinische praktijk. Het doel van dit proefschrift was het evalueren van de effecten van de implementatie van deze T2T behandelstrategie. In Hoofdstuk 2 werden de eerstejaars resultaten gepresenteerd van de implementatie van de T2T strategie waarbij werd gestreefd naar het bereiken van remissie (gedefinieerd als een DAS28 < 2.6). Na zes en twaalf maanden follow-up was het percentage patiënten dat in remissie was hoog (respectievelijk 47% en 58%) en remissie werd snel bereikt. De eerste radiologische uitkomsten lieten zien dat er weinig radiologische schade was opgetreden en bij de meerderheid van de
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patiënten werd geen klinisch relevante radiologische progressie waargenomen. Optimaal gebruik van methotrexaat (MTX) (monotherapie gevolgd door combinatietherapie met andere conventionele disease-modifying antirheumatic drugs (DMARDs) indien nodig) bleek succesvol te zijn in het bereiken van het behandeldoel. In het eerste jaar kreeg slechts 10% van de patiënten anti-tumour necrosis factor α (anti-TNF) therapie voorgeschreven. Deze studie heeft laten zien dat een T2T strategie in combinatie met geprotocolleerde medicatiestappen haalbaar en succesvol is in het bereiken van remissie bij patiënten met recent gediagnosticeerde RA in de dagelijkse klinische praktijk. In hoofdstuk 3 werd getracht de vraag te beantwoorden of een behandelstrategie waarbij wordt gestreefd naar tight control van de ziekteactiviteit (ook wel T2T) effectiever is om remissie te bereiken na een jaar bij patiënten met vroege RA dan de reguliere behandeling (‘usual care’). De behandelstrategieën van twee vroege RA inceptie cohorten uit twee verschillende regio’s met patiënten die voldeden aan de American College of Rheumatology (ACR) classificatie criteria voor RA (2) zijn met elkaar vergeleken. Patiënten in de tight control groep werden behandeld volgens een T2T strategie waarbij gestreefd werd naar het bereiken van remissie (DREAM remissie inductie cohort). Patiënten in de usual care groep werden behandeld zonder DAS28-gestuurde behandelstappen. Na een jaar hadden meer patiënten in de tight control groep remissie bereikt dan in de usual care groep, met remissie percentages van respectievelijk 55% versus 30%. Remissie werd ook sneller bereikt met T2T. Tevens leidde T2T tot een grotere daling in DAS28, een groter aantal patiënten met lage ziekteactiviteit en grotere verbeteringen in fysiek functioneren en in de waardering van de patiënten over hun pijn en algehele gezondheid. In beide groepen werd met name een step-up behandelstrategie toegepast en het aantal patiënten dat anti-TNF middelen kreeg voorgeschreven was vergelijkbaar. De grootste verschillen tussen de behandelstrategieën in de groepen waren dat in de tight control groep bijna alle patiënten startten met MTX, terwijl MTX pas later werd gestart in de usual care groep. Verder werd combinatietherapie vaker voorgeschreven in de tight control groep. De resultaten van deze studie hebben laten zien dat een T2T strategie waarbij wordt gestreefd naar het bereiken van remissie leidt tot een groter aantal patiënten dat remissie bereikt en dit ook sneller bereikt dan bij de reguliere behandeling bij vroege RA. In hoofdstuk 4 werd onderzocht of de gunstige effecten van de T2T strategie, zoals in de voorgaande hoofdstukken is laten zien, behouden blijven op de langere termijn. In dit hoofdstuk presenteerden we de resultaten van T2T met betrekking tot het bereiken van (stabiele) remissie, radiologische progressie, fysiek functioneren en gezondheidsgerelateerde kwaliteit van leven na drie jaar follow-up. Na drie jaar was de meerderheid van de patiënten in remissie, namelijk 62% en stabiele remissie (gedefinieerd als zes maanden of langer) werd geobserveerd bij 71% van de patiënten. Bij de meerderheid van deze patiënten werd stabiele remissie bereikt met behulp van conventionele DMARDs. Ook werden gunstige resultaten gezien met betrekking tot ziekteactiviteit, fysiek functioneren en gezondheidsgerelateerde kwaliteit van leven, waarbij significante verbeteringen werden gezien tijdens de eerste zes maanden van follow-up, waarna de resultaten stabiel bleven. De geobserveerde radiologische schade en progressie waren zeer klein, zelfs na drie
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jaar follow-up. Deze studie heeft laten zien dat de initiële gunstige effecten van T2T behouden blijven op de langere termijn. Het doel van hoofdstuk 5 was om te evalueren in hoeverre de T2T aanbevelingen zijn opgevolgd. We onderzochten of de aanbevelingen resulteerden in het regulier meten van de ziekteactiviteit met behulp van de DAS28 en of de medicatie werd aangepast volgens het behandeladvies (dat wil zeggen het medicatieprotocol), en wat eventueel de redenen waren voor afwijken. De resultaten van deze studie hebben laten zien dat de DAS28 op bijna alle cohortbezoeken is bepaald en dat de behandeling in de meerderheid van de bezoeken overeen kwam met het behandeladvies (69%). In het geval van het niet overeenkomen met de aanbevelingen werd over het algemeen een valide argument voor afwijken gegeven. De voornaamste reden voor afwijken was het gebrek aan overeenstemming tussen de mate van ziekteactiviteit volgens de reumatoloog en de gemeten DAS28. Met een percentage van 69% lijkt de compliantie aan de T2T aanbevelingen optimaal. Het streven naar een percentage van 100% is niet realistisch aangezien de behandeling van patiënten onderhevig is aan bijwerkingen en comorbiditeiten. Deze studie heeft laten zien dat de implementatie van T2T zeer goed haalbaar is in de dagelijkse klinische praktijk. In hoofdstuk 6 werden de resultaten gepresenteerd van een kosteneffectiviteits- en kostenutiliteitsanalyse van een T2T behandelstrategie gericht op het bereiken van remissie in vergelijking met reguliere zorg (usual care) in de behandeling van patiënten met recent gediagnosticeerde RA in de dagelijkse klinische praktijk. De follow-up in deze studie was beperkt tot een periode van drie jaar. Er kan worden aangenomen dat met T2T meer inspanningen en kosten gemoeid zijn in het beginstadium van de ziekte, om daarmee gezondheidswinst en kostenbesparingen op langere termijn te realiseren. Het was de vraag of deze gezondheidsvoordelen opwegen tegen de extra kosten die gemoeid zijn met T2T. Om dit te onderzoeken is dezelfde vergelijking van patiëntengroepen als in hoofdstuk 3 gebruikt. Deze studie laat zien dat T2T effectiever is dan usual care: hogere remissiepercentages en een grotere winst in quality adjusted life years (QALYs) warden geobserveerd. De incrementele kosteneffectiviteitsratio was € 3.591 per patiënt in remissie na twee jaar en T2T was dominant na drie jaar. De incrementele kostenutiliteitsratio was € 19.410 per QALY na twee jaar en T2T was dominant na drie jaar. Na twee jaar was T2T geassocieerd met hogere kosten maar ook met een substantieel hogere effectiviteit in vergelijking met usual care. Na drie jaar wordt T2T waarschijnlijk kostenbesparend. De factoren die de kostenverschillen tussen T2T en usual care bepaalden waren anti-TNF therapie en hospitalisatie. Deze studie heeft laten zien dat T2T kosteneffectief is en deze behandeling de voorkeur verdient boven usual care. Recentelijk heeft de ACR/European League Against Rheumatism (EULAR) nieuwe definities betreffende remissie in RA gepubliceerd. In hoofdstuk 7 werd het patient global assessment (PGA) remissie criterium van de Booleaanse definitie van remissie bediscussieerd. Volgens deze definitie is een patiënt in remissie wanneer de volgende metingen ≤ 1 zijn: aantal pijnlijke gewrichten, aantal gezwollen gewrichten, C-reactief proteïne (mg/dL) en PGA (patiënt algeheel welbevinden op
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een visueel analoge schaal van 0-10). In de dagelijkse praktijk komt het vaak voor dat de patiënt hoger scoort op PGA dan zou worden verwacht op basis van de ziekteactiviteit. Dit suggereert dat de PGA niet louter wordt beïnvloed door het klinische ziekteproces. Daarom is het discutabel of een PGA score ≤ 1 gebruikt zou moeten worden als een criterium bij het bepalen van remissie. In deze studie hebben we de relatie onderzocht tussen het PGA remissie criterium en de klinische bevindingen bij de patiënt. Hieruit bleek dat patiënten regelmatig niet voldeden aan het PGA criterium, ondanks een goede klinische status. Blijkbaar zijn er ook andere factoren die kunnen leiden tot een PGA score die niet voldoet aan het criterium van ≤ 1, in afwezigheid van evidente gewrichtsinflammatie. Deze studie heeft laten zien dat het PGA criterium van de ACR/EULAR definitie van remissie in RA beperkingen heeft bij gebruik in de dagelijkse praktijk. In hoofdstuk 8 werden de bevindingen van de voorgaande hoofdstukken samengevat en bediscussieerd en aanbevelingen voor vervolgonderzoek gegeven. Dit proefschrift heeft laten zien dat het implementeren van een T2T behandelstrategie zeer effectief is in het bereiken van remissie bij patiënten met recent gediagnosticeerde RA in de dagelijkse klinische praktijk. De meerderheid van de patiënten bereikte remissie en dit vond in het algemeen vroeg in het ziekteproces plaats. Op de lange termijn (drie jaar) werd weinig gewrichtsschade, een verbeterd fysiek functioneren en een verbeterde kwaliteit van leven waargenomen. T2T blijkt beter in staat om de ziekte tot rust te brengen dan usual care. Tevens is de behandeling kosteneffectief op de langere termijn. Het is algemeen geaccepteerd dat de behandeling van RA gericht moet zijn op het zo snel mogelijk onderdrukken van de ziekteactiviteit. De hypothese bestaat dat er een “window of opportunity” is waarin het ontstekingsproces meer gevoelig is voor behandeling dan later in het ziekteproces en de mogelijkheid bestaat om de ontstekingen te onderdrukken voordat er schade optreedt. Daarom is het van groot belang dat de ziekte zo snel mogelijk wordt gediagnosticeerd. MTX wordt beschouwd als de hoeksteen van de behandeling van RA, als initiële monotherapie en in combinatietherapieën. Dit proefschrift heeft laten zien dat direct starten met een optimale dosis MTX leidt tot een goede respons bij de meerderheid van de patiënten. In het geval van een suboptimale respons werd een combinatie van MTX en sulfasalazine voorgeschreven. De meerderheid van de patiënten bereikte (stabiele) remissie met een intensieve behandeling met conventionele DMARDs (monotherapie of combinatietherapie). Het voorschrijven van biologicals was slechts bij een klein percentage van de patiënten noodzakelijk. Hoewel een T2T aanpak effectief is gebleken in het onderdrukken van de ziekteactiviteit en het bereiken van remissie zijn de T2T principes nog niet geïmplementeerd in alle reumatologie praktijken. De succesvolle implementatie van T2T, zoals is beschreven in dit proefschrift, wijst erop dat T2T ook haalbaar en effectief is in de dagelijkse klinische praktijk. Observationele data uit registers en cohortonderzoeken, zoals het onderzoek dat is beschreven in dit proefschrift, kunnen belangrijke aanvullende informatie verschaffen ten opzichte van klinische trials. De kracht van deze data ligt in het feit dat zij een betere weergave zijn van de dagelijkse praktijk, met betrekking tot de meer heterogene patiëntenpopulatie en wijze van behandeling. Daardoor kunnen de resultaten van observationele studies eenvoudiger gegeneraliseerd worden naar de algemene RA populatie. Andere
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positieve factoren zijn dat deze studies vaak grotere aantallen patiënten omvatten en een langere follow-up periode hebben dan klinische trials. Het is nu algemeen geaccepteerd dat remissie het therapeutische doel zou moeten zijn bij de behandeling van RA. Desondanks is er op dit moment nog geen eenduidige definitie van remissie beschikbaar. Ook de recent gepubliceerde Booleaanse definitie van remissie door ACR en EULAR lijkt niet optimaal te zijn. In dit proefschrift is remissie gedefinieerd volgens de DAS28 criteria. Echter, bij het streven naar remissie kan in principe elk van de beschikbare definities worden toegepast: het lijkt erop dat streven naar een van tevoren vastgesteld doel belangrijker is dan de exacte definitie van remissie. De uitvoerbaarheid van T2T in de dagelijkse praktijk is afhankelijk van verschillende praktische en logistieke factoren. Onder andere het bereiken van consensus over de te volgen strategie, kennis over het meetinstrument dat gebruikt wordt bij het bepalen van de ziekteactiviteit, het inzetten van reumaverpleegkundigen en een digitaal systeem voor de opslag van data zijn factoren die de implementatie van T2T kunnen faciliteren. Patiënten moeten goed geïnformeerd worden over de toepassingen en het profijt van T2T. Vervolgonderzoek zou zich moeten richten op de werkzaamheid, veiligheid en uitvoering van T2T in patiënten met recent gediagnosticeerde RA op de langere termijn, na drie jaar follow-up. Daarnaast is vervolgonderzoek nodig om te bepalen wat de meest optimale behandelstrategie is, aangezien in het cohortonderzoek dat beschreven is in dit proefschrift slechts één behandelstrategie is geëvalueerd. Niet alle patiënten waren in staat om remissie te bereiken. Het is ook van belang om voor deze patiëntengroep een passende strategie te ontwikkelen. Een aanpak als T2T zou breed omarmd moeten worden om zo de klinische uitkomsten voor patiënten met recent gediagnosticeerde RA te optimaliseren en om zo hun gezondheidsgerelateerde kwaliteit van leven te verbeteren. Gebleken is dat het bereiken van remissie een realistisch doel is in de dagelijkse klinische praktijk en het bereiken van remissie zou dan ook de missie bij de behandeling van RA moeten zijn.
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Reumatologie Valuation Of Quality Of Life In Rheumatoid Arthritis Proefschrift ter verkrijging van de graad van doctor aan de Universiteit Twente, op gezag van de rector magnificus, prof. dr. H. Brinksma, volgens besluit van het College voor Promoties in het openbaar te verdedigen op donderdag 20 december 2012 om 16.45 uur door Laurien Buitinga geboren op 9 maart 1985 te Hengelo (OV)
Promotor: prof. dr. M.A.F.J. van de Laar Assistent-promotoren: dr. E. Taal dr. L.M.A. Braakman-Jansen
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Samenvatting: De snelle vooruitgang in behandeling van reumatoïde artritis (RA) heeft geleid tot een aanzienlijke verbetering in de symptomen van patiënten en uitkomsten. Tegenwoordig is het zelfs zo dat een groot deel van de patiënten in een staat van remissie kan worden gebracht, wat betekent dat er bij deze patiënten geen aanwijsbare ziekteactiviteit en achteruitgang in gewrichtsbeschadiging worden waargenomen. Voor het meten van de klinische toestand van patiënten worden zowel objectieve als subjectieve maten gebruikt. Met name in de afgelopen jaren is het belang van subjectieve, patiëntgerapporteerde uitkomstmaten erkend. Hierdoor is het aantal patiëntgerapporteerde uitkomstmaten aanzienlijk toegenomen, waaronder instrumenten die gezondheidsgerelateerde kwaliteit van leven (KvL) meten. Vanwege het toegenomen gebruik van deze maten in verschillende disciplines is het van belang om de psychometrische eigenschappen van deze instrumenten grondig te evalueren. Bij de afname van instrumenten worden steeds vaker computers gebruikt. Het is daarom ook belangrijk om resultaten die zijn verkregen met een computer te vergelijken met de resultaten die zijn verkregen met een interview of vragenlijst. Voorbeelden van patiëntgerapporteerde uitkomstmaten zijn de zogenoemde ‘Health Assessment Questionnaire’ (HAQ), een maat voor functionele status, en de ‘Medical Outcomes Study Short Form-36’ (SF-36), een maat voor KvL, bestaande uit fysiek, psychologisch en sociaal functioneren. Deze instrumenten zijn uitgebreid gevalideerd bij RA-patiënten. Gezondheidsgerelateerde KvL-maten worden ook gebruikt als uitkomstmaten voor economische analyses ter ondersteuning van vergoedingsbeslissingen. De voorkeur hierbij gaat uit naar instrumenten die waarderingen voor gezondheidstoestanden (‘utiliteiten’) meten vanuit het maatschappelijk perspectief, zoals de EuroQol-5D (EQ-5D) en de Short Form-6D (SF-6D). Er is uitgebreid onderzoek gedaan naar de psychometrische prestaties van de EQ-5D en in mindere mate ook naar die van de SF-6D. Toch is aanvullend onderzoek nodig naar de responsiviteit van deze instrumenten voor verbeteringen in de gezondheid van patiënten. Aangezien het onderzoek naar effectieve behandelingen voor RA zich snel heeft ontwikkeld, is het belangrijk dat gezondheidsgerelateerde KvL-instrumenten veranderingen in de gezondheidstoestand van patiënten als gevolg van deze behandelingen kunnen weergeven. Studies in verschillende ziekten hebben laten zien dat deze instrumenten beperkingen hebben wat betreft hun discriminerend vermogen, omdat er onder andere vloer- en plafondeffecten aanwezig zijn in de utiliteitsscores van deze instrumenten. Tot nu toe is er vooral bij patiënten met RA weinig onderzoek gedaan naar de psychometrische eigenschappen van instrumenten die waarderingen vanuit een patiëntenperspectief meten, namelijk de Time Trade-Off (TTO) en Standard Gamble (SG). Vanwege het feit dat patiënten unieke en uitgebreide kennis van en ervaring met hun ziekte hebben en vanwege het feit dat zij direct worden beïnvloed door interventies, zijn wij van mening dat het belangrijk is om waarderingen van patiënten te verkrijgen. Meer onderzoek is nodig naar de psychometrische eigenschappen van deze zogenoemde ‘directe utiliteitsmaten’ bij RA. Dit proefschrift heeft onderzoek gedaan naar de psychometrische eigenschappen van enkele gezondheidsgerelateerde KvL-instrumenten bij RA-patiënten. Daarnaast is van één van de veelgebruikte directe instrumenten (de TTO) onderzocht of een computerversie als alternatief kan dienen voor de interviewversie. Tot slot is
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onderzoek gedaan naar alternatieve ankers voor de TTO bij RA-patiënten, wat het meten van gezondheidsgerelateerde KvL gericht op het patiëntenperspectief zou kunnen verbeteren. In hoofdstuk 3 werd de responsiviteit van de EQ-5D vergeleken met die van de SF6D bij patiënten met actieve RA die werden behandeld met effectieve TNF-blokkers. Beide instrumenten waren slechts gematigd responsief voor verbetering over een periode van een jaar. De SF-6D was in het algemeen responsiever dan de EQ-5D. Noch systematische vloer- noch systematische plafondeffecten werden gevonden in de utiliteitsscores die de mogelijkheid van de instrumenten om verandering te detecteren zouden kunnen hebben beïnvloed. Toch is de al aanwezige hoge vloer in de SF-6D (utiliteitsscore van 0.30) een beperking voor het gebruik van het instrument bij patiënten met een ernstigere RA. Het is belangrijk op te merken dat, hoewel de SF-6D responsiever was dan de EQ-5D, het gebruik ervan in kostenutiliteitsanalyses (KUAs) zal leiden tot een minder gunstige kosten-utiliteitsratio vanwege het feit dat gemiddelde veranderingen in utiliteitsscores worden gebruikt om het aantal gewonnen Quality-Adjusted Life-Years (QALYs) met een nieuwe gezondheidstechnologie te berekenen. De gemiddelde verandering in de utiliteitsscore van de EQ-5D is groter dan die van de SF-6D. Dit onderstreept de grotere variantie van de EQ-5D, aangezien voor dit instrument een lagere waarde voor de responsiviteit werd gevonden. Echter, het gebruik van de SF-6D zou leiden tot minder onzekerheid wat betreft de relatieve kosten-utiliteit van twee behandelingen. In hoofdstuk 4 werd een computer TTO ontwikkeld en vergeleken met een interview TTO wat betreft praktische bruikbaarheid en mate van overeenstemming. De resultaten lieten zien dat de computer TTO een praktisch bruikbaar en betrouwbaar alternatief was voor de interview TTO. Echter, beide TTO instrumenten gaven niet dezelfde resultaten. Het verschil in de mediaanscore tussen beide TTO’s was een klinisch relevant verschil, wat impliceert dat utiliteiten verkregen met beide TTO’s niet verwisselbaar zijn. Gelukkig werden er geen systematische verschillen gevonden over het bereik van scores. Om er zeker van te zijn dat de computer TTO zonder hulp kan worden voltooid, zouden enige aanpassingen moeten worden gedaan. Aanvullend onderzoek in een grotere steekproef van RA-patiënten is nodig om de gevonden resultaten te bevestigen. In hoofdstuk 5 werd de constructvaliditeit van de TTO onderzocht in een kleine steekproef van RA-patiënten. De voorlopige resultaten lieten zien dat zowel de computer als de interview TTO slecht waren gecorreleerd met, én slecht in staat waren om onderscheid te maken tussen, andere zelfgerapporteerde uitkomstmaten. Na het uitsluiten van mensen die weigerden om jaren in te leveren (‘zero-traders’) verbeterden de resultaten wat betreft convergente validiteit. Mogelijke verklaringen zijn het feit dat de meeste zelfgerapporteerde uitkomstmaten slechts één aspect van het construct KvL meten en dat zij slechts beschrijvend van aard zijn. Bovendien blijkt de TTO vatbaar te zijn voor meetfouten (‘biases’). Een voorbeeld is dat mensen vanwege het feit dat ze verliesangst hebben minder bereid zijn om levensjaren in te leveren, waardoor opwaartse ‘biases’ in hun utiliteitsscores worden gevonden. Een andere belangrijke verklaring zou kunnen zijn dat patiënten hun
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ziekte niet als levensbedreigend zien waardoor zij minder bereid zijn om levensjaren in te ruilen voor perfecte gezondheid. Mogelijk zijn er realistischere ankers voor RApatiënten. Om de huidige TTO te verbeteren zou het gebruik kunnen worden geëvalueerd van ankers die patiënten als realistisch zien. Ook zou een procedure als ‘chaining’ kunnen worden gebruikt, hoewel een ‘chained TTO’ ingewikkelder is en niet uitgebreid is gevalideerd bij chronische ziekten. In hoofdstuk 6 werden toekomstverwachtingen en worst-case toekomstscenario’s van RA-patiënten onderzocht door middel van focusgroepen. Inzicht in verwachtingen en worst-case toekomstscenario’s van patiënten gerelateerd aan hun RA zouden kunnen worden gebruikt in interventies die verwachtingen en toekomstscenario’s in een realistisch perspectief zetten en die patiënten helpen om met hun angsten en zorgen om te kunnen gaan zodat hun KvL verbetert. Worstcase toekomstscenario’s die als realistisch worden gezien door RA-patiënten zouden kunnen worden gebruikt als een alternatief anker voor het anker ‘dood’ in de TTO, wat mogelijk de validiteit en responsiviteit van het instrument verbetert. Verwachtingen en worst-case toekomstscenario’s werden genoemd over afhankelijkheid van anderen, toenemende vermoeidheid, onbekwaamheid hobby’s uit te voeren, onbekwaamheid te lopen en een toenemende afhankelijkheid van medicatie. Vanuit een klinisch oogpunt zijn niet alle verwachtingen en worst-case toekomstscenario’s realistisch. Echter, voor patiënten waren ze wel realistisch. Opmerkelijk was dat in onze studie pijn niet als zorg of probleem werd genoemd in tegenstelling tot in sommige andere studies. Verschillen tussen studies kunnen worden verklaard door de snelle vooruitgang in de behandeling van RA en door verschillen in de vragen die worden gesteld. Daarbij komt dat patiënten, hoewel ze zeker wel pijn ervaarden, hun pijnniveaus vergeleken met de niveaus ten tijde van de diagnose. Sindsdien was de pijn enorm afgenomen. Ook gaven deelnemers aan dat ze gewend waren geraakt aan de pijn; dat ze ermee moesten leren omgaan. Dit kan ook verklaren waarom ze pijn niet als een worst-case toekomstscenario noemden. Een grotere kwantitatieve studie bij RA-patiënten is vereist om de gevonden resultaten te valideren. In hoofdstuk 7 werd een kwantitatieve studie uitgevoerd om te onderzoeken welk van de vijf worst-case toekomstscenario’s uit de focusgroepstudie het meest geschikt was voor patiënten met RA om te gebruiken als anker in de TTO om utiliteiten te verkrijgen. De resultaten lieten zien dat het scenario ‘afhankelijk zijn van anderen’ het meest geschikte scenario was, omdat dit scenario het vaakst werd gekozen als ergste om mee te maken. Geen enkele deelnemer ervaarde deze slechtste toestand op het moment al. In een toestand zijn die in de TTO wordt gebruikt zal utiliteitsscores benedenwaarts vertekenen, wat leidt tot vloereffecten die zorgen voor een onderwaardering in gezondheidsgerelateerde KvL; mensen die deze toestand in de TTO al ervaren zullen automatisch een score van 0 krijgen. Voor deze mensen is het niet mogelijk om een trade-off te doen. Opmerkelijk was dat het scenario ‘afhankelijk zijn van anderen’ het minst werd ervaren, hoewel deze het vaakst werd gekozen als ergste om mee te maken. Het lijkt erop dat patiënten die niet veel ervaring hebben met een toestand, deze toestand het ergste vinden om mee te maken. Echter, er moet opgemerkt worden dat, hoewel het scenario ‘afhankelijk zijn van anderen’ het vaakst door RA-patiënten werd gekozen als ergste
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om mee te maken, 65% van de deelnemers dit scenario niet het vaakst had gekozen. Voor deze 65% kan het gebruik van afhankelijkheid van anderen als anker in de TTO problematisch zijn. Vandaar dat dit scenario zou moeten worden vergeleken met het huidige scenario ‘dood’ om te onderzoeken hoe groot het probleem is. Toch moet worden opgemerkt dat zelfs als het anker ‘eerder overlijden’ het worst-case toekomstscenario voor RA-patiënten blijkt te zijn, dit anker waarschijnlijk niet als een realistisch gevolg van RA wordt gezien, aangezien het niet in de focusgroepstudie werd genoemd als zorg of worst-case toekomstscenario. In hoofdstuk 8 werden de resultaten van het proefschrift samengevat en bediscussieerd en werden sterke kanten en beperkingen van het proefschrift besproken. Verder werden mogelijkheden genoemd voor verbetering van instrumenten en werden aanbevelingen gedaan voor toekomstig onderzoek. Het proefschrift heeft laten zien dat utiliteiten die worden verkregen met huidige meetinstrumenten beperkt zijn vanuit zowel een wetenschappelijk als psychometrisch perspectief, zoals we bij RA-patiënten hebben onderzocht. Aangezien deze instrumenten data verschaffen die een belangrijke rol spelen in economische analyses van gezondheidstechnologieën ter ondersteuning van vergoedingsbeslissingen, is het essentieel dat deze instrumenten responsief zijn en valide data genereren. Vandaar dat het nodig is verbeterde versies van instrumenten te ontwikkelen. Om het meten van gezondheidsgerelateerde KvL dat het patiëntenperspectief weergeeft te verbeteren, is onderzoek gedaan naar alternatieve ankers voor de TTO die realistischer zijn voor RA-patiënten dan het huidige anker ‘dood’. Een andere veelbelovende benadering om het meten van gezondheidsgerelateerde KvL te verbeteren is item respons theorie (IRT). Eerder onderzoek heeft laten zien dat met behulp van Rasch-analyse kan worden aangetoond dat de EQ-5D met vijf niveaus (EQ-5D-5L) inderdaad een breder gezondheidscontinuüm meet dan de originele EQ-5D met drie niveaus. Ook zou met behulp van IRT gekeken kunnen worden of voor de huidige SF-6D de meest informatieve items (uit de SF-36) zijn gekozen. Op deze manier zou de SF-6D kunnen worden verbeterd en zou de hoge vloer kunnen worden verlaagd. Er is ook onderzoek gedaan naar het combineren van Discrete Keuzemodellen met IRT. Dit zou een goede vervolgstap zijn om het meten van gezondheidsgerelateerde KvL gericht op het patiëntenperspectief te verbeteren. In hoofdstuk 8 werden sterke punten van het onderzoek genoemd, zoals het feit dat dit proefschrift als eerste een interview TTO met een equivalente computer TTO heeft vergeleken. Bovendien heeft geen enkele eerdere studie RA-patiënten expliciet gevraagd naar hun toekomstverwachtingen en worst-case toekomstscenario’s. Ook is er niet eerder gekeken naar alternatieve ankers voor de TTO. Echter, er zijn ook een aantal beperkingen te noemen. Zo waren data van beide TTO-studies afkomstig uit een ‘convenience sample’, wat de generaliseerbaarheid van de resultaten beperkt. Echter, andere studies bij RApatiënten hebben ook een slechte constructvaliditeit van een interview TTO gevonden. Verder zijn uitsluitend instrumenten van beschrijvende aard gebruikt om de TTO te valideren. Een andere beperking heeft betrekking op het ziektespecifieke karakter van het gevonden anker. Aangezien uitsluitend RA-patiënten zijn gevraagd naar hun worst-case toekomstscenario als gevolg van hun reuma, is het gevonden worst-case anker niet zomaar toepasbaar bij andere ziekten. Een implicatie hiervan
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is dat deze alternatieve TTO niet direct kan worden gebruikt in KUAs die ziekten vergelijken, omdat instrumenten daarvoor generiek moeten zijn. Tot slot is in de laatste studie het huidige anker ‘dood’ niet meegenomen in de vergelijkingen van de scenario’s. Het is dus niet bekend hoe groot het probleem van het gebruik van het anker ‘dood’ nu eigenlijk is. Echter, ook al zou het anker ‘dood’ het vaakst door RApatiënten worden gekozen als ergste om mee te maken, eerder overlijden wordt waarschijnlijk niet gezien als een realistisch gevolg van RA. Ten slotte werden er in hoofdstuk 8 aanbevelingen gedaan voor vervolgonderzoek. De belangrijkste aanbeveling is dat toekomstig onderzoek de psychometrische eigenschappen van de TTO met een alternatief anker moet vaststellen in grote representatieve steekproeven van RA-patiënten. Ook kan IRT een belangrijke rol spelen bij het verbeteren van het meten van gezondheidsgerelateerde KvL.
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Reumatologie Fatigue In Rheumatoid Arthritis: From Patient Experience To Measurement Proefschrift ter verkrijging van de graad van doctor aan de Universiteit Twente, op gezag van de rector magnificus, prof. dr. H. Brinksma, volgens besluit van het College voor Promoties in het openbaar te verdedigen op donderdag 16 maart 2012 om 14.45 uur door Stephanie Nikolaus geboren op 2 november 1980 te Kleef, Duitsland
Promotor: prof. dr. M.A.F.J. van de Laar Assistent-promotoren: dr. C. Bode dr. E. Taal
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Samenvatting: De inhoud van dit proefschrift brengt de betekenis van vermoeidheid bij RA in kaart vanuit het patienten perspectief en levert een gekalibreerde multidimensionele itembank op. In het kort gezegd houdt het proefschrift de volgende studies in. Ten eerste hebben wij een systematische review naar statistische voorspellers van vermoeidheid en de invloed van vermoeidheid op andere uitkomstmaten uitgevoerd. Daarna werden de moeilijkheden van het meten van behandeleffecten op vermoeidheid bij RA bediscussieerd. Ten tweede hebben wij een item pool voor het meten van vermoeidheid bij RA ontwikkeld door middel van vier op elkaar volgende studies (interview studie, Q-sort studie, Delphi studie en kalibratiestudie). De volgorde van deze studies had een logische opbouw; we zijn begonnen met kwalitatief onderzoek naar de ervaring van patienten en zijn geeindigd met een statistisch gekalibreerde itempool. Deze zullen wij verder gebruiken om een computer adaptieve test (CAT) voor vermoeidheid bij RA te construeren. Hieronder worden de studies kort samengevat. Het eerste artikel in het proefschrift (hoofdstuk 2) geeft een overzicht over de actuele stand van zaken wat betreft onderzoek naar mogelijke oorzaken en consequenties van vermoeidheid bij RA. Daarnaast hebben wij verschillen en overeenkomsten in vermoeidheid tussen patienten met verschillende diagnoses beschreven. Studies toonden voorspellers aan voor vermoeidheid onder ziekte gerelateerde aspecten (bijv. pijn), fysiek functioneren (bijv. lichamelijke beperkingen), cognitief/emotioneel functioneren (bijv. depressie) en sociale aspecten (bijv. negatieve interpersoonlijke gebeurtenissen). Bij vrouwen werden over het algemeen hogere vermoeidheidsniveaus gevonden dan bij mannen. Met betrekking tot de relatie tussen ontstekingsactiviteit (bijv. BSE of/en DAS28) en vermoeidheid bij RA kwamen tegenstrijdige resultaten naar voren. Een hogere mate van vermoeidheid was geassocieerd met ziektegerelateerde aspecten (bijv. ochtendstijfheid), fysiek functioneren (bijv. fysieke kwaliteit van leven), cognitieve/emotionele aspecten (bijv. psychologische stress) en sociale aspecten (bijv. werkvermogen). Patienten met RA rapporteerden een hogere mate van vermoeidheid dan gezonde mensen. Fibromyalgie patienten daarentegen rapporteerden een hogere mate van vermoeidheid dan andere patientengroepen. Het viel op dat de meeste aanwijzingen voor een relatie tussen vermoeidheid en andere variabelen gevonden werden voor pijn, depressie en fysiek functioneren. In veel van de cross-sectionele en ook van de longitudinale studies bleken deze drie variabelen een belangrijke rol te spelen bij het voorspellen van vermoeidheid bij RA. Hoewel verschillende associaties tussen vermoeidheid en andere variabelen gevonden werden, konden wij op basis van de gereviewde literatuur nauwelijks betrouwbare conclusies over causaliteit trekken. Het merendeel van de studies was cross-sectioneel en niet alle longitudinale studies controleerden voor vermoeidheid op baseline. Prospectief longitudinaal onderzoek met adequate statistische analyses is nodig om meer over de multicausale relaties tussen vermoeidheid bij RA en andere variabelen aan te tonen. Hoofdstuk 3 bediscussieert de teleurstellende effecten van biotherapieen op
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vermoeidheid bij RA zoals aangetoond door een recente meta-analyse. Om deze resultaten te verklaren hebben wij twee scenario’s geschetst. Het eerste scenario suggereert dat biotherapieen niet effectief zijn voor het verminderen van vermoeidheid bij RA. We weten nog niet genoeg over de oorzaken en consequenties van vermoeidheid bij RA. Het is nog niet duidelijk hoe vermoeidheid door ontstekingsprocessen beinvloed wordt. Zelfs als biotherapie effect op vermoeidheid heeft, kan vermoeidheid blijven bestaan omdat deze ook gerelateerd is aan psychologische processen. Het tweede scenario gaat over het meten van vermoeidheid. Als we niet in staat zijn vermoeidheid adequaat te meten, kunnen we interventie-effecten op vermoeidheid ook niet goed evalueren. De problemen rondom het meten van vermoeidheid worden ook in de volgende hoofdstukken besproken. De centrale vraag van hoofdstuk 4 is hoe patienten met RA vermoeidheid ervaren. We hebben diepte-interviews uitgevoerd om de ervaring van vermoeidheid van patienten met verschillende niveaus van vermoeidheid systematisch te beschrijven. Daarbij hebben wij ook ervaringen van vermoeidheid vergeleken tussen groepen van patienten (mannen vs. vrouwen en jongere vs. oudere patienten). Zoals gerapporteerd in voorafgaande studies, werd vermoeidheid ervaren als een multidimensioneel, lastig symptoom met verreikende consequenties. Niettemin liet onze studie ook inter- en intra-individuele verschillen zien: emoties, consequenties en omgang met vermoeidheid varieerden voor leeftijd en geslacht. Sommige van deze verschillen waren gerelateerd aan het aantal dagelijkse rollen van patienten. Vooral jongere vrouwen met meerdere dagelijkse rollen waren kwetsbaar voor de negatieve invloed van vermoeidheid. Veel patienten rapporteerden variaties in ernst, frequentie en duur van vermoeidheid, waarbij sommigen zelfs verschillende vormen van vermoeidheid rapporteerden. Een interessant resultaat was dat patienten ook positieve aspecten van vermoeidheid noemden, bijvoorbeeld bewustere keuzes in het leven maken en leren de (gedwongen) rust te waarderen. Na de betekenis van vermoeidheid te hebben beschreven, wilden wij onderzoeken of er bepaalde groepen van patienten bestaan die vermoeidheid op een vergelijkbare manier ervaren en welke kenmerken deze groepen gemeen hebben. In hoofdstuk 5 wordt beschreven hoe we Q-methodologie gebruikt hebben om patronen in de ervaring van vermoeidheid bij RA te vinden. Deelnemers hebben stellingen over vermoeidheid gesorteerd om aan te geven in hoeverre ze op hen van toepassing waren. Met behulp van personen-factoranalyse op de Q-sorts hebben wij patienten over items verdeeld (in plaats van items over personen zoals in gebruikelijke factoranalyse). Elke factor stond voor een groep van patienten met een vergelijkbaar perspectief op de ervaring van vermoeidheid. Fysieke, psychologische en sociale kenmerken van patienten leken met deze ervaringen samen te hangen. We hebben de groepen benoemd als: “Weinig invloed van vermoeidheid”, “Goede omgang en slechte slaap”, “Zoek naar balans”, en “Veel distress”. Deze analyse gaf inzicht in verschillende perspectieven op de ervaring van vermoeidheid in groepen van patienten en welke kenmerken deze patientengroepen gemeen hebben. De studie liet grote inter-individuele verschillen zien in de ervaring van vermoeidheid bij RA; niet alle patienten hadden last van vermoeidheid, maar voor veel RA-patienten was vermoeidheid een belangrijk en een (nog) niet behandelde klacht. Bovendien
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bleek ziekteactiviteit minder belangrijk in relatie tot vermoeidheid dan dagelijkse rollen en taken, wat de relevantie van sociale aspecten voor de ervaring van vermoeidheid onderstreept. De Q-sort studie leverde ook informatie op over welke dimensies van vermoeidheid belangrijk zijn voor RA-patienten en hoe goed individuele items deze dimensies meten. Hoofdstuk 6, 7 en 8 gaan over onze aansluitende Delphi-studie waarin wij aan experts (patienten, verpleegkundigen/reumaconsulenten en reumatologen) gevraagd hebben om items voor het meten van vermoeidheid op hun geschiktheid te beoordelen. Voor de constructie van een CAT is een gekalibreerde itembank nodig. Om een dergelijk itembank voor het uitgebreid kunnen meten van vermoeidheid bij RA te ontwikkelen, hebben wij een omvangrijke verzameling van potentiele items gemaakt om alle dimensies van de vermoeidheidservaring mee te nemen. Alle vertaalde items van de BRAF-MDQ en alle items van de vragenlijsten met acceptabele validiteit voor RA werden geincludeerd. We hebben ook aanvullende items geconstrueerd vanuit ons interviewmateriaal en op basis van de Q-sort studie en andere vragenlijsten. In hoofdstuk 6 wordt het proces van de selectie van items voor de CAT gedetailleerd beschreven. Voor de inhoudelijke evaluatie van onze verzameling van potentiele vermoeidheidsitems wilden wij zowel het perspectief van patienten als ook het perspectief van professionals meenemen. Daarom hebben wij in een Delphi-procedure aan reumatologen, verpleegkundigen/reumaconsulenten en patienten gevraagd om de geselecteerde items en dimensies op relevantie te beoordelen. Deze experts werden ook uitgenodigd om andere dimensies van vermoeidheid en items te nomineren om mee te nemen in een omvangrijke meting van vermoeidheid. Zij konden ook aangeven dat items andere aspecten van RA weergaven (bijv. items die mogelijk beperkingen of ontstekingen reflecteerden) en daarom niet meegenomen zouden moeten worden. We hebben gebruik gemaakt van een vooraf beschreven beslisregel om items voor de ontwikkeling van de itembank te selecteren. De overige items hebben wij aangepast op basis van de commentaren van de deelnemers en in een tweede ronde ter herbeoordeling aangeboden. De procedure eindigde als alle items geselecteerd of geexcludeerd waren. Redenen voor exclusie waren onduidelijke of te extreme formuleringen of overlap met andere aspecten dan vermoeidheid (bijv. lichamelijke beperkingen). Na twee rondes konden wij 245 items selecteren die verdeeld waren over 12 dimensies. De studie leverde een kwalitatief geevalueerde itempool op met potentiele items voor de ontwikkeling van de itembank. De focus van hoofdstuk 7 ligt op de vraag welke dimensies van vermoeidheid gebruikt zouden moeten worden voor een uitgebreide meting van vermoeidheid bij RA. De experts vonden onze dimensies voor het multidimensioneel meten van vermoeidheid bij RA geschikt. Alle van de 12 voorgestelde dimensies werden door de deelnemers als relevant beoordeeld; ernst, frequentie, duur, verandering in vermoeidheid, ervaren oorzaken van vermoeidheid, energie, slaap/rust, lichaamsgevoel, cognitie/concentratie, omgang, negatieve emoties/stemming en consequenties. Er kwamen geen aanvullende dimensies uit de commentaren van de deelnemers naar voren, wat erop duidt dat ons itempool het fenomeen van vermoeidheid in RA goed afdekt. De resultaten gaven ook inzicht in de inhoudsvaliditeit van items uit frequent gebruikte traditionele vragenlijsten (SF-36 subschaal vitaliteit, FACIT-F, POMS
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subschaal fatigue /inertia, MAF) en de BRAF-MDQ zoals gerapporteerd in hoofdstuk 8. Slechts 40% van de items van traditionele vragenlijsten was duidelijk en adequaat in hun oorspronkelijke vorm. Echter, de meeste van de overige items werden na aanpassing geselecteerd en konden in ons itempool worden opgenomen. Hoofdstuk 9 beschrijft de kalibratie van de voorafgaande geevalueerde, face- en inhoudsvalide itempool voor het meten van vermoeidheid bij RA. We hebben de itemfit met de onderliggende dimensies geevalueerd door middel van item response theorie (IRT) en de dimensionele structuur van de itempool onderzocht met factoranalyse. Het was niet mogelijk dat elke patient alle 245 items van de itempool invulde. Daarom hebben wij een item-afnameschema ontwikkeld om zeven verschillende vragenlijstversies te construeren. Daarbij hebben wij gelet op voldoende overlap tussen de versies voor de analyses. Vervolgens vulden 551 patienten met RA een van deze versies in. Met behulp van IRT hebben wij de data voor elke dimensie van vermoeidheid geanalyseerd. Daarvoor hebben wij gebruik gemaakt van het generalized partial credit model (GPCM). Het bleek dat 49 items onvoldoende itemkarakteristieken hadden (slecht discriminatief vermogen en/of model misfit). Deze items hebben wij voor de verdere analyse van de itempool verwijderd. Exploratieve en confirmatorische factoranalyse van de 196 overige items brachten drie dimensies naar voren: ernst, impact en variabiliteit van vermoeidheid. Deze studie leverde een voorlopig gekalibreerde multidimensionele itembank op en liet zien welke dimensies en items, die naar voren waren gekomen uit voorafgaande studies, belangrijk zijn voor de ontwikkeling van een multidimensionele CAT voor vermoeidheid bij RA. Dit proefschrift verschaft inzichten in de betekenis van vermoeidheid bij RA en levert een voorlopig gekalibreerde, multidimensionele itempool op voor het meten van vermoeidheid bij patienten met RA. Voor zijn ontwikkeling hebben wij verschillende stappen uitgevoerd om ervoor te zorgen dat zowel het perspectief van patienten als de zienswijze van professionals meegenomen werd. In de discussie gaan we in op de spanning die tussen de inclusie van het patientenperspectief en statistische analyses kan optreden. Moderne psychometrische methoden zoals IRT lopen het risico face-validiteit van items te verliezen en items te excluderen terwijl deze nodig zijn voor een adequate weerspiegeling van het te meten construct. Op het eerste gezicht lijkt het eenvoudig het patientenperspectief mee te nemen, maar de statistische benadering daarvan is nogal lastig. In de ontwikkeling van ons itempool hebben wij verschillende logischop-elkaar-volgende stappen ondernomen om het patientenperspectief te includeren. Echter, tussen de verschillende studies was ruimte voor interpretatie door de onderzoekers. De vertaling tussen verschillende methoden is niet altijd gemakkelijk en mogelijkerwijs gaat het patientenperspectief deels verloren als statistische methoden worden toegepast. We bediscussieren ook dat het meten van vermoeidheid bij RA, net als wetenschap zelf, een iteratief proces is. Verdere validatie zal nodig zijn om te kijken of items alle aspecten afdekken die door patienten gerapporteerd zijn. Bovendien zullen nieuwe wetenschappelijke inzichten en maatschappelijke veranderingen eisen dat de validatie van meetinstrumenten voor vermoeidheid regelmatig herhaald wordt om de nodige aanpassingen uit te voeren.
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Daarnaast gaan we in op de beperkingen van het proefschrift. Hoofdstuk 2 geeft een overzicht van variabelen die met vermoeidheid bij RA samenhangen en van potentiele causale relaties. Echter, de meeste van de gereviewde studies waren cross-sectioneel en laten geen directe conclusie over causale relaties toe. De Delphi-studie, zoals beschreven in hoofdstuk 6 t/m 8,was zorgvuldig uitgevoerd en hoewel het een goede methode voor ons doeleinden was, kwamen we een paar knelpunten tegen. De studie kostte veel tijd voor deelnemers en onderzoekers en het bleek dat deelnemers de neiging hadden om sommige items op een normatieve manier te beoordelen. Geexcludeerde items kwamen uit interviewmateriaal en uit bestaande vragenlijsten, maar het grootste aantal items was afkomstig uit het interviewmateriaal. Het is een grote uitdaging om geschikte items vanuit interviewmateriaal te ontwikkelen, omdat er geen richtlijnen voor dit proces bestaan. Een andere beperking van de resultaten die in dit proefschrift gepresenteerd worden, is de relatief kleine steekproef van de kalibratiestudie (hoofdstuk 9). De bevindingen van deze studie moeten als voorlopige resultaten beschouwd worden. In het aansluitende project over de verdere ontwikkeling van de CAT-vermoeidheid zullen we meer data verzamelen en verdere analyses uitvoeren. In de discussie vergelijken wij bovendien de dimensies van ons voorlopige itempool met de dimensies van het andere meetinstrument voor vermoeidheid bij RA dat werd ontwikkeld vanuit het patientenperspectief, de BRAF-MDQ. We gaan daarbij in op doeleinden waarvoor de twee instrumenten het meest geschikt zijn. Afsluitend bediscussieren wij mogelijke richtingen voor toekomstig onderzoek. Het is nog onduidelijk in hoeverre vermoeidheid bij RA overlap vertoont met vermoeidheid bij andere ziektes. Bovendien is dringend meer kennis nodig over oorzaken en consequenties van vermoeidheid bij RA. Pas met meer inzicht in de etiologie van vermoeidheid zal het mogelijk zijn de vraag te beantwoorden of het nodig is een specifiek meetinstrument voor RA te gebruiken. Mogelijk kan de CAT in de toekomst gevalideerd worden voor andere (reumatische) aandoeningen. Verder is het waardevol om de CAT in verschillende landen te valideren. De bevindingen in dit proefschrift hebben meer inzicht gegeven in de betekenis van vermoeidheid voor RA. Het is duidelijk dat veel patienten met RA vermoeidheid als onvoorspelbaar en meer extreem ervaren dan gewone vermoeidheid. Bovendien is bekend dat vermoeidheid een multidimensioneel karakter heeft. Onderzoek heeft ideeen naar voren gebracht over potentiele factoren die met vermoeidheid bij RA geassocieerd zijn. Het is duidelijk geworden op welke oorzakelijke factoren toekomstig onderzoek gericht moet zijn. Verder is het belangrijk dat er onderzoek gedaan wordt naar de manier waarop vermoeidheid behandeld of zelfs voorkomen kan worden. Daarvoor is een goed meetinstrument nodig. De resultaten in dit proefschrift voegen een stap toe aan deze uitdagende taak en bieden een degelijke basis voor de constructie van een CAT voor het meten van vermoeidheid bij RA.
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PubMed publicaties per vakgroep Anesthesiologie 1. Intraoperative High-Dose Dexamethasone for Cardiac Surgery: A Randomized Controlled Trial Dieleman JM, Nierich AP, Rosseel PM, van der Maaten JM, Hofland J, Diephuis JC, Schepp RM, Boer C, Moons KG, van Herwerden LA, Tijssen JG, Numan SC, Kalkman CJ, van Dijk D Context: Prophylactic corticosteroids are often administered during cardiac surgery to attenuate the inflammatory response to cardiopulmonary bypass and surgical trauma; however, evidence that routine corticosteroid use can prevent major adverse events is lacking. Objective: To quantify the effect of intraoperative high-dose dexamethasone on the incidence of major adverse events in patients undergoing cardiac surgery. Design, Setting, And Participants: A multicenter, randomized, double-blind, placebo-controlled trial of 4494 patients aged 18 years or older undergoing cardiac surgery with cardiopulmonary bypass at 8 cardiac surgical centers in the Netherlands enrolled between April 13, 2006, and November 23, 2011. Intervention: Patients were randomly assigned to receive a single intraoperative dose of 1 mg/kg dexamethasone (n = 2239) or placebo (n = 2255). Main Outcome Measures: A composite of death, myocardial infarction, stroke, renal failure, or respiratory failure, within 30 days of randomization. Results: Of the 4494 patients who underwent randomization, 4482 (99.7%) could be evaluated for the primary outcome. A total of 157 patients (7.0%) in the dexamethasone group and 191 patients (8.5%) in the placebo group reached the primary study end point (relative risk, 0.83; 95% CI, 0.67-1.01; absolute risk reduction, -1.5%; 95% CI, -3.0% to 0.1%; P = .07). Dexamethasone was associated with reductions in postoperative infection, duration of postoperative mechanical ventilation, and lengths of intensive care unit and hospital stays. In contrast, dexamethasone was associated with higher postoperative glucose levels. Conclusion: In our trial of adults undergoing cardiac surgery, the use of intraoperative dexamethasone did not reduce the 30-day incidence of major adverse events compared with placebo. Trial Registration clinicaltrials.gov Identifier: NCT00293592 JAMA 2012; 308(17):1761-7 Impact factor: 30.026
Totale impact factor: 30.026 Gemiddelde impact factor: 30.026 Aantal artikelen 1e, 2e of laatste auteur: 0 Totale impact factor: 0 Gemiddelde impact factor: 0
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Cardiologie 1. Scanning electron microscopic assessment of coating irregularities and their precursors in Unexpanded durable polymer-based drug-eluting stents Basalus MW, Tandjung K, van Westen T, Sen H, van der Jagt PK, Grijpma DW, Van Apeldoorn AA, von Birgelen C Objectives: To assess and quantify coating irregularities on unexpanded and expanded durable polymer-based drug-eluting stents (DES) to gain insights into the origin of coating irregularities. Background: Previous scanning electron microscopy (SEM) studies in various expanded DES revealed differences in frequency and size of coating irregularities between DES types and specific distribution patterns, however, the origin of these irregularities is unclear. Methods: We assessed at bench side a total of 1,200 SEM images obtained in 30 DES samples (15 expanded and 15 unexpanded) of Cypher Select Plus, Taxus Liberte, Endeavor, Xience V, and Resolute. Results: For most coating irregularities seen on expanded DES (72%; 23/32), a matching irregularity (n=18/24) and/or its precursor (n=11/24) was observed in unexpanded DES. Unexpanded Cypher Select showed (small) crater lesions and cracks together with precursors of 'peeling'. On unexpanded Taxus Liberte, thinning of polymer, small bare metal areas, wrinkles, and one precursor type were found. Unexpanded Endeavor showed cracks, small bare metal areas, crater lesions, and precursors of the latter. Unexpanded Xience V and Resolute mainly revealed crater lesions and their precursors. On unexpanded versus expanded DES, there was no difference in measured frequency of coating irregularities and precursors (p=ns) with the exception of more bare metal areas on expanded Taxus Liberte (p=0.01). Conclusions: Most coating irregularities, or the potential to develop them, are inherent to the unexpanded DES. Important determinants of the formation of coating irregularities may be the stent geometry and the physical properties of the coating, while stent-balloon interaction plays no major role. Catheter Cardiovasc Interv 2012;79:644-653 Impact factor: 2.290
2. How should I treat a patient with significant angina and a severe left anterior descending artery stenosis beyond the insertion of a left internal mammary artery jump graft (diagonal to LAD)? Cockburn J, Poliacikova P, Hildick-Smith D, Colombo A, Buchanan GL, von Birgelen C EuroIntervention 2012;8:400-407 Impact factor: 3.285
3. Fractional flow reserve measurements to identify justified targets for PCI in patients with stable angina: FAME 2 and beyond
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de Man FH, von Birgelen C Cardiovasc Diagn Ther 2012;2:261-263 Impact factor: 0
4. Usefulness and safety of the GuideLiner catheter to enhance intubation and support of guide catheters: insights from the Twente GuideLiner registry de Man FH, Tandjung K, Hartmann M, van Houwelingen KG, Stoel MG, Louwerenburg HW, Basalus MW, Sen H, Lowik MM, von Birgelen C Aims: Optimal ostial seating and adequate back-up of guide catheters are required for challenging percutaneous coronary interventions (PCI). The GuideLiner (GL) (Vascular Solutions Inc., Minneapolis, MN, USA) is a guide catheter extension system that provides active back-up support by deep coronary intubation. We aimed to assess feasibility and safety of GL-use in routine clinical practice. Methods and results: We prospectively recorded patient and procedural details, technical success, and in-hospital outcome of 65 consecutive patients undergoing "5-in-6" Fr GL-facilitated PCI of 70 target vessels. The GL was mainly used for PCI of complex coronary lesions: 97% (68/70) had American Heart Association/American College of Cardiology (AHA/ACC) lesion types B2/C; 53% (37/70) were distally located; and 23% (17/70) were heavily calcified. Indications were to increase back-up of the guide and facilitate stent delivery (59%; 41/70), achievement of coaxial alignment of the guide catheter (29%; 20/70), and selective contrast injections (13%; 9/70). Device success rate was 93% (65/70). There were no major complications and two minor complications managed without clinical sequelae: one air embolism and one stent dislodgement. Conclusions: GL-use resulted in increased back-up and guide catheter alignment for stent delivery in unfavourable tortuous coronary anatomies and complex, heavily calcified, and often distally located lesions, which otherwise may have been considered unsuitable for PCI. Procedural success rate was high and there were no major complications. EuroIntervention 2012;8:336-344 Impact factor: 3.285
5. Conductor externalization of the Riata internal cardioverter defibrillator lead: tip of the iceberg? Report of three cases and review of literature Dorman HG, van Opstal JM, Stevenhagen J, Scholten MF Aims: Recently, concerns about St Jude's Riata lead family have come to light. We present three cases of patients with Riata internal cardioverter defibrillator (ICD) leads with externalized conductors. Methods and Results: All patients had the same insulation defect, with externalized conductors, but differed in presentation and symptoms. These cases, which form 3 of 179 (1.68%) of our total Riata lead population, presented four or more years after
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implantation. This may be an indication that the problem with the Riata lead may well be greater than reported in the recent St Jude Medical device advisory letter. Conclusion: The management of the Riata lead problem is discussed as, up until now, management of patients with an implanted Riata lead has been based on detecting electric abnormalities on regular ICD interrogation only. Europace 2012;14:1161-1164 Impact factor: 1.980
6. Ventricular remodelling is a prerequisite for the induction of dofetilideinduced torsade de pointes arrhythmias in the anaesthetized, complete atrioventricular-block dog Dunnink A, van Opstal JM, Oosterhoff P, Winckels SK, Beekman JD, van der Nagel R, Verduyn CS, Vos MA Introduction: A number of predisposing factors have been suggested to be contributing to drug-induced torsade de pointes (TdP) arrhythmias: short-long-short (SLS) sequence, bradycardia, timing of drug administration, anaesthesia, ventricular remodelling, and altered ventricular activation due to ventricular ectopic beats (SLS) or idioventricular rhythm (IVR). Chronic atrio-ventricular (AV)-block (CAVB) dogs are susceptible to dofetilide-induced TdP. Methods and results: In 32 anaesthetized animals, the relevance of ventricular remodelling for TdP susceptibility was studied by dofetilide [0.025 mg/kg/5 min intravenously (iv)] during bradycardia in the presence (CAVB, n= 18) or absence [acute atrio-ventricular block (AVB), n = 32] of ventricular remodelling. In subprotocols, the possible pro-arrhythmic effects of timing of dofetilide administration: prior to (n= 11), or after creation of AVB (n= 9) and relevance of SLS pacing (n= 17) was investigated during IVR. Dofetilide was also given after AVB when the activation of the ventricles was normal: pacing (1000 ms) from the high septum (n= 7) or abnormal but fixed from the left ventricular apex (n= 5). Torsade de pointes inducibility was defined as reproducible (>/=3 times) occurrence. In acute AV block (AAVB), dofetilide did not induce TdP spontaneously (0 of 32), whereas TdP was seen in 10 out of 18 serially tested dogs in CAVB (P< 0.001). The other factors: timing of dofetilide (0 of 11 vs. 0 of 9), SLS pacing (0 of 17 vs. 1 of 17), or ventricular activation (0 of 7 vs. 0 of 5) did not increase TdP susceptibility. Beat-to-beat variability of repolarization increased after ventricular remodelling and was highest prior to TdP induction. Conclusion: In AAVB dogs, TdP is not spontaneously seen, whereas it is present in CAVB. This implies that ventricular remodelling is a prerequisite for TdP induction in this model. Europace 2012;14:431-436 Impact factor: 1.980
7. Giant coronary aneurysm in Churg-Strauss syndrome
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Hartmann M, Wajon EM, van Houwelingen GK, Stoel MG, von Birgelen C EuroIntervention 2012;8:760-761 Impact factor: 3.285
8. Net clinical benefit of prehospital glycoprotein IIb/IIIa inhibitors in patients with ST-elevation myocardial infarction and high risk of bleeding: effect of tirofiban in patients at high risk of bleeding using CRUSADE bleeding score. Hermanides RS, Ottervanger JP, Ten Berg JM, Gosselink AT, van Houwelingen G, Dambrink JH, Stella PR, Hamm C, van 't Hof AW Aims: The aim of this subanalysis was to assess the net clinical effect of prehospital administration of tirofiban in ST-elevation myocardial infarction (STEMI) patients with high risk of bleeding. Methods: This is a retrospective subanalysis of the On- TIME 2 trial, a multicenter, controlled randomized trial of the effects of high bolus-dose tirofiban given in the ambulance in STEMI patients. Tirofiban was given on top of aspirin, heparin, and clopidogrel. According to CRUSADE, patients with a moderate to very high baseline risk of bleeding were defined as high risk and patients with a very low or low baseline bleeding risk were defined as low risk. Primary endpoint was net adverse clinical events (NACE) at 30 days (defined as the combined incidence of death, recurrent myocardial infarction, urgent target vessel revascularization, stroke, or non-coronary artery bypass graft [CABG]-related major bleeding). Results: Of 1309 patients, a high bleeding risk was present in 291 patients (22.2%). In these high-risk bleeding patients, tirofiban significantly improved after percutaneous coronary intervention (PCI) ST-segment resolution. Administration of tirofiban in high-risk bleeding patients showed no difference in 30-day major adverse cardiac events (MACE) (9.4% vs 13.0%; P=.330; relative risk [RR], 0.72; 95% confidence interval [CI], 0.37-1.39). However, pretreatment with tirofiban was associated with a nonsignificant increase in non-CABG related bleeding (8.6% vs 3.6%; P=.082; RR, 2.38; 95% CI, 0.90-6.39). The net clinical effect (30-day NACE) of tirofiban in this group was balanced (11.5% vs 15.2%; P=.365; RR, 0.76; 95% CI, 0.41-1.38). Conclusion: Prehospital use of tirofiban in STEMI patients with high risk of bleeding improves post-PCI ST-segment resolution, but increases nonsignificantly the risk of non-CABG related bleeding. The net result is a balanced effect on 30-day NACE. Additional studies should clarify how use of bleeding risk scores should modify medical (antiplatelet) therapy. J Invasive Cardiol 2012;24:84-89. Impact factor: 1.841
9. Risk of bleeding after prehospital administration of high dose tirofiban for ST Elevation Myocardial Infarction Hermanides RS, Ottervanger JP, Dambrink JH, Dill T, van Houwelingen G, Ten Berg JM, Kolkman E, Hamm C, van 't Hof AW
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Background: In most patients with ST-elevation myocardial infarction (STEMI), antiplatelet drugs are already administrated in the ambulance, before hospital admission. We investigated the safety of prehospital initiation of a high dose of the glycoprotein IIb/IIIa inhibitor tirofiban on top of aspirin, clopidogrel and heparin. Methods: It concerns a sub-analysis of the On-TIME 2 trial. 1398 patients were enrolled and 1275 patients (91.2%) had clinical follow up. Non CABG-related bleeding was defined according to the TIMI criteria. Logistic regression was used to determine predictors of 30-day bleeding. The independent association between bleeding and mortality (30-day and 1-year) was evaluated using Cox proportional Hazard models. Results: Bleeding (major or minor) was observed in 47 patients (3.7%), with only 13 patients (1%) with major bleeding. The strongest independent determinants of bleeding were age (OR 1.05, 95% CI 1.01-1.08, p=0.011), Killip class >1 at admission (OR 2.5, 95% CI 1.2-5.3, p=0.020) and intra aortic balloon pump (IABP) use (OR 4.2, 95% CI 1.6-11.1, p=0.003). High dose tirofiban was not an independent predictor of bleeding (OR 1.7, 95% CI 0.9-3.2, p=0.116). Bleeding was associated with an increased risk of 30-day mortality (HR 5.5, 95% CI 1.6-7.8, p<0.001) and one-year mortality (HR 3.2, 95% CI 1.4-7.2, p=0.005). Conclusion: Prehospital use of high dose tirofiban is safe and associated with a low risk of bleeding. Age, Killip class >1, IABP use, but not high dose tirofiban are independent determinants of bleeding in STEMI patients. Bleeding is independently associated with 30-day and 1-year mortality. Int J Cardiol 2012;157:86-90 Impact factor: 7.078
10. The effect of pre-hospital glycoprotein IIb-IIIa inhibitors on angiographic outcome in STEMI patients who are candidates for primary PCI Hermanides RS, van Werkum JW, Ottervanger JP, Breet NJ, Gosselink AT, van Houwelingen KG, Dambrink JH, Hamm C, Ten Berg JM, van 't Hof AW Objectives: Aim of this study was to assess the effect of early initiation of high bolus dose tirofiban on top of dual antiplatelet therapy on angiographic outcome before and after primary percutaneous coronary intervention (PCI) in ST-elevation myocardial infraction patients. BACKGROUND: Glycoprotein IIb/IIIa inhibitors are effective inhibitors of platelet aggregation, and have shown to reduce thrombotic complications in patients undergoing PCI. Methods: This is a pre-specified angiographic analysis of the On-TIME 2 trial (N = 984) and its open label run-in phase (N = 414). All angiographic parameters, including quantitative coronary angiography (QCA) were performed in an independent angiographic core lab. Results: Of the 1,398 patients, 709 patients (50.7%) were randomized to prehospital tirofiban. An open infarct related vessel (TIMI 2 or 3 flow) at initial angiography was more often present in the tirofiban group as compared to the no tirofiban group (58.3% vs. 49.7%, P = 0.002). Tirofiban also reduced initial thrombus burden (P for trend = 0.035) as well as thrombus grade 5 (46.9% vs. 54.3%, P =
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0.016) and showed a trend toward a reduction in large thrombus burden (LTB) (69.4% vs. 74.5%, P = 0.055). After PCI, a trend towards a lower corrected TIMI frame count (cTFC) in the tirofiban group was found. A significant interaction was found with time of initiation of study drug, with highest efficacy of tirofiban when given within 76 min after symptom onset, with a significantly lower cTFC after PCI (21.9 +/- 17.6 vs. 23.9 +/- 18.5, P = 0.008, P for interaction P = 0.006). Conclusion: In patients undergoing primary PCI, pre-hospital administration of tirofiban reduces initial thrombus burden and improves initial patency of the infarct related vessel before PCI. Initiation of tirofiban seems to be most effective when given very early after the onset of symptoms; however, this finding needs confirmation in other studies. Clinical Trial Registration: at http://isrctn.org, number ISRCTN06195297 Catheter Cardiovasc Interv 2012;79:956-964 Impact factor: 2.290
11. Impact of analyzing fewer image frames per segment during offline volumetric radiofrequency-based intravascular ultrasound measurements of target lesions prior to percutaneous coronary interventions Huisman J, Hartmann M, Mintz GS, van Houwelingen GK, Stoel MG, de Man FH, Louwerenburg HW, von Birgelen C In the present study, we evaluated the impact of a 50% reduction in number of image frames (every second frame) on the analysis time and variability of offline volumetric radiofrequency-based intravascular ultrasound (RF-IVUS) measurements in target lesions prior to percutaneous coronary interventions (PCI). Volumetric RFIVUS data of vessel geometry and plaque composition are generally obtained by a semi-automated analysis process that includes time-consuming manual contour editing. A reduction in the number of frames used for volumetric analysis may speed up the analysis, but could increase measurement variability. We repeatedly performed offline volumetric analyses in RF-IVUS image sets of 20 mm-long coronary segments that contained 30 de novo lesions prior to PCI. A 50% reduction in frames decreased the analysis time significantly (from 57.5 +/- 7.3 to 35.7 +/- 3.7 min; P < 0.0001) while geometric and compositional RF-IVUS measurements did not differ significantly from measurements obtained from all frames. The variability between measurements on the reduced number of frames versus all frames was comparable to the intra-observer measurement variability. In target lesions prior to PCI, offline volumetric RF-IVUS analyses can be performed using a reduced number of image frames (every second frame). This reduces the time of analysis without substantially increasing measurement variability. Int J Cardiovasc Imaging 2012;28:479-489 Impact factor: 2.285
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12. Multicenter assessment of the reproducibility of volumetric radiofrequency-based intravascular ultrasound measurements in coronary lesions that were consecutively stented Huisman J, Egede R, Rdzanek A, Bose D, Erbel R, Kochman J, Jensen LO, van der Palen J, Hartmann M, Mintz GS, von Birgelen C To assess in a multicenter design the between-center reproducibility of volumetric virtual histology intravascular ultrasound (VH-IVUS) measurements with a semiautomated, computer-assisted contour detection system in coronary lesions that were consecutively stented. To evaluate the reproducibility of volumetric VH-IVUS measurements, experienced analysts of 4 European IVUS centers performed independent analyses (in total 8,052 cross-sectional analyses) to obtain volumetric data of 40 coronary segments (length 20.0 +/- 0.3 mm) from target lesions prior to percutaneous intervention that were performed in the setting of stable (65%) or unstable angina pectoris (35%). Geometric and compositional VH-IVUS measurements were highly correlated for the different comparisons. Overall intraclass correlation for vessel, lumen, plaque volume and plaque burden was 0.99, 0.92, 0.96, and 0.83, respectively; for fibrous, fibro-lipidic, necrotic core and calcified volumes overall intraclass correlation was 0.96, 0.94, 0.98, and 0.99, respectively. Nevertheless, significant differences for both geometrical and compositional measurements were seen. Of the plaque components, fibrous tissue and necrotic core showed on average the highest measurement reproducibility. A central analysis for VH-IVUS multicenter studies of lesions prior to PCI should be pursued. Moreover, it may be problematical to pool VH-IVUS data of individual trials analyzed by independent centers. Int J Cardiovasc Imaging 2012;28:1867-1878 Impact factor: 2.285
13. Feasibility of TWA testing - reply Kraaier K, Scholten MF Neth Heart J 2012;20:248 Impact factor: 1.438
14. Haemodynamic bradycardia in tachycardiomyopathy Mafirad M, Blaauw Y, van Opstal JM, Crijns HJ Neth Heart J 2012;20:184-185 Impact factor: 1.438
15. Infarct tissue characteristics of patients with versus without early revascularization for acute myocardial infarction: a contrast-enhancement cardiovascular magnetic resonance imaging study
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Olimulder MA, Kraaier K, Galjee MA, Scholten MF, van Es J, Wagenaar LJ, van der Palen J, von Birgelen C Histopathological studies have suggested that early revascularization for acute myocardial infarction (MI) limits the size, transmural extent, and homogeneity of myocardial necrosis. However, the long-term effect of early revascularization on infarct tissue characteristics is largely unknown. Cardiovascular magnetic resonance (CMR) imaging with contrast enhancement (CE) allows non-invasive examination of infarct tissue characteristics and left ventricular (LV) dimensions and function in one examination. A total of 69 patients, referred for cardiac evaluation for various clinical reasons, were examined with CE-CMR >1 month (median 6, range 1-213) postacute MI. We compared patients with (n = 33) versus without (n = 36) successful early revascularization for acute MI. Cine-CMR measurements included the LV enddiastolic and end-systolic volumes (ESV), LV ejection fraction (LVEF, %), and wall motion score index (WMSI). CE images were analyzed for core, peri, and total infarct size (%), and for the number of transmural segments. In our population, patients with successful early revascularization had better LVEFs (46 +/- 16 vs. 34 +/- 14%; P < 0.01), superior WMSIs (0.53, range 0.00-2.29 vs. 1.42, range 0.002.59; P < 0.01), and smaller ESVs (121 +/- 70 vs. 166 +/- 82; P = 0.02). However, there was no difference in core (9 +/- 6 vs. 11 +/- 6%), peri (9 +/- 4 vs. 10 +/- 4%), and total infarct size (18 +/- 9 vs. 21 +/- 9%; P > 0.05 for all comparisons); only transmural extent (P = 0.07) and infarct age (P = 0.06) tended to be larger in patients without early revascularization. CMR wall motion abnormalities are significantly better after revascularization; these differences are particularly marked later after infarction. The difference in scar size is more subtle and does not reach significance in this study. Heart Vessels 2012;27:250-257 Impact factor: 2.047
16. Relationship between infarct tissue characteristics and left ventricular remodeling in patients with versus without early revascularization for acute myocardial infarction as assessed with contrast-enhanced cardiovascular magnetic resonance imaging Olimulder MA, Galjee MA, Wagenaar LJ, van Es J, van der Palen J, von Birgelen C Left ventricular (LV) remodeling following myocardial infarction (MI) is the result of complex interactions between various factors, including presence or absence of early revascularization. The impact of early revascularization on the relationship between infarct tissue characteristics and LV remodeling is incompletely known. Therefore, we investigated in patients with versus without successful early revascularization for acute MI potential relations between infarct tissue characteristics and LV remodeling with contrast-enhanced (CE) cardiovascular magnetic resonance (CMR). Patients with versus without successful early revascularization underwent CE-CMR for tissue characterization and assessment of LV remodeling including end-diastolic and end-systolic volumes, LV ejection fraction, and wall motion score index (WMSI). CE-CMR images were analyzed for infarct
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tissue characteristics including core-, peri- and total-infarct size, transmural extent, and regional scar scores. In early revascularized patients (n = 46), a larger area of infarct tissue correlated significantly with larger LV dimensions and a more reduced LV function (r = 0.39-0.68; all P
17. Continuation of vitamin K antagonists as acceptable anticoagulation regimen in patients undergoing pulmonary vein isolation Oude Velthuis B, Stevenhagen J, van Opstal JM, Scholten MF Background: Recent studies have demonstrated that radiofrequency isolation of the pulmonary veins (PVI) is an effective treatment for symptomatic atrial fibrillation. Based on these positive results, non- pharmacological therapy has been incorporated in the guidelines for drug refractory atrial fibrillation, resulting in an increased popularity. The prevention of thromboembolic complications remains an important issue. Methods: In January 2010, we adopted an anticoagulation strategy based on continuation of vitamin K antagonists (VKAs) and selective use of transoesophageal echocardiogram (TEE). We retrospectively analysed the results of this strategy in all patients referred for PVI treatment. VKAs were started for all patients 2 months prior to treatment. Discontinuation of oral anticoagulation was considered 3 months after treatment based on thromboembolic and bleeding risk profile. Bleeding and thromboembolic complications were registered during outpatient clinic follow-up up until 3 months. Results: We performed 151 PVI procedures from January 2010 to March 2011. All patients were seen 6 weeks after discharge. No transient ischaemic accidents or ischaemic cerebrovascular incidents occurred pre-, peri- or postprocedure. Four (2.7%) procedures were complicated by tamponade requiring pericardiocentesis. Conclusion: Our data support the increasing evidence for continuation of periprocedural administration of VKAs complemented by a selective TEE approach as a safe therapy for thromboembolic complications. Neth Heart J 2012;20:12-15 Impact factor: 1.438
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18. Extensive left ventricular hemangioma Oude Velthuis B, van Es J, van Houwelingen G, Toes GJ, Wagenaar L J Am Coll Cardiol 2012;60:e35 Impact factor: 14.156
19. Comparison of biolimus eluted from an erodible stent coating with bare metal stents in acute ST-elevation myocardial infarction (COMFORTABLE AMI trial): rationale and design Raber L, Kelbaek H, Ostoijc M, Baumbach A, Tuller D, von Birgelen C, Roffi M, Pedrazzini G, Kornowski R, Weber K, Heg D, Matter C, Luscher T, Taniwaki M, Meier B, Juni P, Windecker S Aims: Compared with bare metal stents (BMS), early generation drug-eluting stents (DES) reduce the risk of revascularisation in patients with ST-elevation myocardial infarction (STEMI) at the expense of an increased risk of very late stent thrombosis (ST). Durable polymer coatings for controlled drug release have been identified as a potential trigger for these late adverse events and this has led to the development of newer generation DES with durable and biodegradable polymer surface coatings with improved biocompatibility. In a recent all-comers trial, biolimus-eluting stents with a biodegradable polymer surface coating were found to reduce the risk of very late ST by 80% compared with sirolimus-eluting stents with durable polymer, which also translated into a lower risk of cardiac death and myocardial infarction (MI) beyond one year. Methods and Results: The multicentre COMFORTABLE AMI trial (NCT00962416) randomly assigned 1,161 patients to treatment with biolimus-eluting stents with biodegrable polymer and bare metal stents of otherwise identical design at 11 international sites. The primary endpoint is a composite of cardiac death, targetvessel MI and target lesion revascularisation at one year. Assuming a relative risk reduction of 40% in event rates of the primary endpoint in favour of biolimus-eluting stents with biodegradable polymer, 1,064 patients will provide 80% power to demonstrate superiority. Clinical follow-up will be continued through five years. Conclusions: The COMFORTABLE AMI trial will determine whether biolimuseluting stents with biodegradable polymer are superior to bare metal stents of otherwise identical design. This is the first randomised controlled trial (RCT) investigating DES with a biodegradable polymer surface coating for drug release in the treatment of patients with STEMI. EuroIntervention 2012;7:1435-1443 Impact factor: 3.285
20. Effect of biolimus-eluting stents with biodegradable polymer vs bare-metal stents on cardiovascular events among patients with acute myocardial infarction: the COMFORTABLE AMI randomized trial Raber L, Kelbaek H, Ostoijc M, Baumbach A, Heg D, Tuller D, von Birgelen C, Roffi M, Moschovitis A, Khattab AA, Wenaweser P, Bonvini R, Pedrazzini G, Kornowski
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R, Weber K, Trelle S, Luscher TF, Taniwaki M, Matter CM, Meier B, Juni P, Windecker S Context: The efficacy and safety of drug-eluting stents compared with bare-metal stents remains controversial in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). Objective: To compare stents eluting biolimus from a biodegradable polymer with bare-metal stents in primary PCI. Design, setting and patients: A prospective, randomized, single-blinded, controlled trial of 1161 patients presenting with STEMI at 11 sites in Europe and Israel between September 19, 2009, and January 25, 2011. Clinical follow-up was performed at 1 and 12 months. Intervention: Patients were randomized 1:1 to receive the biolimus-eluting stent (n = 575) or the bare-metal stent (n = 582). Main outcome measures: Primary end point was the rate of major adverse cardiac events, a composite of cardiac death, target vessel-related reinfarction, and ischemia-driven target-lesion revascularization at 1 year. Results: Major adverse cardiac events at 1 year occurred in 24 patients (4.3%) receiving biolimus-eluting stents with biodegradable polymer and 49 patients (8.7%) receiving bare-metal stents (hazard ratio [HR], 0.49; 95% CI, 0.30-0.80; P = .004). The difference was driven by a lower risk of target vessel-related reinfarction (3 [0.5%] vs 15 [2.7%]; HR, 0.20; 95% CI, 0.06-0.69; P = .01) and ischemia-driven target-lesion revascularization (9 [1.6%] vs 32 [5.7%]; HR, 0.28; 95% CI, 0.13-0.59; P < .001) in patients receiving biolimus-eluting stents compared with those receiving bare-metal stents. Rates of cardiac death were not significantly different (16 [2.9%] vs 20 [3.5%], P = .53). Definite stent thrombosis occurred in 5 patients (0.9%) treated with biolimus-eluting stents and 12 patients (2.1%; HR, 0.42; 95% CI, 0.151.19; P = .10) treated with bare-metal stents. Conclusion: Compared with a bare-metal stent, the use of biolimus-eluting stents with a biodegradable polymer resulted in a lower rate of the composite of major adverse cardiac events at 1 year among patients with STEMI undergoing primary PCI. Trial Registration: clinicaltrials.gov Identifier: NCT00962416 JAMA 2012;308:777-787. Impact factor: 30.026
21. Comparison of eligible non-enrolled patients and the randomised TWENTE trial population treated with Resolute and Xience V drug-eluting stents Sen H, Tandjung K, Basalus MW, Lowik MM, van Houwelingen GK, Stoel MG, Louwerenburg HW, de Man FH, Linssen GC, Nijhuis R, Nienhuis MB, Verhorst PM, van der Palen J, von Birgelen C Aims: The TWENTE trial recently enrolled more than 80% of all eligible patients, who were randomised to zotarolimus-eluting Resolute or everolimus-eluting Xience V stents. In the present study, we investigated whether eligible, non-enrolled
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patients differed from the randomised TWENTE trial population in baseline characteristics and one-year outcome. Methods and results: Characteristics of 1,709 eligible patients were analysed. Independent external adjudication of clinical events was likewise performed for nonenrolled (n=318) and randomised patients (n=1,391). Non-enrolled and randomised patients did not differ in gender distribution, diabetes mellitus, and clinical presentation, but differed significantly in age and cardiovascular history. Nevertheless, clinical outcome after one year did not differ in the primary composite endpoint target-vessel failure (TVF; 9.8% vs. 8.1%; p=0.34), and its components cardiac death (1.6% vs. 1.2%; p=0.61), target vessel-related myocardial infarction (4.7% vs. 4.6%; p=0.92), and target-vessel revascularisation (3.8% vs. 3.0%; p=0.48). Previous bypass surgery predicted TVF in non-enrolled patients (p=0.001); removal of these patients resulted in identical TVF rates for non-enrolled and randomised patients (7.3% vs. 7.3%; p=0.99). Conclusions: Despite some differences in baseline characteristics, non-enrolled and randomised patients did not differ in one-year outcome, which was favourable for both populations and may be related to the drug-eluting stents used. EuroIntervention 2012;8:664-671 Impact factor: 3.285
22. Obstructive intramyocardial haematoma after percutaneous coronary intervention Slootweg AP, Louwerenburg JW, Mecozzi G, Wagenaar LJ, Verhorst PM Neth Heart J 2012;20:376-378. Impact factor: 1.438
23. Comparison of Frequency of Periprocedural Myocardial Infarction in Patients With and Without Diabetes Mellitus to Those With Previously Unknown but Elevated Glycated Hemoglobin Levels (from the TWENTE Trial) Tandjung K, van Houwelingen KG, Jansen H, Basalus MW, Sen H, Lowik MM, Stoel MG, Louwerenburg JH, de Man FH, Linssen GC, Nijhuis R, Nienhuis MB, van der Palen J, Stolk RP, von Birgelen C In patients without a history of diabetes mellitus, increased levels of glycated hemoglobin (HbA1c) are associated with higher cardiovascular risk. The relation between undetected diabetes and clinical outcome after percutaneous coronary intervention is unknown. To investigate whether these patients may have an increased risk of periprocedural myocardial infarction (PMI), the most frequent adverse event after percutaneous coronary intervention, we assessed patients of the TWENTE trial (a randomized, controlled, second-generation drug-eluting stent trial) in whom HbA1c data were available. Patients were classified as known diabetics or patients without a history of diabetes who were subdivided into undetected diabetics (HbA1c >/=6.5%) and nondiabetics (HbA1c <6.5%). Systematic measurement of cardiac biomarkers and electrocardiographic assessment were performed. One-year
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clinical outcome was also compared. Of 626 patients, 44 (7%) were undetected diabetics, 181 (29%) were known diabetics, and 401 (64%) were nondiabetics. In undetected diabetics the PMI rate was higher than in nondiabetics (13.6% vs 6.1%, p = 0.01) and known diabetics (13.6% vs 3.7%, p = 0.11). Multivariate analysis adjusting for covariates confirmed a significantly higher PMI risk in undetected diabetics compared to nondiabetics (odds ratio 6.13, 95% confidence interval 2.07 to 18.13, p = 0.001) and known diabetics (odds ratio 3.73, 95% confidence interval 1.17 to 11.89, p = 0.03). After 1 year, target vessel MI rate was significantly higher in undetected diabetics (p = 0.02) than in nondiabetics, which was related mainly to differences in PMI. Target vessel failure was numerically larger in unknown diabetics than in nondiabetics, but this difference did not reach statistical significance (13.6% vs 8.0%, p = 0.25). In conclusion, undetected diabetics were shown to have an increased risk of PMI. Am J Cardiol 2012;110:1561-1567 Impact factor: 3.368
24. DUrable polymer-based sTent CHallenge of Promus ElemEnt versus ReSolute integrity (DUTCH PEERS): rationale and study design of a randomized multicenter trial in a Dutch all-comers population Tandjung K, Basalus MW, Sen H, Jessurun GA, Danse PW, Stoel M, Linssen GC, Derks A, van Loenhout TT, Nienhuis MB, Hautvast RW, von Birgelen C Background: Drug-eluting stents (DES) are increasingly used for the treatment of coronary artery disease. An optimized DES performance is desirable to successfully treat various challenging coronary lesions in a broad population of patients. In response to this demand, third-generation DES with an improved deliverability were developed. Promus Element (Boston Scientific, Natick, MA) and Resolute Integrity (Medtronic Vascular, Santa Rosa, CA) are 2 novel third-generation DES for which limited clinical data are available. Accordingly, we designed the current multicenter study to investigate in an all-comers population whether the clinical outcome is similar after stenting with Promus Element versus Resolute Integrity. Methods: DUTCH PEERS is a multicenter, prospective, single-blinded, randomized trial in a Dutch all-comers population. Patients with all clinical syndromes who require percutaneous coronary interventions with DES implantation are eligible. In these patients, the type of DES implanted will be randomized in a 1:1 ratio between Resolute Integrity versus Promus Element. The trial is powered based on a noninferiority hypothesis. For each stent arm, 894 patients will be enrolled, resulting in a total study population of 1,788 patients. The primary end point is the incidence of target vessel failure at 1-year follow-up. Summary: DUTCH PEERS is the first randomized multicenter trial with a head-tohead comparison of Promus Element and Resolute Integrity to investigate the safety and efficacy of these third-generation DES. Am Heart J 2012;163:557-562 Impact factor: 4.651
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25. Incidence of periprocedural myocardial infarction following stent implantation: Comparison between first and second generation drug-eluting stents Tandjung K, Basalus MW, Muurman E, Louwerenburg HW, van Houwelingen KG, Stoel MG, de Man FH, Jansen H, Huisman J, Linssen GC, Droste HT, Nienhuis MB, von Birgelen C Background: First and second generation drug-eluting stents (DES) differ in coating materials, which may influence the incidence of periprocedural myocardial infarction (PMI). Objective: To compare the incidence of PMI between first and second generation DES, using the current Academic Research Consortium (ARC) definition of PMI. Methods: We assessed 800 patients treated with first (Taxus Liberte or Endeavor) or second generation DES (Xience V or Resolute). Each DES group consisted of 200 consecutive patients, who were treated during the transition from first to second generation DES. Routine peri-interventional assessment of cardiac biomarkers was performed to compare the incidence of PMI between DES groups according to the updated definition by the ARC: 2x upper reference limit of creatine kinase (CK), confirmed by CK-MB elevation. Results: In 800 patients, a total of 1522 DES (363 Taxus; 385 Endeavor; 382 Xience V; 392 Resolute) were implanted to treat 1232 lesions. Patient characteristics did not differ between groups. In patients receiving second generation DES, more multivessel PCI were performed (p=0.01). The overall incidence of PMI was 4.75%. Between first and second generation DES, there was no significant difference in PMI (5.5% vs.4.0%; p=0.29). In a multivariate analysis, only the total number of stents implanted (p<0.001) and presentation with acute coronary syndrome (p=0.02) were independent predictors of PMI. Conclusion: Using the revised ARC definition, we found no significant difference in PMI between first and second generation DES. Overall, PMI occurred in 4.75%, which is 58% lower than with use of the historical PMI definition. Catheter Cardiovasc Interv 2012;80:524-530 Impact factor: 2.290
26. Automated TIMI frame counting using 3-d modeling Ten Brinke GA, Slump CH, Stoel MG Three dimensional coronary modeling and reconstruction can assist in the quantitative analysis of coronary flow velocity from 2-d coronary images. In this paper a novel method to assess coronary flow velocity is proposed. First, 3-d models of the coronary arteries are estimated from bi-plane X-ray images using epipolar constraint energy minimization for the selected fiducial points like bifurcations, and subsequently 3-d B-spline energy minimization for the arterial segments. A 4-d model is assembled from a set of 3-d models representing different phases of the cardiac cycle. The 4-d model is fitted to the 2-d image sequences containing basal or hyperemic blood flow information. Then, by counting the frames
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in analogy with TIMI frame counting, an index of the mean coronary flow velocity can be estimated. Our experimental results show that the algorithm correlates with r=0.98 (P<0.0001, 95% CI 0.92-0.99) to the clinical measurements of the TFC. Comput Med Imaging Graph 2012;36:580-588 Impact factor: 1.563
27. Early Bayesian modeling of a potassium lab-on-a-chip for monitoring of heart failure patients at increased risk of hyperkalaemia van de Wetering G, Steuten LMG, von Birgelen C, Adang EM Technological forecasting and social change 79[7], 1268-1279. 2012 Impact factor: 2.214
28. Effect of outpatient exercise training programmes in patients with chronic heart failure: a systematic review van der Meer S, Zwerink M, van Brussel M, van der valk PD, Wajon E, van der Palen J Background: Advantages of outpatient exercise training are reduced waiting lists, better compliance, reduced time investment by the patient with reduced travel expenses, and less dependence on other people to participate. Therefore, this systematic review studies the effects of outpatient exercise training programmes compared with usual care on exercise capacity, exercise performance, quality of life, and safety in patients with chronic heart failure. Design: Systematic review with meta-analysis. Methods: Randomized controlled trials concerning patients with chronic heart failure, with a left ventricular ejection fraction
29. A Completely Subcutaneous Implantable Cardioverter Defibrillator in a Patient With Situs Inversus Totalis van Opstal JM, Blaauw Y, Pison LP J Cardiovasc Electrophysiol 2012;23:333 Impact factor: 3.064 84
30. A Randomized Controlled Trial in Second-Generation Zotarolimus-Eluting Resolute Stents Versus Everolimus-Eluting Xience V Stents in Real-World Patients: The TWENTE Trial von Birgelen C, Basalus MW, Tandjung K, van Houwelingen KG, Stoel MG, Louwerenburg JH, Linssen GC, Said SA, Kleijne MA, Sen H, Lowik MM, van der Palen J, Verhorst PM, de Man FH Objectives: The aim of this study was to compare the safety and efficacy of Resolute zotarolimus-eluting stents (ZES) (Medtronic Cardiovascular, Santa Rosa, California) with Xience V everolimus-eluting stents (EES) (Abbott Vascular Devices, Santa Clara, California) at 1-year follow-up. BACKGROUND: Only 1 randomized trial previously compared these stents. Methods: This investigator-initiated, patient-blinded, randomized noninferiority study had limited exclusion criteria (acute ST-segment elevation myocardial infarctions not eligible). Patients (n = 1,391; 81.4% of eligible population) were randomly assigned to ZES (n = 697) or EES (n = 694). Liberal use of stent post-dilation was encouraged. Cardiac biomarkers were systematically assessed. The primary endpoint was target vessel failure (TVF), a composite of cardiac death, myocardial infarction not clearly attributable to non-target vessels, and clinically indicated targetvessel revascularization. An external independent research organization performed clinical event adjudication (100% follow-up data available). Analysis was by intention-to-treat. Results: Acute coronary syndromes were present in 52% and "off-label" feature in 77% of patients. Of the lesions, 70% were type B2/C; the post-dilation rate was very high (82%). In ZES and EES, TVF occurred in 8.2% and 8.1%, respectively (absolute risk-difference 0.1%; 95% confidence interval: -2.8% to 3.0%, p(noninferiority) = 0.001). There was no significant between-group difference in TVF components. The definite-or-probable stent thrombosis rates were relatively low and similar for ZES and EES (0.9% and 1.2%, respectively, p = 0.59). Definite stent thrombosis rates were also low (0.58% and 0%, respectively, p = 0.12). In EES, probable stent thrombosis beyond day 8 was observed only in patients not adhering to dual antiplatelet therapy. Conclusions: Resolute ZES were noninferior to Xience V EES in treating "realworld" patients with a vast majority of complex lesions and "off-label" indications for drug-eluting stents, which were implanted with liberal use of post-dilation. J Am Coll Cardiol 2012;59:1350-1361 Impact factor: 14.156
31. Social burden and lifestyle in adults with congenital heart disease Zomer AC, Vaartjes I, Uiterwaal CS, van der Velde ET, Sieswerda GJ, Wajon EM, Plomp K, van Bergen PF, Verheugt CL, Krivka E, de Vries CJ, Lok DJ, Grobbee DE, Mulder BJ
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We aimed to evaluate how the presence and severity of congenital heart disease (CHD) influence social life and lifestyle in adult patients. A random sample (n = 1,496) from the CONgenital CORvitia (n = 11,047), the Dutch national registry of adult patients with CHD, completed a questionnaire on educational attainment, employment and marital statuses, and lifestyle (response 76%). The Utrecht Health Project provided a large reference group (n = 6,810) of unaffected subjects. Logistic regression models were used for subgroup analyses and to adjust for age, gender, and socioeconomic status where appropriate. Of all patients 51.5% were men (median age 39 years, interquartile range 29 to 51) with mild (46%), moderate (44%), and severe (10%) CHD. Young (<40-year-old) patients with CHD were more likely to have achieved a lower education (adjusted odds ratios [ORs] 1.6 for men and 1.9 for women, p <0.05 for the 2 comparisons), significantly more often unemployed (adjusted ORs 5.9 and 2.0 for men and women, respectively), and less likely to be in a relationship compared to the reference group (adjusted ORs 8.5 for men and 4.5 for women). These poorer outcomes were seen in all severity groups. Overall, the CHD population smoked less (adjusted OR 0.5, p <0.05), had more sports participation (adjusted OR 1.2, p <0.05), and had less obesity (adjusted OR 0.7, p <0.05) than the reference group. In conclusion, there was a substantial social disadvantage in adult patients with CHD, which was seen in all severity groups and primarily in young men. In contrast, adults with CHD had healthier lifestyles compared to the reference group. Am J Cardiol 2012;109:1657-1663 Impact factor: 3.368
32. Rationale and design of the PRAETORIAN trial: a Prospective, RAndomizEd comparison of subcuTaneOus and tRansvenous ImplANtable cardioverter-defibrillator therapy Olde Nordkamp LR, Knops RE, Bardy GH, Blaauw Y, Boersma LV, Bos JS, Delnoy PP, van Dessel PF, Driessen AH, de Groot JR, Herrman JP, Jordaens LJ, Kooiman KM, Maass AH, Meine M, Mizusawa Y, Molhoek SG, van Opstal J, Tijssen JG, Wilde AA. Background: Implantable cardioverter-defibrillators (ICDs) are widely used to prevent fatal outcomes associated with life-threatening arrhythmic episodes in a variety of cardiac diseases. These ICDs rely on transvenous leads for cardiac sensing and defibrillation. A new entirely subcutaneous ICD overcomes problems associated with transvenous leads. However, the role of the subcutaneous ICD as an adjunctive or primary therapy in patients at risk for sudden cardiac death is unclear. Study design: The PRAETORIAN trial is an investigator-initiated, randomized, controlled, multicenter, prospective 2-arm trial that outlines the advantages and disadvantages of the subcutaneous ICD. Patients with a class I or IIa indication for ICD therapy without an indication for bradypacing or tachypacing are included. A total of 700 patients are randomized to either the subcutaneous or transvenous ICD (1:1). The study is powered to claim noninferiority of the subcutaneous ICD with respect to the composite primary endpoint of inappropriate shocks and ICD-related
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complications. After noninferiority is established, statistical analysis is done for potential superiority. Secondary endpoint comparisons of shock efficacy and patient mortality are also made. Conclusion: The PRAETORIAN trial is a randomized trial that aims to gain scientific evidence for the use of the subcutaneous ICD compared with the transvenous ICD in a population of patients with conventional ICD with respect to major ICD-related adverse events. This trial is registered at ClinicalTrials.gov with trial ID NCT01296022 Am Heart J 2012;163:753-760. Impact factor: 4.651
33. Hybrid thoracoscopic surgical and transvenous catheter ablation of atrial fibrillation. Pison L, La Meir M, van Opstal J, Blaauw Y, Maessen J, Crijns HJ.
Objectives: The purpose of this study was to evaluate the feasibility, safety, and clinical outcomes up to 1 year in patients undergoing combined simultaneous thoracoscopic surgical and transvenous catheter atrial fibrillation (AF) ablation. Background: The combination of the transvenous endocardial approach with the thoracoscopic epicardial approach in a single AF ablation procedure overcomes the limitations of both techniques and should result in better outcomes. Methods: A cohort of 26 consecutive patients with AF who underwent hybrid thoracoscopic surgical and transvenous catheter ablation were followed, with follow-up of up to 1 year. Results: Twenty-six patients (42% with persistent AF) underwent successful hybrid procedures. There were no complications. The mean follow-up period was 470 +/- 154 days. In 23% of the patients, the epicardial lesions were not transmural, and endocardial touch-up was necessary. One-year success, defined according to the Heart Rhythm Society, European Heart Rhythm Association, and European Cardiac Arrhythmia Society consensus statement for the catheter and surgical ablation of AF, was 93% for patients with paroxysmal AF and 90% for patients with persistent AF. Two patients underwent catheter ablation for recurrent AF or left atrial flutter after the hybrid procedure. Conclusions: A combined transvenous endocardial and thoracoscopic epicardial ablation procedure for AF is feasible and safe, with a singleprocedure success rate of 83% at 1 year J Am Coll Cardiol 2012;60:54-61.
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Impact factor: 14.156
Totale impact factor: 147.714 Gemiddelde impact factor: 4.476 Aantal artikelen 1e, 2e of laatste auteur: 21 Totale impact factor: 125.539 Gemiddelde impact factor: 5.978
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Gynaecologie 1. Why do parents prefer to know the fetal sex as part of invasive prenatal testing? Kooper AJ, Pieters JJ, Eggink AJ, Feuth TB, Feenstra I, Wijnberger LD, Rijnders RJ, Quartero RW, Boekkooi PF, van Vugt JM, Smits AP. Objectives: The aim of this study was to determine whether prospective parents, primarily referred for prenatal diagnosis to exclude Down syndrome, prefer to know the fetal sex as part of invasive testing. Methods: In this prospective study 400 pregnant women undergoing amniocentesis were invited to answer a questionnaire, including information about demographic factors, current pregnancy, and previous children. In two open-ended questions they were asked why they wanted to know the fetal sex after amniocentesis or ultrasound investigation. Scores were given for reasons that could have played a role in the wish whether or not to know the sex of their unborn child. Results: A total of 210 (52.5%) questionnaires were completed. Overall, 69.0% wasinterested to know the fetal sex as part of the diagnostic test result. The most important reasons were curiosity (77.8%), "just want to know" (68.0%), and "because it is possible" (66.8%). The overall knowledge of sex chromosomal disorders appeared low and did not seem to affect the parent's wish to know the fetal sex. Almost all women (96.6%) planned to have a 20-week ultrasound scan and 96.2% thought the scan to be reliable in detecting the fetal sex. A minority (28%) was willing to learn the fetal sex by ultrasound examination, whereas 65% preferred to learn the fetal sex only after the amniocentesis. Conclusion: Personal values affect the parental desire to know or not to know the fetal sex. This does not appear to be affected by invasive prenatal testing and/or genetic knowledge of sex chromosomal disorders ISRN Obstet Gynecol 2012;2012:524537 Impact factor: 4.798
2. Long-term follow-up of laparoscopic electrocautery of the ovaries versus ovulation induction with recombinant FSH in clomiphene citrate-resistant women with polycystic ovary syndrome: an economic evaluation. Nahuis MJ, Oude Lohuis E, Kose N, Bayram N, Hompes P, Oosterhuis GJ, Kaaijk EM, Cohlen BJ, Bossuyt PP, van der Veen F, Mol BW, van Wely M. Background: Laparoscopic electrocautery of the ovaries and ovulation induction with gonadotrophins are both second line treatments for women with clomiphene citrate-resistant polycystic ovary syndrome (PCOS). Long-term follow-up after electrocautery versus ovulation induction with gonadotrophins has demonstrated at least comparable chances for a first live born child with a reduced need for ovulation induction or assisted reproduction treatment and increased chances for a second live born child. In this study, we report on the long-term economic consequences of both treatment modalities.
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Methods: Between February 1998 and October 2001, we performed a multi-centre randomized controlled trial (RCT) comparing a strategy of laparoscopic electrocautery of the ovaries, followed by clomiphene citrate and gonadotrophins when anovulation persisted, and a strategy of ovulation induction with gonadotrophins in women with clomiphene citrate-resistant PCOS. Eight to twelve years after randomization we performed a follow-up study on reproductive outcome in these women and the fertility treatments they had needed including data on direct medical costs of pregnancy and delivery. Clinical data included number of treatment cycles, live births, miscarriages, ectopic pregnancies and multiple pregnancies. We calculated mean costs per woman after randomization until the first live birth. Confidence intervals (CIs) were estimated by bootstrapping. Results: We obtained data for an economic analysis on 159 of the 168 randomized women (95%). In total, 71 of 83 women (86%) allocated to the electrocautery strategy and 69 of 85 women (81%) allocated to the gonadotrophin strategy had at least one live birth. Given the equivalence between the two treatment strategies in terms of a first live birth-the primary outcome measure-our analysis focused on the cost difference between the two strategies within a mean follow-up time of 8-12 years. The mean costs per first live birth after randomization were euro11 176 (95% CI: euro9689-euro12 549) for the electrocautery group and euro14 423 (95% CI: euro12 239-euro16 606) for the recombinant FSH group, resulting in significantly lower costs (P < 0.05) per first live birth for women allocated to the electrocautery group (mean difference euro3247; 95% CI: euro650-euro5814). Conclusion: In women with clomiphene-resistant PCOS, laparoscopic electrocautery of the ovaries results in significantly lower costs per live birth than ovulation induction with gonadotrophins for an at least equal effectiveness. Hum Reprod 2012;27:3577-3582. Impact factor: 4.670
3. No effect of the FitFor2 exercise programme on blood glucose, insulin sensitivity, and birthweight in pregnant women who were overweight and at risk for gestational diabetes: results of a randomised controlled trial. Oostdam N, van Poppel MN, Wouters M, Eekhoff E, Bekedam D, Kuchenbecker W, Quartero H, Heres M, van Mechelen W. Objective: To evaluate the effectiveness of an exercise programme for pregnant women who were overweight or obese and at risk for gestational diabetes mellitus (GDM). Design: Randomised controlled trial. Setting Hospitals and midwifery practices in the Netherlands. Population Pregnant women who were overweight or obese and at risk for GDM between 2007 and 2011. Methods: Normal care was compared with an exercise training programme during pregnancy. The training consisted of aerobic and strength exercises, and was aimed at improving maternal fasting blood glucose, insulin sensitivity, and birthweight. Linear regression analyses were performed to determine the effects. Main outcome measures Maternal outcome measures were fasting blood glucose (mmol/l), fasting insulin (pmol/l) and HbA1c (%), body weight (kg), body mass index (kg/m(2) ), and
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daily physical activity (minute/week). Offspring outcome measures were birthweight and fetal growth. Results: A total of 121 women were randomly allocated to either a control (n = 59) or an intervention (n = 62) group. Intention-to-treat analysis showed that the exercise programme did not reduce maternal fasting blood glucose levels nor insulin sensitivity. Also, no effect was found on birthweight. Conclusion: The exercise intervention performed over the second and third trimester of pregnancy had no effects on fasting blood glucose, insulin sensitivity, and birthweight, most probably because of low compliance. The high prevalence of women at risk for GDM calls for further research on possible interventions that can prevent GDM, and other types of interventions to engage this target group in physical activity and exercise. BJOG 2012;119:1098-1107 Impact factor: 3.760
4. Laparoscopy to predict the result of primary cytoreductive surgery in advanced ovarian cancer patients (LapOvCa-trial): a multicentre randomized controlled study. Rutten MJ, Gaarenstroom KN, Van GT, van Meurs HS, Arts HJ, Bossuyt PM, Ter Brugge HG, Hermans RH, Opmeer BC, Pijnenborg JM, Schreuder HW, Schutter EM, Spijkerboer AM, Wensveen CW, Zusterzeel P, Mol BW, Kenter GG, Buist MR. Background: Standard treatment of advanced ovarian cancer is surgery and chemotherapy. The goal of surgery is to remove all macroscopic tumour, as the amount of residual tumour is the most important prognostic factor for survival. When removal off all tumour is considered not feasible, neoadjuvant chemotherapy (NACT) in combination with interval debulking surgery (IDS) is performed. Current methods of staging are not always accurate in predicting surgical outcome, since approximately 40% of patients will have more than 1 cm residual tumour after primary debulking surgery (PDS). In this study we aim to assess whether adding laparoscopy to the diagnostic work-up of patients suspected of advanced ovarian carcinoma may prevent unsuccessful primary debulking surgery for ovarian cancer. Methods: Multicentre randomized controlled trial, including all gynaecologic oncologic centres in the Netherlands and their affiliated hospitals. Patients are eligible when they are planned for PDS after conventional staging. Participants are randomized between direct PDS or additional diagnostic laparoscopy. Depending on the result of laparoscopy patients are treated by PDS within three weeks, followed by six courses of platinum based chemotherapy or with NACT and IDS 3-4 weeks after three courses of chemotherapy, followed by another three courses of chemotherapy. Primary outcome measure is the proportion of PDS's leaving more than one centimetre tumour residual in each arm. In total 200 patients will be randomized. Data will be analysed according to intention to treat. Discussion: Patients who have disease considered to be resectable to less than one centimetre should undergo PDS to improve prognosis. However, there is a need for better diagnostic procedures because the current number of debulking surgeries leaving more than one centimetre residual tumour is still high. Laparoscopy before
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starting treatment for ovarian cancer can be an additional diagnostic tool to predict the outcome of PDS. Despite the absence of strong evidence and despite the possible complications, laparoscopy is already implemented in many countries. We propose a randomized multicentre trial to provide evidence on the effectiveness of laparoscopy before primary surgery for advanced stage ovarian cancer patients. Trial Registration: Netherlands Trial Register number NTR2644 BMC Cancer 2012;12:31. Impact factor:3.333
5. Sentinel node procedure in vulvar carcinoma during pregnancy: A case report Nijman TAJ, Schutter EMJ, Amant F Gynecologic Oncology Reports 2 (2012) 63–64 Impact factor:0
Totale impact factor: 16.561 Gemiddelde impact factor: 3.312 Aantal artikelen 1e, 2e of laatste auteur: 2 Totale impact factor: 4.670 Gemiddelde impact factor: 2.335
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Heelkunde 1. Pancreatitis of biliary origin, optimal timing of cholecystectomy (PONCHO trial): study protocol for a randomized controlled trial. Bouwense SA, Besselink MG, Brunschot S, Bakker OJ, Santvoort HC, Schepers NJ, Boermeester MA, Bollen TL, Bosscha K, Brink MA, Bruno MJ, Consten EC, De Jong CH, Duijvendijk P, Eijck CH, Gerritsen JJ, Goor H, Heisterkamp J, Hingh IH, Kruyt PM, Molenaar IQ, Nieuwenhuijs VB, Rosman C, Schaapherder AF, Scheepers JJ, Spanier MB, Timmer R, Weusten BL, Witteman BJ, Ramshorst B, Gooszen HG, Boerma D. Background: After an initial attack of biliary pancreatitis, cholecystectomy minimizes the risk of recurrent biliary pancreatitis and other gallstone-related complications. Guidelines advocate performing cholecystectomy within 2 to 4 weeks after discharge for mild biliary pancreatitis. During this waiting period, the patient is at risk of recurrent biliary events. In current clinical practice, surgeons usually postpone cholecystectomy for 6 weeks due to a perceived risk of a more difficult dissection in the early days following pancreatitis and for logistical reasons. We hypothesize that early laparoscopic cholecystectomy minimizes the risk of recurrent biliary pancreatitis or other complications of gallstone disease in patients with mild biliary pancreatitis without increasing the difficulty of dissection and the surgical complication rate compared with interval laparoscopic cholecystectomy. Methods: PONCHO is a randomized controlled, parallel-group, assessor-blinded, superiority multicenter trial. Patients are randomly allocated to undergo early laparoscopic cholecystectomy, within 72 hours after randomization, or interval laparoscopic cholecystectomy, 25 to 30 days after randomization. During a 30month period, 266 patients will be enrolled from 18 hospitals of the Dutch Pancreatitis Study Group. The primary endpoint is a composite endpoint of mortality and acute re-admissions for biliary events (that is, recurrent biliary pancreatitis, acute cholecystitis, symptomatic/obstructive choledocholithiasis requiring endoscopic retrograde cholangiopancreaticography including cholangitis (with/without endoscopic sphincterotomy), and uncomplicated biliary colics) occurring within 6 months following randomization. Secondary endpoints include the individual endpoints of the composite endpoint, surgical and other complications, technical difficulty of cholecystectomy and costs. Discussion: The PONCHO trial is designed to show that early laparoscopic cholecystectomy (within 72 hours) reduces the combined endpoint of mortality and re-admissions for biliary events as compared with interval laparoscopic cholecystectomy (between 25 and 30 days) after recovery of a first episode of mild biliary pancreatitis.Trial registration: Current Controlled Trials: ISRCTN72764151 Trials 2012;13:225. Impact factor: 2.206
2. A man with a painful, swollen neck and fever. Busscher MG, Kruijff S
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Lemierre's syndrome is a rare condition mostly secondary caused by an oropharyngeal infection with Fusobacterium necrophorum. We report a 62-year-old man with a classic case of Lemierre's syndrome, most likely caused by a diminished immunity as a result of an underlying chronic lymphatic leukemia Ned Tijdschr Geneeskd 2012;156:A3239. Impact factor: 0
3. Fibrin Sealant for Prevention of Resection Surface-Related Complications After Liver Resection: A Randomized Controlled Trial. de Boer MT, Klaase JM, Verhoef C, van Dam RM, van Gulik TM, Molenaar IQ, Bosscha K, De jong CH, Van der Jagt EJ, Porte RJ. Objective: To evaluate the efficacy of fibrin sealant in reducing resection surfacerelated complications in liver surgery. Background: Bile leakage, bleeding, and abscess formation are major resection surface-related complications after liver resection. It is unclear whether application of fibrin sealant to the resection surface is effective in reducing these complications. Methods: In a multicenter, randomized trial in 310 noncirrhotic patients undergoing liver resection, we compared prophylactic application of fibrin sealant to the resection surface (156 patients) with no application of fibrin sealant (154 patients). In addition to clinical assessments, patients underwent protocolized computerized tomography (CT) scan 1 week postoperatively. Primary endpoint was a composite of postoperative resection surface-related complications (bile leakage, bleeding, or abscess), as adjudicated by a clinical-events committee that was unaware of the study-group assignments. Results: Overall rate of resection surface-related complications was not different between the 2 groups: 24% (38/156 patients) in the fibrin sealant group and 24% (37/154 patients) in the control group. Bile leakage was detected in 14% of patients in the fibrin sealant group and in 14% of controls. CT scans showed a fluid collection at the resection surface 100 mL or more in 28% of patients in the fibrin sealant group and in 26% of controls (P = 0.800). The rate of reinterventions for resection surface-related complications (12% vs 10%; P = 0.492) and severity of complications did also not differ between the 2 groups. Conclusions: This randomized multicenter trial shows that prophylactic application of fibrin sealant at the resection surface after liver resections does not lead to a reduction in the incidence or severity of postoperative bile leakage or other resection surface-related complications. (Controlled trial number, ISRCTN85205641) Ann Surg 2012;256:229-234. Impact factor: 6.329
4. Spatial variation in stage distribution in colorectal cancer in the Netherlands. Elferink MA, Pukkala E, Klaase JM, Siesling S.
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Background: In the Netherlands the incidence of colorectal cancer has increased, mainly in the eastern part of the country. Patient delay due to unawareness or ignorance of symptoms and differences in use of diagnostic tools could have influence on the stage distribution. The aim of this study was to evaluate geographical differences in stage-specific incidence rates of colon and rectal cancer in the Netherlands. Methods: Age-adjusted incidence rates for cancers of the colon and rectum diagnosed in 2001-2005 and registered in the Netherlands Cancer Registry were calculated for each municipality and stage. The incidence for each 500m by 500m grid was estimated as a weighted average of the incidence rates of the neighbouring municipalities. The incidence rates and the stage distribution are both presented as maps. Geographic variation in stage-specific incidence was evaluated using spatial scan statistic. Results: In both colon and rectal cancer, significant spatial variation in stagespecific incidences was found, except for colon cancer of stages III and IV. The regions with a higher stage-specific incidence were almost all in the south eastern part of the Netherlands, however, these differences were not seen in the stage distribution. There were no differences in stage distribution between large cities and the rest of the country. Conclusions: These maps give insight into differences in stage-specific incidences of colon and rectal cancer in the Netherlands. Educational interventions to increase the awareness of symptoms of colorectal cancer may be especially useful for the population in regions with high incidence of advanced stages. Eur J Cancer 2012;48:1119-1125. Impact factor: 5.061
5. Circulating tumor cells, disease recurrence and survival in newly diagnosed breast cancer. Franken B, de Groot MR, Mastboom WJ, Vermes I, van der Palen J, Tibbe AG, Terstappen LW. Introduction: The presence of circulating tumor cells (CTC) is an independent prognostic factor for progression-free survival and breast cancer related death (BRD) for patients with metastatic breast cancer beginning a new line of systemic therapy. The current study was undertaken to explore whether the presence of CTC at the time of diagnosis was associated with recurrence free survival (RFS) and BRD. Methods: In a prospective single center study, CTC were enumerated with the CellSearch system in 30 ml of peripheral blood of 602 patients before undergoing surgery for breast cancer. 97 patients had a benign tumor, 101 did not meet the inclusion criteria of which 48 patients with DCIS, leaving 404 stage I-III patients. Patients were stratified into unfavorable (CTC [greater than or equal to]1) and favorable (CTC = 0) prognostic groups. Results: >1 CTC in 30 ml blood was detected in 15 (15%) benign tumors, in 9 DCIS (19%), in 28 (16%) stage I, 32 (18%) stage II and in 16 (31%) patients with stage III.
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In stage I-III patients 76 (19%) had >1 CTC of whom 16 (21.1%) developed a recurrence. In 328 patients with 0 CTC 38 (11.6%) developed a recurrence. Four year RFS was 88.4% for favorable CTC and 78.9% for unfavorable CTC (p =0.038). 25 patients died of breast cancer related causes and 11 (44%) had >1 CTC. BRD was 4,3% for favorable and 14,5% for unfavorable CTC (p = 0.001). In multivariate analysis >1 CTC was associated with distant disease free survival, but not for overall recurrence free survival. CTC, progesterone receptor and N-stage were independent predictors of BRD in multivariate analysis. Conclusions: Presence of CTC in breast cancer patients before undergoing surgery with curative intend is associated with an increased risk for breast cancer related death. Breast Cancer Res 2012;14:R133. Impact factor: 5.872
6. Evaluation of the adherence to follow-up care guidelines for women with breast cancer. Grandjean I, Kwast AB, de Vries H, Klaase J, Schoevers WJ, Siesling S. Purpose: To evaluate adherence with follow-up criteria as suggested by the national guideline for breast cancer patients. Method: Patients diagnosed with breast cancer in 2003 in two hospitals were identified from the Netherlands Cancer Registry (n = 198). Compliance with the guideline was assessed retrospectively by extracting follow-up care data from patient files for a period of five years. Results: Follow-up data were available for 196 patients. In the first year of followup, fewer consultations were performed compared to guideline standards. In the second through the fifth year of follow-up, more consultations were performed, with nearly double the number of consultations in the third until the fifth year compared to the guideline (p < 0.05). This excess usage was mainly associated with the fact that women had received radiotherapy (p < 0.01). Physical examinations were performed during 97 percent of consultations. Mammograms were performed slightly less often than suggested. Conclusions: Among women receiving follow-up care after breast cancer, more consultations were provided compared to the guideline recommendations. Mammograms were performed slightly less often than recommended. With regard to the performance of physical examinations, the guideline was followed. Eur J Oncol Nurs 2012;16:281-285. Impact factor: 1.685
7. Visualizing breast cancer using the Twente photoacoustic mammoscope: What do we learn from twelve new patient measurements? Heijblom M, Piras D, Xia W, van Hespen JC, Klaase JM, van den Engh FM, van Leeuwen TG, Steenbergen W, Manohar S.
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We acquired images of breast malignancies using the Twente photoacoustic mammoscope (PAM), to obtain more information about the clinical feasibility and limitations of photoacoustic mammography. Results were compared with conventional imaging and histopathology. Ten technically acceptable measurements on patients with malignancies and two measurements on patients with cysts were performed. In the reconstructed volumes of all ten malignant lesions, a confined region with high contrast with respect to the background could be seen. In all malignant cases, the PA contrast of the abnormality was higher than the contrast on x-ray mammography. The PA contrast appeared to be independent of the mammographically estimated breast density and was absent in the case of cysts. Technological improvements to the instrument and further studies on less suspicious lesions are planned to further investigate the potential of PAM. Opt Express 2012;20:11582-11597. Impact factor: 3.546
8. Development and external validation of a new PTA assessment scale. Jacobs B, van EJ, Vernooy LP, Dieperink P, Andriessen TM, Hendriks MP, Van Vugt AB, Emons MA, Borm GF, Vos PE. Background: Post-traumatic amnesia (PTA) is a key symptom of traumatic brain injury (TBI). Accurate assessment of PTA is imperative in guiding clinical decision making. Our aim was to develop and externally validate a short, examiner independent and practical PTA scale, by selecting the most discriminative items from existing scales and using a three-word memory test Methods: Mild, moderate and severe TBI patients and control subjects were assessed in two separate cohorts, one for derivation and one for validation, using a questionnaire comprised of items from existing PTA scales. We tested which individual items best discriminated between TBI patients and controls, represented by sensitivity and specificity. We then created our PTA scale based on these results. This new scale was externally evaluated for its discriminative value using Receiver Operating Characteristic (ROC) analysis and compared to existing PTA scales. Results: The derivation cohort included 126 TBI patients and 31 control subjects; the validation cohort consisted of 132 patients and 30 controls. A set of seven items was eventually selected to comprise the new PTA scale: age, name of hospital, time, day of week, month, mode of transport and recall of three words. This scale demonstrated adequate discriminative values compared to existing PTA scales on three consecutive administrations in the validation cohort. Conclusion: We introduce a valid, practical and examiner independent PTA scale, which is suitable for mild TBI patients at the emergency department and yet still valuable for the follow-up of more severely injured TBI patients. BMC Neurol 2012;12:69. Impact factor: 2.564
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9. Use of Primary Radiotherapy for Rectal Cancer in the Netherlands between 1997 and 2008: A Population-based Study. Jobsen JJ, Aarts MJ, Siesling S, Klaase J, Louwman WJ, Poortmans PM, Lybeert ML, Koning CC, Struikmans H, Coebergh JW. Aims: To describe variation in the utilisation rates of primary radiotherapy for patients with rectal cancer in the Netherlands, focusing on time trends and age effects. Materials and Methods: Data on primary non-metastatic rectal cancer were derived from the population-based cancer registries of four comprehensive cancer centres (regions) in the Netherlands (1997-2008, n=13,055). Results: An increase in the utilisation rate was noted for the four regions, from 3746% in 1997 to 66-76% in 2008, for both genders. This increase was found predominately for preoperative radiotherapy (from 13-31% to 58-67%) and (unsurprisingly) was most pronounced for stage T2-3 patients (from 9-27% to 6880%). The probability of receiving radiotherapy decreased with age: the odds of receiving preoperative radiotherapy was reduced in patients aged 65 years and older, as well as the odds of receiving postoperative radiotherapy in those aged 75 years and older, which remained significant after adjustment for stage, gender and region. Regional differences persisted in multivariable analyses, i.e. the odds of receiving preoperative radiotherapy was reduced in two regions: odds ratio: 0.4 (95% confidence interval: 0.4-0.5) and 0.7 (0.6-0.8). The odds of receiving postoperative radiotherapy was significantly increased in these regions [odds ratio: 2.6 (2.2-3.2) and 1.6 (1.3-1.9), respectively] and reduced in another [odds ratio 0.8 (0.6-0.96)]. Conclusions: The utilisation rate of radiotherapy for rectal cancer increased significantly over time, particularly for preoperative radiotherapy and was most pronounced for T2-3 patients. Due to national multidisciplinary treatment guidelines, regional differences became limited in recent years after adjustment for age and stage of the disease. A low utilisation rate of radiotherapy was seen in women and elderly patients. Clin Oncol (R Coll Radiol) 2012;24:e1-e8. Impact factor: 2.072
10. Sternoclavicular joint tuberculosis Kelderman S, Steenvoorde P, van der valk PD. A 24-year old woman presented with an abscess localized at the median side of the right clavicle. There were no clinical signs of tuberculosis and radiological evaluation was normal. PCR-assay on tuberculosis following aspiration of the pus collection was positive for Mycobacterium tuberculosis. She responded well on regular antituberculosis treatment. Ned Tijdschr Geneeskd 2012;156:A3315 Impact factor:0
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11. Breslow thickness in the Netherlands: a population-based study of 40 880 patients comparing young and elderly patients. Kruijff S, Bastiaannet E, Francken AB, Schaapveld M, van der Aa M, Hoekstra HJ. Background: Melanoma incidence has increased rapidly in the last decades, and predictions show a continuing increase in the years to come. The aim of this study was to assess trends in melanoma incidence, Breslow thickness (BT), and melanoma survival among young and elderly patients in the Netherlands. Methods: Patients diagnosed with invasive melanoma between 1994 and 2008 were selected from the Netherlands Cancer Registry. Incidence (per 100 000) over time was calculated for young (<65 years) and elderly patients (>/=65 years). Distribution of BT for young and elderly males and females was assessed. Regression analysis of the log-transformed BT was used to assess changes over time. Relative survival was calculated as the ratio of observed survival to expected survival. Results: Overall, 40 880 patients were included (42.3% male and 57.7% female). Melanoma incidence increased more rapidly among the elderly (5.4% estimated annual percentage change (EAPC), P<0.0001) than among younger patients (3.9% EAPC, P<0.0001). The overall BT declined significantly over time (P<0.001). Among younger patients, BT decreased for almost all locations. Among elderly males, BT decreased for melanomas in the head and neck region (P=0.001) and trunk (P<0.001), but did not decrease significantly for the other regions. Among elderly females, BT only decreased for melanomas at the trunk (P=0.01). The relative survival of elderly patients was worse compared with that of younger patients (P<0.001). Conclusion: Melanoma incidence increases more rapidly for elderly than for younger patients and the decline in BT is less prominent among elderly patients than among young patients. Campaigns in the Netherlands should focus more on early melanoma detection in the elderly. Br J Cancer 2012;107:570-574. Impact factor: 5.082
12. The current status of S-100B as a biomarker in melanoma. Kruijff S, Hoekstra HJ. Melanoma is the most malignant type of all skin cancer types. It causes over 75% of all skin cancer related mortality. In the Netherlands, the total number of new diagnosed melanoma patients is expected to increase from 2400 patients in 2000 to 4800 patients in 2015. After surgical treatment, 20-28% of melanoma patients present with loco-regional recurrence, 26-60% with regional recurrences, and 1550% with distant metastases. Early detection of lymph node (micro) metastases by means of a sentinel lymph node biopsy (SLNB) is therefore of crucial importance since early lymph node dissection decrease treatment morbidity and improve overall survival. However when patients present with palpable nodes, given the heterogeneity in survival, the suspicion rises that numerous patients have a form of
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subclinical dissemination, which can remain undetected by current modern imaging methods. Biomarkers could illuminate on this matter, although there is very little understanding of their biological significance. It can be expected that the strongest biological markers are surrogates of key biological events. The protein S-100B seems to be the best analyzed biomarker in melanoma. It has the potential to identify high-risk stage III melanoma patients who may benefit from adjuvant systematic treatment. In the stratification of new adjuvant therapeutic trials in patients with loco-regional recurrences, we therefore recommend the use of S-100B in the stratification. Since an effective (adjuvant) therapy for loco-regional metastatic and disseminated melanoma is recently introduced, the use of S-100B seems to alter dramatically in the near future. Eur J Surg Oncol 2012;38:281-285. Impact factor: 2.499
13. Skin autofluorescence is increased in patients with carotid artery stenosis and peripheral artery disease. Noordzij MJ, Lefrandt JD, Loeffen EA, Saleem BR, Meerwaldt R, Lutgers HL, Smit AJ, Zeebregts CJ. Background: Advanced glycation end products (AGEs) have a pivotal role in atherosclerosis. We evaluated skin autofluorescence (SAF), a non-invasive measurement of tissue AGE accumulation, in patients with carotid artery stenosis with and without coexisting peripheral artery occlusive disease (PAOD). SAF was measured using the AGE Reader in 56 patients with carotid artery stenosis and in 56 age- and sex-matched healthy controls without diabetes, renal dysfunction or known atherosclerotic disease. SAF was higher in patients with carotid artery stenosis compared to the control group: mean 2.81 versus 2.46 (P = 0.002), but especially in the younger age group of 50-60 years old: mean 2.82 versus 1.94 (P = 0.000). Patients with carotid artery stenosis and PAOD proved to have an even higher SAF than patients with carotid artery stenosis only: mean 3.28 versus 2.66 (P = 0.003). Backward linear regression analysis showed that age, smoking, diabetes mellitus, renal function and the presence of PAOD were the determinants of SAF, but carotid artery stenosis was not. SAF is increased in patients with carotid artery stenosis and PAOD. The univariate and multivariate associations of SAF with age, smoking, diabetes, renal insufficiency and PAOD suggest that increased SAF can be seen as an indicator of widespread atherosclerosis. Int J Cardiovasc Imaging 2012;28:431-438. Impact factor: 2.648
14. Endovascular treatment of ruptured abdominal aortic aneurysm: is there a long-term benefit at follow-up? Rodel SG, Meerwaldt R, Beuk RJ, Huisman AB, Zeebregts CJ, Geelkerken RH
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Background: Several studies have shown the feasibility of endovascular repair of ruptured abdominal aortic aneurysms (rEVAR). However, the role and value of rEVAR remains controversial due to selection bias and lack of long-term results. In the present study we describe our short- and long-term results of treating patients with rEVAR irrespective of hemodynamic condition and challenging anatomy. Methods: In April 2006 we started the single centre prospective non-randomised Ruptured Aneurysm Study (RASA). During a four year enrolment period all consecutive patients presenting with infrarenal ruptured AAA (rAAA, N.=117) were assessed for preferential rEVAR treatment. A rAAA was defined as extravasation of blood or hematoma outside the AAA due to transmural tear in the infrarenal abdominal aorta wall documented by preoperative computed tomography (CT) angiography examination or during open repair. Patients with challenging anatomy (infrarenal neck length below 15 mm and neck angulation above 60 degrees) were included as part of a damage control concept. Complication and mortality rates were studied at 30 days and yearly afterwards. Results: Thirty-five patients (33% of all admitted rAAA) were treated with rEVAR and 42% of them were considered hemodynamically unstable (systolic blood pressure <100 mmHg) and 30% had challenging AAA anatomy. The mortality rate at 30 days in the rEVAR group was 17%, in the open repair group 31%, and in the entire rAAA group (including abstained patients) 36%. During the first 30 days, 18 rEVAR patients experienced complications with nine re-interventions as a result. Long-term mortality of the rEVAR patients was 34% after a median follow-up of 3.4 years. All deaths after one year follow-up were non-AAA related. Multivariate analysis shows that Hardman index, presence of peripheral arterial obstructive disease and lowest systolic blood pressure during surgery are independently associated with long-term survival. Challenging rAAA anatomy was not associated with impaired survival. Conclusion: Our study shows that rEVAR is feasible irrespective of hemodynamic condition and that it is associated with relative low mortality rates. Challenging rAAA anatomy may not affect overall long-term survival, but six out of ten patients remain unsuitable for rEVAR because of inappropriate anatomy J Cardiovasc Surg (Torino) 2012;53:83-89. Impact factor: 1.510
15. The Ongoing Battle Between Infrapopliteal Angioplasty and Bypass Surgery for Critical Limb Ischemia. Schamp KB, Meerwaldt R, Reijnen MM, Geelkerken RH, Zeebregts CJ. Background: Critical limb ischemia (CLI) represents the extreme of the peripheral arterial occlusive disease spectrum and is associated with high mortality. Limb salvage often requires infrapopliteal revascularization by either angioplasty or bypass surgery. The past decade has witnessed a paradigm shift in CLI management toward endovascular treatment. This narrative review describes the clinical outcome, treatment strategy, and limitations of both modalities.
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Method: A literature search was performed of the PubMed and Cochrane databases. All articles, published until September 2011, describing treatment by infrapopliteal arterial revascularization were included. Results: Angioplasty and bypass surgery are both related to a limb salvage rate of approximately 80% at 3-year follow-up. Patency rates appear to be higher after surgery. A reliable comparison of the two modalities, however, is complicated by various confounders, including patient selection, lesion characteristics, and complication rates. Additionally, most studies did not describe the standard use of best medical treatment or outcome for relief of ischemic pain, wound healing, or functional improvement. Conclusion: Infrapopliteal angioplasty and bypass surgery both provide an acceptable limb salvage rate, but patency appears to be better after bypass surgery. Both modalities are likely to be complementary. Additional randomized trials are indicated to provide a treatment algorithm for patients with CLI and infrapopliteal arterial occlusive disease Ann Vasc Surg 2012;26:1145-1153. Impact factor: 0.985
16 Targeted lymph node biopsy in mediastinoscopy using 3D FDG-PET/CT movies: a feasibility study. Siepel FJ, de Bruin WI, van Duyn EB, Steenvoorde P, Wagenaar NR, Slump CH, van Dalen JA. In non-small-cell lung cancer, positive lymph nodes with increased fluorodeoxyglucose (FDG) uptake may be missed by mediastinoscopy. Lack of pathological confirmation may lead to radical, but unnecessary lung surgery. To minimize these false-negative results, the feasibility and potential value of threedimensional (3D) FDG-PET/computed tomography (CT) movies were investigated to improve targeted lymph node biopsy during mediastinoscopies. PET/CT images were rendered in 3D volumes with multiplanar reconstructions and maximum intensity projections and reviewed in 3D 'fly-through' and 'fly-around' movies. These movies were developed and optimized by the Departments of Surgery and Nuclear Medicine. Twenty-two consecutive patients with non-small-cell lung cancer were included, of whom eight were FDG-PET positive for mediastinal lymph nodes. 3D FDG-PET/CT movies were presented to surgeons before mediastinoscopy. Surgical consequences were investigated, including sensitivity and the negative predictive value of mediastinoscopy. Results were compared with those of a retrospective study in which 3D techniques were not used. During mediastinoscopies, the 3DPET/CT movies were found to be helpful in the surgical localization of FDG-positive lymph nodes. It led to more confidence in the surgical approach. The sensitivity and negative predictive value were 86 and 94%, respectively. Although not statistically significant, these results were higher compared with those of the retrospective study (75 and 92%, respectively). 3D FDG-PET/CT guidance during mediastinoscopy is feasible. The movies seem to lead to targeted biopsy of lymph nodes. They may reduce false-negative mediastinoscopies and improve staging of lung cancer. 3D
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FDG-PET/CT can be seen as a promising tool for further implementation of imageguided surgery Nucl Med Commun 2012;33:439-444 Impact factor: 1.379 17. A 40-year old male presented with a painful cord running over his chest. Steenvoorde P, van Det R This disease, Mondor's disease, is a self-limiting disease caused by a thrombophlebitis of the superficial epigastric and thoracic veins. In this case repetitive injury sustained from running was probably the cause Ned Tijdschr Geneeskd 2012;156:A3222 Impact factor: 0
18. The value of frozen section biopsy in diagnosing necrotizing fasciitis: proposal of a new grading system. Stegeman SA, Nijhuis I, van Leeuwen AM, Bonsing BA, Steenvoorde P Necrotizing fasciitis is a serious disease entity, with only limited pathognomic features. Purpose: In necrotizing fasciitis a rapid diagnosis is necessary in order to reduce morbidity and mortality. In this study the investigation focused on specific features in the frozen section biopsy for diagnosing necrotizing fasciitis Methods: A total of ten patients are described with final pathological examination of resected tissue. Results: A new grading system is suggested for frozen section biopsy in patients with necrotizing fasciitis. In the herein reported study it was found that granulocytes were present in both the frozen section biopsy and in the definitive paraffin coupes, in the subcutis and fascia layer. Conclusion: Frozen section biopsy could be useful in diagnosing necrotizing fasciitis J Tissue Viability 2012;21:13-16 Impact factor: 1.176
19. Abdominal symptoms during physical exercise and the role of gastrointestinal ischaemia: a study in 12 symptomatic athletes. Ter Steege RW, Geelkerken RH, Huisman AB, Kolkman JJ Background: Gastrointestinal (GI) symptoms during exercise may be caused by GI ischaemia. The authors report their experience with the diagnostic protocol and management of athletes with symptomatic exercise-induced GI ischaemia. The value of prolonged exercise tonometry in the diagnostic protocol of these patients was evaluated. 10 3
Methods: Patients referred for GI symptoms during physical exercise underwent a standardised diagnostic protocol, including prolonged exercise tonometry. Indicators of GI ischaemia, as measured by tonometry, were related to the presence of symptoms during the exercise test (S+ and S- tests) and exercise intensity. Results: 12 athletes were specifically referred for GI symptoms during exercise (five males and seven females; median age 29 years (range 15-46 years)). Type of sport was cycling, long-distance running and triathlon. Median duration of symptoms was 32 months (range 7-240 months). Splanchnic artery stenosis was found in one athlete. GI ischaemia was found in six athletes during submaximal exercise. All athletes had gastric and jejunal ischaemia during maximum intensity exercise. No significant difference was found in gastric and jejunal Pco(2) or gradients between S+ and S- tests during any phase of the exercise protocol. In S+ tests, but not in Stests, a significant correlation between lactate and gastric gradient was found. In S+ tests, the regression coefficients of gradients were higher than those in S- tests. Treatment advice aimed at limiting GI ischaemia were successful in reducing complaints in the majority of the athletes. Conclusion: GI ischaemia was present in all athletes during maximum intensity exercise and in 50% during submaximal exercise. Athletes with GI symptoms had higher gastric gradients per mmol/l increase in lactate, suggesting an increased susceptibility for the development of ischaemia during exercise. Treatment advice aimed at limiting GI ischaemia helped the majority of the referred athletes to reduce their complaints. Our results suggest an important role for GI ischaemia in the pathophysiology of their complaints Br J Sports Med 2012;46:931-935. Impact factor: 5.237
20. Splanchnic artery stenosis and abdominal complaints: clinical history is of limited value in detection of gastrointestinal ischemia. Ter Steege RW, Sloterdijk HS, Geelkerken RH, Huisman AB, van der Palen J, Kolkman JJ. Background: Splanchnic artery stenosis is common and mostly asymptomatic and may lead to gastrointestinal ischemia (chronic splanchnic syndrome, CSS). This study was designed to assess risk factors for CSS in the medical history of patients with splanchnic artery stenosis and whether these risk factors can be used to identify patients with high and low risk of CSS. Methods: All patients referred for suspected CSS underwent a standardized workup, including a medical history with questionnaire, duplex ultrasound, gastrointestinal tonometry, and angiography. Definitive diagnosis and treatment advice was made in a multidisciplinary team. Patients with confirmed CSS were compared with no-CSS patients. Results: A total of 270 patients (102 M, 168 F; mean age, 53 years) with splanchnic artery stenosis were analyzed, of whom 109 (40%) had CSS and 161 no CSS. CSSpatients more often reported postprandial pain (87% vs. 72%, p = 0.007), weight loss (85% vs. 70%, p = 0.006), adapted eating pattern (90% vs. 79%, p = 0.005) and diarrhea (35% vs. 22%, p = 0.023). If none of these risk factors were present, the
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probability of CSS was 13%; if all were present, the probability was 60%. Adapted eating pattern (odds ratio (OR) 3.1; 95% confidence interval (CI) 1.08-8.88) and diarrhea (OR 2.6; 95% CI 1.31-5.3) were statistically significant in multivariate analysis. Conclusions: In patients with splanchnic artery stenosis, the clinical history is of limited value for detection of CSS. A diagnostic test to detect ischemia is indispensable for proper selection of patients with splanchnic artery stenosis who might benefit from treatment World J Surg 2012;36:793-799. Impact factor: 2.228
21. Volume-limited versus pressure-limited hemodynamic management in septic and nonseptic shock. Trof RJ, Beishuizen A, Cornet AD, de Wit RJ, Girbes AR, Groeneveld AB. Objectives: To evaluate the effect of hemodynamic management guided by upper limits of cardiac filling volumes or pressures on durations of mechanical ventilation and lengths of stay in critically ill patients with shock. Design: Prospective, randomized, clinical trial. Setting: Mixed intensive care unit of a large teaching hospital and mixed intensive care unit of a tertiary care, academic medical center. Patients: A total 120 septic (n = 72) and nonseptic (n = 48) shock patients, randomized (after stratification) to transpulmonary thermodilution (n = 60) or pulmonary artery catheter (n = 60) between February 2007 and July 2009. Interventions: Hemodynamic management was guided by algorithms including upper limits for fluid resuscitation of extravascular lung water (<10 mL/kg) and global end-diastolic volume index (<850 mL/m) in the transpulmonary thermodilution group and pulmonary artery occlusion pressure (<18-20 mm Hg) in the pulmonary artery catheter group for 72 hrs after enrollment. Measurements and main results: Primary outcomes were ventilator-free days and lengths of stay in the intensive care unit and the hospital. Secondary outcomes included organ failures and mortality. Cardiac comorbidity was more frequent in nonseptic than in septic shock. Ventilator-free days, lengths of stay, organ failures, and 28-day mortality (overall 33.3%) were similar between monitoring groups. Transpulmonary thermodilution (vs. pulmonary artery catheter) monitoring was associated with more days on mechanical ventilation and longer intensive care unit and hospital lengths of stay in nonseptic (p = .001) but not in septic shock. In both conditions, fewer patients met the upper limit of volume than of pressure criteria at baseline and transpulmonary thermodilution (vs. pulmonary artery catheter) monitoring was associated with a more positive fluid balance at 24 hrs. Conclusions: Hemodynamic management guided by transpulmonary thermodilution vs. pulmonary artery catheter in shock did not affect ventilator-free days, lengths of stay, organ failures, and mortality of critically ill patients. Use of the a transpulmonary thermodilution algorithm resulted in more days on mechanical ventilation and intensive care unit length of stay compared with the pulmonary artery catheter algorithm in nonseptic shock but not in septic shock. This may relate to
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cardiac comorbidity and a more positive fluid balance with use of transpulmonary thermodilution in nonseptic shock Crit Care Med 2012;40:1177-1185. Impact factor: 6.124
22. Incidental Findings on Routine Thoracoabdominal Computed Tomography in Blunt Trauma Patients. van Vugt R, Dekker HM, Deunk J, van der Vijver RJ, Van Vugt AB, Kool DR, Brink M, Edwards MJ. Background: Thoracoabdominal MultiDetector-row Computed Tomography (MDCT) is frequently used as a diagnostic tool in trauma patients. One potential side-effect of performing MDCT is the detection of incidental findings and their subsequent consequences on medical treatment. The objective was to evaluate frequency and effects of incidental findings in trauma patients. Methods: The reports of 1,047 consecutive blunt trauma patients (mean age, 40 years) who underwent routine contrast-enhanced thoracoabdominal MDCT were evaluated. Incidental findings were categorized by a trauma radiologist into four hierarchic categories based on their clinical consequences. We recorded additional diagnostic workup and treatment performed in conjunction with these incidental findings. Results: Of the 1,047 patients, 372 (mean age, 56 years; 61% male) had one or more incidental findings on thoracoabdominal MDCT. Complementary investigation or therapy was performed in 72 of these 372 patients; 29 of these patients required additional invasive evaluation or treatment. Nineteen patients underwent surgery due to an incidental finding. Nine patients were diagnosed with a not previously identified malignancy. Conclusions: Routine thoracoabdominal MDCT in the evaluation of trauma patients revealed a significant number of incidental findings. Based on radiologic findings it is possible to decide whether additional follow-up or treatment is necessary J Trauma 2012;72:416-421. Impact factor: 2.348
23. The cardiovascular risk profile of atherosclerotic gastrointestinal ischemia is different from other vascular beds. Veenstra RP, Ter Steege RW, Geelkerken RH, Huisman AB, Kolkman JJ. Background: The distribution of cardiovascular risk factors in patients with chronic gastrointestinal ischemia due to atherosclerosis of the splanchnic vessels (chronic splanchnic syndrome) is not well studied. The aim of this study was to determine the cardiovascular risk factor pattern in patients with chronic splanchnic syndrome. Methods: From April 2003 to September 2007, atherosclerotic risk factors in consecutive patients with chronic splanchnic syndrome were compared prospectively with the general atherosclerotic risk profile in Western Europe and
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worldwide risk profile of coronary heart disease, peripheral artery disease, and cerebral vascular disease. Results: Of 376 analyzed patients, 97 were diagnosed with chronic splanchnic syndrome. Data from 90 patients were available for analysis (7 were excluded because of incomplete data). Mean age was 63 years (range 28-86 years), and 74% were female. Fifty-nine percent of the patients had atherosclerotic disease in other vascular beds. Smoking was reported in 57%, and increased bodyweight in 21%. Hypercholesterolemia was present in 53%, hypertension in 62%, and diabetes in 21%. Conclusions: The atherosclerotic risk profile in patients with chronic splanchnic syndrome differed from other atherosclerotic diseases with a female preponderance, lower incidence of obesity/increased bodyweight, diabetes, hypertension, and hypercholesterolemia. Reduced caloric intake, related to the postprandial pain, may explain the observed differences. Am J Med 2012;125:394-398. Impact factor: 4.768
24. Operatie 80-plusser niet altijd zinloos. Geelkerken RH, Meerwaldt R, Van Vugt AB. Medisch Contact 2012;37. Impact factor: 0
Totale impact factor: 65.319 Gemiddelde impact factor: 2.722 Aantal artikelen 1e, 2e of laatste auteur: 11 Totale impact factor: 22.818 Gemiddelde impact factor: 2.074
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Intensive Care 1. Age dependency of coagulation parameters during childhood and puberty. Appel IM, Grimminck B, Geerts J, Stigter R, Cnossen MH, Beishuizen A Background: Use of age-adjusted reference values is crucial for correct diagnosis and management of thrombotic and haemorrhagic disease in children. They vary with utilized reagents and analyzers. Objectives: We established reference values on Sysmex CA-1500 System and in parallel on the Behring BCS System using reagents from Siemens Healthcare Diagnostics Products GmbH. Methods: After informed consent, blood samples were obtained from 218 healthy children and 52 healthy adults; grouped as 1-6 months (n=29); 7-12 months (n=25); 1-5 years (n=57); 6-10 years (n=57), 11-18 years (n=50) and >19 years (n=52). Results: Most coagulation parameters demonstrate good comparability between analyzers with exception of PT and APTT. Single coagulation factors fibrinogen, FII, FIX, FXI and XII were significantly decreased in the youngest children; strongest age-dependency was found for coagulation inhibitors Protein C and S, both significantly decreased in infancy and young childhood. We confirmed that high levels of von Willebrand factor are found in the youngest children without increased levels of factor VIII followed by decreased von Willebrand levels in the subsequent age group. In children with blood group O a less distinct increase in time was found, compared to individuals with one of the other blood groups. Conclusions: The correlation between the CA-1500 and the BCS system was remarkable. Differences were most pronounced between children <12 months and older children and adults, confirming the phenomenon of developmental haemostasis. The rationale for age-related changes in the haemostatic system remains unraveled. Our results underline the need for age-specific reference ranges. J Thromb Haemost 2012;10:2254-2263. Impact factor: 6.081
2. Red blood cell transfusion compared with gelatin solution and no infusion after cardiac surgery: effect on microvascular perfusion, vascular density, hemoglobin, and oxygen saturation. Atasever B, van der Kuil M, Boer C, Vonk A, Schwarte L, Girbes AR, Ince C, Beishuizen A, Groeneveld AB. Background: After cardiac surgery, red blood cell (RBC) transfusion may improve systemic hemodynamics and thereby microvascular blood flow and O(2) delivery (DO(2) ). Study, design and methods: In a nonrandomized prospective observational study on post-cardiac surgery patients, systemic hemodynamics and microvascular blood flow, vascular density (sidestream dark-field imaging), hemoglobin (Hb) content, and saturation (reflectance spectrophotometry) were measured before and 1 hour after start of transfusion of 1 to 2 units of leukoreduced RBCs (270 +/- 203 mL), 500 mL of gelatin solution, or control (no infusion), when patients were considered clinically
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hypovolemic with (RBC group, n = 12) or without (gelatin group, n = 14) anemia (Hb < 10 g/dL) or not (n = 13), respectively. Results: Systemic Hb was lower and increased in the RBC transfusion but not in gelatin and control groups. There were no differences in changes in systemic DO(2) , O(2) uptake, and extraction between groups. RBC transfusion, compared with gelatin or control, increased medium-sized vascular density, Hb content, and saturation in the microcirculation, while blood flow remained unchanged. Changes of microvascular Hb and saturation paralleled changes in systemic Hb. Conclusion: The data argue in favor of efficacy of RBC transfusion after cardiac surgery. RBC transfusion increases systemic Hb and this in turn increases mediumsized vascular density and DO(2) in the sublingual microcirculation, independently of systemic hemodynamics and volume status. Transfusion 2012;52:2452-2458 Impact factor: 3.526
3. Are religion and religiosity important to end-of-life decisions and patient autonomy in the ICU? Bulow HH, Sprung CL, Baras M, Carmel S, Svantesson M, Benbenishty J, Maia PA, Beishuizen A, Cohen S, Nalos D. Background: This study explored differences in end-of-life (EOL) decisions and respect for patient autonomy of religious members versus those only affiliated to that particular religion (affiliated is a member without strong religious feelings). Methods: In 2005 structured questionnaires regarding EOL decisions were distributed in six European countries to ICUs in 142 hospital ICUs. This sub-study of the original data analyzed answers from Protestants, Catholics and Jews. Results: A total of 304 physicians, 386 nurses, 248 patients and 330 family members were included in the study. Professionals wanted less treatment (ICU admission, CPR, ventilator treatment) than patients and family members. Religious respondents wanted more treatment and were more in favor of life prolongation, and they were less likely to want active euthanasia than those affiliated. Southern nurses and doctors favored euthanasia more than their Northern colleagues. Three quarters of doctors and nurses would respect a competent patient's refusal of a potentially life-saving treatment. No differences were found between religious and affiliated professionals regarding patient's autonomy. Inter-religious differences were detected, with Protestants most likely to follow competent patients' wishes and the Jewish respondents least likely to do so, and Jewish professionals more frequently accepting patients' wishes for futile treatment. However, these findings on autonomy were due to regional differences, not religious ones. Conclusions: Health-care professionals, families and patients who are religious will frequently want more extensive treatment than affiliated individuals. Views on active euthanasia are influenced by both religion and region, whereas views on patient autonomy are apparently more influenced by region. Intensive Care Med 2012;38:1126-1133. Impact factor: 5.258
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4. Continuous electroencephalography monitoring for early prediction of neurological outcome in postanoxic patients after cardiac arrest: A prospective cohort study. Cloostermans MC, van Meulen FB, Eertman CJ, Hom HW, van Putten MJ. Background: To evaluate the value of continuous electroencephalography in early prognostication in patients treated with hypothermia after cardiac arrest. Design: Prospective cohort study. Setting: Medical intensive care unit. Patients: Sixty patients admitted to the intensive care unit for therapeutic hypothermia after cardiac arrest. Intervention: None. Measurements and main results: In all patients, continuous electroencephalogram and daily somatosensory evoked potentials were recorded during the first 5 days of admission or until intensive care unit discharge. Neurological outcomes were based on each patient's best achieved Cerebral Performance Category score within 6 months. Twenty-seven of 56 patients (48%) achieved good neurological outcome (Cerebral Performance Category score 1-2).At 12 hrs after resuscitation, 43% of the patients with good neurological outcome showed continuous, diffuse slow electroencephalogram rhythms, whereas this was never observed in patients with poor outcome.The sensitivity for predicting poor neurological outcome of low-voltage and isoelectric electroencephalogram patterns 24 hrs after resuscitation was 40% (95% confidence interval 19%-64%) with a 100% specificity (confidence interval 86%-100%), whereas the sensitivity and specificity of absent somatosensory evoked potential responses during the first 24 hrs were 24% (confidence interval 10%-44%) and 100% (confidence interval: 87%-100%), respectively. The negative predictive value for poor outcome of low-voltage and isoelectric electroencephalogram patterns was 68% (confidence interval 50%-81%) compared to 55% (confidence interval 40%-60%) for bilateral somatosensory evoked potential absence, both with a positive predictive value of 100% (confidence interval 63%-100% and 59%-100% respectively). Burst-suppression patterns after 24 hrs were also associated with poor neurological outcome, but not inevitably so. Conclusions: In patients treated with hypothermia, electroencephalogram monitoring during the first 24 hrs after resuscitation can contribute to the prediction of both good and poor neurological outcome. Continuous patterns within 12 hrs predicted good outcome. Isoelectric or low-voltage electroencephalograms after 24 hrs predicted poor outcome with a sensitivity almost two times larger than bilateral absent somatosensory evoked potential responses. Crit Care Med 2012;40:2867-2875. Impact factor: 6.124
5. Risk factors and outcome of changes in adrenal response to ACTH in the course of critical illness. de Jong MF, Beishuizen A, van Schijndel RJ, Girbes AR, Groeneveld AB.
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Background: To evaluate the concept of critical illness-related corticosteroid insufficiency (CIRCI) by studying the clinical significance, in terms of risk factors and outcome, of changes in the cortisol response to repeated adrenocorticotropic hormone (ACTH) testing in the course of critical illness. Patients and methods: In a retrospective study in a medical-surgical intensive care unit (ICU) of a university hospital, we retrospectively included 54 consecutive patients during a 3-year period, who underwent 2 conventional 250 mug ACTH tests at an interval >24 hours, because of >/=6 hours hypotension requiring repeated fluid challenges or vasopressor/inotropic treatment, while corticosteroid treatment was not (yet) initiated. Serum cortisol was measured immediately before and 30 and 60 minutes after intravenous injection of 250 mug of ACTH. Patients were divided into those with an increase (>/=0, n = 27) or a decrease (n = 27) in time in delta (Delta) cortisol in response to ACTH and with a Deltacortisol <100 (n = 11) and >/=100 nmol/L (n = 43) at the second ACTH test. Results: Changes in Deltacortisol in time were paralleled by changes in Deltacortisol/albumin, with a higher frequency of septic shock, persistently high disease severity, increased renal replacement therapy, and decreased platelet counts in the course of disease with a decrease in Deltacortisol in time. Similar trends in increased disease severity were observed when Deltacortisol remained or fell to <100 nmol/L. A decrease in Deltacortisol between the 2 tests, particularly to <100 nmol/L, was associated with increased mortality (18 nonsurvivors in the ICU). Conclusions: The findings favor the concept of dynamic adrenal function rather than poor reproducibility of the ACTH test, so that development of CIRCI, particularly in complicated septic shock and indicated by a fall in Deltacortisol (to <100 nmol/L) upon ACTH, correlates to a poor prognosis, independently of baseline cortisol, cortisol binding in blood, and disease severity. Intensive Care Med 2012;27:37-44. Impact factor: 5.258
6. Pulsatile flow during cardiopulmonary bypass preserves postoperative microcirculatory perfusion irrespective of systemic hemodynamics. Koning NJ, Vonk AB, van Barneveld LJ, Beishuizen A, Atasever B, van den Brom CE, Boer C. The onset of nonpulsatile cardiopulmonary bypass is known to deteriorate microcirculatory perfusion, but it has never been investigated whether this may be prevented by restoration of pulsatility during extracorporeal circulation. We therefore investigated the distinct effects of nonpulsatile and pulsatile flow on microcirculatory perfusion during on-pump cardiac surgery. Patients undergoing coronary artery bypass graft surgery were randomized into a nonpulsatile (n = 17) or pulsatile (n = 16) cardiopulmonary bypass group. Sublingual mucosal microvascular perfusion was measured at distinct perioperative time intervals using sidestream dark field imaging, and quantified as the level of perfused small vessel density and microvascular flow index (vessel diameter < 20 mum). Microcirculation measurements were paralleled by hemodynamic and free hemoglobin analyses. The pulse wave during pulsatile bypass estimated 58 +/- 17% of the baseline blood
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pressure waveform. The observed reduction in perfused vessel density during aorta cross-clamping was only restored in the pulsatile flow group and increased from 15.5 +/- 2.4 to 20.3 +/- 3.7 mm/mm(2) upon intensive care admission (P < 0.01). The median postoperative microvascular flow index was higher in the pulsatile group [2.6 (2.5-2.9)] than in the nonpulsatile group [2.1 (1.7-2.5); P = 0.001]. Pulsatile flow was not associated with augmentation of free hemoglobin production and was paralleled by improved oxygen consumption from 70 +/- 14 to 82 +/- 16 ml.min(-1).m(-2) (P = 0.01) at the end of aortic cross-clamping. In conclusion, pulsatile cardiopulmonary bypass preserves microcirculatory perfusion throughout the early postoperative period, irrespective of systemic hemodynamics. This observation is paralleled by an increase in oxygen consumption during pulsatile flow, which may hint toward decreased microcirculatory heterogeneity during extracorporeal circulation and preservation of microcirculatory perfusion throughout the perioperative period. J Appl Physiol 2012;112:1727-1734. Impact factor: 3.484
7. Steroidogenesis in the adrenal dysfunction of critical illness: impact of etomidate. Molenaar N, Bijkerk RM, Beishuizen A, Hempen CM, de Jong MF, Vermes I, Van der Sluijs V, Girbes AR, Groeneveld J. Introduction: This study was aimed at characterizing basal and adrenocorticotropic hormone (ACTH)-induced steroidogenesis in septic and non-septic patients with a suspicion of critical illness-related corticosteroid insufficiency (CIRCI), taking the use of etomidate inhibiting 11beta-hydroxylase into account. Method: A prospective study. Setting: A mixed surgical/medical intensive care unit (ICU) of a university hospital. Patients: 62 critically ill patients with a clinical suspicion of CIRCI. Interventions: Patients underwent a 250 ug ACTH test (n=67). ACTH, adrenal steroids, substrates and precursors (modified tandem mass spectrometry) were also measured. Clinical characteristics including use of etomidate to facilitate intubation (n=14 within 72 hours of ACTH testing) were recorded. Results: At the time of ACTH testing, patients suffered from septic (n=43) or nonseptic critical illness (n=24). Baseline cortisol directly related to sepsis and endogenous ACTH, independent of etomidate use. Etomidate was associated with a lower baseline cortisol and cortisol/11beta-deoxycortisol ratio as well as higher 11beta-deoxycortisol reflecting 11beta-hydroxylase inhibition, in non-sepsis than in sepsis. Cortisol increases <250 mmol/L upon exogenous ACTH were associated with relatively low baseline cholesterol, and high endogenous ACTH with low cortisol/ACTH ratio, independent of etomidate. Although cortisol increases upon exogenous ACTH were lower in sepsic than non-sepsic patients, etomidate was associated with diminished increases in cortisol upon exogenous ACTH, so that its use increased, albeit non-significantly. Low cortisol increases to exogenous ACTH from 38 to 57%, in both conditions.
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Conclusions: A single dose of etomidate may attenuate stimulated more than basal cortisol synthesis. However, it may only partly contribute, particularly in the stressed septic patient, to the adrenal dysfunction of CIRCI, on top of substrate deficiency. Crit Care 2012;16:R121. Impact factor: 4.718
8. Alkaline phosphatase for treatment of sepsis-induced acute kidney injury: a prospective randomized double-blind placebo-controlled trial. Pickkers P, Heemskerk S, Schouten J, Laterre PF, Vincent JL, Beishuizen A, Jorens PG, Spapen H, Bulitta M, Peters WH, van der Hoeven JG. Introduction: To evaluate whether alkaline phosphatase (AP) treatment improves renal function in sepsis-induced acute kidney injury (AKI), a prospective, doubleblind, randomized, placebo-controlled study in critically ill patients with severe sepsis or septic shock with evidence of AKI was performed. Methods: Thirty-six adult patients with severe sepsis or septic shock according to Systemic Inflammatory Response Syndrome criteria and renal injury defined according to the AKI Network criteria were included. Dialysis intervention was standardized according to Acute Dialysis Quality Initiative consensus. Intravenous infusion of alkaline phosphatase (bolus injection of 67.5 U/kg body weight followed by continuous infusion of 132.5 U/kg/24 h for 48 hours, or placebo) starting within 48 hours of AKI onset and followed up to 28 days post-treatment. The primary outcome variable was progress in renal function variables (endogenous creatinine clearance, requirement and duration of renal replacement therapy, RRT) after 28 days. The secondary outcome variables included changes in circulating inflammatory mediators, urinary excretion of biomarkers of tubular injury, and safety. Results: There was a significant (P = 0.02) difference in favor of AP treatment relative to controls for the primary outcome variable. Individual renal parameters showed that endogenous creatinine clearance (baseline to Day 28) was significantly higher in the treated group relative to placebo (from 50 +/- 27 to 108 +/- 73 mL/minute (mean +/- SEM) for the AP group; and from 40 +/- 37 to 65 +/- 30 mL/minute for placebo; P = 0.01). Reductions in RRT requirement and duration did not reach significance. The results in renal parameters were supported by significantly more pronounced reductions in the systemic markers C-reactive protein, Interleukin-6, LPS-binding protein and in the urinary excretion of Kidney Injury Molecule-1 and Interleukin-18 in AP-treated patients relative to placebo. The Drug Safety Monitoring Board did not raise any issues throughout the trial. Conclusion: The improvements in renal function suggest alkaline phosphatase is a promising new treatment for patients with severe sepsis or septic shock with AKI. TRIAL REGISTRATION: www.clinicaltrials.gov: NCTNCT00511186 Crit Care 2012;16:R14. Impact factor: 4.718
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9. Effect of anticoagulation regimens on handling of interleukin-6 and -8 during continuous venovenous hemofiltration in critically ill patients with acute kidney injury. Schilder L, Azam NS, Ter Wee PM, Girbes AR, Beishuizen A, Paauw NJ, Beelen RH, Groeneveld AB. Objective: During continuous venovenous hemofiltration (CVVH) to replace renal function in acute kidney injury (AKI), anticoagulation of the filter is routinely required. A survival benefit for citrate has been reported, possibly due to reduced proinflammatory effects of the filter (bioincompatibility). We hypothesized that the type of anticoagulation modulates the immune response to, and clearance by CVVH of interleukin-6 (IL-6) and -8 (IL-8). Methods: Three anticoagulation regimens were compared: trisodium citrate (n=17), unfractionated heparin (n=8) and no anticoagulation in case of bleeding tendency (n=13). Immediately before initiation of CVVH (cellulose triacetate membrane) prefilter blood was drawn. Thereafter, at 10, 60, 180 and 720min, samples were collected from the pre- and postfilter blood and from ultrafiltrate. IL-6 and IL-8 were determined by ELISA. Results: High inlet levels of IL-6 and IL-8, particularly in the no anticoagulation group, were associated with non-survival. The inlet concentrations and mass rates of IL-6 and IL-8 decreased during CVVH. The course of fluxes across the filter were similar for the groups, however. Although increasing in time for IL-6 in the no anticoagulation group, mass removal and adsorption of IL-6 and IL-8 were low and did not differ among the anticoagulation groups. Conclusions: Blood to membrane contact, adsorption/clearance and anticoagulation do not increase nor attenuate high circulating levels of IL-6 and IL-8 during CVVH for AKI. This renders the hypothesis that the reported survival benefit for citrate anticoagulation is based on a reduction of bioincompatibility unlikely. Cytokine 2012;60:601-607. Impact factor: 2.518
10. Hemodynamic treatment algorithms should follow physiology or they fail to improve outcome. Trof RJ, Groeneveld AB. Crit Care Med 2012;40:2924-2925. Impact factor: 6.124 11. Results of questionable management protocols are inherently questionable. Trof RJ, Groeneveld AJ. Crit Care Med 2012;40:2536-2537. Impact factor: 6.124
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12. Transpulmonary thermodilution: The jury is out. Trof RJ, Groeneveld AB. Crit Care Med 2012;40:3109-3110. Impact factor: 6.124
13. Volume-limited versus pressure-limited hemodynamic management in septic and nonseptic shock. Trof RJ, Beishuizen A, Cornet AD, de Wit RJ, Girbes AR, Groeneveld AB. Objectives: To evaluate the effect of hemodynamic management guided by upper limits of cardiac filling volumes or pressures on durations of mechanical ventilation and lengths of stay in critically ill patients with shock. Design: Prospective, randomized, clinical trial. Setting: Mixed intensive care unit of a large teaching hospital and mixed intensive care unit of a tertiary care, academic medical center. Patients: A total 120 septic (n = 72) and nonseptic (n = 48) shock patients, randomized (after stratification) to transpulmonary thermodilution (n = 60) or pulmonary artery catheter (n = 60) between February 2007 and July 2009. Interventions: Hemodynamic management was guided by algorithms including upper limits for fluid resuscitation of extravascular lung water (<10 mL/kg) and global end-diastolic volume index (<850 mL/m) in the transpulmonary thermodilution group and pulmonary artery occlusion pressure (<18-20 mm Hg) in the pulmonary artery catheter group for 72 hrs after enrollment. Measurements and main results: Primary outcomes were ventilator-free days and lengths of stay in the intensive care unit and the hospital. Secondary outcomes included organ failures and mortality. Cardiac comorbidity was more frequent in nonseptic than in septic shock. Ventilator-free days, lengths of stay, organ failures, and 28-day mortality (overall 33.3%) were similar between monitoring groups. Transpulmonary thermodilution (vs. pulmonary artery catheter) monitoring was associated with more days on mechanical ventilation and longer intensive care unit and hospital lengths of stay in nonseptic (p = .001) but not in septic shock. In both conditions, fewer patients met the upper limit of volume than of pressure criteria at baseline and transpulmonary thermodilution (vs. pulmonary artery catheter) monitoring was associated with a more positive fluid balance at 24 hrs. Conclusions: Hemodynamic management guided by transpulmonary thermodilution vs. pulmonary artery catheter in shock did not affect ventilator-free days, lengths of stay, organ failures, and mortality of critically ill patients. Use of the a transpulmonary thermodilution algorithm resulted in more days on mechanical ventilation and intensive care unit length of stay compared with the pulmonary artery catheter algorithm in nonseptic shock but not in septic shock. This may relate to cardiac comorbidity and a more positive fluid balance with use of transpulmonary thermodilution in nonseptic shock. Crit Care Med 2012;40:1177-1185. Impact factor: 6.124
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14. Endocrine late sequelae in long-term survivors of childhood non-Hodgkin lymphoma. van Waas M, Neggers SJ, Te Winkel ML, Beishuizen A, Pieters R, van den HeuvelEibrink MM. Aim of this study was to investigate the long-term endocrine effects of treatment of childhood non-Hodgkin lymphoma (NHL). Patients and methods: A single-center cohort of 84 survivors (22 females) was included in this retrospective study. Median age was 21 years (9-40 years) and time after cessation of therapy 12 years (4-30 years). Height, weight, percentage fat, lean body mass (LBM), bone mineral content (BMC), bone mineral density of total body (BMD(TB)) and bone mineral density of lumbar spine (BMD(LS)) were measured. Thyroid-stimulating hormone (TSH), free thyroxin (fT4), insulin-like growth factor-1 (IGF-1), inhibin B and anti-mullerian hormone (AMH) levels were measured. Results were compared with Dutch controls. Results: Height was lower in survivors [mean standard deviation score (SDS) -0.36, P = 0.002], but further analysis showed that shorter stature was already present at diagnosis (mean SDS -0.28, P = 0.023). Body mass index, percentage fat, BMC, BMD(TB) and BMD(LS) were not different from controls. LBM was lower in survivors (mean SDS -0.47, P = 0.008). TSH, fT4 and IGF-1 were normal in all survivors. Three of 20 adult females had low AMH levels and 23 of 42 adult males had low inhibin B levels. Conclusions: Twelve years after cessation of treatment, NHL survivors did not develop adiposity, osteoporosis or thyroid disease. Male survivors may be at risk for infertility. Ann Oncol 2012;23:1626-1632. Impact factor: 7.384
15. The effect of blood transfusion on pulmonary permeability in cardiac surgery patients: a prospective multicenter cohort study. Vlaar AP, Cornet AD, Hofstra JJ, Porcelijn L, Beishuizen A, Kulik W, Vroom MB, Schultz MJ, Groeneveld AB, Juffermans NP. There is an association between blood transfusion and pulmonary complications in cardiac surgery. Mediators of increased pulmonary vascular leakage after transfusion are unknown. We hypothesized that factors may include antibodies or bioactive lipids, which have been implicated in transfusion-related acute lung injury.Study, design and methods: We performed a prospective cohort study in two university hospital intensive care units in the Netherlands. Pulmonary vascular permeability was measured in cardiac surgery patients after receiving no, restrictive (one or two transfusions), or multiple (five or more transfusions) transfusions (n=20 per group). The pulmonary leak index (PLI), using (67) Ga-labeled transferrin, was determined within 3 hours postoperatively. Blood products were screened for bioactive lipid accumulation and the presence of antibodies.
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Results: The PLI was elevated in all groups after cardiac surgery. Transfused patients had a higher PLI compared to nontransfused patients (33x10(-3) +/- 20x10(3) vs. 23x10(-3) +/- 11x10(-3)/min, p<0.01). The amount of red blood cell (RBC) products, but not of fresh-frozen plasma or platelets, was associated with an increase in PLI (beta, 1.6 [0.2-3.0]). Concerning causative factors in the blood product, neither the level of bioactive lipids nor the presence of antibodies was associated with an increase in PLI. Patient factors such as surgery risk and time on cardiopulmonary bypass did not influence the risk of pulmonary leakage after blood transfusion. Conclusions: Transfusion in cardiothoracic surgery patients is associated with an increase in pulmonary capillary permeability, an effect that was dose dependent for RBC products. The level of bioactive lipids or the presence of HLA or HNA antibodies in the transfused products were not associated with increased pulmonary capillary permeability. Transfusion 2012;52:82-90. Impact factor: 3.526
16. Optimal protein and energy nutrition decreases mortality in mechanically ventilated, critically ill patients: a prospective observational cohort study. Weijs PJ, Stapel SN, de Groot SD, Driessen RH, de Jong E, Girbes AR, Strack van Schijndel RJ, Beishuizen A. Background: Optimal nutrition for patients in the intensive care unit has been proposed to be the provision of energy as determined by indirect calorimetry and the provision of protein of at least 1.2 g/kg. Methods: Prospective observational cohort study in a mixed medical-surgical intensive care unit in an academic hospital. In total, 886 consecutive mechanically ventilated patients were included. Nutrition was guided by indirect calorimetry and protein provision of at least 1.2 g/kg. Cumulative intakes were calculated for the period of mechanical ventilation. Cox regression was used to analyze the effect of protein + energy target achieved or energy target achieved versus neither target achieved on 28-day mortality, with adjustments for sex, age, body mass index, Acute Physiology and Chronic Health Evaluation II, diagnosis, and hyperglycemic index. Results: Patients' mean age was 63 +/- 16 years; body mass index, 26 +/- 6; and Acute Physiology and Chronic Health Evaluation II, 23 +/- 8. For neither target, energy target, and protein + energy target, energy intake was 75% +/- 15%, 96% +/5%, and 99% +/- 5% of target, and protein intake was 72% +/- 20%, 89% +/- 10%, and 112% +/- 12% of target, respectively. Hazard ratios (95% confidence interval) for energy target and protein + energy target were 0.83 (0.67-1.01) and 0.47 (0.310.73) for 28-day mortality. Conclusions: Optimal nutritional therapy in mechanically ventilated, critically ill patients, defined as protein and energy targets reached, is associated with a decrease in 28-day mortality by 50%, whereas only reaching energy targets is not associated with a reduction in mortality.
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JPEN J Parenter Enteral Nutr 2012;36:60-68. Impact factor: 2.486
Totale impact factor: 79.577 Gemiddelde impact factor: 4.974 Aantal artikelen 1e, 2e of laatste auteur: 7 Totale impact factor: 38.321 Gemiddelde impact factor: 5.474
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Interne Geneeskunde 1. Kidney injury during VEGF inhibitor therapy. den Deurwaarder ES, Desar IM, Steenbergen EJ, Mulders PF, Wetzels FM, van Herpen CM. Antiangiogenic therapy targeting vascular endothelial growth factor (VEGF) or its receptor (VEGFR) has proven its effect in the treatment of several types of cancer, including renal cell carcinoma (RCC). However, treatment can be accompanied by notable adverse effects. Mild proteinuria and hypertension are often seen, but sometimes nephrotic range proteinuria and/or renal insufficiency develop. In recent years insight into the toxic effects of anti-VEGF therapy in the kidney has increased. A few biopsies have been done and thrombotic microangiopathy is reported in the majority of cases. However, other patterns of kidney injury have been described as illustrated by the case of a 62-year-old patient who presented two years after initiation of the VEGFR inhibitor cediranib with a nephrotic syndrome and acute renal failure. Kidney biopsy disclosed focal segmental glomerulosclerosis (FS GS) and interstitial nephritis. Partial remission was achieved after stopping the cediranib and a short course of prednisone. We review the different forms of kidney injury that could be caused by anti-VEGF therapy. Neth J Med 2012;70:267-271. Impact factor: 2.383
2. Circulating tumor cells, disease recurrence and survival in newly diagnosed breast cancer. Franken B, de Groot MR, Mastboom WJ, Vermes I, van der Palen J, Tibbe AG, Terstappen LW Background: The presence of circulating tumor cells (CTC) is an independent prognostic factor for progression-free survival and breast cancer related death (BRD) for patients with metastatic breast cancer beginning a new line of systemic therapy. The current study was undertaken to explore whether the presence of CTC at the time of diagnosis was associated with recurrence free survival (RFS) and BRD. Methods: In a prospective single center study, CTC were enumerated with the CellSearch system in 30 ml of peripheral blood of 602 patients before undergoing surgery for breast cancer. 97 patients had a benign tumor, 101 did not meet the inclusion criteria of which 48 patients with DCIS, leaving 404 stage I-III patients. Patients were stratified into unfavorable (CTC [greater than or equal to]1) and favorable (CTC = 0) prognostic groups. Results: >1 CTC in 30 ml blood was detected in 15 (15%) benign tumors, in 9 DCIS (19%), in 28 (16%) stage I, 32 (18%) stage II and in 16 (31%) patients with stage III. In stage I-III patients 76 (19%) had >1 CTC of whom 16 (21.1%) developed a recurrence. In 328 patients with 0 CTC 38 (11.6%) developed a recurrence. Four year RFS was 88.4% for favorable CTC and 78.9% for unfavorable CTC (p =0.038).
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25 patients died of breast cancer related causes and 11 (44%) had >1 CTC. BRD was 4,3% for favorable and 14,5% for unfavorable CTC (p = 0.001). In multivariate analysis >1 CTC was associated with distant disease free survival, but not for overall recurrence free survival. CTC, progesterone receptor and N-stage were independent predictors of BRD in multivariate analysis. Conclusions: Presence of CTC in breast cancer patients before undergoing surgery with curative intend is associated with an increased risk for breast cancer related death. Breast Cancer Res 2012;14:R133. Impact factor: 5.872
3. Temporary antiretroviral treatment during primary HIV-1 infection has a positive impact on health-related quality of life: data from the Primo-SHM cohort study. Grijsen M, Koster G, van Vonde3ren M, van Kasteren M, Kootstra G, Steingrover R, de Wolf F, Prins J, Nieuwkerk P. Objectives: The aim of the study was to compare health-related quality of life (HRQL) over 96 weeks in patients receiving no treatment or 24 or 60 weeks of combination antiretroviral therapy (cART) during primary HIV-1 infection (PHI). Methods: A multicentre prospective cohort study of PHI patients, with an embedded randomized trial, was carried out. HRQL was assessed with the Medical Outcomes Study Health Survey for HIV (MOS-HIV) and a symptom checklist administered at weeks 0, 8, 24, 36, 48, 60, 72, 84 and 96. Mixed linear models were used for the analysis of differences in HRQL among the three groups. Results: A total of 112 patients were included in the study: 28 received no treatment, 45 received 24 weeks of cART and 39 received 60 weeks of cART. Over 96 weeks of follow-up, the groups receiving 24 and 60 weeks of cART had better cognitive functioning than the no-treatment group (P = 0.005). Patients receiving 60 weeks of cART had less pain (P = 0.004), better role functioning (P = 0.001), better physical functioning (P = 0.02) and a better physical health summary score (P = 0.006) than the groups receiving no treatment or 24 weeks of cART. Mental health was better in patients receiving 24 weeks of cART than in patients in the notreatment group or the group receiving 60 weeks of cART (P = 0.02). At week 8, patients in the groups receiving 24 and 60 weeks of cART reported more nausea (P = 0.002), diarrhoea (P < 0.001), abdominal pain (P = 0.02), stomach pain (P = 0.049) and dizziness (P = 0.01) than those in the no-treatment group. These differences had disappeared by week 24. Conclusions: Temporary cART during PHI had a significant positive impact on patients' HRQL as compared with no treatment, despite the initial, short-term occurrence of more physical symptoms, probably related to drug toxicity. HIV Med 2012;13:630-635. Impact factor: 3.155
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4. No treatment versus 24 or 60 weeks of antiretroviral treatment during primary HIV infection: the randomized Primo-SHM trial. Grijsen ML, Steingrover R, Wit FW, Jurriaans S, Verbon A, Brinkman K, van der Ende ME, Soetekouw R, de WF, Lange JM, Schuitemaker H, Prins JM, Vermeulen JN, Nievaard M, Slegtenhorst B, Doevelaar H, Koevoets W, Nobe HE, Henderiks A, Pijnappel FJ, Rijnders BJ, Padmos I, van ZL, Been S, Kauffmann RH, Schippers EF, Korte R, van Ijperen JM, ten Kate RW, Hulshoff N, Schoemaker-Ransijn M, Kroon FP, Dorama W, Moons CA, Lowe SH, Schreij G, van der Geest S, Oude Lashof AM, Schippers J, Bronsveld W, van TG, van HD, van Vonderen MG, Faber S, Rotteveel S, ten Napel CH, Kootstra GJ, Heins H, van den Berk GE, Blok WL, Frissen PH, Schouten WE, Schrijnders L, van EA, Verhage DW, Groot M, Brokking W, Mulder JW, van Kasteren ME, Juttmann JR, Kuipers M, Veenstra J, Lettinga KD, Koopmans PP, Bosch M, Hoepelman IM, Mudrikova T, de K, I. Background: The objective of this study was to assess the benefit of temporary combination antiretroviral therapy (cART) during primary HIV infection (PHI). Methods and findings: Adult patients with laboratory evidence of PHI were recruited in 13 HIV treatment centers in the Netherlands and randomly assigned to receive no treatment or 24 or 60 wk of cART (allocation in a 1ratio1ratio1 ratio); if therapy was clinically indicated, participants were randomized over the two treatment arms (allocation in a 1ratio1 ratio). Primary end points were (1) viral set point, defined as the plasma viral load 36 wk after randomization in the no treatment arm and 36 wk after treatment interruption in the treatment arms, and (2) the total time that patients were off therapy, defined as the time between randomization and start of cART in the no treatment arm, and the time between treatment interruption and restart of cART in the treatment arms. cART was (re)started in case of confirmed CD4 cell count < 350 cells/mm(3) or symptomatic HIV disease. In total, 173 participants were randomized. The modified intention-to-treat analysis comprised 168 patients: 115 were randomized over the three study arms, and 53 randomized over the two treatment arms. Of the 115 patients randomized over the three study arms, mean viral set point was 4.8 (standard deviation 0.6) log(10) copies/ml in the no treatment arm, and 4.0 (1.0) and 4.3 (0.9) log(10) copies/ml in the 24- and 60-wk treatment arms (between groups: p < 0.001). The median total time off therapy in the no treatment arm was 0.7 (95% CI 0.0-1.8) y compared to 3.0 (1.9-4.2) and 1.8 (0.5-3.0) y in the 24- and 60-wk treatment arms (log rank test, p < 0.001). In the adjusted Cox analysis, both 24 wk (hazard ratio 0.42 [95% CI 0.250.73]) and 60 wk of early treatment (hazard ratio 0.55 [0.32-0.95]) were associated with time to (re)start of cART. Conclusions: In this trial, temporary cART during PHI was found to transiently lower the viral set point and defer the restart of cART during chronic HIV infection. PLoS Med 2012;9:e1001196. Impact factor: 15.253
5. Raynaud-like phenomenon in two patients on nilotinib. Hazenberg CL, Ossenkoppele GJ, Smit WM.
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Br J Haematol 2012;158:431. Impact factor: 4.942
6. Impact of antiretroviral therapy on tuberculosis incidence among HIVpositive patients in high-income countries. HIV-CAUSAL Collaboration, inclusef ten Napel CH, Kootstra GJ, Background: The lower tuberculosis incidence reported in human immunodeficiency virus (HIV)-positive individuals receiving combined antiretroviral therapy (cART) is difficult to interpret causally. Furthermore, the role of unmasking immune reconstitution inflammatory syndrome (IRIS) is unclear. We aim to estimate the effect of cART on tuberculosis incidence in HIV-positive individuals in highincome countries. Methods: The HIV-CAUSAL Collaboration consisted of 12 cohorts from the United States and Europe of HIV-positive, ART-naive, AIDS-free individuals aged >/=18 years with baseline CD4 cell count and HIV RNA levels followed up from 1996 through 2007. We estimated hazard ratios (HRs) for cART versus no cART, adjusted for time-varying CD4 cell count and HIV RNA level via inverse probability weighting. Results: Of 65 121 individuals, 712 developed tuberculosis over 28 months of median follow-up (incidence, 3.0 cases per 1000 person-years). The HR for tuberculosis for cART versus no cART was 0.56 (95% confidence interval [CI], 0.440.72) overall, 1.04 (95% CI, 0.64-1.68) for individuals aged >50 years, and 1.46 (95% CI, 0.70-3.04) for people with a CD4 cell count of <50 cells/muL. Compared with people who had not started cART, HRs differed by time since cART initiation: 1.36 (95% CI, 0.98-1.89) for initiation <3 months ago and 0.44 (95% CI, 0.34-0.58) for initiation >/=3 months ago. Compared with people who had not initiated cART, HRs <3 months after cART initiation were 0.67 (95% CI, 0.38-1.18), 1.51 (95% CI, 0.98-2.31), and 3.20 (95% CI, 1.34-7.60) for people <35, 35-50, and >50 years old, respectively, and 2.30 (95% CI, 1.03-5.14) for people with a CD4 cell count of <50 cells/muL. Conclusions: Tuberculosis incidence decreased after cART initiation but not among people >50 years old or with CD4 cell counts of <50 cells/muL. Despite an overall decrease in tuberculosis incidence, the increased rate during 3 months of ART suggests unmasking IRIS. Clin Infect Dis 2012;54:1364-1372. Impact factor: 9.374
7. Leaky cell syndrome: a rare cause of pseudohyperkalaemia. Lukens MV, de Mare A, Kerbert-Dreteler MJ, van den Bergh FA Life-threatening situations of hyperkalaemia are often caused by renal failure, hyperglycaemia or medication. However pseudohyperkalaemia, a falsely elevated potassium concentration, is usually caused by haemolysis, repeated clenching of the fist during venepuncture or abnormal cell numbers. Another rare cause of
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pseudohyperkalaemia is familial pseudohyperkalaemia, an autosomal dominantly inherited trait, with increased leakage of potassium from erythrocytes. Under normal in vivo conditions, this increased leakage is compensated by augmented activity of the Na(+)/K(+) ATPase pump. However, after venepuncture the blood cools down to room temperature, reducing the activity of the Na(+)/K(+) ATPase pump whereby the increased potassium leakage becomes more apparent. Here, we present a Dutch patient with extreme familial pseudohyperkalaemia. Interestingly, his two children also show increased potassium leakage at room temperature, albeit at a lower level. Despite the low prevalence of familial pseudohyperkalaemia, it can have important clinical implications and rapid recognition is desired. Ann Clin Biochem 2012;49:97-100. Impact factor: 1.922
8. Favorable effect of priming with granulocyte colony-stimulating factor in remission induction of acute myeloid leukemia restricted to dose escalation of cytarabine. Pabst T, Vellenga E, van PW, Schouten HC, Graux C, Vekemans MC, Biemond B, Sonneveld P, Passweg J, Verdonck L, Legdeur MC, Theobald M, Jacky E, Bargetzi M, Maertens J, Ossenkoppele GJ, Lowenberg B. The clinical value of chemotherapy sensitization of acute myeloid leukemia (AML) with G-CSF priming has remained controversial. Cytarabine is a key constituent of remission induction chemotherapy. The effect of G-CSF priming has not been investigated in relationship with variable dose levels of cytarabine. We randomized 917 AML patients to receive G-CSF (456 patients) or no G-CSF (461 patients) at the days of chemotherapy. In the initial part of the study, 406 patients were also randomized between 2 cytarabine regimens comparing conventional-dose (199 patients) versus escalated-dose (207 patients) cytarabine in cycles 1 and 2. We found that patients after induction chemotherapy plus G-CSF had similar overall survival (43% vs 40%, P = .88), event-free survival (37% vs 31%, P = .29), and relapse rates (34% vs 36%, P = .77) at 5 years as those not receiving G-CSF. However, patients treated with the escalated-dose cytarabine regimen benefited from G-CSF priming, with improved event-free survival (P = .01) and overall survival (P = .003), compared with patients without G-CSF undergoing escalated-dose cytarabine treatment. A significant survival advantage of sensitizing AML for chemotherapy with G-CSF was not apparent in the entire study group, but it was seen in patients treated with escalated-dose cytarabine during remission induction. The HOVON-42 study is registered under The Netherlands Trial Registry (www.trialregister.nl) as #NTR230 Blood 2012;119:5367-5373. Impact factor: 9.060
9. A randomized phase II study investigating the addition of the specific COX-2 inhibitor celecoxib to docetaxel plus carboplatin as first-line chemotherapy for
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stage IC to IV epithelial ovarian cancer, Fallopian tube or primary peritoneal carcinomas: the DoCaCel study. Reyners AK, de ML, Erdkamp FL, Smit WM, Hoekman K, Lalisang RI, de GH, Wymenga AN, Polee M, Hollema H, van Vugt MA, Schaapveld M, Willemse PH. Background: In ovarian cancer, cyclooxygenase-2 (COX-2) overexpression is prognostic for poor survival. We investigated the efficacy of celecoxib (C), a selective COX-2 inhibitor, added to docetaxel (Taxotere)/carboplatin (DC) in advanced ovarian cancer.Patients and methods: In a phase II, randomized study, 400 mg celecoxib b.i.d. was added to first-line DC treatment (DCC). Celecoxib was to be continued after DC termination up to 3 years. Study end points were tolerability, progression-free survival (PFS) and overall survival (OS). Results: 151 of 196 eligible patients were diagnosed with stage IIIC/IV disease. Median follow-up for patients alive was 32.3 months. Celecoxib was used during a mean of 8.5 months. Twenty-three of 97 DCC patients stopped celecoxib prematurely, mainly due to skin reactions. Complete biochemical response was achieved in 51/78 DC patients (65%) versus 57/78 DCC patients (75%, not significant). In both study arms, median PFS was 14.3 months and median OS 34 months. COX-2 was expressed in 82% of 120 tumor samples retrospectively recovered. The PFS and OS of patients with intermediate/high COX-2 expression were similar to that in the other patients. Conclusion: Celecoxib did not influence PFS and OS, but interpretation of results is hampered by premature celecoxib discontinuation. Ann Oncol 2012;23:2896-2902. Impact factor: 7.384
10. Bortezomib Induction and Maintenance Treatment in Patients With Newly Diagnosed Multiple Myeloma: Results of the Randomized Phase III HOVON-65/ GMMG-HD4 Trial. Sonneveld P, Schmidt-Wolf IG, van der Holt B, El JL, Bertsch U, Salwender H, Zweegman S, Vellenga E, Broyl A, Blau IW, Weisel KC, Wittebol S, Bos GM, Stevens-Kroef M, Scheid C, Pfreundschuh M, Hose D, Jauch A, van d, V, Raymakers R, Schaafsma MR, Kersten MJ, van Marwijk-Kooy M, Duehrsen U, Lindemann W, Wijermans PW, Lokhorst HM, Goldschmidt HM. Purpose: We investigated whether bortezomib during induction and maintenance improves survival in newly diagnosed multiple myeloma (MM). Patients and methods: 827 eligible patients with newly diagnosed symptomatic MM were randomly assigned to receive induction therapy with vincristine, doxorubicin, and dexamethasone (VAD) or bortezomib, doxorubicin, and dexamethasone (PAD) followed by high-dose melphalan and autologous stem-cell transplantation. Maintenance consisted of thalidomide 50 mg (VAD) once per day or bortezomib 1.3 mg/m(2) (PAD) once every 2 weeks for 2 years. The primary analysis was progression-free survival (PFS) adjusted for International Staging System (ISS) stage.
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Results: Complete response (CR), including near CR, was superior after PAD induction (15% v 31%; P < .001) and bortezomib maintenance (34% v 49%; P < .001). After a median follow-up of 41 months, PFS was superior in the PAD arm (median of 28 months v 35 months; hazard ratio [HR], 0.75; 95% CI, 0.62 to 0.90; P = .002). In multivariate analysis, overall survival (OS) was better in the PAD arm (HR, 0.77; 95% CI, 0.60 to 1.00; P = .049). In high-risk patients presenting with increased creatinine more than 2 mg/dL, bortezomib significantly improved PFS from a median of 13 months to 30 months (HR, 0.45; 95% CI, 0.26 to 0.78; P = .004) and OS from a median of 21 months to 54 months (HR, 0.33; 95% CI, 0.16 to 0.65; P < .001). A benefit was also observed in patients with deletion 17p13 (median PFS, 12 v 22 months; HR, 0.47; 95% CI, 0.26 to 0.86; P = .01; median OS, 24 months v not reached at 54 months; HR, 0.36; 95% CI, 0.18 to 0.74; P = .003). Conclusion: Bortezomib during induction and maintenance improves CR and achieves superior PFS and OS J Clin Oncol 2012;30:2946-2955. Impact factor: 18.038
11. Two sides of the medallion: poor treatment tolerance but better survival by standard chemotherapy in elderly patients with advanced-stage diffuse large B-cell lymphoma. van de Schans SA, Wymenga AN, van Spronsen DJ, Schouten HC, Coebergh JW, Janssen-Heijnen Background: We investigated treatment of unselected elderly patients with diffuse large B-cell lymphoma (DLBCL) and its subsequent impact on treatment tolerance and survival. Patients and methods: Data from all 419 advanced-stage DLBCL patients, aged 75 or older and newly diagnosed between 1997 and 2004, were included from five regional population-based cancer registries in The Netherlands. Subsequent data on comorbidity, performance status, treatment, motives for adaptations or refraining from chemotherapy and toxic effects was collected from the medical records. Follow-up was completed until 1st January 2009. Results: Only 46% of patients received the standard therapy [aggressive chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP)-like chemotherapy]. Motives for withholding chemotherapy were refusal by patient/family, poor performance status or estimated short life expectancy. Of all patients receiving CHOP-like chemotherapy, only 56% could complete at least six cycles. Grade 3 or 4 toxicity occurred in 67% of patients receiving standard therapy. The independent effect of therapy on survival remained after correction for the ageadjusted International Prognostic Index. Conclusions: Standard therapy was applied less often in elderly patients with a subsequent independent negative impact on survival. Furthermore, high toxicity rate and the impossibility of the majority of patients to complete treatment were seen. This implies that better treatment strategies should be devised including a proper selection of senior patients for this aggressive chemotherapy.
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ML Ann Oncol 2012;23:1280-1286. Impact factor: 7.384
12. Long-term complications in patients with poor immunological recovery despite virological successful HAART in Dutch ATHENA cohort. van Lelyveld SF, Gras L, Kesselring A, Zhang S, de WF, Wensing AM, Hoepelman AI, Including ten Napel CH, Kootstra GJ Objective: We investigated the risk of AIDS and serious non-AIDS-defining diseases (non-ADDs) according to the degree of immunological recovery after 2 years of virological successful antiretroviral therapy (HAART).Design: Retrospective observational cohort study including HIV-infected patients treated with HAART resulting in viral suppression (<500 copies/ml). Methods: Patients were grouped according to their CD4 cell count after 2 years of HAART: CD4 cell count less than 200 cells/mul (group A), 200-350 cells/mul (group B), 351-500 cells/mul (group C) or more than 500 cells/mul (group D). Analysis was done to assess predictors for poor immunological recovery and the occurrence of a composite endpoint [death, AIDS, malignancies, liver cirrhosis and cardiovascular events (CVEs)], non-ADDs, CVEs and non-AIDS-defining malignancies (nonADMs). Results: Three thousand and sixty-eight patients were included. Older age, lower CD4 cell nadir and lower plasma HIV-RNA at the start of HAART were independent predictors for a poor immunological recovery. The composite endpoint, non-ADDs and CVE were observed most frequently in group A (overall log rank, P < 0.0001, P = 0.002 and P = 0.01). In adjusted analyses, age was a strong independent predictor for all endpoints. Compared with group A, patients in group D had a lower risk for the composite endpoint [hazard ratio 0.54 (95% confidence interval [CI] 0.330.87]; patients in group B had a lower risk for CVEs [hazard ratio 0.34 (95% CI 0.140.86)]. Conclusion: Poor immunological recovery despite virological successful HAART is associated with a higher risk for overall morbidity and mortality and CVEs in particular. This study underlines the importance of starting HAART at higher CD4 cell counts, particularly in older patients. AIDS 2012;26:465-474. Impact factor: 6.407
13. Increased adjuvant treatment and improved survival in elderly stage III colon cancer patients in The Netherlands. van Steenbergen LN, Lemmens VE, Rutten HJ, Wymenga AN, Nortier JW, JanssenHeijnen ML Background: We determined to what extent patients with colon cancer stage III >/=75 years received adjuvant chemotherapy and the impact on overall and disease-specific survival.
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Patients and methods: Data from The Netherlands Cancer Registry on all 8051 patients with colon cancer stage III >/=75 years diagnosed in 1997-2009 were included. Trends in adjuvant chemotherapy administration were analysed and multivariable overall and disease-specific survival analyses were performed. Results: The proportion of stage III colon cancer patients >/=75 years who received adjuvant chemotherapy increased from 12% in 1997-2000 to 23% in 2007-2009 (P < 0.0001), with a marked age gradient and large geographic variation. Five-year overall survival increased over time from 28% in 1997-2000 to 35% in 2004-2006 (P < 0.0001). Sixty percent of patients died of colorectal cancer. Adjuvant chemotherapy was the strongest positive predictor of survival in this retrospective study (hazard ratio = 0.5; 95% confidence interval: 0.4-0.5). Conclusion: There has been an increase in administration of adjuvant chemotherapy to elderly patients with stage III colon cancer in The Netherlands since 1997. Survival of elderly patients with stage III colon cancer increased over time, at least partly due to stage migration. The large effect of adjuvant chemotherapy on survival in this study is likely to be associated with the selection of fitter patients for adjuvant treatment. Impact
Ann Oncol 2012;23:2805-2811. factor: 7.384
14. Infections and inflammatory diseases as risk factors for venous thrombosis. A systematic review Tichelaar YI, Kluin-Nelemans HJ, Meijer K Inflammation and venous thrombosis are intertwined. Only in the recent 15 years clinical epidemiological studies have focussed on inflammatory or infectious diseases as risk factors for venous thrombosis. Although a few reviews and many case reports or studies on these topic has been written, a review reporting relative or absolute risks for venous thrombosis has not been published yet. We performed a systematic review using Medline, Pubmed and Embase and found 31 eligible articles. Inflammatory bowel disease, ANCA-associated vasculitis, infections in general and more specifically, human immunodeficiency virus, pneumonia and urinary tract infections are associated with an increased risk of venous thrombosis. Thromb Haemost. 2012;107(5):827-37 Impact factor: 6.081
15. The acute phase reaction explains only a part of initially elevated factor VIII:C levels: a prospective cohort study in patients with venous thrombosis Tichelaar V, Mulder A, Kluin-Nelemans H, Meijer K We determined in a prospective cohort of patients treated with vitamin K antagonists for venous thrombosis, the course of factor VIII (FVIII:C), C-reactive protein (CRP) and fibrinogen levels, to assess the influence of the acute phase reaction on FVIII:C levels. Second, we hypothesized that patients with preceding infectious symptoms
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might have higher levels of FVIII:C at baseline than patients without those. We included 75 patients. Blood was sampled at baseline, once during treatment (t=1) and at the end of treatment (t=2). Mean levels of FVIII:C were 207, 186 and 175IU/dL (p for trend 0.003) at baseline, t=1 and t=2 respectively. Eight-eight percent of patients had an elevated FVIII:C at baseline, 75% at t=1 and 72% at t=2 (p for trend 0.045). Mean levels of FVIII:C were not different in patients with or without preceding infectious symptoms (206 versus 205IU/dL respectively). A baseline CRP level below 62mg/L could best distinguish between patients who will keep an elevated FVIII:C and those who will drop below 150IU/dL. We conclude that FVIII:C levels are partially influenced by the acute phase reaction, especially in patients who keep a persistent elevated FVIII:C during treatment. Preceding infectious symptoms did not influence baseline FVIII:C levels. Thromb Res. 2012;129(2):183-6 Impact factor: 2.799
Totale impact factor: 107.438 Gemiddelde impact factor: 7.163 Aantal artikelen 1e, 2e of laatste auteur: 6 Totale impact factor: 36.036 Gemiddelde impact factor: 6.006
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Kindergeneeskunde 1. Inspiratory airflow limitation after exercise challenge in cold air in asthmatic children. Driessen JM, van der Palen J, van Aalderen WM, de Jongh FH, Thio BJ Methacholine and histamine can lead to inspiratory flow limitation in asthmatic children and adults. This has not been analyzed after indirect airway stimuli, such as exercise. The aim of the study was to analyze airflow limitation after exercise in cold, dry air. 72 asthmatic children with mild to moderate asthma (mean age 13.2 +/- 2.2 yrs) performed a treadmill exercise challenge. A fall of >10% in FEV(1) was the threshold for expiratory flow limitation and a fall of >25% of MIF(50) was the threshold for inspiratory flow limitation. The occurrence of wheeze, stridor and cough were quantified before and after exercise. After exercise, the mean fall in FEV(1) was 17.7 +/- 14.6%, while the mean fall in MIF(50) was 25.4 +/- 15.8%; no correlation was found between fall in FEV(1) and MIF(50) (R(2): 0.04; p = 0.717). 53 of the 72 children showed an inspiratory and/or expiratory airflow limitation. 38% (20/53) of these children showed an isolated expiratory flow limitation, 45% (24/53) showed both expiratory and inspiratory flow limitation and 17% (9/53) showed an isolated inspiratory flow limitation. The fall in FEV(1) peaked 9 min after exercise and correlated to expiratory wheeze. The fall in MIF(50) peaked 15 min after exercise and correlated to inspiratory stridor. The time difference in peak fall between FEV(1) and MIF(50) was statistically significant (5.9 min; p < 0.001, 99% CI: 2.3-9.5 min). In conclusion, this study shows that an exercise challenge in asthmatic children can give rise to inspiratory airflow limitation, which may give rise to asthma like symptoms. Respir Med 2012;106:1362-1368. Impact factor: 2.585
2. Effect of an intranasal corticosteroid on exercise induced bronchoconstriction in asthmatic children. Kersten ET, van Leeuwen JC, Brand PL, Duiverman EJ, de Jongh FH, Thio BJ, Driessen JM Allergic rhinitis and exercise induced bronchoconstriction (EIB) are common in asthmatic children. The aim of this study was to investigate whether treatment of allergic rhinitis with an intranasal corticosteroid protects against EIB in asthmatic children. Methods: This was a double-blind, randomized, placebo-controlled, parallel group study. Subjects aged 12-17 years, with mild-to-moderate asthma, intermittent allergic rhinitis and >/= 10% fall in FEV(1) at a screening exercise challenge were randomized to 22 +/- 3 days treatment with intranasal fluticasone furoate or placebo. The primary outcome was change in exercise induced fall in FEV(1) . Secondary outcomes were changes in the area under the curve (AUC), asthma control questionnaire (ACQ), pediatric asthma quality of life questionnaire (PAQLQ), and exhaled nitric oxide (FeNO).
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Results: Twenty-five children completed the study. Mean exercise induced fall in FEV(1) (+/- SD) decreased significantly (95% CI: 0.7-18.2%, P = 0.04) in the fluticasone furoate group from 28.4 +/- 15.8% to 19.0 +/- 13.8%, compared to the placebo group (27.4 +/- 16.0% to 27.4 +/- 19.2%). The change in AUC was not significantly different between treatment groups. However, within the fluticasone furoate group the AUC decreased significantly (P = 0.01). Although total PAQLQ score did not improve, the activity limitation domain score improved significantly within the fluticasone furoate group (P = 0.03). No significant changes were observed in FeNO and ACQ. Conclusion: Treatment of allergic rhinitis in asthmatic children with an intranasal corticosteroid reduces EIB and tends to improve quality of life. Pediatr Pulmonol 2012;47:27-35. Impact factor: 2.375
3. Beneficial Effects of Growth Hormone Treatment on Cognition in Children with Prader-Willi Syndrome: A Randomized Controlled Trial and Longitudinal Study. Siemensma EP, Tummers-de Lind van Wijngaarden RF, Festen DA, Troeman ZC, van Alfen-van der Velden AA, Otten BJ, Rotteveel J, Odink RJ, Bindels-de Heus GC, van Leeuwen M, Haring DA, Oostdijk W, Bocca G, Mieke Houdijk EC, van Trotsenburg AS, Hoorweg-Nijman JJ, van Wieringen H, Vreuls RC, Jira PE, Schroor EJ, van Pinxteren-Nagler E, Pilon JW, Lunshof LB, Hokken-Koelega AC. Background:Knowledge about the effects of GH treatment on cognitive functioning in children with Prader-Willi syndrome (PWS) is limited. Methods: Fifty prepubertal children aged 3.5 to 14 yr were studied in a randomized controlled GH trial during 2 yr, followed by a longitudinal study during 4 yr of GH treatment. Cognitive functioning was measured biennially by short forms of the WPPSI-R or WISC-R, depending on age. Total IQ (TIQ) score was estimated based on two subtest scores. Results: During the randomized controlled trial, mean sd scores of all subtests and mean TIQ score remained similar compared to baseline in GH-treated children with PWS, whereas in untreated controls mean subtest sd scores and mean TIQ score decreased and became lower compared to baseline. This decline was significant for the Similarities (P = 0.04) and Vocabulary (P = 0.03) subtests. After 4 yr of GH treatment, mean sd scores on the Similarities and Block design subtests were significantly higher than at baseline (P = 0.01 and P = 0.03, respectively), and scores on Vocabulary and TIQ remained similar compared to baseline. At baseline, children with a maternal uniparental disomy had a significantly lower score on the Block design subtest (P = 0.01) but a larger increment on this subtest during 4 yr of GH treatment than children with a deletion. Lower baseline scores correlated significantly with higher increases in Similarities (P = 0.04) and Block design (P < 0.0001) sd scores. Conclusions: Our study shows that GH treatment prevents deterioration of certain cognitive skills in children with PWS on the short term and significantly improves
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abstract reasoning and visuospatial skills during 4 yr of GH treatment. Furthermore, children with a greater deficit had more benefit from GH treatment. J Clin Endocrinol Metab 2012;97:2307-2314. Impact factor: 6.430
4. Equal Virulence of Rhinovirus and Respiratory Syncytial Virus in Infants Hospitalized for Lower Respiratory Tract Infection. van Leeuwen JC, Goossens LK, Hendrix RM, van der Palen J, Lusthusz A, Thio BJ Respiratory syncytial virus (RSV) and rhinovirus (RV) are predominant viruses associated with lower respiratory tract infection in infants. We compared the symptoms of lower respiratory tract infection caused by RSV and RV in hospitalized infants. RV showed the same symptoms as RSV, so on clinical grounds, no difference can be made between these pathogens. No relation between polymerase chain reaction cycle threshold value and length of hospital stay was found. Pediatr Infect Dis J 2012;31:84-86. Impact factor:3.569
5. Superior mesenteric artery aneurysm in a 9-year-old boy with classical Ehlers-Danlos syndrome. de Leeuw K, Goorhuis JF, Tielliu IF, Symoens S, Malfait F, de Paepe A, van Tintelen JP, Hulscher JB. A 9-year-old boy with the classical type of Ehlers-Danlos syndrome (EDS) developed a symptomatic aneurysm of the superior mesenteric artery. His EDS diagnosis had been confirmed biochemically and genetically. Vascular complications are known to be associated with the vascular type of EDS, but this is the first report of a child with classical EDS who developed a major vascular complication. Clinicians should be aware that severe vascular complications albeit rare, can also occur in classical EDS. Am J Med Genet A 2012;158A:626-629. Impact factor: 2.304
6. Additional value of upper GI tract endoscopy in the diagnostic assessment of childhood IBD. Hummel TZ, ten Kate FJ, Reitsma JB, Benninga MA, Kindermann A Objectives: For the choice of treatment in children with inflammatory bowel disease (IBD), it is important to make a distinction between Crohn disease (CD) and ulcerative colitis (UC). To look for pathognomonic features of CD, upper gastrointestinal tract (UGT) endoscopy has become part of the routine evaluation of children with suspected IBD; however, pathological changes can also be found in 13 1
the UGT in patients with UC. The aims of the present study were to establish the role of UGT involvement in the diagnostic assessment of suspected IBD in children and to detect histopathological changes in the UGT mucosa, which can distinguish CD from non-CD (UC and non-IBD). Methods: Biopsies (colon, ileum, duodenum, stomach, esophagus) from children suspected of having IBD who underwent endoscopy between 2003 and 2008 were reassessed by a blinded, expert pathologist. The histological findings of the UGT were compared with the diagnosis based on ileocolonic biopsies and the final diagnosis. Results: In 11% of the children with CD, the diagnosis was based solely on the finding of granulomatous inflammation in the UGT. Focal cryptitis of the duodenum and focally enhanced gastritis were found significantly more frequently in children with CD compared with children with UC and non-IBD, with a specificity and positive predictive value of 99% and 93% and 87.1% and 78.6%, respectively. Conclusions: Histology on ileocolonic biopsies alone is insufficient for a correct diagnosis of CD or UC in children. UGT endoscopy should, therefore, be performed in the diagnostic assessment of all children suspected of having IBD. J Pediatr Gastroenterol Nutr. 2012;54(6):753-7 Impact factor: 2.196
Totale impact factor: 19,459 Gemiddelde impact factor: 3.243 Aantal artikelen 1e, 2e of laatste auteur: 5 Totale impact factor: 13.029 Gemiddelde impact factor: 2.606
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Klinische Chemie 1. Dexamethasone suppression test: development of a method for simultaneous determination of cortisol and dexamethasone in human plasma by liquid chromatography/tandem mass spectrometry. Hempen C, Elfering S, Mulder AH, van den Bergh FA, Maatman RG Background: Dexamethasone is a synthetic glucocorticoid and is analogous to cortisol. It is used in the low-dose overnight dexamethasone suppression test (LDODST) to diagnose hypercortisolism in patients suspected to be suffering from Cushing's syndrome (CS). Measuring plasma dexamethasone in conjunction with measuring the amount of cortisol following the LDODST may allow clinicians to improve the diagnosis of CS. Methods: Plasma samples were cleaned up by solid-phase extraction before analysis. Liquid chromatographic separation was carried out under reversed-phase conditions prior to detection by tandem mass spectrometry. The analytes were determined in the presence of deuterated internal standards cortisol-d4 and dexamethasone-d4. Results: Limit of quantitation (LOQ) was 1.89 nmol/L for dexamethasone and <0.02 mumol/L for cortisol. Recoveries of both analytes ranged from 80.2% to 114.4%. Intra- and interassay coefficients of variation were <15%. The concentration of dexamethasone and cortisol was determined in 62 patients after performing LDODST. Dexamethasone concentrations ranged from 3.0 to 21.5 nmol/L (median 7.4 nmol/L) for 57 of these samples. For five patients the concentration was
0.22 mumol/L). Conclusions: A method for the simultaneous measurement of dexamethasone and cortisol in human plasma by liquid chromatography/tandem mass spectrometry has been developed and validated. The method is suitable for controlling the compliance to the LDODST and for determining the cortisol plasma concentration after the test. The interpretation of LDODSTs was improved by the simultaneous determination of both analytes. Ann Clin Biochem 2012;49:170-176. Impact factor: 1.922
2. Evaluation of Prevent ID and Quantum Blue rapid tests for fecal calprotectin. Hessels J, Douw G, Yildirim DD, Meerman G, van Herwaarden MA, van den Bergh FA Background: Tests for fecal calprotectin are usually either enzyme-linked immunosorbent assays (ELISA) or a time-resolved fluorimetric immunoassay (TRFIA). These time-consuming tests are performed only once every 1 or 2 weeks. Before the results of the tests are known most patients have already undergone colonoscopy. A rapid test, performed on outpatients, could minimize the number of
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necessary colonoscopies. To establish optimal cut-off values minimizing the necessity for colonoscopies, we compared two commercially available rapid tests with a quantitative TRFIA. Methods: Fecal samples were collected from 85 patients with lower gastrointestinal complaints. Calprotectin was measured using quantitative TRFIA as well as using two rapid tests: Prevent ID CalDetect and Quantum Blue calprotectin. We used the TRFIA method as the golden standard with a cut-off value of 50 mug/g. The percentage correct classification, sensitivity, specificity and positive and negative predictive value were calculated for both rapid tests at various cut-off levels. Results: Correlation between both of the rapid tests with TRFIA was significant. Quantum Blue calprotectin (kappa 0.77) correlated better than Prevent ID CalDetect (kappa 0.46). Optimal cut-off levels for Prevent ID CalDetect and Quantum Blue calprotectin rapid tests were 15 mug/g and 40 mug/g with a reduction in the number of necessary colonoscopies of 39% and 62%, respectively. Conclusions: The Quantum Blue calprotectin rapid test demonstrated better analytical performance than the Prevent ID CalDetect in reducing the number of colonoscopies. Furthermore, the former test has the advantage of using a point of care reader for quantitative measurement and for establishing an optimal cut-off level. Clin Chem Lab Med 2012;50:1079-1082. Impact factor: 3.009
3. Leaky cell syndrome: a rare cause of pseudohyperkalaemia. Lukens MV, de Mare A, Kerbert-Dreteler MJ, van den Bergh FA Life-threatening situations of hyperkalaemia are often caused by renal failure, hyperglycaemia or medication. However pseudohyperkalaemia, a falsely elevated potassium concentration, is usually caused by haemolysis, repeated clenching of the fist during venepuncture or abnormal cell numbers. Another rare cause of pseudohyperkalaemia is familial pseudohyperkalaemia, an autosomal dominantly inherited trait, with increased leakage of potassium from erythrocytes. Under normal in vivo conditions, this increased leakage is compensated by augmented activity of the Na(+)/K(+) ATPase pump. However, after venepuncture the blood cools down to room temperature, reducing the activity of the Na(+)/K(+) ATPase pump whereby the increased potassium leakage becomes more apparent. Here, we present a Dutch patient with extreme familial pseudohyperkalaemia. Interestingly, his two children also show increased potassium leakage at room temperature, albeit at a lower level. Despite the low prevalence of familial pseudohyperkalaemia, it can have important clinical implications and rapid recognition is desired. Ann Clin Biochem 2012;49:97-100. Impact factor: 1.922
4. Steroidogenesis in the adrenal dysfunction of critical illness: impact of etomidate.
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Molenaar N, Bijkerk RM, Beishuizen A, Hempen CM, de Jong MF, Vermes I, Van der Sluijs V, Girbes AR, Groeneveld J. Bacground: This study was aimed at characterizing basal and adrenocorticotropic hormone (ACTH)-induced steroidogenesis in septic and non-septic patients with a suspicion of critical illness-related corticosteroid insufficiency (CIRCI), taking the use of etomidate inhibiting 11beta-hydroxylase into account. Method: A prospective study. Setting: A mixed surgical/medical intensive care unit (ICU) of a university hospital. Patients: 62 critically ill patients with a clinical suspicion of CIRCI. Interventions: Patients underwent a 250 ug ACTH test (n=67). ACTH, adrenal steroids, substrates and precursors (modified tandem mass spectrometry) were also measured. Clinical characteristics including use of etomidate to facilitate intubation (n=14 within 72 hours of ACTH testing) were recorded. Results: At the time of ACTH testing, patients suffered from septic (n=43) or nonseptic critical illness (n=24). Baseline cortisol directly related to sepsis and endogenous ACTH, independent of etomidate use. Etomidate was associated with a lower baseline cortisol and cortisol/11beta-deoxycortisol ratio as well as higher 11beta-deoxycortisol reflecting 11beta-hydroxylase inhibition, in non-sepsis than in sepsis. Cortisol increases <250 mmol/L upon exogenous ACTH were associated with relatively low baseline cholesterol, and high endogenous ACTH with low cortisol/ACTH ratio, independent of etomidate. Although cortisol increases upon exogenous ACTH were lower in sepsic than non-sepsic patients, etomidate was associated with diminished increases in cortisol upon exogenous ACTH, so that its use increased, albeit non-significantly. Low cortisol increases to exogenous ACTH from 38 to 57%, in both conditions. Conclusions: A single dose of etomidate may attenuate stimulated more than basal cortisol synthesis. However, it may only partly contribute, particularly in the stressed septic patient, to the adrenal dysfunction of CIRCI, on top of substrate deficiency. Crit Care 2012;16:R121. Impact factor: 4.718
5. Madam, why are you so sour? Veldhuijzen N, Kamphuis S, van den Bergh F, Spronk P, Braber A. Eur J Anaesthesiol 2012;29:398-400. Impact factor: 2.792
6. High-yield cell ordering and deterministic cell-in-droplet encapsulation using Dean flow in a curved microchannel Kemna EW, Schoeman RM, Wolbers F, Vermes I, Weitz DA, van den Berg A In this article high-yield (77%) and high-speed (2700 cells s(-1)) single cell droplet encapsulation is described using a Dean-coupled inertial ordering of cells in a simple curved continuous microchannel. By introducing the Dean force, the particles will
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order to one equilibrium position after travelling less than 1 cm. We use a planar curved microchannel structure in PDMS to spatially order two types of myeloid leukemic cells (HL60 and K562 cells), enabling deterministic single cell encapsulation in picolitre drops. An efficiency of up to 77% was reached, overcoming the limitations imposed by Poisson statistics for random cell loading, which yields only 37% of drops containing a single cell. Furthermore, we confirm that > 90% of the cells remain viable. The simple planar structure and high throughput provided by this passive microfluidic approach makes it attractive for implementation in lab on a chip (LOC) devices for single cell applications using droplet-based platforms. Lab on a chip 2012; 12(16):2881-7 Impact factor: 5.697
Totale impact factor: 20.200 Gemiddelde impact factor: 3.367 Aantal artikelen 1e, 2e of laatste auteur: 4 Totale impact factor: 12.690 Gemiddelde impact factor: 3.173
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Klinische Farmacie 1. Dopamine agonists and ischemic complications in Parkinson's disease: a nested case-control study. Arbouw ME, Movig KL, Guchelaar HJ, Neef C, Egberts TC Background: It has been suggested that ergoline dopamine agonists can cause ischemic complications. The effect of dopamine agonists in general on the prevalence of ischemic events in patients with Parkinson's disease (PD) has not been studied. Objective: Our aim was to investigate the association between the use of dopamine agonists and hospitalization due to ischemic events in patients with PD. Methods: We performed a nested case-control study using the PHARMO Institute for Drug Outcome Research database. All patients issued at least one prescription for levodopa after the age of 55 years between 1994 and 2006 were initially identified. Cases were patients who were hospitalized for the first time after November 1997 for an ischemic event and were matched to as many as four controls. Exposure to dopamine agonists during the year preceding the index date was identified. Results: The study population consisted of 542 cases and 2,155 controls. The mean effect of dopamine agonist use 1 year prior to the index date on ischemic events requiring hospitalization is shown with 95% probability in the 0.95-1.49 range. Stratified results according to the type of dopamine agonist showed no risk differences between ergoline and nonergoline agonists. Conclusions: This study does not support an association between dopamine agonist use and an increased risk of ischemic events requiring hospitalization. Eur J Clin Pharmacol 2012;68:88. Impact factor: 2.741
2. Rituximab-induced thrombocytopenia: a cohort study. Giezen TJ, Mantel-Teeuwisse AK, Ten Berg MJ, Straus SM, Leufkens HG, van Solinge WW, Egberts TC The combined information of drug exposure and laboratory test results on an individual patient level obtained in daily clinical practice can add important information about the safety of a drug. Thrombocytopenia is a know adverse drug reaction of rituximab, which has already been identified during the pre-registration trials, but knowledge on incidence and risk factors in clinical practice is limited. We, therefore, aimed to estimate the incidence and explore risk factors for the development of rituximab-induced thrombocytopenia (a platelet count <100x10(9) platelets/ L) in clinical practice. 90 patients were eligible for inclusion of which 27 developed thrombocytopenia (cumulative incidence: 30%) within 30 days after administration of rituximab and 18 patients developed grade 3/4 thrombocytopenia (cumulative incidence: 20%). Patients with and without thrombocytopenia were compared to explore risk factors. Patients with a relatively low platelet count (217 vs.
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324x10(9) /L, p=0.011) before administration of rituximab had a higher risk for the development of thrombocytopenia and although not statistically significant, patients treated with rituximab within the oncology setting (OR: 4.7 95% CI: 1.0-23.3), independent of concomitant use of cytostatics, as compared to the auto-immune diseases and patients with a high platelet distribution width (PDW) (16.1 vs. 15.8, p=0.051). In conclusion, the incidence of rituximab-induced thrombocytopenia was higher than identified during the clinical trials. Healthcare professionals should consider thrombocytopenia as a relevant reaction during treatment with rituximab. More frequent monitoring of the platelet count is especially advised in patients treated in the oncology indication and/ or with a low platelet count and high PDW. Eur J Haematol. 2012 Sep;89(3):256-66 Impact factor: 2.548
3. Effects of short-term addition of NSAID to diuretics and/or RAAS-inhibitors on blood pressure and renal function. Nygard P, Jansman FG, Kruik-Kolloffel WJ, Barnaart AF, Brouwers JR Background: The combined post-operative use of diuretics and/or reninangiotensin-aldosterone system (RAAS) inhibitors may increase the risk of nonsteroidal anti-inflammatory drug (NSAID) associated renal failure because of a drug-drug interaction. Objective: The aim of this study was to investigate the effect of the short-term (<4 days) post-operative combined use of NSAIDs with diuretics and/or RAAS inhibitors on renal function and blood pressure. Setting: One teaching hospital in the Netherlands. Method: The study-design was a prospective, observational cohort-study. Based on postoperative treatment with NSAIDs, the intervention-group was compared to a control-group (no NSAIDs treatment). Main outcome measure: Systolic blood pressure and renal function expressed by the estimated glomular filtration rate (eGFR) calculated with the modification of renal desease formula. Results: 97 patients were included in the intervention-group, 53 patients in the control-group. Patient characteristics were comparable except for one variable: 'combined use of a diuretic with a RAAS inhibitor' which was higher in the controlgroup (62 vs. 43 %, p = 0.046). Odds ratio for clinically relevant increase in systolic blood pressure was 0.66 (CI95 % 0.3-1.5). Odds ratio for clinical relevant decrease in renal function was 2.44 (CI95 % 1.1-5.2). On day 4 eGFR of 3 patients in the intervention- and 1 in the control-group was <50 ml/min/1.73 m(2). Conclusion: Odds ratios showed no significant difference of a clinically relevant increase in systolic blood pressure but showed a higher risk for a clinically relevant decrease in renal function in the intervention group. However this decrease resulted in a relevant impaired renal function (<50 ml/min/1.73 m(2)) in only 3 patients in the interventiongroup and 1 patient in the control-group. In the post-operative patient, without preexisting impaired renal function, concurrent diuretics and/or reninangiotensinaldosterone system inhibitor therapy can be combined with short-term NSAID treatment.
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Int J Clin Pharm 2012;34:468-474. Impact factor:1.200
4. Biosimilars: what clinicians should know. Weise M, Bielsky MC, De SK, Ehmann F, Ekman N, Giezen TJ, Gravanis I, Heim HK, Heinonen E, Ho K, Moreau A, Narayanan G, Kruse NA, Reichmann G, Thorpe R, van AL, Vleminckx C, Wadhwa M, Schneider CK Biosimilar medicinal products ('biosimilars') have become a reality in the EU and will soon be available in the US. Despite an established legal pathway for biosimilars in the EU since 2005 and increasing and detailed regulatory guidance on data requirements for their development and licensing, many clinicians, particularly oncologists, are reluctant to consider biosimilars as a treatment option for their patients. Major concerns voiced about biosimilars relate to their pharmaceutical quality, safety (especially immunogenicity), efficacy (particularly in 'extrapolated' indications), and interchangeability with the originator product. In this article, the members and experts of the Working Party on Similar Biological Medicinal Products (BMWP) of the European Medicines Agency (EMA) address these issues. A clear understanding of the scientific principles of the biosimilar concept and access to unbiased information on licensed biosimilars are important for physicians to make informed and appropriate treatment choices for their patients. This will become even more important with the advent of biosimilar monoclonal antibodies. The issues also highlight the need for improved communication between physicians, learned societies, and regulators. Blood 2012;120:5111-5117. Impact factor: 9.060
Totale impact factor: 15.549 Gemiddelde impact factor: 3.887 Aantal artikelen 1e, 2e of laatste auteur: 2 Totale impact factor: 5.289 Gemiddelde impact factor: 2.645
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Klinische Psychologie 1.Suppressors of interictal discharges in idiopathic childhood occipital epilepsy of Gastaut. Rots ML, de Vos CC, Smeets-Schouten JS, Portier R, van Putten MJ. Idiopathic childhood occipital epilepsy of Gastaut (ICOE-G) is a rare form of epilepsy, characterized by visual hallucinations, periods of blindness, motor seizures, and migraine-like symptoms. A characteristic EEG feature is fixation-off sensitivity: epileptiform discharges are suppressed by visual input. Here, we present an 11-year-old girl suffering from ICOE-G, who was studied to identify potential additional suppressors of the epileptiform discharges. Epilepsy Behav 2012;25:189-191. Impact factor: 1.844
2. Decision rules for assessment of chronic solvent-induced encephalopathy: Results in 2370 patients. Verberk MM, van der Hoek JA, van Valen E, Wekking EM, van Hout MS, Hageman G, van der Laan G, van Dijk F For the diagnosis of patients suspected of chronic solvent-induced encephalopathy (CSE), it would be helpful if the applied cognitive tests show a characteristic profile of impairment in this disease. We investigated the existence of such a profile. In 1997-2006 two expert teams in The Netherlands systematically examined 2370 patients referred for evaluation of suspected CSE. The procedure included two selection steps: (1) intake interview, using criteria of exposure, development of symptoms and absence of non-solvent causes, and (2) seven tests of the computerized Neurobehavioural Evaluation System (NES). Patients showing negligible impairments were considered free from CSE and were not further examined. The third step comprised a neuropsychological, neurological and exposure evaluation. Explicit decision rules for the diagnosis of CSE were developed, including a minimum score for cognitive impairment summarizing 25 cognitive tests. These rules were retroactively applied to 563 patients, comprising 513 patients who had regularly completed all diagnostic steps and a sample of 50 out of the approximately 450 patients with negligible impairments on the NES, who were fully examined. The data from this sample were extrapolated to the original number of 450. In the combined population of 963 patients, a calculated 301 patients were given the diagnosis 'Solely CSE', 242 'CSE and other disease', 158 'Other Disease' and 262 'No (known) disease'. In the Solely CSE patients, the most impaired tests regarded Verbal Fluency & -Similarities, Motor Speed and Simple Attention. A profile of test results that might support the identification of patients with CSE amongst the other referred patients, was not found. The diverging results of related cognitive tests indicate that the use of a core test battery is needed to improve comparability. We consider the decision rules as a step towards a more objective assessment of CSE.
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Neurotoxicology 2012;33:742-752. Impact factor: 2.652
3.Monitoring device acceptance in implantable cardioverter defibrillator patients using the Florida Patient Acceptance Survey. Versteeg H, Starrenburg A, Denollet J, van der Palen J, Sears SF, Pedersen SS. Background: Patient device acceptance might be essential in identifying patients at risk for adverse patient-reported outcomes following implantation of an implantable cardioverter defibrillator (ICD). We examined the validity and reliability of the Florida Patient Acceptance Scale (FPAS) and identified correlates of device acceptance in a Dutch cohort of ICD patients. Methods: Patients with a first-time ICD (N = 272, mean age = 59.2 +/- 11.9, 82% men) recruited from the Erasmus Medical Center, Rotterdam, or the Medisch Spectrum Twente, Enschede, The Netherlands completed the FPAS, the Type D Scale, and the Hospital Anxiety and Depression Scale. Results: Exploratory and confirmatory factor analyses indicated that eliminating three items from the FPAS, leaving 12 items contributing to three factors, is equivalent to the original four-factor version of the FPAS. The abbreviated FPAS had a high internal consistency both for the total scale and all subscales, with Cronbach's alphas ranging from 0.76 to 0.82. Anxiety (odds ratio [OR]: 9.75; 95% confidence interval [CI]: 2.38-39.87; P = 0.002), depression (OR: 2.96; 95% CI: 0.98-8.93; P = 0.05), and the distressed (Type D) personality (OR: 5.04; 95% CI: 1.50-16.92; P = 0.01), but not demographic and clinical factors including shocks, were significant independent correlates of poor device acceptance. Conclusion: A shortened 12-item, three-factor version of the FPAS was shown to be a valid and internally consistent instrument to assess device acceptance in Dutch ICD patients. Psychological but not clinical factors were the primary correlates of device acceptance, which underlines the importance of taking into account the patient's psychological profile when seeking to identify patients at risk for adjustment difficulties after ICD implantation. Pacing Clin Electrophysiol 2012;35:283-293. Impact factor: 1.746
4. The Coping with Attention and Memory Complaints Questionnaire (CAMQ): psychometric evaluation of an instrument in suspected chronic solventinduced encephalopathy (CSE). Visser I, de Boer AG, Wekking EM, van Vliet J, van Hout MS, Schmand B, van der Laan G, Schene AH, van Dijk FJ. Long-term occupational exposure to organic solvents may induce chronic solventinduced encephalopathy (CSE), leading to neuropsychological impairments. We developed the Coping with Attention and Memory Complaints Questionnaire (CAMQ), an instrument for the assessment of coping strategies in patients
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suspected of CSE with neuropsychological complaints. Items for the CAMQ were based on existing coping dimensions and constructed by experts. The psychometric properties of the CAMQ were evaluated in a sample of 307 workers suspected of CSE. Factor analysis revealed four coping subscales: active coping, avoidance, acceptance, and seeking social support, all with good internal consistency (alphas .71-.78) and good test-retest reliability (ICCs .67-.82). The subscales demonstrated moderate correlations with related external constructs such as anxiety and depression, locus of control, meta-memory, mastery and generic coping styles. In conclusion, this study: (1) shows that the newly developed CAMQ is a reliable instrument, and (2) provides evidence for its validity in assessing coping with complaints of memory and attention in CSE-suspected patients. These results may serve for further study on coping with complaints of memory and attention, psychological adjustment and well-being in CSE patients. Neuropsychol Rehabil 2012;22:794-808. Impact factor: 2.011
Totale impact factor: 8.253 Gemiddelde impact factor: 2.063 Aantal artikelen 1e, 2e of laatste auteur: 1 Totale impact factor: 1.746 Gemiddelde impact factor: 1.746
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Laboratorium voor Microbiologie 1. Mycobacterium bovis infection in a young Dutch adult: transmission from an elderly human source? Akkerman O, van der Loo K, Nijmeijer D, van der Werf T, Mulder B, Kremer K, van SD, van der Zanden A. A young female health professional was diagnosed with pulmonary tuberculosis caused by Mycobacterium bovis. Source finding and contact tracing was initiated by the regional municipal health service using both tuberculin skin test and QuantiFERON((R))-TB Gold (QFT-GIT (IGRA). The strain appeared near-identical to that of an elderly Dutch patient. Med Microbiol Immunol 2012;201:397-400. Impact factor: 1.545
2. Mosquito Feeding Assays to Determine the Infectiousness of Naturally Infected Plasmodium falciparum Gametocyte Carriers. Bousema T, Dinglasan RR, Morlais I, Gouagna LC, van WT, Awono-Ambene PH, Bonnet S, Diallo M, Coulibaly M, Tchuinkam T, Mulder B, Targett G, Drakeley C, Sutherland C, Robert V, Doumbo O, Toure Y, Graves PM, Roeffen W, Sauerwein R, Birkett A, Locke E, Morin M, Wu Y, Churcher TS Background: In the era of malaria elimination and eradication, drug-based and vaccine-based approaches to reduce malaria transmission are receiving greater attention. Such interventions require assays that reliably measure the transmission of Plasmodium from humans to Anopheles mosquitoes. Methods: We compared two commonly used mosquito feeding assay procedures: direct skin feeding assays and membrane feeding assays. Three conditions under which membrane feeding assays are performed were examined: assays with i) whole blood, ii) blood pellets resuspended with autologous plasma of the gametocyte carrier, and iii) blood pellets resuspended with heterologous control serum. Results: 930 transmission experiments from Cameroon, The Gambia, Mali and Senegal were included in the analyses. Direct skin feeding assays resulted in higher mosquito infection rates compared to membrane feeding assays (odds ratio 2.39, 95% confidence interval 1.94-2.95) with evident heterogeneity between studies. Mosquito infection rates in membrane feeding assays and direct skin feeding assays were strongly correlated (p<0.0001). Replacing the plasma of the gametocyte donor with malaria naive control serum resulted in higher mosquito infection rates compared to own plasma (OR 1.92, 95% CI 1.68-2.19) while the infectiousness of gametocytes may be reduced during the replacement procedure (OR 0.60, 95% CI 0.52-0.70). Conclusions: Despite a higher efficiency of direct skin feeding assays, membrane feeding assays appear suitable tools to compare the infectiousness between individuals and to evaluate transmission-reducing interventions. Several aspects of
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membrane feeding procedures currently lack standardization; this variability makes comparisons between laboratories challenging and should be addressed to facilitate future testing of transmission-reducing interventions. PLoS One 2012;7:e42821. Impact factor: 3.730
3. Vijf jaar Urineweginfecties in het Verpleeghuis. Hasper HJ, Hendrix R, van der Palen J. Tijdschrift voor ouderengeneeskunde 2012;207-210. Impact factor: 0
4. Detection of new methicillin-resistant Staphylococcus aureus that carry novel genetic homologue and important virulence determinants. Sabat AJ, Koksal M, Akkerboom V, Monecke S, Kriegeskorte A, Hendrix R, Ehricht R, Kock R, Becker K, Friedrich AW In this study, 18 methicillin-resistant Staphylococcus aureus (MRSA) isolates harboring staphylococcal cassette chromosome mec (SCCmec) XI recovered in the Dutch-German Euregio were characterized by DNA microarrays. In contrast to previous data, we found two MRSA strains of different clonal lineages possessing SCCmec XI that carried important virulence determinants. The worrysome emergence of such toxigenic MRSA strains raises concerns that MRSA with enhanced virulence potential and impaired detectability by standard molecular assays may spread in Europe. J Clin Microbiol 2012;50:3374-3377. Impact factor: 4.068
5. Equal Virulence of Rhinovirus and Respiratory Syncytial Virus in Infants Hospitalized for Lower Respiratory Tract Infection. van Leeuwen JC, Goossens LK, Hendrix RM, van der Palen J, Lusthusz A, Thio BJ. Respiratory syncytial virus (RSV) and rhinovirus (RV) are predominant viruses associated with lower respiratory tract infection in infants. We compared the symptoms of lower respiratory tract infection caused by RSV and RV in hospitalized infants. RV showed the same symptoms as RSV, so on clinical grounds, no difference can be made between these pathogens. No relation between polymerase chain reaction cycle threshold value and length of hospital stay was found. Pediatr Infect Dis J 2012;31:84-86. Impact factor: 3.569
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Totale impact factor: 12.912 Gemiddelde impact factor: 2.582 Aantal artikelen 1e, 2e of laatste auteur: 1 Totale impact factor: 0 Gemiddelde impact factor: 0
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Longziekten 1. Inspiratory airflow limitation after exercise challenge in cold air in asthmatic children. Driessen JM, van der Palen J, van Aalderen WM, de Jongh FH, Thio BJ Methacholine and histamine can lead to inspiratory flow limitation in asthmatic children and adults. This has not been analyzed after indirect airway stimuli, such as exercise. The aim of the study was to analyze airflow limitation after exercise in cold, dry air. 72 asthmatic children with mild to moderate asthma (mean age 13.2 +/- 2.2 yrs) performed a treadmill exercise challenge. A fall of >10% in FEV(1) was the threshold for expiratory flow limitation and a fall of >25% of MIF(50) was the threshold for inspiratory flow limitation. The occurrence of wheeze, stridor and cough were quantified before and after exercise. After exercise, the mean fall in FEV(1) was 17.7 +/- 14.6%, while the mean fall in MIF(50) was 25.4 +/- 15.8%; no correlation was found between fall in FEV(1) and MIF(50) (R(2): 0.04; p = 0.717). 53 of the 72 children showed an inspiratory and/or expiratory airflow limitation. 38% (20/53) of these children showed an isolated expiratory flow limitation, 45% (24/53) showed both expiratory and inspiratory flow limitation and 17% (9/53) showed an isolated inspiratory flow limitation. The fall in FEV(1) peaked 9 min after exercise and correlated to expiratory wheeze. The fall in MIF(50) peaked 15 min after exercise and correlated to inspiratory stridor. The time difference in peak fall between FEV(1) and MIF(50) was statistically significant (5.9 min; p < 0.001, 99% CI: 2.3-9.5 min). In conclusion, this study shows that an exercise challenge in asthmatic children can give rise to inspiratory airflow limitation, which may give rise to asthma like symptoms. Respir Med 2012;106:1362-1368. Impact factor: 2.585
2. Excellent adherence and no contamination by physiotherapists involved in a randomized controlled trial on reactivation of COPD patients: a qualitative process evaluation study. Effing TW, Krabbenbos M, Pieterse ME, van der valk PD, Zielhuis GA, Kerstjens HA, van der Palen J. Background: To assess the adherence of physiotherapists to the study protocol and the occurrence of contamination bias during the course of a randomized controlled trial with a recruitment period of 2 years and a 1-year follow-up (COPE-II study). Study, design and setting: In the COPE-II study, intervention patients received a standardized physiotherapeutic reactivation intervention (COPE-active) and control patients received usual care. The latter could include regular physiotherapy treatment. Information about the adherence of physiotherapists with the study protocol was collected by performing a single interview with both intervention and control patients. Patients were only interviewed when they were currently receiving
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physiotherapy. Interviews were performed during two separate time periods, 10 months apart. Nine characteristics of the COPE-active intervention were scored. Scores were converted into percentages (0%, no aspects of COPE-active; 100%, full implementation of COPE-active). Results: Fifty-one patients were interviewed (first period: intervention n = 14 and control n = 10; second period: intervention n = 18 and control n = 9). Adherence with the COPE-active protocol was high (median scores: period 1, 96.8%; period 2, 92.1%), and large contrasts in scores between the intervention and control group were found (period 1: 96.8% versus 22.7%; period 2: 92.1% versus 25.0%). The scores of patients treated by seven physiotherapists who trained patients of both study groups were similar to the scores of patients treated by physiotherapists who only trained patients of one study group. Conclusion: The adherence of physiotherapists with the COPE-active protocol was high, remained unchanged over time, and no obvious contamination bias occurred. Int J Chron Obstruct Pulmon Dis 2012;7:337-344. Impact factor: 0
3. Self-management programmes for COPD: moving forward. Effing TW, Bourbeau J, Vercoulen J, Apter AJ, Coultas D, Meek P, van der valk PD, Partridge MR, van der Palen J. Self-management is of increasing importance in chronic obstructive pulmonary disease (COPD) management. However, there is confusion over what processes are involved, how the value of self-management should be determined, and about the research priorities. To gain more insight into and agreement about the content of programmes, outcomes, and future directions of COPD self-management, a group of interested researchers and physicians, all of whom had previously published on this subject and who had previously collaborated on other projects, convened a workshop. This article summarises their initial findings. Self-management programmes aim at structural behaviour change to sustain treatment effects after programmes have been completed. The programmes should include techniques aimed at behavioural change, be tailored individually, take the patient's perspective into account, and may vary with the course of the patient's disease and comorbidities. Assessment should include process variables. This report is a step towards greater conformity in the field of self-management. To enhance clarity regarding effectiveness, future studies should clearly describe their intervention, be properly designed and powered, and include outcomes that focus more on the acquisition and practice of new skills. In this way more evidence and a better comprehension on self-management programmes will be obtained, and more specific formulation of guidelines on self-management made possible. Chron Respir Dis 2012;9:27-35. Impact factor: 1.519
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4. Circulating tumor cells in small-cell lung cancer: a predictive and prognostic factor. Hiltermann TJ, Pore MM, van den Berg A, Timens W, Boezen HM, Liesker JJ, Schouwink JH, Wijnands WJ, Kerner GS, Kruyt FA, Tissing H, Tibbe AG, Terstappen LW, Groen HJ Background: Initial response of small-cell lung cancer (SCLC) to chemotherapy is high, and recurrences occur frequently, leading to early death. This study investigated the prognostic value of circulating tumor cells (CTCs) in patients with SCLC and whether changes in CTCs can predict response to chemotherapy. Patients and methods: In this multicenter prospective study, blood samples for CTC analysis were obtained from 59 patients with SCLC before, after one cycle, and at the end of chemotherapy. CTCs were measured using CellSearch((R)) systems. Results: At baseline, lower numbers of CTCs were observed for 21 patients with limited SCLC (median = 6, range 0-220) compared with 38 patients with extensive stage (median = 63, range 0-14 040). Lack of measurable CTCs (27% of patients) was associated with prolonged survival (HR 3.4; P
5. Sternoclavicular joint tuberculosis Kelderman S, Steenvoorde P, van der valk PD. A 24-year old woman presented with an abscess localized at the median side of the right clavicle. There were no clinical signs of tuberculosis and radiological evaluation was normal. PCR-assay on tuberculosis following aspiration of the pus collection was positive for Mycobacterium tuberculosis. She responded well on regular antituberculosis treatment. Ned Tijdschr Geneeskd 2012;156:A3315. Impact factor: 0
6. Regional respiratory time constants during lung recruitment in highfrequency oscillatory ventilated preterm infants. Miedema M, de Jongh FH, Frerichs I, van Veenendaal MB, van Kaam AH. Background: To assess the regional respiratory time constants of lung volume changes during stepwise lung recruitment before and after surfactant treatment in high-frequency oscillatory ventilated preterm infants.
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Methods: A stepwise oxygenation-guided recruitment procedure was performed before and after surfactant treatment in high-frequency oscillatory ventilated preterm infants. Electrical impedance tomography was used to continuously record changes in lung volume during the recruitment maneuver. Time constants were determined for all incremental and decremental pressure steps, using one-phase exponential decay curve fitting. Data were analyzed for the whole cross section of the chest and the ventral and dorsal lung regions separately. Results: Before surfactant treatment, the time constants of the incremental pressure steps were significantly longer (median 27.3 s) than those in the decremental steps (16.1 s). Regional analysis showed only small differences between the ventral and dorsal lung regions. Following surfactant treatment, the time constants during decremental pressure steps almost tripled to 44.3 s. Furthermore, the time constants became significantly (p < 0.01) longer in the dorsal (61.2 s) than into the ventral (40.3 s) lung region. Conclusions: Lung volume stabilization during stepwise oxygenation-guided lung recruitment in high-frequency oscillatory ventilated preterm infants with respiratory distress syndrome is usually completed within 5 min and is dependent on the position of ventilation on the pressure volume curve, the surfactant status, and the region of interest of the lung. Intensive Care Med 2012;38:294-299. Impact factor: 5.258
7. The effect of airway pressure and oscillation amplitude on ventilation in preterm infants. Miedema M, de Jongh FH, Frerichs I, van Veenendaal MB, van Kaam AH We determined the effect of lung recruitment and oscillation amplitude on regional oscillation volume and functional residual capacity (FRC) in high-frequency ventilated (HFV) preterm infants with respiratory distress syndrome (RDS).Changes in lung volume, oscillation volume and carbon dioxide levels were recorded in 10 infants during a stepwise recruitment procedure and an increase in pressure amplitude of 5 cmH2O using electrical impedance tomography and transcutaneous monitoring. The pressures at maximal respiratory system compliance, maximal oscillation volume and minimal carbon dioxide levels were determined. Impedance data were analysed for the chest cross-section and predefined regions of interest.Despite the fixed pressure amplitude, the oscillation volume changed during the incremental pressure steps following a parabolic pattern, with an inverse relation to the carbon dioxide pressures. The pressures corresponding with maximal compliance, maximal oscillation volume and minimal carbon dioxide were similar and highly correlated. Regional analysis showed similar findings. The increase in pressure amplitude resulted in increased oscillation volumes and decreased carbon dioxide levels, while FRC remained unchanged.In HFV preterm infants with RDS, oscillation volumes are closely related to the position of ventilation in the pressurevolume envelope and the applied pressure amplitude. Changes in pressure amplitude do not seem to affect FRC.
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Eur Respir J 2012;40:479-484. Impact factor: 6.355
8. Telemonitoring of Daily Activity and Symptom Behavior in Patients with COPD. Tabak M, Vollenbroek-Hutten MM, van der valk PD, van der Palen J, Tonis TM, Hermens HJ. Objectives. This study investigated the activity behavior of patients with COPD in detail compared to asymptomatic controls, and the relationship between subjective and objective activities (awareness), and readiness to change activity behavior. Methods: Thirty-nine patients with COPD (66.0 years; FEV(1)% predicted: 44.9%) and 21 healthy controls (57.0 years) participated. Objective daily activity was assessed by accelerometry and expressed as amount of activity in counts per minute (cpm). Patients' baseline subjective activity and stage of change were assessed prior to measurements. Results: Mean daily activity in COPD patients was significantly lower compared to the healthy controls (864 +/- 277 cpm versus 1162 +/- 282 cpm, P < 0.001). COPD patients showed a temporary decrease in objective activities in the early afternoon. Objective and subjective activities were significantly moderately related and most patients (55.3%) were in the maintenance phase of the stages of change. Conclusions: COPD patients show a distinctive activity decrease in the early afternoon. COPD patients are moderately aware of their daily activity but regard themselves as physically active. Therefore, future telemedicine interventions might consider creating awareness of an active lifestyle and provide feedback that aims to increase and balance activity levels. Int J Telemed Appl 2012;2012:438736. Impact factor: 0
9. Effect of outpatient exercise training programmes in patients with chronic heart failure: a systematic review. van der Meer S, Zwerink M, van Brussel M, van der valk PD, Wajon E, van der Palen J. Background: Advantages of outpatient exercise training are reduced waiting lists, better compliance, reduced time investment by the patient with reduced travel expenses, and less dependence on other people to participate. Therefore, this systematic review studies the effects of outpatient exercise training programmes compared with usual care on exercise capacity, exercise performance, quality of life, and safety in patients with chronic heart failure. Design: Systematic review with meta-analysis. Methods: Randomized controlled trials concerning patients with chronic heart failure, with a left ventricular ejection fraction
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Results: Twenty-two studies were included. VO(2)max, 6-min walking test, and quality of life showed significant differences in favour of the intervention group of 1.85 ml/kg/min, 47.9 m, and 6.9 points, respectively. In none of the studies, a significant relationship was found between exercise training and adverse events. Conclusion: This meta-analysis illustrates the efficacy and safety of outpatient training programmes for patients with chronic heart failure. Eur J Cardiovasc Prev Rehabil 2012;19:795-803. Impact factor: 2.634
10. Seroprevalence and risk factors for Coxiella burnetii (Q fever) seropositivity in dairy goat farmers' households in The Netherlands, 2009-2010 Schimmer B, Lenferink A, Schneeberger P, Aangenend H, Vellema P, Hautvast J, van Duynhoven Y Community Q fever epidemics occurred in The Netherlands in 2007-2009, with dairy goat and dairy sheep farms as the implicated source. The aim of the study was to determine the seroprevalence and risk factors for seropositivity in dairy goat farmers and their household members living or working on these farms. Sera of 268 people living or working on 111 dairy goat farms were tested for Coxiella burnetii IgG and IgM antibodies using immunofluorescence assay. Seroprevalences in farmers, spouses and children (12-17 years) were 73.5%, 66.7%, and 57.1%, respectively. Risk factors for seropositivity were: performing three or more daily goat-related tasks, farm location in the two southern provinces of the country, proximity to bulk milk-positive farms, distance from the nearest stable to residence of 10 meters or less, presence of cats and multiple goat breeds in the stable, covering stable air spaces and staff not wearing farm boots. Goat farmers have a high risk to acquire this occupational infection. Clinicians should consider Q fever in this population presenting with compatible symptoms to allow timely diagnosis and treatment to prevent severe sequelae. Based on the risk factors identified, strengthening general biosecurity measures is recommended such as consistently wearing boots and protective clothing by farm staff to avoid indirect transmission and avoiding access of companion animals in the goat stable. Furthermore, it provides an evidence base for continuation of the current vaccination policy for small ruminants, preventing spread from contaminated farms to other farms in the vicinity. Finally, vaccination of seronegative farmers and household members could be considered. PLoS One. 2012;7(7):e42364. Impact factor: 3.730
Totale impact factor: 29.341 Gemiddelde impact factor: 2.934 Aantal artikelen 1e, 2e of laatste auteur: 7 Totale impact factor: 19.372 Gemiddelde impact factor: 2.767
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MDL 1. The 2012 revised Dutch national guidelines for the treatment of chronic hepatitis B virus infection. Buster EH, Baak BC, Bakker CM, Beuers UH, Brouwer JT, Drenth JP, van Erpecum KJ, van HB, Honkoop P, Kerbert-Dreteler MJ, Koek GH, van Nieuwkerk KM, van SH, van der Spek BW, Tan AC, Vrolijk JM, Janssen HL. In 2008, the Netherlands Association of Gastroenterologists and Hepatologists (Nederlands Vereniging van Maag-Darm-Leverartsen) published the Dutch national guidelines for the treatment of chronic hepatitis B virus infection. New insights into the treatment of chronic hepatitis B with relevance for clinical practice have been adopted in these concise, revised guidelines. The most important changes include the choice of initial antiviral therapy, licensing of tenofovir for the treatment of chronic hepatitis B and the management of antiviral resistance. Neth J Med 2012;70:381-385. Impact factor: 2.383
2. Abdominal symptoms during physical exercise and the role of gastrointestinal ischaemia: a study in 12 symptomatic athletes. Ter Steege RW, Geelkerken RH, Huisman AB, Kolkman JJ. Background: Gastrointestinal (GI) symptoms during exercise may be caused by GI ischaemia. The authors report their experience with the diagnostic protocol and management of athletes with symptomatic exercise-induced GI ischaemia. The value of prolonged exercise tonometry in the diagnostic protocol of these patients was evaluated. Methods: Patients referred for GI symptoms during physical exercise underwent a standardised diagnostic protocol, including prolonged exercise tonometry. Indicators of GI ischaemia, as measured by tonometry, were related to the presence of symptoms during the exercise test (S+ and S- tests) and exercise intensity. Results: 12 athletes were specifically referred for GI symptoms during exercise (five males and seven females; median age 29 years (range 15-46 years)). Type of sport was cycling, long-distance running and triathlon. Median duration of symptoms was 32 months (range 7-240 months). Splanchnic artery stenosis was found in one athlete. GI ischaemia was found in six athletes during submaximal exercise. All athletes had gastric and jejunal ischaemia during maximum intensity exercise. No significant difference was found in gastric and jejunal Pco(2) or gradients between S+ and S- tests during any phase of the exercise protocol. In S+ tests, but not in Stests, a significant correlation between lactate and gastric gradient was found. In S+ tests, the regression coefficients of gradients were higher than those in S- tests. Treatment advice aimed at limiting GI ischaemia were successful in reducing complaints in the majority of the athletes. 15 2
Conclusion: GI ischaemia was present in all athletes during maximum intensity exercise and in 50% during submaximal exercise. Athletes with GI symptoms had higher gastric gradients per mmol/l increase in lactate, suggesting an increased susceptibility for the development of ischaemia during exercise. Treatment advice aimed at limiting GI ischaemia helped the majority of the referred athletes to reduce their complaints. Our results suggest an important role for GI ischaemia in the pathophysiology of their complaints. Br J Sports Med 2012;46:931-935. Impact factor: 3.668
3. Review article: the pathophysiology and management of gastrointestinal symptoms during physical exercise, and the role of splanchnic blood flow. Ter Steege RW, Kolkman JJ. Background: The prevalence of exercise-induced gastrointestinal (GI) symptoms has been reported up to 70%. The pathophysiology largely remains unknown. Aim: To review the physiological and pathophysiological changes of the GI-tract during physical exercise and the management of the most common gastrointestinal symptoms. Methods: Search of the literature published in the English and Dutch languages using the Pubmed database to review the literature that focused on the relation between splanchnic blood flow (SBF), development of ischaemia, postischaemic endotoxinemia and motility. Results: During physical exercise, the increased activity of the sympathetic nervous system (SNS) redistributes blood flow from the splanchnic organs to the working muscles. With prolonged duration and/or intensity, the SBF may be decreased by 80% or more. Most studies point in the direction of increased SNS-activity as central driving force for reduction in SBF. A severely reduced SBF may frequently cause GI ischaemia. GI-ischaemia combined with reduced vagal activity probably triggers changes in GI-motility and GI absorption derangements. GI-symptoms during physical exercise may be prevented by lowering the exercise intensity, preventing dehydration and avoiding the ingestion of hypertonic fluids. Conclusions: Literature on the pathophysiology of exercise-induced GI-symptoms is scarce. Increased sympathetic nervous system activity and decreased splanchnic blood flow during physical exercise seems to be the key factor in the pathogenesis of exercise-induced GI-symptoms, and this should be the target for symptom reduction. Aliment Pharmacol Ther 2012;35:516-528. Impact factor: 4.548
4. Splanchnic artery stenosis and abdominal complaints: clinical history is of limited value in detection of gastrointestinal ischemia. Ter Steege RW, Sloterdijk HS, Geelkerken RH, Huisman AB, van der Palen J, Kolkman JJ.
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Background: Splanchnic artery stenosis is common and mostly asymptomatic and may lead to gastrointestinal ischemia (chronic splanchnic syndrome, CSS). This study was designed to assess risk factors for CSS in the medical history of patients with splanchnic artery stenosis and whether these risk factors can be used to identify patients with high and low risk of CSS. Methods: All patients referred for suspected CSS underwent a standardized workup, including a medical history with questionnaire, duplex ultrasound, gastrointestinal tonometry, and angiography. Definitive diagnosis and treatment advice was made in a multidisciplinary team. Patients with confirmed CSS were compared with no-CSS patients. Results: A total of 270 patients (102 M, 168 F; mean age, 53 years) with splanchnic artery stenosis were analyzed, of whom 109 (40%) had CSS and 161 no CSS. CSSpatients more often reported postprandial pain (87% vs. 72%, p = 0.007), weight loss (85% vs. 70%, p = 0.006), adapted eating pattern (90% vs. 79%, p = 0.005) and diarrhea (35% vs. 22%, p = 0.023). If none of these risk factors were present, the probability of CSS was 13%; if all were present, the probability was 60%. Adapted eating pattern (odds ratio (OR) 3.1; 95% confidence interval (CI) 1.08-8.88) and diarrhea (OR 2.6; 95% CI 1.31-5.3) were statistically significant in multivariate analysis. Conclusions: In patients with splanchnic artery stenosis, the clinical history is of limited value for detection of CSS. A diagnostic test to detect ischemia is indispensable for proper selection of patients with splanchnic artery stenosis who might benefit from treatment. World J Surg 2012;36:793-799. Impact factor: 2.228
5.The cardiovascular risk profile of atherosclerotic gastrointestinal ischemia is different from other vascular beds. Veenstra RP, Ter Steege RW, Geelkerken RH, Huisman AB, Kolkman JJ. Background: The distribution of cardiovascular risk factors in patients with chronic gastrointestinal ischemia due to atherosclerosis of the splanchnic vessels (chronic splanchnic syndrome) is not well studied. The aim of this study was to determine the cardiovascular risk factor pattern in patients with chronic splanchnic syndrome. Methods: From April 2003 to September 2007, atherosclerotic risk factors in consecutive patients with chronic splanchnic syndrome were compared prospectively with the general atherosclerotic risk profile in Western Europe and worldwide risk profile of coronary heart disease, peripheral artery disease, and cerebral vascular disease. Results: Of 376 analyzed patients, 97 were diagnosed with chronic splanchnic syndrome. Data from 90 patients were available for analysis (7 were excluded because of incomplete data). Mean age was 63 years (range 28-86 years), and 74% were female. Fifty-nine percent of the patients had atherosclerotic disease in other vascular beds. Smoking was reported in 57%, and increased bodyweight in 21%.
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Hypercholesterolemia was present in 53%, hypertension in 62%, and diabetes in 21%. Conclusions: The atherosclerotic risk profile in patients with chronic splanchnic syndrome differed from other atherosclerotic diseases with a female preponderance, lower incidence of obesity/increased bodyweight, diabetes, hypertension, and hypercholesterolemia. Reduced caloric intake, related to the postprandial pain, may explain the observed differences. Am J Med 2012;125:394-398. Impact factor: 4.768
6. Hyperamylasemia and pancreatitis following spiral enteroscopy. Teshima CW, Aktas H, Kuipers EJ, Mensink PB Background: Acute pancreatitis is a significant potential complication with doubleballoon enteroscopy. Hyperamylasemia is frequently observed after both doubleballoon enteroscopy and single-balloon enteroscopy but often without associated pancreatitis. Whether the same phenomenon occurs with spiral enteroscopy is currently unknown. Aims: To determine the incidence of pancreatitis and hyperamylasemia following spiral enteroscopy. Methods: A prospective cohort study of consecutive patients undergoing proximal spiral enteroscopy was conducted. Serum amylase levels were measured immediately before and following the procedure, combined with observation for clinical signs of pancreatitis. Results: A total of 32 patients underwent proximal spiral enteroscopy, with a mean total procedure time of 51 min (range 30 min to 100 min) and mean depth of insertion of 240 cm (range 50 cm to 350 cm). The diagnostic yield was 50%, with 31% of all procedures being therapeutic. While no patients exhibited signs that raised suspicion of pancreatitis, hyperamylasemia was common (20%). Hyperamylasemia was not significantly associated with procedure duration or depth of insertion but was linked to patients with Peutz-Jeghers syndrome and with the use of propofol sedation, suggesting that it may be more common in difficult cases. Conclusions: Postprocedural hyperamylasemia occurred frequently with proximal spiral enteroscopy, while no associated pancreatitis was observed. This finding suggests that hyperamylasemia may not necessarily reflect pancreatic injury nor portend a risk for pancreatitis. Can J Gastroenterol. 2012;26(9):603-6 Impact factor: 1.532
7. Patients with chronic gastrointestinal ischemia have a higher cardiovascular disease risk and mortality. Sana A, van Noord D, Mensink PB, Kooij S, van Dijk K, Bravenboer B, Lieverse AG, Sijbrands EJ, Langendonk JG, Kuipers EJ.
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Objectives: We determined the prevalence of classical risk factors for atherosclerosis and mortality risk in patients with CGI. Methods: A case-control study was conducted. Patients referred with suspected CGI underwent a standard work-up including risk factors for atherosclerosis, radiological imaging of abdominal vessels and tonometry. Cases were patients with confirmed atherosclerotic CGI. Controls were healthy subjects previously not known with CGI. The mortality risk was calculated as standardized mortality ratio derived from observed mortality, and was estimated with ten-year risk of death using SCORE and PREDICT. Results: Between 2006 and 2009, 195 patients were evaluated for suspected CGI. After a median follow-up of 19 months, atherosclerotic CGI was diagnosed in 68 patients. Controls consisted of 132 subjects. Female gender, diabetes, hypercholesterolemia, a personal and family history of cardiovascular disease (CVD), and current smoking are highly associated with CGI. After adjustment, female gender (OR 2.14 95% CI 1.05-4.36), diabetes (OR 5.59, 95% CI 1.95-16.01), current smoking (OR 5.78, 95% CI 2.27-14.72), and history of CVD (OR 21.61, 95% CI 8.40-55.55) remained significant. CGI patients >55 years had a higher median ten-year risk of death (15% vs. 5%, P = 0.001) compared to controls. During followup of 116 person-years, standardized mortality rate was higher in CGI patients (3.55; 95% CI 1.70-6.52). Conclusions: Patients with atherosclerotic CGI have an increased estimated CVD risk, and severe excess mortality. Secondary cardiovascular prevention therapy should be advocated in patients with CGI. Atherosclerosis. 2012;224(1):235-41. Impact factor: 3.706
8. Small bowel diagnostics: current place of small bowel endoscopy. Aktas H, Mensink PB. The small intestine has been difficult to examine by traditional endoscopic and radiologic techniques. Until the end of the last century, the small bowel follow through was the primary diagnostic tool for suspected small bowel disease. In recent years capsule endoscopy, deep enteroscopy using balloon-assisted or spiral techniques, computerized tomography and magnetic resonance enteroclysis or enterography have facilitated the diagnosis, monitoring, and management of patients with small bowel diseases. These technologies are complementary, each with its advantages and limitations. In the present article, we will discuss the different options and indications for modern diagnostic methods for visualization of the small bowel. We also try to provide a clinical rationale for the use of these different diagnostic options in less established, newly emerging, indications for small bowel evaluation. Best Pract Res Clin Gastroenterol. 2012;26(3):209-20. Impact factor: 3.155
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9. Single-balloon enteroscopy-assisted direct percutaneous endoscopic jejunostomy. Aktas H, Mensink PB, Kuipers EJ, van Buuren H. Direct percutaneous endoscopic jejunostomy (DPEJ) has emerged as a viable alternative for percutaneous endoscopic gastrostomy with jejunal extension (PEG-J) in patients who cannot tolerate gastric feeding. Reportedly, DPEJ placement with regular endoscopes fails in up to one-third of cases. The aim of the current study was to assess the efficacy and safety of single-balloon enteroscopy (SBE)-assisted DPEJ. The DPEJ placement technique was comparable to conventional PEG placement. A total of 12 DPEJ procedures were performed in 11 patients (mean age 55 years [range 24-83 years]; seven males). SBE-assisted DPEJ was successful in 11 of the 12 procedures (92%). Post-procedural complications included gastroparesis and aspiration pneumonia in one case each. We conclude that SBEassisted DPEJ placement seems a safe and successful approach for patients requiring jejunal enteral feeding. Endoscopy. 2012;44(2):210-2. Impact factor: 5.735
10. Small bowel Crohn's disease: MR enteroclysis and capsule endoscopy compared to balloon-assisted enteroscopy. Wiarda BM, Mensink PB, Heine DG, Stolk M, Dees J, Hazenberg H, Stoker J, van der Woude CJ, Kuipers EJ. New modalities are available to visualize the small bowel in patients with Crohn's disease (CD). The aim of this study was to compare the diagnostic yield of magnetic resonance enteroclysis (MRE) and capsule endoscopy (CE) to balloon-assisted enteroscopy (BAE) in patients with suspected or established CD of the small bowel. Consecutive, consenting patients first underwent MRE followed by CE and BAE. Patients with high-grade stenosis at MRE did not undergo CE. Reference standard for small bowel CD activity was a combination of BAE and an expert panel consensus diagnosis. Analysis included 38 patients, 27 (71%) females, mean age 36 (20-74) years, with suspected (n = 20) or established (n = 18) small bowel CD: 16 (42%) were diagnosed with active CD, and 13 (34%) by MRE with suspected highgrade stenosis, who consequently did not undergo CE. The reference standard defined high-grade stenosis in 10 (26%) patients. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value of MRE and CE for small bowel CD activity were 73 and 57%, 90 and 89%, 88 and 67%, and 78 and 84%, respectively. CE was complicated by capsule retention in one patient. MRE has a higher sensitivity and PPV than CE in small bowel CD. The use of CE is considerably limited by the high prevalence of stenotic lesions in these patients. Abdom Imaging. 2012;37(3):397-403 Impact factor: 1.905
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11. Single-balloon enteroscopy, magnetic resonance enterography, and abdominal US useful for evaluation of small-bowel disease in children with (suspected) Crohn's disease. de Ridder L, Mensink PB, Lequin MH, Aktas H, de Krijger RR, van der Woude CJ, Escher JC. Background: The usefulness of single-balloon enteroscopy (SBE) has not been evaluated in children with known or suspected Crohn's disease (CD). Objective: The objectives of this study are to evaluate the diagnostic yield of SBE for pediatric CD by comparing it with US and magnetic resonance enterography (MRE). Design: Single-center prospective study. Setting: Tertiary-care referral hospital. Patients: Between February 2009 and April 2010, 20 pediatric patients (ages 8-18 years) with suspected inflammatory bowel disease (IBD) or with a previous diagnosis of CD with suspected persistent small-bowel disease were enrolled. Interventions: All patients underwent proximal and distal SBE, 17 patients also underwent US combined with Doppler flow measurements, and 18 underwent MRE. Main outcome measurements: The findings of US with Doppler flow measurements and MRE were compared with those with SBE. Results: The mean patient age was 15.0 years (range 11.3-18 years, 70% male). Of 14 patients with suspected IBD, 8 had a diagnosis of CD made after SBE. Activity in the small bowel was found in 14 patients (70%) with both suspected and previously diagnosed CD. Twelve patients (60%) had small-bowel disease that was out of reach of conventional endoscopy. Three patients (15%) had small-bowel activity solely in the jejunum, which was not detected by either MRE or US. Limitations: Single-center study with small sample size. Conclusions: SBE can be used in children to accurately assess small-bowel disease and CD. Small-bowel activity may be identified by SBE in some patients in whom it may not be apparent despite use of conventional upper endoscopy, ileocolonoscopy, US with Doppler flow measurements, or MRE. Gastrointest Endosc. 2012;75(1):87-94. Impact factor: 5.210
12. Acute obscure-overt gastrointestinal bleeding: capsule endoscopy first? Mensink PB. Endoscopy 2012;44:335-336. Impact factor: 5.735
13. Small bowel endoscopy. Mensink PB. Best Pract Res Clin Gastroenterol 2012;26:207-208.
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Impact factor: 3.155
Totale impact factor: 47.728 Gemiddelde impact factor: 3.671 Aantal artikelen 1e, 2e of laatste auteur: 12 Totale impact factor: 41.639 Gemiddelde impact factor: 3.470
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Medical School Twente 1. Cost-effectiveness of an Intensive Smoking Cessation Intervention for COPD Outpatients. Christenhusz LC, Prenger R, Pieterse ME, Seydel ER, van der Palen J. Background: To determine the cost-effectiveness of a high-intensity smoking cessation program (SmokeStop Therapy; SST) versus a medium-intensity treatment (Minimal Intervention Strategy for Lung patients [LMIS]) for chronic obstructive pulmonary disease outpatients. Methods: The cost-effectiveness analysis was based on a randomized controlled trial investigating the effectiveness of the SST compared with the LMIS with 12month follow-up. The primary outcome measure was the cotinine-validated continuous abstinence rate based on intention to treat. A health care perspective was adopted, with outcomes assessed in terms of (incremental) additional quitters gained, exacerbations prevented, and hospital days prevented. Health care resource use, associated with smoking cessation, was collected at baseline and 12 months after the start of the interventions. Monte Carlo simulations were performed to evaluate the robustness of the results. Results: The average patient receiving SST generated euro581 in health care costs, including the costs of the smoking cessation program, versus euro595 in the LMIS. The SST is also associated with a lower average number of exacerbations (0.38 vs. 0.60) and hospital days (0.39 vs. 1) per patient and a higher number of quitters (20 vs. 9) at lower total costs. This leads to a dominance of the SST compared with the LMIS. Conclusions:The high-intensive SST is more cost-effective than the mediumintensive LMIS after 1 year. This is associated with cost savings per additional quitter, prevented exacerbations, and hospital days at lower or equal costs. Nicotine Tob Res 2012;14:657-663. Impact factor: 2.477
2. Alexithymia is not a stable personality trait in patients with substance use disorders. de Haan HA, Joosten E, Wijdeveld T, Boswinkel P, van der Palen J, De Jong CA. The construct of alexithymia as a vulnerability factor for Substance Use Disorders (SUD) is under debate, because of conflicting research results regarding alexithymia as a state or trait phenomenon. The absolute and relative stability of alexithymia were evaluated in a pre-post design as part of a randomised controlled trial, controlling for several co-variates. Assessments were done with the Toronto Alexithymia Scale (TAS-20) and Addiction Severity Index (EuropASI) at baseline and follow-up of a three months inpatient Cognitive Behavioural Therapy (CBT) with or without a Shared Decision Making intervention for 187 SUD-patients. Paired sample t-tests and ANOVA's were performed to assess absolute stability, Intra Class Correlations for relative stability and multivariate linear regression models to
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evaluate the relation between co-variates and change in alexithymia. Mean level reduction of total TAS-20 and two subfactors demonstrated no absolute stability, but change in alexithymia differed for low, moderate and high alexithymics. Relative stability of alexithymia was moderate to high for the total population, but differed for low, moderate and high alexithymics. EuropASI "psychiatry" domain, covering anxiety and depression, was related to alexithymia, but CBT-related variables were not. In conclusion, alexithymia is partly a state-dependent phenomenon, but not a stable personality trait in this SUD-population. Psychiatry Res 2012;198:123-129. Impact factor: 2.456
3. The Level of Alexithymia in Alcohol-Dependent Patients Does Not Influence Outcomes after Inpatient Treatment. de Haan HA, Schellekens AF, van der Palen J, Verkes RJ, Buitelaar JK, De Jong CA Background: The inability of individuals with Alcohol Use Disorders (AUD) to recognize and describe their feelings and cravings may be due to alexithymia. Previous researches have shown evidence for a negative influence of alexithymia on treatment outcomes in patients with AUD. Therefore, it was hypothesized that high alexithymic patients with AUD would benefit less from cognitive behavioral therapy (CBT) compared with low alexithymic patients. Methods: One hundred alcohol-dependent inpatients (DSM IV) were assessed with the Mini International Neuropsychiatric Interview for psychiatric disorders, the Toronto Alexithymia Scale (TAS-20), and the European Addiction Severity Index (EuropASI). Baseline alexithymia, as a categorical and continuous variable, was used to compare or relate baseline demographic and addiction characteristics, time in treatment, abstinence, and differences in addiction severity at 1-year follow-up. Analyses were performed using chi(2) test, analysis of variance or Kruskal-Wallis, paired t-tests or Wilcoxon's signed rank tests, multivariate logistic, and linear regression models, as appropriate. Results: The prevalence of high alexithymia (TAS-20 > 61) was 45%. The total TAS-20 score correlated negatively with years of education (r = -.21; p = .04) and positively with the psychiatry domain of the EuropASI (r = .23; p = .04). Alexithymia showed no relation to abstinence, time in treatment, or change in severity of alcoholrelated problems on the EuropASI. Conclusion: High alexithymic patients with AUD do benefit equally from inpatient CBT-like treatment as low alexithymic patients with AUD. Scientific significance: Multimethod alexithymia assessments with an observer scale have been advised to judge the relationship with resulting outcome in CBT. Am J Drug Alcohol Abuse 2012;38:299-304. Impact factor: 1.733
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4. Effects of consuming alcohol mixed with energy drinks versus consuming alcohol only on overall alcohol consumption and negative alcohol-related consequences. de Haan L, de Haan HA, van der Palen J, Olivier B, Verster JC Background: The aim of this study was to examine differences in alcohol consumption and its consequences when consumed alone and when mixed with energy drinks. Methods: A survey was conducted among Dutch students at Utrecht University and the College of Utrecht. We collected data on alcohol consumption and alcoholrelated consequences of alcohol consumed alone and/or alcohol mixed with energy drinks (AMED). The data were analyzed using a retrospective within-subject design, comparing occasions when subjects consumed AMED with those when they consumed alcohol only in the past 30 days. Results: A representative sample of 6002 students completed the survey, including 1239 who consumed AMED. Compared with consuming alcohol only, when consuming AMED, students consumed significantly fewer alcoholic drinks on an average drinking day (6.0 versus 5.4, respectively), and reported significantly fewer drinking days in the previous month (9.2 versus 1.4), significantly fewer days being drunk (1.9 versus 0.5), and significantly fewer occasions of consuming more than four (female)/five (male) alcoholic drinks (4.7 versus 0.9). The maximum number of mixed alcoholic drinks (4.5) in the previous month was significantly lower when compared with occasions when they consumed alcohol only (10.7). Accordingly, the mean duration of a drinking session was significantly shorter when mixing alcoholic drinks (4.0 versus 6.0 hours). Finally, when consuming AMED, significantly fewer alcohol-related consequences were reported (2.6) for the previous year, including driving a car while intoxicated, taking foolish risks, or being injured or hurt, as compared with alcohol-related consequences when consuming alcohol only (4.9). Conclusion: Mixing alcohol with energy drinks decreases overall alcohol consumption, and decreases the likelihood of experiencing negative alcohol-related consequences. Int J Gen Med 2012;5:953-960. Impact factor: 0
5. The (a)-Symptomatic Vertebral Fracture: A Frequently Discovered Entity With Clinical Relevance in Fracture Patients Screened on Osteoporosis. de Klerk G, Hegeman JH, Bronkhorst P, van der Palen J, van der Velde D, Duis HJ. Aim: Description of the prevalence of vertebral fractures in a fracture and osteoporosis outpatient clinic (FO-Clinic) and evaluation of the value of spinal radiographs by screening on osteoporosis. Design: Retrospective data collection, description, and analysis. Methods: All patients admitted to the FO-Clinic during the period of December 2005 until October 2006 were enrolled in this study. At the FO-Clinic spinal radiographs were obtained and bone mineral density (BMD) was measured by Dual energy Xray-Absorptiometry (DXA).
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Results: During the study period, a total of 176 patients were screened at our FOClinic. In 41.5% of these patients, a vertebral fracture was diagnosed. There appeared to be an indication for anti-osteoporotic medication in 95 of the 176 patients. Of these 95 patients, 77% could be identified by spinal radiographs. Moreover, only 36% of all patients with a vertebral fracture did suffer from osteoporosis. Conclusion: The prevalence of vertebral fractures in patients screened at an FOClinic is high and spinal radiographs can identify up to 77% of patients in which antiosteoporotic medication should be considered. However, fracture risk is not only dependent on bone quality but also on bone density. Therefore, the preferred method of screening on osteoporosis is DXA with vertebral fracture assessment and, if necessary, spinal radiographs. If DXA is not available, spinal radiographs might be used as a first step in osteoporosis screening. Geriatr Orthop Surg Rehabil 2012;3:74-78. Impact factor: 0
6. Inspiratory airflow limitation after exercise challenge in cold air in asthmatic children. Driessen JM, van der Palen J, van Aalderen WM, de Jongh FH, Thio BJ. Methacholine and histamine can lead to inspiratory flow limitation in asthmatic children and adults. This has not been analyzed after indirect airway stimuli, such as exercise. The aim of the study was to analyze airflow limitation after exercise in cold, dry air. 72 asthmatic children with mild to moderate asthma (mean age 13.2 +/- 2.2 yrs) performed a treadmill exercise challenge. A fall of >10% in FEV(1) was the threshold for expiratory flow limitation and a fall of >25% of MIF(50) was the threshold for inspiratory flow limitation. The occurrence of wheeze, stridor and cough were quantified before and after exercise. After exercise, the mean fall in FEV(1) was 17.7 +/- 14.6%, while the mean fall in MIF(50) was 25.4 +/- 15.8%; no correlation was found between fall in FEV(1) and MIF(50) (R(2): 0.04; p = 0.717). 53 of the 72 children showed an inspiratory and/or expiratory airflow limitation. 38% (20/53) of these children showed an isolated expiratory flow limitation, 45% (24/53) showed both expiratory and inspiratory flow limitation and 17% (9/53) showed an isolated inspiratory flow limitation. The fall in FEV(1) peaked 9 min after exercise and correlated to expiratory wheeze. The fall in MIF(50) peaked 15 min after exercise and correlated to inspiratory stridor. The time difference in peak fall between FEV(1) and MIF(50) was statistically significant (5.9 min; p < 0.001, 99% CI: 2.3-9.5 min). In conclusion, this study shows that an exercise challenge in asthmatic children can give rise to inspiratory airflow limitation, which may give rise to asthma like symptoms. Respir Med 2012;106:1362-1368. Impact factor: 2.585
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7. Excellent adherence and no contamination by physiotherapists involved in a randomized controlled trial on reactivation of COPD patients: a qualitative process evaluation study. Effing TW, Krabbenbos M, Pieterse ME, van der valk PD, Zielhuis GA, Kerstjens HA, van der Palen J. Background: To assess the adherence of physiotherapists to the study protocol and the occurrence of contamination bias during the course of a randomized controlled trial with a recruitment period of 2 years and a 1-year follow-up (COPE-II study). Study, design and setting: In the COPE-II study, intervention patients received a standardized physiotherapeutic reactivation intervention (COPE-active) and control patients received usual care. The latter could include regular physiotherapy treatment. Information about the adherence of physiotherapists with the study protocol was collected by performing a single interview with both intervention and control patients. Patients were only interviewed when they were currently receiving physiotherapy. Interviews were performed during two separate time periods, 10 months apart. Nine characteristics of the COPE-active intervention were scored. Scores were converted into percentages (0%, no aspects of COPE-active; 100%, full implementation of COPE-active). Results: Fifty-one patients were interviewed (first period: intervention n = 14 and control n = 10; second period: intervention n = 18 and control n = 9). Adherence with the COPE-active protocol was high (median scores: period 1, 96.8%; period 2, 92.1%), and large contrasts in scores between the intervention and control group were found (period 1: 96.8% versus 22.7%; period 2: 92.1% versus 25.0%). The scores of patients treated by seven physiotherapists who trained patients of both study groups were similar to the scores of patients treated by physiotherapists who only trained patients of one study group. Conclusion: The adherence of physiotherapists with the COPE-active protocol was high, remained unchanged over time, and no obvious contamination bias occurred. Int J Chron Obstruct Pulmon Dis 2012;7:337-344. Impact factor: 0
8. Self-management programmes for COPD: moving forward. Effing TW, Bourbeau J, Vercoulen J, Apter AJ, Coultas D, Meek P, van der valk PD, Partridge MR, van der Palen J. Self-management is of increasing importance in chronic obstructive pulmonary disease (COPD) management. However, there is confusion over what processes are involved, how the value of self-management should be determined, and about the research priorities. To gain more insight into and agreement about the content of programmes, outcomes, and future directions of COPD self-management, a group of interested researchers and physicians, all of whom had previously published on this subject and who had previously collaborated on other projects, convened a workshop. This article summarises their initial findings. Self-management programmes aim at structural behaviour change to sustain treatment effects after programmes have been completed. The programmes should include techniques
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aimed at behavioural change, be tailored individually, take the patient's perspective into account, and may vary with the course of the patient's disease and comorbidities. Assessment should include process variables. This report is a step towards greater conformity in the field of self-management. To enhance clarity regarding effectiveness, future studies should clearly describe their intervention, be properly designed and powered, and include outcomes that focus more on the acquisition and practice of new skills. In this way more evidence and a better comprehension on self-management programmes will be obtained, and more specific formulation of guidelines on self-management made possible. Chron Respir Dis 2012;9:27-35. Impact factor: 1.519
9. Circulating tumor cells, disease recurrence and survival in newly diagnosed breast cancer. Franken B, de Groot MR, Mastboom WJ, Vermes I, van der Palen J, Tibbe AG, Terstappen LW. Background: The presence of circulating tumor cells (CTC) is an independent prognostic factor for progression-free survival and breast cancer related death (BRD) for patients with metastatic breast cancer beginning a new line of systemic therapy. The current study was undertaken to explore whether the presence of CTC at the time of diagnosis was associated with recurrence free survival (RFS) and BRD. Methods: In a prospective single center study, CTC were enumerated with the CellSearch system in 30 ml of peripheral blood of 602 patients before undergoing surgery for breast cancer. 97 patients had a benign tumor, 101 did not meet the inclusion criteria of which 48 patients with DCIS, leaving 404 stage I-III patients. Patients were stratified into unfavorable (CTC [greater than or equal to]1) and favorable (CTC = 0) prognostic groups. Results: >1 CTC in 30 ml blood was detected in 15 (15%) benign tumors, in 9 DCIS (19%), in 28 (16%) stage I, 32 (18%) stage II and in 16 (31%) patients with stage III. In stage I-III patients 76 (19%) had >1 CTC of whom 16 (21.1%) developed a recurrence. In 328 patients with 0 CTC 38 (11.6%) developed a recurrence. Four year RFS was 88.4% for favorable CTC and 78.9% for unfavorable CTC (p =0.038). 25 patients died of breast cancer related causes and 11 (44%) had >1 CTC. BRD was 4,3% for favorable and 14,5% for unfavorable CTC (p = 0.001). In multivariate analysis >1 CTC was associated with distant disease free survival, but not for overall recurrence free survival. CTC, progesterone receptor and N-stage were independent predictors of BRD in multivariate analysis. Conclusions: Presence of CTC in breast cancer patients before undergoing surgery with curative intend is associated with an increased risk for breast cancer related death. Breast Cancer Res 2012;14:R133. Impact factor: 5.872
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10. Vijf jaar Urineweginfecties in het Verpleeghuis. Hasper HJ, Hendrix R, van der Palen J. Tijdschrift voor ouderengeneeskunde 2012;207-210. Impact factor: 0
11. Morningness and eveningness: When do patients take their antiepileptic drugs? Hofstra WA, van der Palen J, de Weerd AW. Almost one-third of epilepsy patients continue to have seizures despite adequate drug treatment. Chronotherapy (based on dynamic changes in drug pharmacology and disease-related processes) could be a promising treatment option. We aimed to explore whether different circadian types adjust administration times of anti-epileptic drugs (AEDs) as a step in exploring chronotherapeutic possibilities. We performed a questionnaire-based study to compare behavior of different circadian types in relation to times of taking drugs. Circadian type was determined by the Morningness-Eveningness Questionnaire. Results clearly show that morning types are taking their AEDs significantly earlier than do evening types on free days. Times of taking AEDs in the morning on work days also differ significantly between morning and evening types. Regardless of circadian type, drugs on free days are taken later than on working days. In conclusion, our study shows that patients adapt times of taking medication to their circadian type. Epilepsy Behav 2012;23:320-323. Impact factor: 1.844
12. Multicenter assessment of the reproducibility of volumetric radiofrequency-based intravascular ultrasound measurements in coronary lesions that were consecutively stented. Huisman J, Egede R, Rdzanek A, Bose D, Erbel R, Kochman J, Jensen LO, van der Palen J, Hartmann M, Mintz GS, von Birgelen C To assess in a multicenter design the between-center reproducibility of volumetric virtual histology intravascular ultrasound (VH-IVUS) measurements with a semiautomated, computer-assisted contour detection system in coronary lesions that were consecutively stented. To evaluate the reproducibility of volumetric VH-IVUS measurements, experienced analysts of 4 European IVUS centers performed independent analyses (in total 8,052 cross-sectional analyses) to obtain volumetric data of 40 coronary segments (length 20.0 +/- 0.3 mm) from target lesions prior to percutaneous intervention that were performed in the setting of stable (65%) or unstable angina pectoris (35%). Geometric and compositional VH-IVUS measurements were highly correlated for the different comparisons. Overall intraclass correlation for vessel, lumen, plaque volume and plaque burden was 0.99, 0.92, 0.96, and 0.83, respectively; for fibrous, fibro-lipidic, necrotic core and calcified volumes overall intraclass correlation was 0.96, 0.94, 0.98, and 0.99, respectively. Nevertheless, significant differences for both geometrical and compositional
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measurements were seen. Of the plaque components, fibrous tissue and necrotic core showed on average the highest measurement reproducibility. A central analysis for VH-IVUS multicenter studies of lesions prior to PCI should be pursued. Moreover, it may be problematical to pool VH-IVUS data of individual trials analyzed by independent centers. Int J Cardiovasc Imaging 2012;28:1867-1878. Impact factor: 2.648
13. Sequence of radiotherapy and chemotherapy in breast cancer after breastconserving surgery. Jobsen JJ, van der Palen J, Brinkhuis M, Ong F, Struikmans H Background: The optimal sequence of radiotherapy and chemotherapy in breastconserving therapy is unknown. Methods and materials: From 1983 through 2007, a total of 641 patients with 653 instances of breast-conserving therapy (BCT), received both chemotherapy and radiotherapy and are the basis of this analysis. Patients were divided into three groups. Groups A and B comprised patients treated before 2005, Group A radiotherapy first and Group B chemotherapy first. Group C consisted of patients treated from 2005 onward, when we had a fixed sequence of radiotherapy first, followed by chemotherapy. Results: Local control did not show any differences among the three groups. For distant metastasis, no difference was shown between Groups A and B. Group C, when compared with Group A, showed, on univariate and multivariate analyses, a significantly better distant metastasis-free survival. The same was noted for diseasefree survival. With respect to disease-specific survival, no differences were shown on multivariate analysis among the three groups. Conclusion: Radiotherapy, as an integral part of the primary treatment of BCT, should be administered first, followed by adjuvant chemotherapy. Int J Radiat Oncol Biol Phys 2012;82:e811-e817. Impact factor: 4.764
14. Consequences of Delirium After Cardiac Operations. Koster S, Hensens AG, Schuurmans MJ, van der Palen J. Background: Delirium is a transient mental syndrome characterized by disturbances in consciousness, cognition, and perception. The risk that delirium will develop is increased in patients who undergo cardiac operations, especially the elderly. Generally, delirium during hospital admission is independently associated with many negative consequences, such as higher mortality, increased length of hospital stay, nursing home placement after admission, and cognitive and functional decline. Methods: This prospective follow-up study used the Short Form 36-Item questionnaire, the Cognitive Failure Questionnaire, and a purpose-designed
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questionnaire to assess 300 patients who underwent elective cardiac operations at 6 months after the procedure. Postoperative delirium developed in 52 patients (17%). Mortality and readmission were also assessed. Results: Delirium after cardiac procedures is associated with increased mortality (13.5% vs 2.0% in patients without), more hospital readmissions (45.7% vs 26.5%), and reduced quality of life. It is also associated with reduced cognitive functioning, including failures in attention, memory, perception, and motor function, and with functional dysfunction such as independency in activities of daily living and mobility. Conclusions: Postoperative delirium after cardiac operations is associated with many important consequences. These findings provide justification for intervention studies to evaluate whether delirium prevention, early recognition, or treatment strategies might improve postoperative functional and cognitive function. Ann Thorac Surg 2012;93:705-711. Impact factor: 3.454
15. The prognostic value of tumour-stroma ratio in triple-negative breast cancer. Moorman AM, Vink R, Heijmans HJ, van der Palen J, Kouwenhoven EA. Background: Triple-negative cancer constitutes one of the most challenging groups of breast cancer given its aggressive clinical behaviour, poor outcome and lack of targeted therapy. Until now, profiling techniques have not been able to distinguish between patients with a good and poor outcome. Recent studies on tumour-stroma, found it to play an important role in tumour growth and progression. Objective: To evaluate the prognostic value of the tumour-stroma ratio (TSR) in triple-negative breast cancer. Methods: One hundred twenty four consecutive triple-negative breast cancer patients treated in our hospital were selected and evaluated. For each patient the Haematoxylin-Eosin (H&E) stained histological sections were evaluated for percentage of stroma. Patients with less than 50% stroma were classified as stromalow and patients with >/= 50% stroma were classified as stroma-high. Results: Of 124 triple-negative breast cancer patients, 40% had a stroma-high and 60% had a stroma-low tumour. TSR was assessed by two investigators (kappa 0.74). The 5-years relapse-free period (RFP) and overall survival (OS) were 85% and 89% in the stroma-low and 45% and 65% in the stroma-high group. In a multivariate cox-regression analysis, stroma amount remained an independent prognostic variable for RFP (HR 2.39; 95% CI 1.07-5.29; p = 0.033) and OS (HR 3.00; 95% CI 1.08-8.32; 0.034). Conclusion: TSR is a strong independent prognostic variable in triple-negative breast cancer. It is simple to determine, reproducible and can be easily incorporated into routine histological examination. This parameter can help optimize risk stratification and might lead to future targeted therapies. Eur J Surg Oncol 2012;38:307-313. Impact factor: 2.499
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16. Infarct tissue characteristics of patients with versus without early revascularization for acute myocardial infarction: a contrast-enhancement cardiovascular magnetic resonance imaging study. Olimulder MA, Kraaier K, Galjee MA, Scholten MF, van Es J, Wagenaar LJ, van der Palen J, von Birgelen C Histopathological studies have suggested that early revascularization for acute myocardial infarction (MI) limits the size, transmural extent, and homogeneity of myocardial necrosis. However, the long-term effect of early revascularization on infarct tissue characteristics is largely unknown. Cardiovascular magnetic resonance (CMR) imaging with contrast enhancement (CE) allows non-invasive examination of infarct tissue characteristics and left ventricular (LV) dimensions and function in one examination. A total of 69 patients, referred for cardiac evaluation for various clinical reasons, were examined with CE-CMR >1 month (median 6, range 1-213) postacute MI. We compared patients with (n = 33) versus without (n = 36) successful early revascularization for acute MI. Cine-CMR measurements included the LV enddiastolic and end-systolic volumes (ESV), LV ejection fraction (LVEF, %), and wall motion score index (WMSI). CE images were analyzed for core, peri, and total infarct size (%), and for the number of transmural segments. In our population, patients with successful early revascularization had better LVEFs (46 +/- 16 vs. 34 +/- 14%; P < 0.01), superior WMSIs (0.53, range 0.00-2.29 vs. 1.42, range 0.002.59; P < 0.01), and smaller ESVs (121 +/- 70 vs. 166 +/- 82; P = 0.02). However, there was no difference in core (9 +/- 6 vs. 11 +/- 6%), peri (9 +/- 4 vs. 10 +/- 4%), and total infarct size (18 +/- 9 vs. 21 +/- 9%; P > 0.05 for all comparisons); only transmural extent (P = 0.07) and infarct age (P = 0.06) tended to be larger in patients without early revascularization. CMR wall motion abnormalities are significantly better after revascularization; these differences are particularly marked later after infarction. The difference in scar size is more subtle and does not reach significance in this study. Heart Vessels 2012;27:250-257. Impact factor: 2.047
17. Relationship between infarct tissue characteristics and left ventricular remodeling in patients with versus without early revascularization for acute myocardial infarction as assessed with contrast-enhanced cardiovascular magnetic resonance imaging. Olimulder MA, Galjee MA, Wagenaar LJ, van Es J, van der Palen J, von Birgelen C. Left ventricular (LV) remodeling following myocardial infarction (MI) is the result of complex interactions between various factors, including presence or absence of early revascularization. The impact of early revascularization on the relationship between infarct tissue characteristics and LV remodeling is incompletely known. Therefore, we investigated in patients with versus without successful early revascularization for acute MI potential relations between infarct tissue characteristics and LV remodeling with contrast-enhanced (CE) cardiovascular
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magnetic resonance (CMR). Patients with versus without successful early revascularization underwent CE-CMR for tissue characterization and assessment of LV remodeling including end-diastolic and end-systolic volumes, LV ejection fraction, and wall motion score index (WMSI). CE-CMR images were analyzed for infarct tissue characteristics including core-, peri- and total-infarct size, transmural extent, and regional scar scores. In early revascularized patients (n = 46), a larger area of infarct tissue correlated significantly with larger LV dimensions and a more reduced LV function (r = 0.39-0.68; all P
18. The role of cognition in cost-effectiveness analyses of behavioral interventions. Prenger R, Braakman-Jansen LM, Pieterse ME, van der Palen J, Seydel ER. Background: Behavioral interventions typically focus on objective behavioral endpoints like weight loss and smoking cessation. In reality, though, achieving full behavior change is a complex process in which several steps towards success are taken. Any progress in this process may also be considered as a beneficial outcome of the intervention, assuming that this increases the likelihood to achieve successful behavior change eventually. Until recently, there has been little consideration about whether partial behavior change at follow-up should be incorporated in costeffectiveness analyses (CEAs). The aim of this explorative review is to identify CEAs of behavioral interventions in which cognitive outcome measures of behavior change are analyzed. Methods: Data sources were searched for publications before May 2011. Results: Twelve studies were found eligible for inclusion. Two different approaches were found: three studies calculated separate incremental cost-effectiveness ratios for cognitive outcome measures, and one study modeled partial behavior change into the final outcome. Both approaches rely on the assumption, be it implicitly or explicitly, that changes in cognitive outcome measures are predictive of future behavior change and may affect CEA outcomes. Conclusion: Potential value of cognitive states in CEA, as a way to account for partial behavior change, is to some extent recognized but not (yet) integrated in the field. In conclusion, CEAs should consider, and where appropriate incorporate measures of partial behavior change when reporting effectiveness and hence costeffectiveness.
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Cost Eff Resour Alloc 2012;10:3. Impact factor: 1.680
19. Comparison of eligible non-enrolled patients and the randomised TWENTE trial population treated with Resolute and Xience V drug-eluting stents. Sen H, Tandjung K, Basalus MW, Lowik MM, van Houwelingen GK, Stoel MG, Louwerenburg HW, de Man FH, Linssen GC, Nijhuis R, Nienhuis MB, Verhorst PM, van der Palen J, von Birgelen C The TWENTE trial recently enrolled more than 80% of all eligible patients, who were randomised to zotarolimus-eluting Resolute or everolimus-eluting Xience V stents. In the present study, we investigated whether eligible, non-enrolled patients differed from the randomised TWENTE trial population in baseline characteristics and one-year outcome. Methods and results: Characteristics of 1,709 eligible patients were analysed. Independent external adjudication of clinical events was likewise performed for nonenrolled (n=318) and randomised patients (n=1,391). Non-enrolled and randomised patients did not differ in gender distribution, diabetes mellitus, and clinical presentation, but differed significantly in age and cardiovascular history. Nevertheless, clinical outcome after one year did not differ in the primary composite endpoint target-vessel failure (TVF; 9.8% vs. 8.1%; p=0.34), and its components cardiac death (1.6% vs. 1.2%; p=0.61), target vessel-related myocardial infarction (4.7% vs. 4.6%; p=0.92), and target-vessel revascularisation (3.8% vs. 3.0%; p=0.48). Previous bypass surgery predicted TVF in non-enrolled patients (p=0.001); removal of these patients resulted in identical TVF rates for non-enrolled and randomised patients (7.3% vs. 7.3%; p=0.99). Conclusions: Despite some differences in baseline characteristics, non-enrolled and randomised patients did not differ in one-year outcome, which was favourable for both populations and may be related to the drug-eluting stents used. EuroIntervention 2012;8:664-671. Impact factor: 3.173
20. Telemonitoring of Daily Activity and Symptom Behavior in Patients with COPD. Tabak M, Vollenbroek-Hutten MM, van der valk PD, van der Palen J, Tonis TM, Hermens HJ. Objectives: This study investigated the activity behavior of patients with COPD in detail compared to asymptomatic controls, and the relationship between subjective and objective activities (awareness), and readiness to change activity behavior. Methods: Thirty-nine patients with COPD (66.0 years; FEV(1)% predicted: 44.9%) and 21 healthy controls (57.0 years) participated. Objective daily activity was assessed by accelerometry and expressed as amount of activity in counts per
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minute (cpm). Patients' baseline subjective activity and stage of change were assessed prior to measurements. Results: Mean daily activity in COPD patients was significantly lower compared to the healthy controls (864 +/- 277 cpm versus 1162 +/- 282 cpm, P < 0.001). COPD patients showed a temporary decrease in objective activities in the early afternoon. Objective and subjective activities were significantly moderately related and most patients (55.3%) were in the maintenance phase of the stages of change. Conclusions: COPD patients show a distinctive activity decrease in the early afternoon. COPD patients are moderately aware of their daily activity but regard themselves as physically active. Therefore, future telemedicine interventions might consider creating awareness of an active lifestyle and provide feedback that aims to increase and balance activity levels. Int J Telemed Appl 2012;2012:438736. Impact factor: 0
21. Comparison of Frequency of Periprocedural Myocardial Infarction in Patients With and Without Diabetes Mellitus to Those With Previously Unknown but Elevated Glycated Hemoglobin Levels (from the TWENTE Trial). Tandjung K, van Houwelingen KG, Jansen H, Basalus MW, Sen H, Lowik MM, Stoel MG, Louwerenburg JH, de Man FH, Linssen GC, Nijhuis R, Nienhuis MB, van der Palen J, Stolk RP, von Birgelen C In patients without a history of diabetes mellitus, increased levels of glycated hemoglobin (HbA1c) are associated with higher cardiovascular risk. The relation between undetected diabetes and clinical outcome after percutaneous coronary intervention is unknown. To investigate whether these patients may have an increased risk of periprocedural myocardial infarction (PMI), the most frequent adverse event after percutaneous coronary intervention, we assessed patients of the TWENTE trial (a randomized, controlled, second-generation drug-eluting stent trial) in whom HbA1c data were available. Patients were classified as known diabetics or patients without a history of diabetes who were subdivided into undetected diabetics (HbA1c >/=6.5%) and nondiabetics (HbA1c <6.5%). Systematic measurement of cardiac biomarkers and electrocardiographic assessment were performed. One-year clinical outcome was also compared. Of 626 patients, 44 (7%) were undetected diabetics, 181 (29%) were known diabetics, and 401 (64%) were nondiabetics. In undetected diabetics the PMI rate was higher than in nondiabetics (13.6% vs 6.1%, p = 0.01) and known diabetics (13.6% vs 3.7%, p = 0.11). Multivariate analysis adjusting for covariates confirmed a significantly higher PMI risk in undetected diabetics compared to nondiabetics (odds ratio 6.13, 95% confidence interval 2.07 to 18.13, p = 0.001) and known diabetics (odds ratio 3.73, 95% confidence interval 1.17 to 11.89, p = 0.03). After 1 year, target vessel MI rate was significantly higher in undetected diabetics (p = 0.02) than in nondiabetics, which was related mainly to differences in PMI. Target vessel failure was numerically larger in unknown diabetics than in nondiabetics, but this difference did not reach statistical significance (13.6% vs 8.0%, p = 0.25). In conclusion, undetected diabetics were shown to have an increased risk of PMI.
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Am J Cardiol 2012;110:1561-1567. Impact factor: 3.209
22. Splanchnic artery stenosis and abdominal complaints: clinical history is of limited value in detection of gastrointestinal ischemia. Ter Steege RW, Sloterdijk HS, Geelkerken RH, Huisman AB, van der Palen J, Kolkman JJ. Background: Splanchnic artery stenosis is common and mostly asymptomatic and may lead to gastrointestinal ischemia (chronic splanchnic syndrome, CSS). This study was designed to assess risk factors for CSS in the medical history of patients with splanchnic artery stenosis and whether these risk factors can be used to identify patients with high and low risk of CSS. Methods: All patients referred for suspected CSS underwent a standardized workup, including a medical history with questionnaire, duplex ultrasound, gastrointestinal tonometry, and angiography. Definitive diagnosis and treatment advice was made in a multidisciplinary team. Patients with confirmed CSS were compared with no-CSS patients. Results: A total of 270 patients (102 M, 168 F; mean age, 53 years) with splanchnic artery stenosis were analyzed, of whom 109 (40%) had CSS and 161 no CSS. CSSpatients more often reported postprandial pain (87% vs. 72%, p = 0.007), weight loss (85% vs. 70%, p = 0.006), adapted eating pattern (90% vs. 79%, p = 0.005) and diarrhea (35% vs. 22%, p = 0.023). If none of these risk factors were present, the probability of CSS was 13%; if all were present, the probability was 60%. Adapted eating pattern (odds ratio (OR) 3.1; 95% confidence interval (CI) 1.08-8.88) and diarrhea (OR 2.6; 95% CI 1.31-5.3) were statistically significant in multivariate analysis. Conclusions: In patients with splanchnic artery stenosis, the clinical history is of limited value for detection of CSS. A diagnostic test to detect ischemia is indispensable for proper selection of patients with splanchnic artery stenosis who might benefit from treatment. World J Surg 2012;36:793-799. Impact factor: 2.228
23. Gain in lung function after weight reduction in severely obese children. van de Griendt EJ, van der Baan-Slootweg OH, van Essen-Zandvliet EE, van der Palen J, Tamminga-Smeulders CL, Benninga MA, van Aalderen WM. Aim: The primary objective of this prospective cohort study was to determine the effect of weight loss on pulmonary function values in extremely obese children. Methods: Obese children participated in a 26-week in-hospital or outpatient multidisciplinary treatment programme. Waist circumference was measured and pulmonary function tests were performed at enrolment and after 6 months.
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Results: The data of 112 children were analysed. The children had a mean age of 14.4 (range 8.5-18.9) years and 62.5% were girls. The mean SD score-body mass index (SDS-BMI) was +3.38 at baseline and +2.91 after the intervention. Lung function improved significantly: functional vital capacity increased by 3.08% (95% CI 1.16% to 5.00%) of the predicted value, forced expiratory volume in 1 s (FEV(1)) by 2.91% (95% CI 1.11% to 4.71%) of the predicted value, total lung capacity by 2.27% (95% CI 1.16% to 5.00%) of the predicted value, and expiratory reserve volume (ERV) by 14.8% (95% CI 8.66% to 20.88%) of the predicted value. The increase in ERV correlated with the reduction in SDS-BMI and with the reduction in waist circumference. FEV(1) did not correlate with the reduction in either SDS-BMI or waist circumference. Conclusions: Weight loss in severely obese children correlated with an improvement in lung function, especially ERV. The improvement in ERV correlated with the decrease in SDS-BMI and waist circumference. Arch Dis Child 2012;97:1039-1042. Impact factor: 3.051
24. Effect of outpatient exercise training programmes in patients with chronic heart failure: a systematic review. van der Meer S, Zwerink M, van Brussel M, van der valk PD, Wajon E, van der Palen J. Background: Advantages of outpatient exercise training are reduced waiting lists, better compliance, reduced time investment by the patient with reduced travel expenses, and less dependence on other people to participate. Therefore, this systematic review studies the effects of outpatient exercise training programmes compared with usual care on exercise capacity, exercise performance, quality of life, and safety in patients with chronic heart failure.Design: Systematic review with meta-analysis.Methods: Randomized controlled trials concerning patients with chronic heart failure, with a left ventricular ejection fraction
25. Equal Virulence of Rhinovirus and Respiratory Syncytial Virus in Infants Hospitalized for Lower Respiratory Tract Infection. van Leeuwen JC, Goossens LK, Hendrix RM, van der Palen J, Lusthusz A, Thio BJ.
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Respiratory syncytial virus (RSV) and rhinovirus (RV) are predominant viruses associated with lower respiratory tract infection in infants. We compared the symptoms of lower respiratory tract infection caused by RSV and RV in hospitalized infants. RV showed the same symptoms as RSV, so on clinical grounds, no difference can be made between these pathogens. No relation between polymerase chain reaction cycle threshold value and length of hospital stay was found. Pediatr Infect Dis J 2012;31:84-86. Impact factor: 3.569
26. Monitoring device acceptance in implantable cardioverter defibrillator patients using the Florida Patient Acceptance Survey. Versteeg H, Starrenburg A, Denollet J, van der Palen J, Sears SF, Pedersen SS. Background: Patient device acceptance might be essential in identifying patients at risk for adverse patient-reported outcomes following implantation of an implantable cardioverter defibrillator (ICD). We examined the validity and reliability of the Florida Patient Acceptance Scale (FPAS) and identified correlates of device acceptance in a Dutch cohort of ICD patients. Methods: Patients with a first-time ICD (N = 272, mean age = 59.2 +/- 11.9, 82% men) recruited from the Erasmus Medical Center, Rotterdam, or the Medisch Spectrum Twente, Enschede, The Netherlands completed the FPAS, the Type D Scale, and the Hospital Anxiety and Depression Scale. Results: Exploratory and confirmatory factor analyses indicated that eliminating three items from the FPAS, leaving 12 items contributing to three factors, is equivalent to the original four-factor version of the FPAS. The abbreviated FPAS had a high internal consistency both for the total scale and all subscales, with Cronbach's alphas ranging from 0.76 to 0.82. Anxiety (odds ratio [OR]: 9.75; 95% confidence interval [CI]: 2.38-39.87; P = 0.002), depression (OR: 2.96; 95% CI: 0.98-8.93; P = 0.05), and the distressed (Type D) personality (OR: 5.04; 95% CI: 1.50-16.92; P = 0.01), but not demographic and clinical factors including shocks, were significant independent correlates of poor device acceptance. Conclusion: A shortened 12-item, three-factor version of the FPAS was shown to be a valid and internally consistent instrument to assess device acceptance in Dutch ICD patients. Psychological but not clinical factors were the primary correlates of device acceptance, which underlines the importance of taking into account the patient's psychological profile when seeking to identify patients at risk for adjustment difficulties after ICD implantation. Pacing Clin Electrophysiol 2012;35:283-293. Impact factor: 1.746
27. A Randomized Controlled Trial in Second-Generation Zotarolimus-Eluting Resolute Stents Versus Everolimus-Eluting Xience V Stents in Real-World Patients: The TWENTE Trial.
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von Birgelen C, Basalus MW, Tandjung K, van Houwelingen KG, Stoel MG, Louwerenburg JH, Linssen GC, Said SA, Kleijne MA, Sen H, Lowik MM, van der Palen J, Verhorst PM, de Man FH. Objectives: The aim of this study was to compare the safety and efficacy of Resolute zotarolimus-eluting stents (ZES) (Medtronic Cardiovascular, Santa Rosa, California) with Xience V everolimus-eluting stents (EES) (Abbott Vascular Devices, Santa Clara, California) at 1-year follow-up. Background: Only 1 randomized trial previously compared these stents. Methods: This investigator-initiated, patient-blinded, randomized noninferiority study had limited exclusion criteria (acute ST-segment elevation myocardial infarctions not eligible). Patients (n = 1,391; 81.4% of eligible population) were randomly assigned to ZES (n = 697) or EES (n = 694). Liberal use of stent post-dilation was encouraged. Cardiac biomarkers were systematically assessed. The primary endpoint was target vessel failure (TVF), a composite of cardiac death, myocardial infarction not clearly attributable to non-target vessels, and clinically indicated targetvessel revascularization. An external independent research organization performed clinical event adjudication (100% follow-up data available). Analysis was by intention-to-treat. Results: Acute coronary syndromes were present in 52% and "off-label" feature in 77% of patients. Of the lesions, 70% were type B2/C; the post-dilation rate was very high (82%). In ZES and EES, TVF occurred in 8.2% and 8.1%, respectively (absolute risk-difference 0.1%; 95% confidence interval: -2.8% to 3.0%, p(noninferiority) = 0.001). There was no significant between-group difference in TVF components. The definite-or-probable stent thrombosis rates were relatively low and similar for ZES and EES (0.9% and 1.2%, respectively, p = 0.59). Definite stent thrombosis rates were also low (0.58% and 0%, respectively, p = 0.12). In EES, probable stent thrombosis beyond day 8 was observed only in patients not adhering to dual antiplatelet therapy. Conclusions: Resolute ZES were noninferior to Xience V EES in treating "realworld" patients with a vast majority of complex lesions and "off-label" indications for drug-eluting stents, which were implanted with liberal use of post-dilation. (The RealWorld Endeavor Resolute Versus XIENCE V Drug-Eluting SteNt Study: Head-tohead Comparison of Clinical Outcome After Implantation of Second Generation Drug-eluting Stents in a Real World Scenario; NCT01066650) J Am Coll Cardiol 2012;59:1350-1361. Impact factor: 14.086
Totale impact factor: 70.507 Gemiddelde impact factor: 2.611 Aantal artikelen 1e, 2e of laatste auteur: 9 Totale impact factor: 19.277 Gemiddelde impact factor: 2.142
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Mond- kaak- en aangezichtschirurgie 1. Subjective Alveolar Nerve Function After Bilateral Sagittal Split Osteotomy or Distraction Osteogenesis of Mandible. Baas EM, Horsthuis RB, de Lange J. Purpose: The present retrospective cohort study compared the subjective inferior alveolar nerve (IAN) function after distraction osteogenesis (DOG) and bilateral sagittal split osteotomy (BSSO) in mandibular advancement surgery. Materials and methods: Treatment consisted of correction of a retrognathic mandible using DOG (30 patients) or BSSO (35 patients). Subjective IAN function was recorded using a questionnaire 1 year after surgery. A total of 130 IANs were evaluated. Results: In 37 nerves (28.5%), an IAN disturbance was observed. In this group of 37 nerves, BSSO had been performed in 26 (70.3%) and DOG in 11 (29.7%). After eliminating confounders (eg, age, amount of advancement, gender), no significant difference (odds ratio 0.652, 95% confidence interval 0.221 to 1.920) was found. Age was significantly related to subjective IAN disturbances for women but not for men. This was seen in women older than 22 years and increased for women older than 36 years to an odds ratio of 22.8 (95% confidence interval 2.580 to 201.488). Satisfaction also correlated with age, independent of gender. Conclusion: No difference was found in subjective IAN disturbances after 1 year between DOG and BSSO for lengthening the mandible. J Oral Maxillofac Surg 2012;70:910-918. Impact factor: 1.333
Totale impact factor: 1.333 Gemiddelde impact factor: 1.333 Aantal artikelen 1e, 2e of laatste auteur: 1 Totale impact factor: 1.333 Gemiddelde impact factor: 1.333
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Neurochirurgie 1. Spinal Cord Stimulation With Hybrid Lead Relieves Pain in Low Back and Legs. de Vos CC, Dijkstra C, Lenders MW, Holsheimer J Objective: The failed back surgery syndrome (FBSS) is the most common chronic pain syndrome. Whereas it is relatively easy to achieve pain relief in the lower limbs of FBSS patients with spinal cord stimulation (SCS), it is difficult to manage low back pain with SCS. The performance of a paddle-shaped SCS lead that can be inserted surgically as well as percutaneously (a hybrid lead) was evaluated in a prospective study on the relief of low back pain and leg pain in patients with FBSS. Materials and Methods: Patients with FBSS being eligible for SCS were enrolled in the study, and a hybrid lead was placed surgically. Outcome measures included pain scores for low back and leg pain assessed by visual analog scale (VAS), pain medication, and patient satisfaction. These scores were assessed before and at regular intervals after implantation. Results: It was shown that a single hybrid lead, generally positioned over the physiological midline of the spinal cord, is capable of alleviating both low back and leg pain in patients with FBSS. Forty-five subjects were eligible for SCS and received trial stimulation. Forty-two of them had a successful trial period and were converted to a permanent system. Their average VAS score at baseline was 8.0 for lower limb pain and 7.5 for low back pain. After six months of SCS, these average VAS scores were reduced to 3.2 and 3.5, respectively, and also pain medication was reduced significantly. Conclusion: SCS with a hybrid lead in subjects with FBSS is safe, and causes significant pain relief in both the low back and the lower limbs. Neuromodulation 2012;15:118-123. Impact factor: 1.190
2. A 71-year-old woman with an intracranial dural-based mesenchymal chondrosarcoma. Vergeer RA, Vink R, Avenarius JK, Driesse MJ. Intracranial mesenchymal chondrosarcoma is a rare, high-grade malignancy with the highest prevalence in young adults. Because of its rarity, most data regarding survival are limited to case studies and small series. We present a 71-year-old woman with an intracranial dural based mesenchymal chondrosarcoma located in the anterior skull base, to our knowledge the oldest patient reported with this tumor. J Clin Neurosci 2012;19:1170-1171. Impact factor: 1.253
Totale impact factor: 2.433
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Gemiddelde impact factor: 1.222 Aantal artikelen 1e, 2e of laatste auteur: 2 Totale impact factor: 2.433 Gemiddelde impact factor: 1.222
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Neurologie 1. Motor unit number index (MUNIX) versus motor unit number estimation (MUNE): A direct comparison in a longitudinal study of ALS patients Boekestein WA, Schelhaas HJ, van Putten MJ, Stegeman DF, Zwarts MJ, van Dijk JP. Objective: To evaluate how the motor unit number index (MUNIX) is related to highdensity motor unit number estimation (HD-MUNE) in healthy controls and patients with amyotrophic lateral sclerosis (ALS). Methods: Both MUNIX and HD-MUNE were performed on the thenar muscles in 18 ALS patients and 24 healthy controls. Patients were measured at baseline, within 2weeks, and after 4 and 8months. Clinical evaluation included Medical Research Council (MRC) scale and the ALS functional rating scale (ALSFRS). Results: There was a significant positive correlation between MUNE and MUNIX values in ALS patients (r=0.49 at baseline; r=0.56 at 4months; r=0.56 at 8months, all p<0.05), but not in healthy controls. After 8months, both MUNE and MUNIX values of the ALS patients decreased significantly more compared to MRC scale, ALS functional rating scale (ALSFRS) and compound muscle action potential (CMAP) (p<0.05). There was no significant difference in relative decline of MUNIX and HDMUNE values. Conclusions: In ALS patients, MUNIX and HD-MUNE are significantly correlated. MUNIX has an almost equivalent potential in detecting motor neuron loss compared to HD-MUNE. SIGNIFICANCE: MUNIX could serve as a reliable and sensitive marker for monitoring disease progression in ALS. Clin Neurophysiol 2012;123:1644-1649. Impact factor: 3.144
2. Continuous electroencephalography monitoring for early prediction of neurological outcome in postanoxic patients after cardiac arrest: A prospective cohort study. Cloostermans MC, van Meulen FB, Eertman CJ, Hom HW, van Putten MJ. Objective: To evaluate the value of continuous electroencephalography in early prognostication in patients treated with hypothermia after cardiac arrest. Design: Prospective cohort study. Setting: Medical intensive care unit. Patients: Sixty patients admitted to the intensive care unit for therapeutic hypothermia after cardiac arrest. Intervention: None. Measurements and main results: In all patients, continuous electroencephalogram and daily somatosensory evoked potentials were recorded during the first 5 days of admission or until intensive care unit discharge. Neurological outcomes were based on each patient's best achieved Cerebral Performance Category score within 6 months. Twenty-seven of 56 patients (48%) achieved good neurological outcome
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(Cerebral Performance Category score 1-2).At 12 hrs after resuscitation, 43% of the patients with good neurological outcome showed continuous, diffuse slow electroencephalogram rhythms, whereas this was never observed in patients with poor outcome.The sensitivity for predicting poor neurological outcome of low-voltage and isoelectric electroencephalogram patterns 24 hrs after resuscitation was 40% (95% confidence interval 19%-64%) with a 100% specificity (confidence interval 86%-100%), whereas the sensitivity and specificity of absent somatosensory evoked potential responses during the first 24 hrs were 24% (confidence interval 10%-44%) and 100% (confidence interval: 87%-100%), respectively. The negative predictive value for poor outcome of low-voltage and isoelectric electroencephalogram patterns was 68% (confidence interval 50%-81%) compared to 55% (confidence interval 40%-60%) for bilateral somatosensory evoked potential absence, both with a positive predictive value of 100% (confidence interval 63%-100% and 59%-100% respectively). Burst-suppression patterns after 24 hrs were also associated with poor neurological outcome, but not inevitably so. Conclusions: In patients treated with hypothermia, electroencephalogram monitoring during the first 24 hrs after resuscitation can contribute to the prediction of both good and poor neurological outcome. Continuous patterns within 12 hrs predicted good outcome. Isoelectric or low-voltage electroencephalograms after 24 hrs predicted poor outcome with a sensitivity almost two times larger than bilateral absent somatosensory evoked potential responses. Crit Care Med 2012;40:2867-2875. Impact factor: 6.124
3. Revised practice guideline 'Management of patients with mild traumatic head/brain injury de Kruijk JR, Nederkoorn PJ, Reijners EP, Hageman G. Recently the out-of-date Dutch guideline 'Mild traumatic head/brain injury' dating from 2001 was revised under the supervision of the Dutch Institute for Healthcare Improvement (CBO). The revised guideline gives underpinned decision rules for the referral of patients to hospital, carrying out diagnostic imaging investigations, and formulating indications for admission. Mild head-brain injury is no longer an indication for a conventional skull radiograph. Adults and children aged 6 years and older no longer have to be woken regularly if they are allowed home. The guideline can be used in both primary care and on the Emergency Departments of hospitals and is applicable to both adults and children. The guideline does not address the rehabilitation or long-term care of patients with mild traumatic head/brain injury, but it does give advice on reducing the risk of long-term symptoms. Regional implementation of the guideline in primary and secondary care is recommended. Ned Tijdschr Geneeskd 2012;156:A4195. Impact factor: 0
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4. Mutations in potassium channel kcnd3 cause spinocerebellar ataxia type 19. Duarri A, Jezierska J, Fokkens M, Meijer M, Schelhaas HJ, den Dunnen WF, van Dijk F, Verschuuren-Bemelmans C, Hageman G, van d, V, Kusters B, van de Warrenburg BP, Kremer B, Wijmenga C, Sinke RJ, Swertz MA, Kampinga HH, Boddeke E, Verbeek DS. Objective: To identify the causative gene for the neurodegenerative disorder spinocerebellar ataxia type 19 (SCA19) located on chromosomal region 1p21-q21. Methods: Exome sequencing was used to identify the causal mutation in a large SCA19 family. We then screened 230 ataxia families for mutations located in the same gene (KCND3, also known as Kv4.3) using high-resolution melting. SCA19 brain autopsy material was evaluated, and in vitro experiments using ectopic expression of wild-type and mutant Kv4.3 were used to study protein localization, stability, and channel activity by patch-clamping. Results: We detected a T352P mutation in the third extracellular loop of the voltagegated potassium channel KCND3 that cosegregated with the disease phenotype in our original family. We identified 2 more novel missense mutations in the channel pore (M373I) and the S6 transmembrane domain (S390N) in 2 other ataxia families. T352P cerebellar autopsy material showed severe Purkinje cell degeneration, with abnormal intracellular accumulation and reduced protein levels of Kv4.3 in their soma. Ectopic expression of all mutant proteins in HeLa cells revealed retention in the endoplasmic reticulum and enhanced protein instability, in contrast to wild-type Kv4.3 that was localized on the plasma membrane. The regulatory beta subunit Kv channel interacting protein 2 was able to rescue the membrane localization and the stability of 2 of the 3 mutant Kv4.3 complexes. However, this either did not restore the channel function of the membrane-located mutant Kv4.3 complexes or restored it only partially. Interpretation: KCND3 mutations cause SCA19 by impaired protein maturation and/or reduced channel function. Ann Neurol 2012;72:870-880 Impact factor: 11.193
5. Meanfield modeling of propofol-induced changes in spontaneous EEG rhythms. Hindriks R, van Putten MJ. During the maintenance period of propofol-induced general anesthesia, specific changes in spontaneous EEG rhythms can be observed. These comprise increased delta and theta power and the emergence of alpha oscillations over frontal regions. In this study we use a meanfield model of the thalamo-cortical system to reproduce these changes and to elucidate the underlying mechanisms. The model is able to reproduce the most dominant changes in the EEG and suggests that they are caused by the amplification of resonances within the thalamo-cortical system. Specifically, while observed increases in delta and alpha power are reflections of amplified resonances in the respective frequency bands, increases in theta power are caused indirectly by spectral power leakage from delta and alpha bands. The
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model suggests that these changes are brought about through increased inhibition within local cortical interneuron circuits. These results are encouraging and motivate more extensive use of neural meanfield models in elucidating the physiological mechanisms underlying the effects of pharmacological agents on macroscopic brain dynamics. Neuroimage 2012;60:2323-2334 Impact factor: 6.252
6. Thalamo-cortical mechanisms underlying changes in amplitude and frequency of human alpha oscillations. Hindriks R, van Putten MJ. Although a large number of studies has been devoted to establishing correlations between changes in amplitude and frequency of EEG alpha oscillations and cognitive processes, it is currently unclear through which physiological mechanisms such changes are brought about. In this study we use a biophysical model of EEG generation to gain a fundamental understanding of the functional changes within the thalamo-cortical system that might underly such alpha responses. The main result of this study is that, although the physiology of the thalamo-cortical system is characterized by a large number of parameters, alpha responses effectively depend on only three variables. Physiologically, these variables determine the resonance properties of feedforward, cortico-thalamo-cortical, and intra-cortical circuits. By examining the effect of modulations of these resonances on the amplitude and frequency of EEG alpha oscillations, it is established that the model can reproduce the variety of experimentally observed alpha responses, as well as the experimental finding that changes in alpha amplitude are typically an order of magnitude larger than changes in alpha frequency. The modeling results are also in line with the fact that alpha responses often correlate linearly with indices characterizing cognitive processes. By investigating the effect of synaptic and intrinsic neuronal parameters, we find that alpha responses reflect changes in cortical activation, which is consistent with the hypothesis that alpha activity serves to selectively inhibit cortical regions during cognitive processing demands. As an example of how these analyses can be applied to specific experimental protocols, we reproduce benzodiazepineinduced alpha responses and clarify the putative underlying thalamo-cortical mechanisms. The findings reported in this study provide a fundamental physiological framework within which alpha responses observed in specific experimental protocols can be understood. Neuroimage 2012;70C:150-163 Impact factor: 6.252
7. Ischemic cerebral damage: an appraisal of synaptic failure. Hofmeijer J, van Putten MJ. In the human brain, approximately 30% of the energy is spent on synaptic transmission. Disappearance of synaptic activity is the earliest consequence of
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cerebral ischemia. The changes of synaptic function are generally assumed to be reversible and persistent damage is associated with membrane failure and neuronal death. However, there is overwhelming experimental evidence of isolated, but persistent, synaptic failure resulting from mild or moderate cerebral ischemia. Early failure results from presynaptic damage with impaired transmitter release. Proposed mechanisms include dysfunction of adenosine triphosphate-dependent calcium channels and a disturbed docking of glutamate-containing vesicles resulting from impaired phosphorylation. We review energy distribution among neuronal functions, focusing on energy usage of synaptic transmission. We summarize the effect of ischemia on neurotransmission and the evidence of long-lasting synaptic failure as a cause of persistent symptoms in patients with cerebral ischemia. Finally, we discuss the implications of synaptic failure in the diagnosis of cerebral ischemia, including the limited sensitivity of diffusion-weighted MRI in those cases in which damage is presumably limited to the synapses. Stroke 2012;43:607-615 Impact factor: 6.158
8. Morningness and eveningness: When do patients take their antiepileptic drugs? Hofstra WA, van der Palen J, de Weerd AW. Almost one-third of epilepsy patients continue to have seizures despite adequate drug treatment. Chronotherapy (based on dynamic changes in drug pharmacology and disease-related processes) could be a promising treatment option. We aimed to explore whether different circadian types adjust administration times of anti-epileptic drugs (AEDs) as a step in exploring chronotherapeutic possibilities. We performed a questionnaire-based study to compare behavior of different circadian types in relation to times of taking drugs. Circadian type was determined by the Morningness-Eveningness Questionnaire. Results clearly show that morning types are taking their AEDs significantly earlier than do evening types on free days. Times of taking AEDs in the morning on work days also differ significantly between morning and evening types. Regardless of circadian type, drugs on free days are taken later than on working days. In conclusion, our study shows that patients adapt times of taking medication to their circadian type. Epilepsy Behav 2012;23:320-323 Impact factor: 1.844
9. Levels of heparin-releasable TFPI are increased in first-ever lacunar stroke patients. Knottnerus IL, Winckers K, Ten CH, Hackeng TM, Lodder J, Rouhl RP, Staals J, Govers-Riemslag JW, Bekers O, van Oostenbrugge RJ Objectives: New insights in the pathophysiology of lacunar stroke (LS) suggest that it is caused by increased permeability of the blood-brain barrier due to endothelial
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activation. Because endothelial cells are the major production and storage site of tissue factor pathway inhibitor (TFPI), this protein can be used as marker of endothelial activation. In this observational study we measured the different pools of TFPI, as a marker of endothelial function, in first-ever lacunar stroke patients. Methods: We determined antigen levels of total and free full-length (FL) TFPI using ELISA in 149 patients and 42 controls. Heparin-releasable free FL TFPI was determined in a random subset of 17 patients and 15 controls. By brain MRI, we classified LS patients as having isolated lacunar infarct (ILA) or silent ischemic lesions (SILs). Results: Plasma levels of total TFPI were highest in patients with SILs compared with those with ILA, but this association disappeared after correction for age and levels of low-density lipoprotein cholesterol. However, levels of heparin-releasable free FL TFPI were higher in patients than in controls. Conclusions: Although ambient plasma levels of total TFPI were not different in subtypes of LS, the increased levels of heparin-releasable TFPI in patients suggest a role of endothelial activation in the pathogenesis of LS. Neurology 2012;78:493-498 Impact factor: 8.249
10. Dynamic indices do not predict volume responsiveness in routine clinical practice. Lansdorp B, Lemson J, van Putten MJ, de Keijzer A, van der Hoeven JG, Pickkers P Background: Dynamic indices, including pulse pressure, systolic pressure, and stroke volume variation (PPV, SPV, and SVV), are accurate predictors of fluid responsiveness under strict conditions, for example, controlled mechanical ventilation using conventional tidal volumes (TVs) in the absence of cardiac arrhythmias. However, in routine clinical practice, these prerequisites are not always met. We evaluated the effect of regularly used ventilator settings, different calculation methods, and the presence of cardiac arrhythmias on the ability of dynamic indices to predict fluid responsiveness in sedated, mechanically ventilated patients. Methods: We prospectively evaluated 47 fluid challenges in 29 consecutive cardiac surgery patients. Patients were divided into different groups based on TV. Dynamic indices were calculated in various ways: calculation over 30 s, breath-by-breath (with and without excluding arrhythmias), and with correction for TV. Results: The predictive value was optimal in the group ventilated with TVs >7 ml kg(-1) with correction for TV, calculated breath-by-breath, and with exclusion of arrhythmias [area under the curve (AUC)=0.95, 0.93, and 0.90 for PPV, SPV, and SVV, respectively]. Including patients ventilated with lower TVs decreased the predictive value of all dynamic indices, while calculating dynamic indices over 30 s and not excluding cardiac arrhythmias further reduced the AUC to 0.51, 0.63, and 0.51 for PPV, SPV, and SVV, respectively. Conclusions: PPV, SPV, and SVV are the only reliable predictors of fluid responsiveness under strict conditions. In routine clinical practice, factors including
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low TV, cardiac arrhythmias, and the calculation method can substantially reduce their predictive value. Br J Anaesth 2012;108:395-401 Impact factor: 4.237
11. Behavioral measures and EEG monitoring using the Brain Symmetry Index during the Wada test in children. Peters JM, Tomas-Fernandez M, van Putten MJ, Loddenkemper T. EEG monitoring is used routinely during the Wada test in children. We quantified EEG asymmetry using the Brain Symmetry Index (BSI) to reduce subjectivity of EEG interpretation. Clinical and procedural variables were obtained and EEG data were retrieved from 46 patients with a total of 89 injections. The BSI, the absolute value of the relative difference of the average spectral density of the right and left hemisphere, was calculated over time for all EEGs. Lateralized slowing was correctly identified in all procedures. Asymmetry was minimal at baseline (BSI 0.16) and increased with injection of amobarbital (BSI 0.49). Various patterns of the BSI were seen in distinct clinical and procedural scenarios. In this retrospective analysis, the BSI could not predict an unsuccessful Wada procedure. Our results suggest application of the BSI during the Wada test in children is feasible. Real-time calculation of the BSI during EEG monitoring in the angiography suite is warranted for further validation. Epilepsy Behav 2012;23:247-253 Impact factor: 1.844
12. Suppressors of interictal discharges in idiopathic childhood occipital epilepsy of Gastaut. Rots ML, de Vos CC, Smeets-Schouten JS, Portier R, van Putten MJ. Idiopathic childhood occipital epilepsy of Gastaut (ICOE-G) is a rare form of epilepsy, characterized by visual hallucinations, periods of blindness, motor seizures, and migraine-like symptoms. A characteristic EEG feature is fixation-off sensitivity: epileptiform discharges are suppressed by visual input. Here, we present an 11-year-old girl suffering from ICOE-G, who was studied to identify potential additional suppressors of the epileptiform discharges. Epilepsy Behav 2012;25:189-191 Impact factor: 1.844
13 Vascular inflammation in cerebral small vessel disease. Rouhl RP, Damoiseaux JG, Lodder J, Theunissen RO, Knottnerus IL, Staals J, Henskens LH, Kroon AA, de Leeuw PW, Tervaert JW, van Oostenbrugge RJ.
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Cerebral small vessel disease (CSVD) is considered to be caused by an increased permeability of the blood-brain barrier and results in enlargement of Virchow Robin spaces (VRs), white matter lesions, brain microbleeds, and lacunar infarcts. The increased permeability of the blood-brain barrier may relate to endothelial cell activation and activated monocytes/macrophages. Therefore, we hypothesized that plasma markers of endothelial activation (adhesion molecules) and monocyte/macrophage activation (neopterin) relate to CSVD manifestations. In 163 first-ever lacunar stroke patients and 183 essential hypertensive patients, we assessed CSVD manifestations on brain magnetic resonance imaging (MRI) and levels of C-reactive protein (CRP), neopterin, as well as circulating soluble adhesion molecules (sICAM-1, sVCAM-1, sE-selectin, sP-selectin). Neopterin, sICAM-1 and sVCAM-1 levels were higher in patients with extensive CSVD manifestations than in those without (p < 0.01). Neopterin levels independently related to higher numbers of enlarged Virchow Robin spaces (p < 0.001). An inflammatory process with activated monocytes/macrophages may play a role in the increased permeability of the blood brain barrier in patients with CSVD. Neurobiol Aging 2012;33:1800-1806 Impact factor: 6.166
14. New oral anticoagulants for atrial fibrillation: a neurologist's view van Dijk EJ, Koudstaal PJ, Roos YB, Brouwers PJ, Kappelle LJ. Recent randomized controlled trials have shown that new oral anticoagulants (dabigatran, rivaroxaban en apixaban) in patients with atrial fibrillation are equally or more effective in preventing cerebral infarction than vitamin K antagonists (VKA).New oral anticoagulants cause significant less intracranial haemorrhages. - These results also apply to patients at high risk for complications such as those with a history of cerebral infarction, and those aged 75 years and over. It is not known whether patients in the acute phase after cerebral infarction and those with blood pressure exceeding 180/110 mmHg benefit as well.- Monitoring anticoagulation is no longer needed in patients using these new oral anticoagulants, which makes daily use easier but provides less insight into medication compliance. - There is no need to switch medication in patients who respond well to VKA. However, new oral anticoagulants should be considered in patients who have problems with VKA and who have a de novo indication for anticoagulation.- Practical issues such as interaction with other drugs, medication compliance, antagonizing, monitoring of the anticoagulation and asymptomatic deteriorating renal function should be studied further. Ned Tijdschr Geneeskd 2012;156:A5283. Impact factor: 0
15. Progressive Muscle Atrophy and Weakness After Treatment by Mantle Field Radiotherapy in Hodgkin Lymphoma Survivors.
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van Leeuwen-Segarceanu EM, Dorresteijn LD, Pillen S, Biesma DH, Vogels OJ, van Alfen.N. Purpose: To describe the damage to the muscles and propose a pathophysiologic mechanism for muscle atrophy and weakness after mantle field radiotherapy in Hodgkin lymphoma (HL) survivors. Methods and materials: We examined 12 patients treated by mantle field radiotherapy between 1969 and 1998. Besides evaluation of their symptoms, the following tests were performed: dynamometry; ultrasound of the sternocleidomastoid, biceps, and antebrachial flexor muscles; and needle electromyography of the neck, deltoid, and ultrasonographically affected arm muscles. Results: Ten patients (83%) experienced neck complaints, mostly pain and muscle weakness. On clinical examination, neck flexors were more often affected than neck extensors. On ultrasound, the sternocleidomastoid was severely atrophic in 8 patients, but abnormal echo intensity was seen in only 3 patients. Electromyography of the neck muscles showed mostly myogenic changes, whereas the deltoid, biceps, and antebrachial flexor muscles seemed to have mostly neurogenic damage. Conclusions: Many patients previously treated by mantle field radiotherapy develop severe atrophy and weakness of the neck muscles. Neck muscles within the radiation field show mostly myogenic damage, and muscles outside the mantle field show mostly neurogenic damage. The discrepancy between echo intensity and atrophy suggests that muscle damage is most likely caused by an extrinsic factor such as progressive microvascular fibrosis. This is also presumed to cause damage to nerves within the radiated field, resulting in neurogenic damage of the deltoid and arm muscles. Int J Radiat Oncol Biol Phys 2012;82:612-618 Impact factor: 4.524
16.The N20 in post-anoxic coma: Are you listening? van Putten MJ. Objective: Persistent absence of the median nerve N20 response in patients suffering from postanoxic coma after a cardiac arrest is invariably associated with a poor outcome. Preservation of the N20 response, however, does not indicate a good recovery. We wish to improve our understanding on this issue. Methods: We discuss the limited specificity of the presence of the N20 response regarding a favourable outcome and the selective neuronal damage that may be responsible for this clinical scenario. We also present EEG and SSEP data from post-anoxic patients. Results: We show data from a patient suffering from a severe post-anoxic encephalopathy, with a nearly flat EEG recording, but preserved N20 responses obtained after median nerve stimulation and propose a simple model for these observations. Conclusions: Somatosensory neurons have both "receiving" and "sending" properties, where the latter mainly reflects cortical synaptic function. After hypoxic
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insults, these two modes may be selectively damaged. Preservation of the N20 reflects an intact "receiving mode", while the EEG mainly reflects the "sending mode". SIGNIFICANCE: Insight into the physiological processes underlying the generation of the SSEP and the EEG is relevant in clinical decision making and may guide novel monitoring strategies. Clin Neurophysiol 2012;123:1460-1464 Impact factor: 3.144
17. Decision rules for assessment of chronic solvent-induced encephalopathy: Results in 2370 patients. Verberk MM, van der Hoek JA, van VE, Wekking EM, van Hout MS, Hageman G, van der Laan G, van DF. For the diagnosis of patients suspected of chronic solvent-induced encephalopathy (CSE), it would be helpful if the applied cognitive tests show a characteristic profile of impairment in this disease. We investigated the existence of such a profile. In 1997-2006 two expert teams in The Netherlands systematically examined 2370 patients referred for evaluation of suspected CSE. The procedure included two selection steps: (1) intake interview, using criteria of exposure, development of symptoms and absence of non-solvent causes, and (2) seven tests of the computerized Neurobehavioural Evaluation System (NES). Patients showing negligible impairments were considered free from CSE and were not further examined. The third step comprised a neuropsychological, neurological and exposure evaluation. Explicit decision rules for the diagnosis of CSE were developed, including a minimum score for cognitive impairment summarizing 25 cognitive tests. These rules were retroactively applied to 563 patients, comprising 513 patients who had regularly completed all diagnostic steps and a sample of 50 out of the approximately 450 patients with negligible impairments on the NES, who were fully examined. The data from this sample were extrapolated to the original number of 450. In the combined population of 963 patients, a calculated 301 patients were given the diagnosis 'Solely CSE', 242 'CSE and other disease', 158 'Other Disease' and 262 'No (known) disease'. In the Solely CSE patients, the most impaired tests regarded Verbal Fluency & -Similarities, Motor Speed and Simple Attention. A profile of test results that might support the identification of patients with CSE amongst the other referred patients, was not found. The diverging results of related cognitive tests indicate that the use of a core test battery is needed to improve comparability. We consider the decision rules as a step towards a more objective assessment of CSE. Neurotoxicology 2012;33:742-752 Impact factor: 2.652
18. Analysis of stability and bifurcations of fixed points and periodic solutions of a lumped model of neocortex with two delays. Visser S, Meijer HG, van Putten MJ, van Gils SA.
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A lumped model of neural activity in neocortex is studied to identify regions of multistability of both steady states and periodic solutions. Presence of both steady states and periodic solutions is considered to correspond with epileptogenesis. The model, which consists of two delay differential equations with two fixed time lags, is mainly studied for its dependency on varying connection strength between populations. Equilibria are identified, and using linear stability analysis, all transitions are determined under which both trivial and non-trivial fixed points lose stability. Periodic solutions arising at some of these bifurcations are numerically studied with a twoparameter bifurcation analysis. J Math Neurosci 2012;2:8 Impact factor: 0
19. Quantitative electroencephalography in a swine model of cerebral arterial gas embolism. Weenink RP, Vrijdag XC, van Putten MJ, Hollmann MW, Stevens MF, van Gulik TM, van Hulst RA. Objective: Cerebral arterial gas embolism (CAGE) is a serious hazard in cardiovascular surgery and other invasive procedures. We used a swine model of CAGE to determine if quantitative electroencephalography (qEEG) is a useful tool in diagnosis and prognostication of CAGE. Methods: 0.05ml/kg of air was injected into the ascending pharyngeal artery in 16 pigs. Intracranial pressure, lactate in brain microdialysate and brain oxygen tension were measured during 4h after embolization. The qEEG parameters mean amplitude (MAMP), alpha-delta ratio (ADR), spectral edge frequency (SEF(90)), spatial brain symmetry index (sBSI) and temporal brain symmetry index (tBSI) were calculated. Results: MAMP and tBSI but not ADR, SEF(90) and sBSI correlate with intracranial pressure, brain lactate and brain oxygen tension after 4h. Early levels of MAMP and tBSI can predict intracranial pressure, brain lactate and brain oxygen tension after 4h. Conclusions: MAMP and tBSI can and are sensitive for cerebral injury predict outcome in a swine model of CAGE. SIGNIFICANCE: This study provides evidence for the utility of qEEG for diagnosis and prognosis in CAGE. Further studies are necessary to investigate the use of this method in patients. Clin Neurophysiol 2012;123:411-417 Impact factor: 3.144 Totale impact factor: 76.771 Gemiddelde impact factor: 4.041 Aantal artikelen 1e, 2e of laatste auteur: 10 Totale impact factor: 43.011
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Gemiddelde impact factor: 4.301
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Nucleaire Geneeskunde 1. Targeted lymph node biopsy in mediastinoscopy using 3D FDG-PET/CT movies: a feasibility study. Siepel FJ, de Bruin WI, van Duyn EB, Steenvoorde P, Wagenaar NR, Slump CH, van Dalen JA In non-small-cell lung cancer, positive lymph nodes with increased fluorodeoxyglucose (FDG) uptake may be missed by mediastinoscopy. Lack of pathological confirmation may lead to radical, but unnecessary lung surgery. To minimize these false-negative results, the feasibility and potential value of threedimensional (3D) FDG-PET/computed tomography (CT) movies were investigated to improve targeted lymph node biopsy during mediastinoscopies. PET/CT images were rendered in 3D volumes with multiplanar reconstructions and maximum intensity projections and reviewed in 3D 'fly-through' and 'fly-around' movies. These movies were developed and optimized by the Departments of Surgery and Nuclear Medicine. Twenty-two consecutive patients with non-small-cell lung cancer were included, of whom eight were FDG-PET positive for mediastinal lymph nodes. 3D FDG-PET/CT movies were presented to surgeons before mediastinoscopy. Surgical consequences were investigated, including sensitivity and the negative predictive value of mediastinoscopy. Results were compared with those of a retrospective study in which 3D techniques were not used. During mediastinoscopies, the 3DPET/CT movies were found to be helpful in the surgical localization of FDG-positive lymph nodes. It led to more confidence in the surgical approach. The sensitivity and negative predictive value were 86 and 94%, respectively. Although not statistically significant, these results were higher compared with those of the retrospective study (75 and 92%, respectively). 3D FDG-PET/CT guidance during mediastinoscopy is feasible. The movies seem to lead to targeted biopsy of lymph nodes. They may reduce false-negative mediastinoscopies and improve staging of lung cancer. 3D FDG-PET/CT can be seen as a promising tool for further implementation of imageguided surgery. Nucl Med Commun. 2012;33(4):439-44 Impact factor: 1.379
Totale impact factor: 1.379 Gemiddelde impact factor: 1.379 Aantal artikelen 1e, 2e of laatste auteur: 1 Totale impact factor: 1.379 Gemiddelde impact factor: 1.379
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Orthopedie 1. Streamlining the generation of an osteogenic graft by 3D culture of unprocessed bone marrow on ceramic scaffolds. Chatterjea A, Renard AJ, Jolink C, van Blitterswijk CA, Boer JD. Mesenchymal stromal cells are present in very low numbers in the bone marrow, necessitating their selective expansion on tissue culture plastic prior to their use in tissue-engineering applications. MSC expansion is laborious, time consuming, unphysiological and not economical, thus calling for automated bioreactor-based strategies. We and others have shown that osteogenic grafts can be cultured in bioreactors by seeding either 2D-expanded cells or by direct seeding of the mononuclear fraction of bone marrow. To further streamline this protocol, we assessed in this study the possibility of seeding the cells onto porous calcium phosphate ceramics directly from unprocessed bone marrow. Using predetermined volumes of bone marrow from multiple human donors with different nucleated cell counts, we were able to grow a confluent cell sheath on the scaffold surface in 3 weeks. Cells of stromal, endothelial and haematopoietic origin were detected, in contrast to grafts grown from 2D expanded cells, where only stromal cells could be seen. Upon implantation in nude mice, similar quantities of bone tissue were generated as compared to that obtained by using the conventional number of culture expanded cells from the same donor. We conclude that human osteogenic grafts can be efficiently prepared by direct seeding of cells from unprocessed bone marrow. Copyright (c) 2011 John Wiley & Sons, Ltd. J Tissue Eng Regen Med 2012;6:103-112 Impact factor: 2.826
2. A Similar Approach in Bracing of Adolescent Scoliosis and Kyphosis with the Use of Growth Itself in Thoracolumbar Lordotic Intervention (TLI). Van Loon PJ, Roukens M, Thunnissen FB, Munneke J. Using older and new concepts on aetiology a new brace technique with thoracolumbar lordotic intervention in adolescent scoliotic and kyphotic deformities was created. The technique with symmetrical forces in the sagittal plane only on the thoracolumbar joint and its effect on the formative function of the extending muscles is explained. Stud Health Technol Inform 2012;176:68-72 Impact factor: 0
3. Ever-present factors in healthy children that can deform their spines. Opposition to Dickson's paradigm on lordosis. Van Loon PJ
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Revision of older knowledge on spinal deformities shows causing factors in all day life and the source of rotational forces in men in respiration. The role of lordosis as a causative factor can change towards a correcting force, supported by different studies. The thoracolumbar spine is the originating area of many deforming processes. Stud Health Technol Inform 2012;176:63-67 Impact factor: 0
Totale impact factor: 2.826 Gemiddelde impact factor: 0.942 Aantal artikelen 1e, 2e of laatste auteur: 3 Totale impact factor: 2.826 Gemiddelde impact factor: 0.942
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Pathologie 1. Association between the PRNP 1368 polymorphism and the occurrence of sporadic Creutzfeldt-Jakob disease. Bratosiewicz-Wasik J, Smolen-Dzirba J, Rozemuller AJ, Jansen C, Spliet W, Jansen GH, Wasik TJ, Liberski PP. Creutzfeldt-Jakob disease (CJD) is a rare transmissible neurodegenerative disorder. The etiology of sporadic form of CJD remains unsolved. In addition to the codon 129 polymorphism, polymorphisms in the non-coding region of PRNP are considered as important factors in sCJD development. To assess a possible association between PRNP 1368 SNP and sCJD, we compared the genotype, allele and haplotype frequencies of the 1368 SNP among 46 sCJD patients of Dutch origin with the respective frequencies in healthy controls. We detected a significant association between sCJD and 1368T/T genotype. A significant difference was also observed in 1368 alleles' distribution. In the haplotype analysis, haplotype 1368C-129G was associated with decreased risk of sCJD in Dutch population. Our findings support the hypothesis that genetic variations in the regulatory region of the PRNP gene may influence the pathogenesis of sCJD. Prion 2012;6 Impact factor: 2.133
2. Association of the PRNP regulatory region polymorphisms with the occurrence of sporadic Creutzfeldt-Jakob disease. Bratosiewicz-Wasik J, Smolen-Dzirba J, Watala C, Rozemuller AJ, Jansen C, Spliet W, Jansen GH, Wasik TJ, Liberski PP The prion protein (PrP) plays a central role in the pathogenesis of Creutzfeldt-Jakob disease and other transmissible spongiform encephalopathies (TSEs). Mutations in the coding region of the prion protein (PRNP) gene are linked to inherited forms of TSEs whereas aetiology of sporadic CJD (sCJD) remains obscure. It remains unclear whether the primary DNA sequence at non-coding region of PRNP gene influences development of the sCJD. Several recent reports showed non-coding region polymorphisms associated with sCJD but other could not support those findings. To test the hypothesis that there is a relationship between SNPs polymorphisms of PRNP non-coding regions and susceptibility to sCJD, we compared the primary structure of the regulatory region of the PRNP in 45 Dutch sCJD patients and in 135 healthy controls. We found a significant linkage of +310 C allele (OR 0.27, 95% CI 0.09-0.77; P = 0.009) and +310G/C genotype (OR 0.33, 95% CI 0.11-0.98; P = 0.048) with sCJD. No differences in frequencies of genotypes and allele of -101C/G and +258 G/A polymorphisms were found between sCJD patients and controls. We found two haplotypes protecting from sCJD (C-V in block 1 and G-C in block 2) and one susceptible haplotype for sCJD (G-G in block 2). Our findings support the hypothesis that polymorphism in the regulatory region of the PRNP gene may play an important role in the pathogenesis of sCJD.
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Folia Neuropathol 2012;50:68-73 Impact factor: 1.547
3. Streamlining the generation of an osteogenic graft by 3D culture of unprocessed bone marrow on ceramic scaffolds. Chatterjea A, Renard AJ, Jolink C, van Blitterswijk CA, Boer JD. Mesenchymal stromal cells are present in very low numbers in the bone marrow, necessitating their selective expansion on tissue culture plastic prior to their use in tissue-engineering applications. MSC expansion is laborious, time consuming, unphysiological and not economical, thus calling for automated bioreactor-based strategies. We and others have shown that osteogenic grafts can be cultured in bioreactors by seeding either 2D-expanded cells or by direct seeding of the mononuclear fraction of bone marrow. To further streamline this protocol, we assessed in this study the possibility of seeding the cells onto porous calcium phosphate ceramics directly from unprocessed bone marrow. Using predetermined volumes of bone marrow from multiple human donors with different nucleated cell counts, we were able to grow a confluent cell sheath on the scaffold surface in 3 weeks. Cells of stromal, endothelial and haematopoietic origin were detected, in contrast to grafts grown from 2D expanded cells, where only stromal cells could be seen. Upon implantation in nude mice, similar quantities of bone tissue were generated as compared to that obtained by using the conventional number of culture expanded cells from the same donor. We conclude that human osteogenic grafts can be efficiently prepared by direct seeding of cells from unprocessed bone marrow. Copyright (c) 2011 John Wiley & Sons, Ltd. J Tissue Eng Regen Med 2012;6:103-112 Impact factor: 2.826
4. Langerhans cell histiocytosis first presenting in the skin in adults: frequent association with a second hematological malignancy. Edelbroek JR, Vermeer MH, Jansen PM, Stoof TJ, van der Linden MM, Horvath B, van Baarlen J, Willemze R. Background: Langerhans cell histiocytosis (LCH) in adults first presenting in the skin is rare. Guidelines for staging, treatment and follow-up are lacking.Objective: The aim of the study was to better define staging procedures, treatment results and clinical course in adult patients with LCH first presenting in the skin. Methods: Eighteen adult patients with LCH first presenting in the skin were collected from five centers collaborating in the Dutch Cutaneous Lymphoma Group. Clinical records and (skin) biopsy specimens were reviewed and follow-up data were obtained. A literature search on adult patients with LCH presenting in the skin was performed. Results: Staging procedures showed extracutaneous disease in three of 16 patients who were adequately staged. One patient had a histologically confirmed lytic LCH
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bone lesion, while two patients had a myelodysplastic syndrome. During follow-up two of 18 patients developed extracutaneous localizations of LCH. Five patients developed a second hematological malignancy, including (myelo)monocytic leukemia (two cases), histiocytic sarcoma (one case), diffuse large B-cell lymphoma (one case) and peripheral T-cell lymphoma (one case). Review of the literature revealed six other adult patients with a second hematologic malignancy preceding or following a diagnosis of LCH. Conclusions: The results of the present study suggest an increased risk of a second hematological malignancy in adult patients with LCH presenting in the skin. Extensive staging at presentation and long term follow-up is therefore warranted in such patients. Br J Dermatol 2012;167:1287-1294 Impact factor: 3.759
5. Human prion diseases in the Netherlands (1998-2009): clinical, genetic and molecular aspects. Jansen C, Parchi P, Capellari S, Ibrahim-Verbaas CA, Schuur M, Strammiello R, Corrado P, Bishop MT, van Gool WA, Verbeek MM, Baas F, van SW, Spliet WG, Jansen GH, van Duijn CM, Rozemuller AJ. Prion diseases are rare and fatal neurodegenerative disorders that can be sporadic, inherited or acquired by infection. Based on a national surveillance program in the Netherlands we describe here the clinical, neuropathological, genetic and molecular characteristics of 162 patients with neuropathologically confirmed prion disease over a 12-year period (1998-2009). Since 1998, there has been a relatively stable mortality of Creutzfeldt-Jakob disease (CJD) in the Netherlands, ranging from 0.63 to 1.53 per million inhabitants per annum. Genetic analysis of the codon 129 methionine/valine (M/V) polymorphism in all patients with sporadic CJD (sCJD) showed a trend for under-representation of VV cases (7.0%), compared with sCJD cohorts in other Western countries, whereas the MV genotype was relatively overrepresented (22,4%). Combined PrP(Sc) and histopathological typing identified all sCJD subtypes known to date, except for the VV1 subtype. In particular, a "pure" phenotype was demonstrated in 60.1% of patients, whereas a mixed phenotype was detected in 39.9% of all sCJD cases. The relative excess of MV cases was largely accounted for by a relatively high incidence of the MV 2K subtype. Genetic analysis of the prion protein gene (PRNP) was performed in 161 patients and showed a mutation in 9 of them (5.6%), including one FFI and four GSS cases. Iatrogenic CJD was a rare phenomenon (3.1%), mainly associated with dura mater grafts. Three patients were diagnosed with new variant CJD (1.9%) and one with variably protease-sensitive prionopathy (VPSPr). Post-mortem examination revealed an alternative diagnosis in 156 patients, most commonly Alzheimer's disease (21.2%) or vascular causes of dementia (19.9%). The mortality rates of sCJD in the Netherlands are similar to those in other European countries, whereas iatrogenic and genetic cases are relatively rare. The unusual incidence of the VV2 sCJD subtype compared to that reported to date in other Western countries deserves further investigation.
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PLoS One 2012;7:e36333 Impact factor: 3.730
6. Sequence of radiotherapy and chemotherapy in breast cancer after breastconserving surgery. Jobsen JJ, van der Palen J, Brinkhuis M, Ong F, Struikmans H. Purpose: The optimal sequence of radiotherapy and chemotherapy in breastconserving therapy is unknown. Methods and materials: From 1983 through 2007, a total of 641 patients with 653 instances of breast-conserving therapy (BCT), received both chemotherapy and radiotherapy and are the basis of this analysis. Patients were divided into three groups. Groups A and B comprised patients treated before 2005, Group A radiotherapy first and Group B chemotherapy first. Group C consisted of patients treated from 2005 onward, when we had a fixed sequence of radiotherapy first, followed by chemotherapy. Results: Local control did not show any differences among the three groups. For distant metastasis, no difference was shown between Groups A and B. Group C, when compared with Group A, showed, on univariate and multivariate analyses, a significantly better distant metastasis-free survival. The same was noted for diseasefree survival. With respect to disease-specific survival, no differences were shown on multivariate analysis among the three groups. Conclusion: Radiotherapy, as an integral part of the primary treatment of BCT, should be administered first, followed by adjuvant chemotherapy. Int J Radiat Oncol Biol Phys 2012;82:e811-e817 Impact factor: 4.524
7. Catechol Pyrazolinones as Trypanocidals: Fragment-Based Design, Synthesis and Pharmacological Evaluation of Nanomolar Inhibitors of Trypanosomal Phosphodiesterase B1. Orrling KM, Jansen C, Vu XL, Balmer V, Bregy P, Shanmugham A, England P, Cos P, Maes L, Adams E, van de Bogaart E, Chatelain E, Ioset JR, Stolpe A, Zorg S, Veerman J, Seebeck T, Sterk GJ, de Esch IJ, Leurs R. Trypanosomal phosphodiesterases B1 and B2 (TbrPDEB1 and TbrPDEB2) play an important role in the life cycle of Trypanosoma brucei, the causative parasite of human African trypanosomiasis (HAT), also known as African sleeping sickness. We used homology modelling and docking studies to guide fragment growing into the parasite-specific P-pocket in the enzyme binding site. The resulting catechol pyrazolinones act as potent TbrPDEB1 inhibitors with IC50 values down to 49 nM. The compounds also block parasite proliferation (e.g. VUF13525 (20b): T. brucei rhodesiense IC50 = 60 nM, T. brucei brucei IC50 = 520 nM, T. cruzi = 7.6 microM), inducing a typical multiple nuclei- and kinetoplast phenotype without being generally cytotoxic. The mode of action of 20b was investigated with recombinantly
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engineered trypanosomes expressing a cAMP-sensitive FRET sensor, confirming a dose-response related increase of intracellular cAMP levels in trypanosomes. Our findings further validate the TbrPDEB family as antitrypanosomal target. J Med Chem 2012;55:8745-8756 Impact factor: 5.614
8. Extensive left ventricular hemangioma. Oude Velthuis B, van Es J, van Houwelingen G, Toes GJ, Wagenaar L. J Am Coll Cardiol 2012;60:e35 Impact factor: 14.086
9. Consensus classification of human prion disease histotypes allows reliable identification of molecular subtypes: an inter-rater study among surveillance centres in Europe and USA. Parchi P, de BL, Saverioni D, Cohen ML, Ferrer I, Gambetti P, Gelpi E, Giaccone G, Hauw JJ, Hoftberger R, Ironside JW, Jansen C, Kovacs GG, Rozemuller A, Seilhean D, Tagliavini F, Giese A, Kretzschmar HA The current classification of human sporadic prion diseases recognizes six major phenotypic subtypes with distinctive clinicopathological features, which largely correlate at the molecular level with the genotype at the polymorphic codon 129 (methionine, M, or valine, V) in the prion protein gene and with the size of the protease-resistant core of the abnormal prion protein, PrP(Sc) (i.e. type 1 migrating at 21 kDa and type 2 at 19 kDa). We previously demonstrated that PrP(Sc) typing by Western blotting is a reliable means of strain typing and disease classification. Limitations of this approach, however, particularly in the interlaboratory setting, are the association of PrP(Sc) types 1 or 2 with more than one clinicopathological phenotype, which precludes definitive case classification if not supported by further analysis, and the difficulty of fully recognizing cases with mixed phenotypic features. In this study, we tested the inter-rater reliability of disease classification based only on histopathological criteria. Slides from 21 cases covering the whole phenotypic spectrum of human sporadic prion diseases, and also including two cases of variant Creutzfeldt-Jakob disease (CJD), were distributed blindly to 13 assessors for classification according to given instructions. The results showed good-to-excellent agreement between assessors in the classification of cases. In particular, there was full agreement (100 %) for the two most common sporadic CJD subtypes and variant CJD, and very high concordance in general for all pure phenotypes and the most common subtype with mixed phenotypic features. The present data fully support the basis for the current classification of sporadic human prion diseases and indicate that, besides molecular PrP(Sc) typing, histopathological analysis permits reliable disease classification with high interlaboratory accuracy. Acta Neuropathol 2012;124:517-529 Impact factor: 9.734
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10. Neuroinflammation and common mechanism in Alzheimer's disease and prion amyloidosis: amyloid-associated proteins, neuroinflammation and neurofibrillary degeneration. Rozemuller AJ, Jansen C, Carrano A, van Haastert ES, Hondius D, van der Vies SM, Hoozemans JJ. Background: In cases with a long (>1 year) clinical duration of prion disease, the prion protein can form amyloid deposits. These cases do not show accumulation of 4-kDa beta-amyloid, which is observed in amyloid deposits in Alzheimer's disease (AD). In AD, amyloid is associated with inflammation and neurofibrillary degeneration, and it is elusive whether prion amyloid is associated with these changes as well. Objectives: The presence of inflammation and neurofibrillary degeneration was evaluated in prion amyloidosis. Material and methods: Cortical areas of variant Creutzfeldt-Jakob disease (CJD; n = 3), young sporadic CJD (n = 4), different Gerstmann-Straussler-Scheinker's disease patients (n = 5) and AD cases (n = 5) were examined using immunohistochemistry and specific stainings for amyloid. Results: In both AD and prion disease cases, which were negative for 4-kDa betaamyloid, parenchymal and vascular amyloid deposits were positive for amyloidassociated proteins such as complement protein and were associated with microglia clusters. Tau and ubiquitin were found near prion plaques in some of the Gerstmann-Straussler-Scheinker's disease and sporadic CJD cases and also near vascular prion amyloid deposits. In variant CJD cases, occasionally, microglia clustering was found in plaques but no ubiquitin or complement proteins and hardly tau protein. Conclusions: In both AD and prion disease amyloid formation, irrespective of the protein involved, there seems to be a neuroinflammatory response with secondary neurofibrillary degeneration. Neurodegener Dis 2012;10:301-304 Impact factor: 3.410
11. A 71-year-old woman with an intracranial dural-based mesenchymal chondrosarcoma. Vergeer RA, Vink R, Avenarius JK, Driesse MJ. Intracranial mesenchymal chondrosarcoma is a rare, high-grade malignancy with the highest prevalence in young adults. Because of its rarity, most data regarding survival are limited to case studies and small series. We present a 71-year-old woman with an intracranial dural based mesenchymal chondrosarcoma located in the anterior skull base, to our knowledge the oldest patient reported with this tumor. J Clin Neurosci 2012;19:1170-1171 Impact factor: 1.253
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12. Assessment of Helicobacter pylori eradication in patients on NSAID treatment. Vonkeman HH, de Leest HT, van de Laar MA, van Baarlen J, Steen KS, Lems WF, Bijlsma JW, Kuipers EJ, Houben HH, Janssen M, Dijkmans BA. Background: In this post-hoc analysis of a randomized, double blind, placebo controlled trial, we measured the sensitivity and specificity of Helicobacter pylori IgG-antibody titer changes, hematoxylin and eosin (H&E) stains, immunohistochemical (IHC) stains and culture results in NSAID using patients, following H. pylori eradication therapy or placebo. Methods: 347 NSAID using patients who were H. pylori positive on serological testing for H. pylori IgG-antibodies were randomized for H. pylori eradication therapy or placebo. Three months after randomization, gastric mucosal biopsies were taken for H. pylori culture and histological examination. At 3 and 12 months, blood samples were taken for repeated serological testing. The gold standard for H. pylori infection was based on a positive culture or both a positive histological examination and a positive serological test. Sensitivity, specificity and receiver operating curves (ROC) were calculated. Results: H. pylori eradication therapy was successful in 91 % of patients. Culture provided an overall sensitivity of 82 %, and 73 % after eradication, with a specificity of 100 %. Histological examination with either H&E or IHC stains provided sensitivities and specificities between 93 % and 100 %. Adding IHC to H&E stains did not improve these results. The ROC curve for percent change in H. pylori IgGantibody titers had good diagnostic power in identifying H. pylori negative patients, with an area under the ROC curve of 0.70 (95 % CI 0.59 to 0.79, P = 0.085) at 3 months and 0.83 (95 % CI 0.76 to 0.89, P < 0.0001) at 12 months. A cut-off point of at least 21 % decrease in H. pylori IgG-antibody titers at 3 months and 58 % at 12 months provided a sensitivity of 64 % and 87 % and a specificity of 81 % and 74 % respectively, for successful eradication of H. pylori. Conclusions: In NSAID using patients, following H. pylori eradication therapy or placebo, histological examination of gastric mucosal tissue biopsies provided good sensitivity and specificity ratios for evaluating success of H. pylori eradication therapy. A percentual H. pylori IgG-antibody titer change has better sensitivity and specificity than an absolute titer change or a predefined H. pylori IgG-antibody titer cut-off point for evaluating success of H. pylori eradication therapy. BMC Gastroenterol 2012;12:133 Impact factor: 2.110
Totale impact factor: 54.726 Gemiddelde impact factor: 4.561 Aantal artikelen 1e, 2e of laatste auteur: 4 Totale impact factor: 13.647 Gemiddelde impact factor: 3.412
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Radiologie 1. Visualizing breast cancer using the Twente photoacoustic mammoscope: What do we learn from twelve new patient measurements? Heijblom M, Piras D, Xia W, van Hespen JC, Klaase JM, van den Engh FM, van Leeuwen TG, Steenbergen W, Manohar S. We acquired images of breast malignancies using the Twente photoacoustic mammoscope (PAM), to obtain more information about the clinical feasibility and limitations of photoacoustic mammography. Results were compared with conventional imaging and histopathology. Ten technically acceptable measurements on patients with malignancies and two measurements on patients with cysts were performed. In the reconstructed volumes of all ten malignant lesions, a confined region with high contrast with respect to the background could be seen. In all malignant cases, the PA contrast of the abnormality was higher than the contrast on x-ray mammography. The PA contrast appeared to be independent of the mammographically estimated breast density and was absent in the case of cysts. Technological improvements to the instrument and further studies on less suspicious lesions are planned to further investigate the potential of PAM. Opt Express 2012;20:11582-11597 Impact factor: 3.546 2. Endovascular treatment of ruptured abdominal aortic aneurysm: is there a long-term benefit at follow-up? Rodel SG, Meerwaldt R, Beuk RJ, Huisman AB, Zeebregts CJ, Geelkerken RH. Aim: Several studies have shown the feasibility of endovascular repair of ruptured abdominal aortic aneurysms (rEVAR). However, the role and value of rEVAR remains controversial due to selection bias and lack of long-term results. In the present study we describe our short- and long-term results of treating patients with rEVAR irrespective of hemodynamic condition and challenging anatomy. Methods: In April 2006 we started the single centre prospective non-randomised Ruptured Aneurysm Study (RASA). During a four year enrolment period all consecutive patients presenting with infrarenal ruptured AAA (rAAA, N.=117) were assessed for preferential rEVAR treatment. A rAAA was defined as extravasation of blood or hematoma outside the AAA due to transmural tear in the infrarenal abdominal aorta wall documented by preoperative computed tomography (CT) angiography examination or during open repair. Patients with challenging anatomy (infrarenal neck length below 15 mm and neck angulation above 60 degrees) were included as part of a damage control concept. Complication and mortality rates were studied at 30 days and yearly afterwards. Results: Thirty-five patients (33% of all admitted rAAA) were treated with rEVAR and 42% of them were considered hemodynamically unstable (systolic blood pressure <100 mmHg) and 30% had challenging AAA anatomy. The mortality rate at 30 days in the rEVAR group was 17%, in the open repair group 31%, and in the entire rAAA group (including abstained patients) 36%. During the first 30 days, 18
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rEVAR patients experienced complications with nine re-interventions as a result. Long-term mortality of the rEVAR patients was 34% after a median follow-up of 3.4 years. All deaths after one year follow-up were non-AAA related. Multivariate analysis shows that Hardman index, presence of peripheral arterial obstructive disease and lowest systolic blood pressure during surgery are independently associated with long-term survival. Challenging rAAA anatomy was not associated with impaired survival. Conclusion: Our study shows that rEVAR is feasible irrespective of hemodynamic condition and that it is associated with relative low mortality rates. Challenging rAAA anatomy may not affect overall long-term survival, but six out of ten patients remain unsuitable for rEVAR because of inappropriate anatomy. J Cardiovasc Surg (Torino) 2012;53:83-89 Impact factor: 1.559
3. Abdominal symptoms during physical exercise and the role of gastrointestinal ischaemia: a study in 12 symptomatic athletes. Ter Steege RW, Geelkerken RH, Huisman AB, Kolkman JJ. Background: Gastrointestinal (GI) symptoms during exercise may be caused by GI ischaemia. The authors report their experience with the diagnostic protocol and management of athletes with symptomatic exercise-induced GI ischaemia. The value of prolonged exercise tonometry in the diagnostic protocol of these patients was evaluated. Methods: Patients referred for GI symptoms during physical exercise underwent a standardised diagnostic protocol, including prolonged exercise tonometry. Indicators of GI ischaemia, as measured by tonometry, were related to the presence of symptoms during the exercise test (S+ and S- tests) and exercise intensity. Results: 12 athletes were specifically referred for GI symptoms during exercise (five males and seven females; median age 29 years (range 15-46 years)). Type of sport was cycling, long-distance running and triathlon. Median duration of symptoms was 32 months (range 7-240 months). Splanchnic artery stenosis was found in one athlete. GI ischaemia was found in six athletes during submaximal exercise. All athletes had gastric and jejunal ischaemia during maximum intensity exercise. No significant difference was found in gastric and jejunal Pco(2) or gradients between S+ and S- tests during any phase of the exercise protocol. In S+ tests, but not in Stests, a significant correlation between lactate and gastric gradient was found. In S+ tests, the regression coefficients of gradients were higher than those in S- tests. Treatment advice aimed at limiting GI ischaemia were successful in reducing complaints in the majority of the athletes. Conclusion: GI ischaemia was present in all athletes during maximum intensity exercise and in 50% during submaximal exercise. Athletes with GI symptoms had higher gastric gradients per mmol/l increase in lactate, suggesting an increased susceptibility for the development of ischaemia during exercise. Treatment advice aimed at limiting GI ischaemia helped the majority of the referred athletes to reduce their complaints. Our results suggest an important role for GI ischaemia in the pathophysiology of their complaints.
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Br J Sports Med 2012;46:931-935 Impact factor: 3.668
4. Splanchnic artery stenosis and abdominal complaints: clinical history is of limited value in detection of gastrointestinal ischemia. Ter Steege RW, Sloterdijk HS, Geelkerken RH, Huisman AB, van der Palen J, Kolkman JJ. Background: Splanchnic artery stenosis is common and mostly asymptomatic and may lead to gastrointestinal ischemia (chronic splanchnic syndrome, CSS). This study was designed to assess risk factors for CSS in the medical history of patients with splanchnic artery stenosis and whether these risk factors can be used to identify patients with high and low risk of CSS. Methods: All patients referred for suspected CSS underwent a standardized workup, including a medical history with questionnaire, duplex ultrasound, gastrointestinal tonometry, and angiography. Definitive diagnosis and treatment advice was made in a multidisciplinary team. Patients with confirmed CSS were compared with no-CSS patients. Results: A total of 270 patients (102 M, 168 F; mean age, 53 years) with splanchnic artery stenosis were analyzed, of whom 109 (40%) had CSS and 161 no CSS. CSSpatients more often reported postprandial pain (87% vs. 72%, p = 0.007), weight loss (85% vs. 70%, p = 0.006), adapted eating pattern (90% vs. 79%, p = 0.005) and diarrhea (35% vs. 22%, p = 0.023). If none of these risk factors were present, the probability of CSS was 13%; if all were present, the probability was 60%. Adapted eating pattern (odds ratio (OR) 3.1; 95% confidence interval (CI) 1.08-8.88) and diarrhea (OR 2.6; 95% CI 1.31-5.3) were statistically significant in multivariate analysis. Conclusions: In patients with splanchnic artery stenosis, the clinical history is of limited value for detection of CSS. A diagnostic test to detect ischemia is indispensable for proper selection of patients with splanchnic artery stenosis who might benefit from treatment. World J Surg 2012;36:793-799 Impact factor: 2.362
5. The cardiovascular risk profile of atherosclerotic gastrointestinal ischemia is different from other vascular beds. Veenstra RP, Ter Steege RW, Geelkerken RH, Huisman AB, Kolkman JJ. Background: The distribution of cardiovascular risk factors in patients with chronic gastrointestinal ischemia due to atherosclerosis of the splanchnic vessels (chronic splanchnic syndrome) is not well studied. The aim of this study was to determine the cardiovascular risk factor pattern in patients with chronic splanchnic syndrome. Methods: From April 2003 to September 2007, atherosclerotic risk factors in consecutive patients with chronic splanchnic syndrome were compared
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prospectively with the general atherosclerotic risk profile in Western Europe and worldwide risk profile of coronary heart disease, peripheral artery disease, and cerebral vascular disease. Results: Of 376 analyzed patients, 97 were diagnosed with chronic splanchnic syndrome. Data from 90 patients were available for analysis (7 were excluded because of incomplete data). Mean age was 63 years (range 28-86 years), and 74% were female. Fifty-nine percent of the patients had atherosclerotic disease in other vascular beds. Smoking was reported in 57%, and increased bodyweight in 21%. Hypercholesterolemia was present in 53%, hypertension in 62%, and diabetes in 21%. Conclusions: The atherosclerotic risk profile in patients with chronic splanchnic syndrome differed from other atherosclerotic diseases with a female preponderance, lower incidence of obesity/increased bodyweight, diabetes, hypertension, and hypercholesterolemia. Reduced caloric intake, related to the postprandial pain, may explain the observed differences. Am J Med 2012;125:394-398 Impact factor: 4.768
6. A 71-year-old woman with an intracranial dural-based mesenchymal chondrosarcoma. Vergeer RA, Vink R, Avenarius JK, Driesse MJ. Intracranial mesenchymal chondrosarcoma is a rare, high-grade malignancy with the highest prevalence in young adults. Because of its rarity, most data regarding survival are limited to case studies and small series. We present a 71-year-old woman with an intracranial dural based mesenchymal chondrosarcoma located in the anterior skull base, to our knowledge the oldest patient reported with this tumor. J Clin Neurosci 2012;19:1170-1171. Impact factor: 1.253
7. Natural history of pain in patients with conservatively treated osteoporotic vertebral compression fractures: results from VERTOS II. Venmans A, Klazen CA, Lohle PN, Mali WP, van Rooij WJ Background and purpose: We analyzed the natural course of conservatively treated osteoporotic vertebral compression fractures from VERTOS II, a randomized trial of vertebroplasty and conservative therapy in 202 patients with vertebral compression fractures. We assessed the proportion of patients who developed chronic back pain and possible risk factors. Materials and methods: In VERTOS II, the VAS score was assessed at regular intervals until 1 year follow-up. We followed 95 conservatively treated patients until sufficient pain relief, defined as a VAS score ≤3. These patients were censured at the involved follow-up interval. In addition, baseline clinical and imaging data, and class of pain medication used in patients with a VAS score ≤3 at any follow-up
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interval were compared with those in patients with a VAS score >3 at every followup by using logistic regression analysis. Results: During 1 year of follow-up, 57 of 95 patients (60%) had sufficient pain relief with VAS scores ≤3. Thirty-eight patients (40%) still had pain with VAS-scores ≥4 at the last follow-up interval of 12 months, despite the use of higher class pain medication. Statistical analysis showed no risk factors. Conclusions: In the VERTOS II trial, most conservatively treated patients with acute osteoporotic compression fractures had sufficient pain relief during the first 3 months. However, after 1 year, a substantial proportion of patients still had disabling pain despite higher class pain medication used. There were no predictors for the development of chronic pain. Patients with continuing pain ≥3 months after the fracture may be candidates for vertebroplasty. AJNR Am J Neuroradiol. 2012;33(3):519-21 Impact factor: 3.167
Totale impact factor: 20.323 Gemiddelde impact factor: 2.903 Aantal artikelen 1e, 2e of laatste auteur: 1 Totale impact factor: 3.167 Gemiddelde impact factor: 3.167
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Radiotherapie 1. Sequence of radiotherapy and chemotherapy in breast cancer after breastconserving surgery. Jobsen JJ, van der Palen J, Brinkhuis M, Ong F, Struikmans H. Purpose: The optimal sequence of radiotherapy and chemotherapy in breastconserving therapy is unknown. Methods and materials: From 1983 through 2007, a total of 641 patients with 653 instances of breast-conserving therapy (BCT), received both chemotherapy and radiotherapy and are the basis of this analysis. Patients were divided into three groups. Groups A and B comprised patients treated before 2005, Group A radiotherapy first and Group B chemotherapy first. Group C consisted of patients treated from 2005 onward, when we had a fixed sequence of radiotherapy first, followed by chemotherapy. Results: Local control did not show any differences among the three groups. For distant metastasis, no difference was shown between Groups A and B. Group C, when compared with Group A, showed, on univariate and multivariate analyses, a significantly better distant metastasis-free survival. The same was noted for diseasefree survival. With respect to disease-specific survival, no differences were shown on multivariate analysis among the three groups. Conclusion: Radiotherapy, as an integral part of the primary treatment of BCT, should be administered first, followed by adjuvant chemotherapy. Int J Radiat Oncol Biol Phys 2012;82:e811-e817. Impact factor: 4.105
2. Use of Primary Radiotherapy for Rectal Cancer in the Netherlands between 1997 and 2008: A Population-based Study Jobsen JJ, Aarts MJ, Siesling S, Klaase J, Louwman WJ, Poortmans PM, Lybeert ML, Koning CC, Struikmans H, Coebergh JW. Aims: To describe variation in the utilisation rates of primary radiotherapy for patients with rectal cancer in the Netherlands, focusing on time trends and age effects. Materials and methods: Data on primary non-metastatic rectal cancer were derived from the population-based cancer registries of four comprehensive cancer centres (regions) in the Netherlands (1997-2008, n=13,055). Results: An increase in the utilisation rate was noted for the four regions, from 3746% in 1997 to 66-76% in 2008, for both genders. This increase was found predominately for preoperative radiotherapy (from 13-31% to 58-67%) and (unsurprisingly) was most pronounced for stage T2-3 patients (from 9-27% to 6880%). The probability of receiving radiotherapy decreased with age: the odds of receiving preoperative radiotherapy was reduced in patients aged 65 years and older, as well as the odds of receiving postoperative radiotherapy in those aged 75 years and older, which remained significant after adjustment for stage, gender and
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region. Regional differences persisted in multivariable analyses, i.e. the odds of receiving preoperative radiotherapy was reduced in two regions: odds ratio: 0.4 (95% confidence interval: 0.4-0.5) and 0.7 (0.6-0.8). The odds of receiving postoperative radiotherapy was significantly increased in these regions [odds ratio: 2.6 (2.2-3.2) and 1.6 (1.3-1.9), respectively] and reduced in another [odds ratio 0.8 (0.6-0.96)]. Conclusions: The utilisation rate of radiotherapy for rectal cancer increased significantly over time, particularly for preoperative radiotherapy and was most pronounced for T2-3 patients. Due to national multidisciplinary treatment guidelines, regional differences became limited in recent years after adjustment for age and stage of the disease. A low utilisation rate of radiotherapy was seen in women and elderly patients. Clin Oncol (R Coll Radiol ) 2012;24:e1-e8. Impact factor: 2.072
3. Brachytherapy after external beam radiotherapy and limited surgery preserves bladders for patients with solitary pT1-pT3 bladder tumors. Koning CC, Blank LE, Koedooder C, van Os RM, van de Kar M, Jansen E, Battermann JJ, Beijert M, Gernaat C, van Herpen KA, Hoekstra C, Horenblas S, Jobsen JJ, Krol AD, Lybeert ML, van Onna IE, Pelger RC, Poortmans P, Pos FJ, Steen-Banasik E, Slot A, Visser A, Pieters BR. Background: Several French, Belgian and Dutch radiation oncologists have reported good results with the combination of limited surgery after external beam radiotherapy (EBRT) followed by brachytherapy in early-stage muscle-invasive bladder cancer. Patients and Methods: Data from 12 of 13 departments which are using this approach have been collected retrospectively, in a multicenter database, resulting in 1040 patients: 811 males and 229 females with a median age of 66 years, range 2892 years. Results were analyzed according to tumor stage and diameter, histology grade, age and brachytherapy technique, continuous low-dose rate (CLDR) and pulsed dose rate (PDR). Results: At 1, 3 and 5 years, the local recurrence-free probability was 91%, 80% and 75%, metastasis-free probability was 91%, 80% and 74%, disease-free probability was 85%, 68% and 61% and overall survival probability was 91%, 74% and 62%, respectively. The differences in the outcome between the contributing departments were small. After multivariate analysis, the only factor influencing the local control rate was the brachytherapy technique. Toxicity consisted mainly of 24 fistula, 144 ulcers/necroses and 93 other types. Conclusions: EBRT followed by brachytherapy, combined with limited surgery, offers excellent results in terms of bladder sparing for selected groups of patients suffering from bladder cancer. Ann Oncol 2012;23:2948-2953. Impact factor: 6.425
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4. Mapping Use of Radiotherapy for Patients with Non-small Cell Lung Cancer in the Netherlands between 1997 and 2008. Koning CC, Aarts MJ, Struikmans H, Poortmans PM, Lybeert ML, Jobsen JJ, Coebergh JW, Janssen-Heijnen ML, Visser O, Louwman WJ, Burgers JA. Aim: After the publication of several reports that the utilisation rate of radiotherapy for patients with non-small cell lung cancer (NSCLC) varies for both medical and non-medical reasons, the utilisation of radiotherapy was studied in four regions in the Netherlands. Materials and methods: Data from 1997-2008 were collected from the populationbased cancer registries of four comprehensive cancer centres ('regions'), which represent about half of the Dutch population, resulting in 24 185 non-metastatic patients with NSCLC. Treatment had to be started or planned within 6 months of diagnosis. We evaluated the utilisation of radiotherapy according to age, gender and period for each region. Results: The utilisation of radiotherapy alone decreased over time (from 35 to 19%), whereas the utilisation of radiotherapy in combination with chemotherapy increased (from 5 to 19%). The total utilisation rate remained rather stable at about 40%. The differences between the four regions remained in general no more than 15%. Elderly patients with stage I and II disease had increased odds of receiving radiotherapy (>/=75 versus <50 years: odds ratio 2.6, 95% confidence interval 2.0-3.3, whereas this was the opposite for patients with stage III disease: odds ratio 0.5, 95% confidence interval 0.4-0.6). For 17-24% of all patients, especially the elderly, best supportive care was applied. Conclusions: In the Netherlands, with good accessibility to medical care and wellimplemented national guidelines, variation between the four regions is limited for the treatment of non-metastatic NSCLC with radiotherapy. Clin Oncol (R Coll Radiol ) 2012;24:e46-e53. Impact factor: 2.072
5. Increased risks of third primary cancers of non-breast origin among women with bilateral breast cancer. Kwast AB, Liu L, Roukema JA, Voogd AC, Jobsen JJ, Coebergh JW, Soerjomataram I, Siesling S Background: This study examined the risk of third cancer of non-breast origin (TNBC) among women with bilateral breast cancer (BBC; either synchronous or metachronous), focussing on the relation with breast cancer treatment. Methods: Risk was assessed, among 8752 Dutch women diagnosed with BBC between 1989 and 2008, using standardised incidence ratios (SIR) and Cox regression analyses to estimate the hazard ratio (HR) of TNBC for different treatment modalities. Results: Significant increased SIRs were observed for all TNBCs combined, haematological malignancies, stomach, colorectal, non-melanoma skin, lung, head and neck, endometrial, and ovarian cancer. A 10-fold increased risk was found for
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ovarian cancer among women younger than 50 years (SIR=10.0, 95% confidence interval (CI)=5.3-17.4). Radiotherapy was associated with increased risks of all TNBCs combined (HR=1.3; 95%CI=1.1-1.6, respectively). Endocrine therapy was associated with increased risks of all TNBCs combined (HR=1.2; 95%CI=1.0-1.5), haematological malignancies (HR=2.0; 95%CI=1.1-3.9), and head and neck cancer (HR=3.3; 95%CI=1.1-10.4). After chemotherapy decreased risks were found for all TNBCs combined (HR=0.63; 95%CI=0.5-0.87). Conclusion: Increased risk of TNBC could be influenced by genetic factors (ovarian cancer) or an effect of treatment (radiotherapy and endocrine therapy). More insight in the TNBC risk should further optimise and individualise treatment and surveillance protocols in (young) women with BBC.British Journal of Cancer advance online publication, 19 June 2012; doi:10.1038/bjc.2012.270 www.bjcancer.com Br J Cancer 2012;107:549-555. Impact factor: 4.023
6. Five-year quality of life of endometrial cancer patients treated in the randomised Post Operative Radiation Therapy in Endometrial Cancer (PORTEC-2) trial and comparison with norm data. Nout RA, Putter H, Jurgenliemk-Schulz IM, Jobsen JJ, Lutgens LC, van der SteenBanasik EM, Mens JW, Slot A, Stenfert Kroese MC, Nijman HW, van de Poll-Franse LV, Creutzberg CL. Background: The PORTEC-2 trial showed efficacy and reduced side-effects of vaginal brachytherapy (VBT) compared with external beam pelvic radiotherapy (EBRT) for patients with high-intermediate risk endometrial cancer. The current analysis was done to evaluate long-term health related quality of life (HRQL), and compare HRQL of patients to an age-matched norm population. Methods: Patients were randomly allocated to EBRT (n=214) or VBT (n=213). HRQL was assessed using EORTC QLQ-C30 and subscales from PR25 and OV28 (bladder, bowel, sexual symptoms); and compared to norm data. Findings: Median follow-up was 65 months; 348 (81%) patients were evaluable for HRQL (EBRT n=166, VBT n=182). At baseline, patient functioning was at lowest level, increasing during and after radiotherapy to reach a plateau after 12 months, within range of scores of the norm population. VBT patients reported better social functioning (p=0.005) and lower symptom scores for diarrhoea, faecal leakage, need to stay close to a toilet and limitation in daily activities due to bowel symptoms (p0.001), compared to EBRT. There were no differences in sexual functioning or symptoms between the treatment groups; however, sexual functioning was lower and sexual symptoms more frequent in both treatment groups compared to the norm population.Interpretation: Patients who received EBRT reported clinically relevant higher levels of bowel symptoms and related limitations in daily activities with lower social functioning, 5 years after treatment. VBT provides a better HRQL, which remained similar to that of an age-matched norm population, except for sexual symptoms which were more frequent in both treatment groups. Eur J Cancer 2012;48:1638-1648
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Impact factor: 5.536
7. Improved risk assessment of endometrial cancer by combined analysis of MSI, PI3K-AKT, Wnt/beta-catenin and P53 pathway activation. Nout RA, Bosse T, Creutzberg CL, Jurgenliemk-Schulz IM, Jobsen JJ, Lutgens LC, van der Steen-Banasik EM, van ER, Ter Haar NT, Smit VT Objective: To investigate if analysis of genetic alterations in the main pathways involved in endometrioid type carcinogenesis (PI3K-AKT, Wnt/beta-catenin, P53activation and MSI) improves the current risk assessment based on clinicopathological factors. Methods: Formalin fixed paraffin embedded (FFPE) primary tumor samples of 65 patients with FIGO-stage I endometrioid type endometrial cancer (EEC) were selected from the randomized PORTEC-2 trial. Tumors were stained by immunohistochemistry for P53, PTEN and beta-catenin. Tumor DNA was isolated for sequence analysis of TP53 (exons 4 to 8), hotspot mutation analysis of KRAS (exon 1) and PI3K (exon 9 and 20) and microsatellite-instability (MSI) analysis including MLH1 promotor-methylation status. Univariate and multivariate analyses for disease-free survival (DFS) using Cox regression models were performed. Results: P53 status (HR 6.7, 95%CI 1.75-26.0, p=0.006) and MSI were the strongest single genetic prognostic factors for decreased DFS, while high PI3K-AKT pathway activation showed a trend and beta-catenin was not prognostic. The combination of multiple activated pathways was the most powerful prognostic factor for decreased DFS (HR 5.0; 95%CI 1.59-15.6 p=0.006). Multiple pathway activation, found in 8% of patients, was strongly associated with aggressive clinical course. In contrast, 40% of patients had no alterations in the investigated pathways and had a very low risk of disease progression. Conclusions: Activation of multiple oncogenic pathways in EEC was the most powerful prognostic factor for decreased DFS, resulting in an individual risk assessment superior to the current approach based on clinicopathological factors. Gynecol Oncol 2012;126:466-473. Impact factor: 3.888
8. Trends in the use of primary radiotherapy for cancer in the Netherlands in patients with breast, prostate, rectal and lung tumours. Struikmans H, Aarts MJ, Jobsen JJ, Koning CC, Poortmans PM, Louwman MW, Coebergh JW. Objective: To provide insight in the application of radiotherapy as part of primary treatment of patients with cancer in the Netherlands. Design: Retrospective, descriptive population-based study. Method: Data concerning patients with breast, prostate, rectal and non-small cell lung cancer were selected from the Netherlands Cancer Registry in 4 regions, covering 50% of the Dutch population. The selection concerned data from 1997-
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2008 and, except for prostate cancer, only patients without distant metastases were included. Results: Between 1997 and 2008, the use of primary external radiotherapy increased approximately 7% in breast cancer patients and approximately 30% in rectal cancer patients. In the latter group preoperative radiotherapy strongly increased, while postoperative radiotherapy decreased. For prostate cancer there was an increase in brachytherapy (9%). The use of external beam radiotherapy in patients with prostate cancer and non-small cell lung cancer remained the same. Regional differences in the extent of use of radiotherapy for breast and rectal cancer clearly decreased. These differences remained limited for external beam radiotherapy in prostate and non-small cell lung cancer. Older patients less often received radiotherapy. Conclusion: The increase in use of radiotherapy for breast cancer is explained by the increase in breast conserving surgery. The trends in use in patients with rectal cancer and breast cancer are presumably related to the implementation of multidisciplinary practice guidelines. The implementation of these guidelines probably also contributed to the decrease in regional differences in the use of radiotherapy. Ned Tijdschr Geneeskd 2012;156:A4426 Impact factor: 0
9. Parenthood in Survivors of Hodgkin Lymphoma: An EORTC-GELA General Population Case-Control Study. van der Kaaij MA, Heutte N, Meijnders P, Abeilard-Lemoisson E, Spina M, Moser LC, Allgeier A, Meulemans B, Dubois B, Simons AH, Lugtenburg PJ, Aleman BM, Noordijk EM, Ferme C, Thomas J, Stamatoullas A, Fruchart C, Brice P, Gaillard I, Doorduijn JK, Sebban C, Smit WG, Bologna S, Roesink JM, Ong F, Andre MP, Raemaekers JM, Henry-Amar M, Kluin-Nelemans HC. Purpose: We investigated the impact of Hodgkin lymphoma (HL) on parenthood, including factors influencing parenthood probability, by comparing long-term HL survivors with matched general population controls. Patients and methods: A Life Situation Questionnaire was sent to 3,604 survivors treated from 1964 to 2004 in successive clinical trials. Responders were matched with controls (1:3 or 4) for sex, country, education, and year of birth (10-year groups). Controls were given an artificial date of start of treatment equal to that of their matched case. The main end point was presence of biologic children after treatment, which was evaluated by using conditional logistic regression analysis. Logistic regression analysis was used to analyze factors influencing spontaneous post-treatment parenthood. Results: all, 1,654 French and Dutch survivors were matched with 6,414 controls. Median follow-up was 14 years (range, 5 to 44 years). After treatment, the odds ratio (OR) for having children was 0.77 (95% CI, 0.68 to 0.87; P < .001) for survivors compared with controls. Of 898 survivors who were childless before treatment, 46.7% achieved post-treatment parenthood compared with 49.3% of 3,196 childless controls (OR, 0.87; P = .08). Among 756 survivors with children before treatment,
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12.4% became parents after HL treatment compared with 22.2% of 3,218 controls with children before treatment (OR, 0.49; P < .001). Treatment with alkylating agents, second-line therapy, and age older than 35 years at treatment appeared to reduce the chances of spontaneous post-treatment parenthood. Conclusion: Survivors of HL had slightly but significantly fewer children after treatment than matched general population controls. The difference concerned only survivors who had children before treatment and appears to have more personal than biologic reasons. The chance of successful post-treatment parenthood was 76%. J Clin Oncol 2012;30:3854-3863 Impact factor: 18.372
10. Premature ovarian failure and fertility in long-term survivors of Hodgkin's lymphoma: a European Organisation for Research and Treatment of Cancer Lymphoma Group and Groupe d'Etude des Lymphomes de l'Adulte Cohort Study. van der Kaaij MA, Heutte N, Meijnders P, Abeilard-Lemoisson E, Spina M, Moser EC, Allgeier A, Meulemans B, Simons AH, Lugtenburg PJ, Aleman BM, Noordijk EM, Ferme C, Thomas J, Stamatoullas A, Fruchart C, Brice P, Gaillard I, Bologna S, Ong F, Eghbali H, Doorduijn JK, Morschhauser F, Sebban C, Roesink JM, Bouteloup M, Van HA, Raemaekers JM, Henry-Amar M, Kluin-Nelemans HC Purpose: In this large cohort of Hodgkin's lymphoma survivors with long follow-up, we estimated the impact of treatment regimens on premature ovarian failure (POF) occurrence and motherhood, including safety of nonalkylating chemotherapy and dose-response relationships for alkylating chemotherapy and age at treatment. Patients and methods: The Life Situation Questionnaire was sent to 1,700 women treated in European Organisation for Research and Treatment of Cancer and Groupe d'Etude des Lymphomes de l'Adulte trials between 1964 and 2004. Women treated between ages 15 and 40 years and currently not using hormonal contraceptives (n = 460) were selected to assess occurrence of POF. Cumulative POF risk was estimated using the life-table method. Predictive factors were assessed by Cox regression analysis. Results: Median follow-up was 16 years (range, 5 to 45 years). Cumulative risk of POF after alkylating chemotherapy was 60% (95% CI, 41% to 79%) and only 3% (95% CI, 1% to 7%) after nonalkylating chemotherapy (doxorubicin, bleomycin, vinblastine, and dacarbazine; epirubicin, bleomycin, vinblastine, and prednisone). Dose relationship between alkylating chemotherapy and POF occurrence was linear. POF risk increased by 23% per year of age at treatment. In women treated without alkylating chemotherapy at age younger than 32 years and age 32 years or older, cumulative POF risks were 3% (95% CI, 1% to 16%) and 9% (95% CI, 4% to 18%), respectively. If menstruation returned after treatment, cumulative POF risk was independent of age at treatment. Among women who ultimately developed POF, 22% had one or more children after treatment, compared with 41% of women without POF.
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Conclusion: Nonalkylating chemotherapy carries little to no excess risk of POF. Dose-response relationships for alkylating chemotherapy and age at treatment are both linear. Timely family planning is important for women at risk of POF. J Clin Oncol 2012;30:291-299
Impact factor: 18.372 Totale impact factor: 64.865 Gemiddelde impact factor: 6.487 Aantal artikelen 1e, 2e of laatste auteur: 2 Totale impact factor:6.177 Gemiddelde impact factor: 3.089
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Reumatologie 1. Gait analysis of the lower limb in patients with rheumatoid arthritis: a systematic review. Baan H, Dubbeldam R, Nene AV, van de Laar MA. Introduction: In rheumatoid arthritis (RA), signs and symptoms of feet and ankle are common. To evaluate the dynamic function of feet and ankles, namely walking, a variety of gait studies have been published. In this systematic review, we provide a systematic overview of the available gait studies in RA, give a clinimetrical assignment, and review the general conclusions regarding gait in RA. Methods: A systematic literature search within the databases PubMed, CINAHL, sportdiscus, Embase, and Scopus was described and performed and delivered 78 original gait studies that were included for further data extraction. Results: The clinimetrical quality of the 78 included RA gait studies measured according a tailored QUADAS item list and proposed clinimetrical criteria by Terwee and coworkers are moderate. General conclusions regarding the walking abnormalities of RA patients point to a slower walk, longer double support time, and avoidance of extreme positions. Frequently found static features in RA are hallux valgus, pes planovalgus, and hind foot abnormalities. Conclusions: Gait studies in RA patients show moderate clinimetrical properties, but are a challenging way of expressing walking disability. Future gait research should focus on more uniformity in methodology. When this need is satisfied, more clinical applicable conclusions can be drawn. Semin Arthritis Rheum 2012;41:768-788. Impact factor: 4.053
2. Experience of aging in patients with rheumatic disease: A comparison with the general population. Bode C, Taal E, Westerhof GJ, van Gessel L, van de Laar MA. Objectives: Self-perceptions of aging have been shown to predict mental and physical health and even longevity. This study examined the aging perceptions of patients with rheumatic disease and compared them with the general Dutch population. Methods: Consecutive patients visiting a rheumatology clinic completed the Personal Experience of Aging Scale (PEAS) subscales: physical decline, social loss, continuous growth, and two sentence stems from the SELE instrument (What I like/do not like about getting older ...) as qualitative measures of the subjective experience of aging. A representative sample from the general Dutch population between 40 and 85 years was used as a comparison group. Participants included in this study were 208 patients with a rheumatic disease and 975 persons from the Dutch Aging Survey (DAS). Results: Both quantitative and qualitative data showed that patients perceived aging more strongly as physical decline. These negative experiences did not extend to
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social and psychological domains of aging. Age-group comparisons revealed that patients in middle adulthood experienced physical aging similar to older people without a rheumatic disease. Conclusion: The negative experience of aging in patients is limited to the physical domain and does not extend to other domains of life. The negative experience of physical aging even in middle-aged groups warrants further studies on its effects on mental and physical health outcomes and health behavior in patients with rheumatic disease. Aging Ment Health 2012;16:666-672. Impact factor: 1.677
3. Productivity loss due to absenteeism and presenteeism by different instruments in patients with RA and subjects without RA. Braakman-Jansen LM, Taal E, Kuper IH, van de Laar MA. Objectives: To explore the impact of at-work productivity loss on the total productivity cost by different instruments in patients recently diagnosed with RA and controls without RA. Methods: Cross-sectional data were collected from outpatients with RA between December 2007 and February 2008. The control group was formed by subjects without RA matched on age and gender. Absenteeism and presenteeism were estimated by the Quantity and Quality (QQ) Questionnaire, Work Productivity and Activity Impairment Questionnaire General Health V2.0 (WPAI-GH) and Health and Labor Questionnaire (HLQ) questionnaires. Differences between groups were tested by Mann-Whitney U-test. Costs were valued by the human capital approach. Results: Data were available from 62 patients with a paid job and 61 controls. QQand WPAI-GH scores of presenteeism were moderately correlated (r = 0.61) while the HLQ presenteeism score correlated poorly with the other instruments (r = 0.34). The contribution of presenteeism on total productivity costs was estimated at approximately 70% in the RA group. The mean costs per person per week due to presenteeism varied between euro79 and euro318 per week in the RA group, dependent on the instrument used. The costs due to presenteeism were about two to four times higher in the RA group compared with the control group. Conclusion: This study indicates that the impact of presenteeism on the total productivity costs in patients with RA is high. However, work productivity in individuals without RA was not optimal either, which implies a risk of overestimation of cost when a normal score is not taken into account. Finally, different presenteeism instruments lead to different results. Rheumatology (Oxford) 2012;51:354-361. Impact factor: 4.212
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4. Comparative responsiveness of the EuroQol-5D and Short Form 6D to improvement in patients with rheumatoid arthritis treated with tumor necrosis factor blockers: results of the Dutch Rheumatoid Arthritis Monitoring registry. Buitinga L, Braakman-Jansen LM, Taal E, Kievit W, Visser H, van Riel PL, van de Laar MA. Objective: For cost-utility analyses of health technologies, utilities are commonly measured with the EuroQol-5D (EQ-5D) or the Short Form 6D (SF-6D). Although most studies in rheumatoid arthritis (RA) found the SF-6D to be more responsive than the EQ-5D, evidence is not convincing. The aim of this study was to compare the responsiveness of the EQ-5D and SF-6D to improvement in RA patients treated with tumor necrosis factor (TNF) blockers. Methods: Data from 278 RA patients included in the Dutch Rheumatoid Arthritis Monitoring registry were used. Internal responsiveness over 1 year was evaluated by using standardized response means (SRMs). External responsiveness was evaluated by using receiver operating characteristic curves based on perceived health change (self-reported health transition item Short Form 36) and change in disease activity (European League Against Rheumatism response criteria based on the Disease Activity Score in 28 joints). Results: The scores of the EQ-5D and SF-6D changed moderately over 1 year (SRMs 0.50 and 0.67, respectively). The SF-6D was significantly more responsive to treatment than the EQ-5D. The EQ-5D and SF-6D were moderately able to correctly classify patients according to health transition (areas under the curve [AUCs] 0.67 and 0.72, respectively) and change in disease activity (AUCs 0.71 and 0.65, respectively). Conclusion: The EQ-5D and SF-6D were only moderately responsive to improvement in RA patients treated with TNF blockers. Overall, the SF-6D was more responsive than the EQ-5D. Arthritis Care Res (Hoboken ) 2012;64:826-832 Impact factor: 3.731
5. Construct validity of the interview Time Trade-Off and computer Time TradeOff in patients with rheumatoid arthritis: A cross-sectional observational pilot study. Buitinga L, Braakman-Jansen LM, Taal E, van de Laar MA. Background: The Time Trade-Off (TTO) is a widely used instrument for valuing preference-based healthrelated quality of life (HRQoL). The TTO reveals preferences for own current health ('utilities') on a scale anchored between death (0) and perfect health (1). Limited information on the external validity of the TTO is available. Aim of this pilot study was to examine the construct validity of both an interview TTO and a computer-based TTO in patients with rheumatoid arthritis (RA). Methods: Thirty patients visiting the outpatient rheumatology clinic participated. Construct validity was assessed by measuring convergent and discriminative validity. Convergent validity was assessed by calculating Spearman's correlations between the utilities obtained from the TTOs and pain, general health (rating
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scales), health-related quality of life (SF-36 and SF-6D) and functional status (HAQDI). Discriminative power of both TTO measures was determined by comparing median utilities between worse and better health outcomes. Results: Correlations of both TTO measures with HRQoL, general health, pain and functional status were poor (absolute values ranging from .05 to .26). Both TTOs appeared to have no discriminative value among groups of RA patients who had a worse or better health status defined by six health outcome measures. About onethird of respondents were zero-traders on each of the TTO measures. After excluding zero-traders from analysis, the correlations improved considerably. Conclusions: Both the interview TTO and computer TTO showed poor construct validity in RA patients when using measures of HRQol, general health, pain and functional status as reference measures. Possibly, the validity of the TTO improves when using an anchor that is more realistic to RA patients than the anchor 'death'. BMC Musculoskelet Disord 2012;13:112. Impact factor: 1.875
6. Future Expectations and Worst-Case Future Scenarios of Patients with Rheumatoid Arthritis: A Focus Group Study. Buitinga L, Braakman-Jansen LM, Taal E, van de Laar MA. Objective: Over the past 15 years, developments in the treatment of rheumatoid arthritis (RA) have resulted in better clinical outcomes. The aim of the present study was to explore how patients think their RA will influence their lives in the future, and which of these future expectations would be the worst for them to experience. Methods: A focus group study was performed in 16 RA patients. Three groups were heterogeneously composed, based on age group (18-40, 40-65, 65-80), gender and having a paid job or not. Patients were asked about the expected future impact of RA and worst-case future scenarios. Transcripts were coded by three researchers under the main components of the International Classification of Functioning, Disability and Health. The codes were discussed until agreement was reached about all codes. Results: Dependency on others, increasing dependency on medication, inability to walk, activity limitations and worsening fatigue were mentioned as worst-case future scenarios. Further concerns were raised about the acceptance of RA and possible disappearance of physicians' expertise. Nevertheless, hope and positive feelings were expressed toward continuous medication improvements. Conclusion: The present study provided insight into RA patients' future expectations and worst-case future scenarios. The results may be of help in the development of support interventions to put concerns and worst-case future scenarios into a realistic perspective. Furthermore, insight into patients' worst-case future scenarios could be used to improve the validity and responsiveness of the Time Trade-Off, an instrument to measure preference-based health-related quality of life. Copyright (c) 2012 John Wiley & Sons, Ltd. Musculoskeletal Care 2012;10:240-247. Impact factor: 0
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7. Worst-case future scenarios of patients with rheumatoid arthritis: a crosssectional study. Buitinga L, Braakman-Jansen LM, Taal E, van de Laar MA. Objective: The time trade-off is a health-related quality of life instrument that measures valuations for health states (utilities) by asking patients to value their health state anchored on a scale between death (0) and perfect health (1). Dying earlier is not perceived as a realistic worst-case consequence of the disease by RA patients. Of the previous focus groups study on RA patients, five worst-case future scenarios emerged. The aim of this study was to examine which potential worstcase scenario was the most appropriate for RA patients to use in utility calculation. Methods: In a cross-sectional study of 74 consecutive RA patients visiting the rheumatology outpatient clinic, participants were presented with descriptions of the five worst-case future scenarios. In pairwise comparisons, patients had to choose the scenario that would be the worst to experience. The worst-case future scenario was defined by the scenario that was chosen by a significantly greater proportion of participants than could be expected based on chance (20%). Therefore, analysis based on a single fraction () was used and 95% CI was calculated. Results: The scenario being dependent on others was chosen most often as the worst to experience [by 35% of participants (95% CI 24%, 46%)] and significantly more often than could be expected based on chance ( = 0.35, z = 6.45, P = 0.00). Conclusion: The scenario being dependent on others is likely to be the most appropriate worst-case future scenario for RA patients. Using an alternative anchor could improve the validity and responsiveness of the time trade-off in RA patients. Rheumatology (Oxford) 2012;51:2027-2033. Impact factor: 4.212
8. The prevalence of clinical remission in RA patients treated with anti-TNF: results from the Dutch Rheumatoid Arthritis Monitoring (DREAM) registry. de Punder YM, Fransen J, Kievit W, Houtman PM, Visser H, van de Laar MA, van Riel PL. Objectives: To evaluate the prevalence of clinical remission and minimal disease activity according to the ACR/European League Against Rheumatism (EULAR) remission, DAS-28 <2.6 and minimal disease activity (MDA) criteria, and to compare the extent of residual disease activity with disability in RA patients after 6 months of treatment with anti-TNF. Methods: In the Dutch Rheumatoid Arthritis Monitoring (DREAM) biologic registry the prevalence of DAS-28 <2.6, MDA and ACR/EULAR remission criteria was assessed. Residual disease activity during MDA or remission was assessed as the percentage of patients with swollen and tender joints, elevated acute-phase reactants and general health on a visual analogue scale (VAS). Disability was evaluated with the HAQ score.
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Results: Prevalence of DAS-28 <2.6 was 27%, prevalence of MDA was 34% and ACR/EULAR remission was reached by 6% of patients. Residual disease activity was present mostly in the most lenient criteria and occurred most frequently on the level of swollen joint count and VAS score: at least one swollen joint in DAS-28 <2.6, MDA and ACR/EULAR remission was present in, respectively, 51, 54 and 34% of the patients. VAS >1 occurred in, respectively, 67, 69 and 0% of the patients. Modification of the cut-point of the patient-reported outcome increased the prevalence of ACR/EULAR remission, but also the level of disability. Conclusion: MDA and DAS-28 <2.6 are reachable treatment targets in RA with anti-TNF, although residual disease activity might still be present. In turn, ACR/EULAR remission criteria leave little residual disease activity, but might be too stringent for use in daily clinical practice due to the strict cut-point in the patientreported outcome. Rheumatology (Oxford) 2012;51:1610-1617 Impact factor: 4.212
9. Evaluation of separate quantitative radiographic features adds to the prediction of incident radiographic osteoarthritis in individuals with recent onset of knee pain: 5-year follow-up in the CHECK cohort. Kinds MB, Marijnissen AC, Vincken KL, Viergever MA, Drossaers-Bakker KW, Bijlsma JW, Bierma-Zeinstra SM, Welsing PM, Lafeber FP. Objective: Detailed radiographic evaluation might enable the identification of osteoarthritis (OA) earlier in the disease. This study evaluated whether and which separate quantitative features on knee radiographs of individuals with recent onset knee pain are associated with incidence of radiographic OA and persistence and/or progression of clinical OA during 5-year follow-up. Method: From the Cohort Hip & Cohort Knee study participants with knee pain at baseline were evaluated. Radiographic OA development was defined as Kellgren & Lawrence (K&L) grade >/= II at 5-year follow-up. Clinical OA was defined as persistent knee pain and as progression of Westen Ontario & McMaster Universities Osteoarthritis index (WOMAC) pain and function score during follow-up. At baseline radiographic damage was determined by quantitative measurement of separate features using Knee Images Digital Analysis, and by K&L-grading. Results: Measuring osteophyte area [odds ratio (OR) =7.0] and minimum joint space width (OR=0.7), in addition to demographic and clinical characteristics, improved the prediction of radiographic OA 5 years later [area under curve receiver operating characteristic=0.74 vs 0.64 without radiographic features]. When the predictive score (based on multivariate regression coefficients) was larger than the cut-off for optimal specificity, the chance of incident radiographic OA was 54% instead of the prior probability of 19%. Evaluating separate quantitative features performed slightly better than K&L-grading (AUC=0.70). Radiographic characteristics hardly added to prediction of clinical OA. Conclusion: In individuals with onset knee pain, radiographic characteristics added to the prediction of radiographic OA development 5 years later. Quantitative radiographic evaluation in individuals with suspected OA is worthwhile when determining treatment strategies and designing clinical trials.
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Osteoarthritis Cartilage 2012;20:548-556. Impact factor: 4.262
10. Dutch translation and cross-cultural adaptation of the PROMIS(R) physical function item bank and cognitive pre-test in Dutch arthritis patients. Oude Voshaar MA, Ten Klooster PM, Taal E, Krishnan E, van de Laar MA. Patient-reported physical function is an established outcome domain in clinical studies in rheumatology. To overcome the limitations of the current generation of questionnaires, the Patient-Reported Outcomes Measurement Information System (PROMIS(R)) project in the USA has developed calibrated item banks for measuring several domains of health status in people with a wide range of chronic diseases. The aim of this study was to translate and cross-culturally adapt the PROMIS physical function item bank to the Dutch language and to pretest it in a sample of patients with arthritis. Methods: The items of the PROMIS physical function item bank were translated using rigorous forward-backward protocols and the translated version was subsequently cognitively pretested in a sample of Dutch patients with rheumatoid arthritis. Results: Few issues were encountered in the forward-backward translation. Only 5 of the 124 items to be translated had to be rewritten because of culturally inappropriate content. Subsequent pretesting showed that overall, questions of the Dutch version were understood as they were intended, while only one item required rewriting. Conclusions: Results suggest that the translated version of the PROMIS physical function item bank is semantically and conceptually equivalent to the original. Future work will be directed at creating a Dutch-Flemish final version of the item bank to be used in research with Dutch speaking populations. Arthritis Res Ther 2012;14:R47. Impact factor: 4.302
11.Tramadol/paracetamol fixed-dose combination in the treatment of moderate to severe pain. Pergolizzi JV, Jr., Van de Laar M, Langford R, Mellinghoff HU, Merchante IM, Nalamachu S, O'Brien J, Perrot S, Raffa RB. Pain is the most common reason patients seek medical attention and pain relief has been put forward as an ethical obligation of clinicians and a fundamental human right. However, pain management is challenging because the pathophysiology of pain is complex and not completely understood. Widely used analgesics such as nonsteroidal anti-inflammatory drugs (NSAIDs) and paracetamol (acetaminophen) have been associated with adverse events. Adverse event rates are of concern, especially in long-term treatment or at high doses. Paracetamol and NSAIDs are available by prescription, over the counter, and in combination preparations.
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Patients may be unaware of the risk associated with high dosages or long-term use of paracetamol and NSAIDs. Clinicians should encourage patients to disclose all medications they take in a "do ask, do tell" approach that includes patient education about the risks and benefits of common pain relievers. The ideal pain reliever would have few risks and enhanced analgesic efficacy. Fixed-dose combination analgesics with two or more agents may offer additive or synergistic benefits to treat the multiple mechanisms of pain. Therefore, pain may be effectively treated while toxicity is reduced due to lower doses. One recent fixed-dose combination analgesic product combines tramadol, a centrally acting weak opioid analgesic, with low-dose paracetamol. Evidence-based guidelines recognize the potential value of combination analgesics in specific situations. The current guideline-based paradigm for pain treatment recommends NSAIDs for ongoing use with analgesics such as opioids to manage flares. However, the treatment model should evolve how to use low-dose combination products to manage pain with occasional use of NSAIDs for flares to avoid long-term and high-dose treatment with these analgesics. A next step in pain management guidelines should be targeted therapy when possible, or lowdose combination therapy or both, to achieve maximal efficacy with minimal toxicity. J Pain Res 2012;5:327-346. Impact factor: 0
12. A tight control treatment strategy aiming for remission in early rheumatoid arthritis is more effective than usual care treatment in daily clinical practice: a study of two cohorts in the Dutch Rheumatoid Arthritis Monitoring registry. Schipper LG, Vermeer M, Kuper HH, Hoekstra MO, Haagsma CJ, Den Broeder AA, van Riel PL, Fransen J, van de Laar MA. Background: There is strong evidence from clinical trials that a 'treat to target' strategy is effective in reaching remission in rheumatoid arthritis (RA). However, the question is whether these results can be translated into daily clinical practice and clinical remission is a reachable target indeed.Objective: The study aims to investigate whether in early RA a treatment strategy aiming at Disease Activity Score (DAS) 28 <2.6 is more effective than 'usual care' treatment for reaching clinical remission after 1 year. Methods: Two early RA inception cohorts from two different regions including patients who fulfilled the American College of Rheumatology criteria for RA were compared. Patients in the tight-control cohort (n=126) were treated according to a DAS28-driven step-up treatment strategy starting with methotrexate, addition of sulphasalazine (SSZ) and exchange of SSZ by anti-tumour necrosis factor in case of failure. Patients in the usual-care cohort (n=126) were treated with methotrexate or SSZ, without DAS28-guided treatment decisions. The primary outcome was the percentage remission (DAS28<2.6) at 1 year. Time to first remission and change in DAS28 were secondary outcomes. Results: After 1 year, 55% of tight-control patients had a DAS28<2.6 versus 30% of usual care patients (OR 3.1, 95% CI 1.8 to 5.2). The median time to first remission was 25 weeks for tight control and more than 52 weeks for usual care (p<0.0001). The DAS28 decreased with -2.5 in tight control and -1.5 in usual care (p<0.0001).
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Conclusion: In early RA, a tight control treatment strategy aiming for remission leads to more rapid DAS28 remission and higher percentages of remission after 1 year than does a usual care treatment. Ann Rheum Dis 2012;71:845-850 Impact factor: 9.111
13. Modern psychometrics applied in rheumatology--A systematic review. Siemons L, Ten Klooster PM, Taal E, Glas CA, van de Laar MA. background: Although item response theory (IRT) appears to be increasingly used within health care research in general, a comprehensive overview of the frequency and characteristics of IRT analyses within the rheumatic field is lacking. An overview of the use and application of IRT in rheumatology to date may give insight into future research directions and highlight new possibilities for the improvement of outcome assessment in rheumatic conditions. Therefore, this study systematically reviewed the application of IRT to patient-reported and clinical outcome measures in rheumatology. Methods: Literature searches in PubMed, Scopus and Web of Science resulted in 99 original English-language articles which used some form of IRT-based analysis of patient-reported or clinical outcome data in patients with a rheumatic condition. Both general study information and IRT-specific information were assessed. Results: Most studies used Rasch modeling for developing or evaluating new or existing patient-reported outcomes in rheumatoid arthritis or osteoarthritis patients. Outcomes of principle interest were physical functioning and quality of life. Since the last decade, IRT has also been applied to clinical measures more frequently. IRT was mostly used for evaluating model fit, unidimensionality and differential item functioning, the distribution of items and persons along the underlying scale, and reliability. Less frequently used IRT applications were the evaluation of local independence, the threshold ordering of items, and the measurement precision along the scale. Conclusion: IRT applications have markedly increased within rheumatology over the past decades. To date, IRT has primarily been applied to patient-reported outcomes, however, applications to clinical measures are gaining interest. Useful IRT applications not yet widely used within rheumatology include the crosscalibration of instrument scores and the development of computerized adaptive tests which may reduce the measurement burden for both the patient and the clinician. Also, the measurement precision of outcome measures along the scale was only evaluated occasionally. Performed IRT analyses should be adequately explained, justified, and reported. A global consensus about uniform guidelines should be reached concerning the minimum number of assumptions which should be met and best ways of testing these assumptions, in order to stimulate the quality appraisal of performed IRT analyses. BMC Musculoskelet Disord 2012;13:216. Impact factor: 1.875
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14. Disability due to gouty arthritis. Ten Klooster PM, Vonkeman HE, van de Laar MA. Purpose of review: Disability, or activity limitation, is a common problem in patients with gout. This study explores recent studies examining the nature and extent of disability in gout and addresses the merits and limitations of current self-reported measures of disability. Recent findings: Gout has a significant impact on patients' ability to perform normal self-care activities, recreational and social activities, and work. Comparative studies indicate that gout patients' physical functioning is strongly reduced and comparable to those with other severe rheumatic conditions. Moreover, gout has been shown to result in substantial work absence and reduced productivity. However, few studies have thoroughly examined the concept of disability in gout. Additionally, assessment of disability due to gout still seems particularly challenging and it is unclear whether current measurement instruments are sufficiently valid and accurate. Summary: Gout-related disability is an underestimated and understudied problem. More qualitative and quantitative studies are needed that examine the concept of disability in gout and its impact on patients' lives, both during and between disease flares. Moreover, future studies should try to identify gout-specific disability issues and examine the relevance and comprehensiveness of existing measures to further improve the assessment of disability in gout. Curr Opin Rheumatol 2012;24:139-144. Impact factor: 5.191
15. Further validation of the 5-item Perceived Efficacy in Patient-Physician Interactions (PEPPI-5) scale in patients with osteoarthritis. Ten Klooster PM, Oostveen JC, Zandbelt LC, Taal E, Drossaert CH, Harmsen EJ, van de Laar MA. Objective: To examine the structural validity, internal consistency, test-retest reliability, and construct validity of the 5-item Perceived Efficacy in Patient-Physician Interactions (PEPPI-5) scale in patients with osteoarthritis (OA). Methods: A cross-sectional sample of 224 outpatients with OA completed a survey containing the Dutch PEPPI-5 and other standardized measures assessing perceived health-management skills, general self-efficacy, social support, and health-related quality of life. A subsample of 100 patients completed the PEPPI-5 again approximately 3 weeks later. Results: Confirmatory factor analysis demonstrated good fit for a unidimensional model of the PEPPI-5. Additionally, the scale showed high internal consistency (alpha=0.92) and fair test-retest reliability (ICC=0.68). As hypothesized, the PEPPI-5 was strongly correlated with perceived health-management skills, moderately with social support and psychosocial aspects of health, and not with physical aspects of health. Contrary to expectations, however, it was not correlated with general selfefficacy.
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Conclusion: The Dutch PEPPI-5 demonstrated adequate validity and reliability in patients with OA. PRACTICE IMPLICATIONS: The PEPPI-5 is a brief and appropriate tool for measuring self-efficacy of patients with OA to interact with their physicians. Additional research into its sensitivity to change is needed before it can be confidently recommended as an outcome measure in intervention studies. Patient Educ Couns 2012;87:125-130 Impact factor: 2.305
16. Minimal clinically important improvement and patient acceptable symptomatic state in pain and function in rheumatoid arthritis, ankylosing spondylitis, chronic back pain, hand osteoarthritis, and hip and knee osteoarthritis: The reflect multinational study. Tubach F, Ravaud P, Martin-Mola E, Awada H, Bellamy N, Bombardier C, Felson D, Hassouni N, Hochberg M, Logeart I, Matucci-Cerinic M, Van de Laar M, van der Heijde D, Dougados M Objective: To estimate the Minimum Clinically Important Improvement (MCII) and Patient Acceptable Symptomatic State (PASS) values for 4 generic outcomes in 5 rheumatic diseases and 7 countries. Methods: We conducted a multinational (Australia, France, Italy, Lebanon, Morocco, Spain, The Netherlands), 4-week cohort study involving 1,532 patients which were prescribed NSAISDs for ankylosing spondylitis, chronic back pain, hand osteoarthritis, hip and/or knee osteoarthritis or rheumatoid arthritis. The MCII and PASS values were estimated with the 75(th) percentile approach for 4 generic outcomes: pain, patient global assessment, functional disability and physician global assessment, all normalized to a 0-100 score. Results: For the whole sample, the estimated MCII values for absolute change at 4 weeks (95% confidence interval [95% CI]) were -17 (-18, -15) for pain; -15 (-16, -14) for patient global assessment; -12 (-13, -11) for functional disability assessment; and -14 (-15, -14) for physician global assessment. For the whole sample, the estimated PASS values were 42 (40, 44) for pain; 43 (41, 45) for patient global assessment; 43 (41, 44) for functional disability assessment; and 39 (37, 40) for physician global assessment. Estimates were consistent across diseases and countries (for subgroups >/=20 patients). Conclusion: This work allows for promoting the use of values of MCII (15/100 for absolute improvement, 20% for relative improvement) and PASS (40/100) in reporting the results of trials of any of the 5 involved rheumatic diseases with pain, patient global assessment, physical function or physician global assessment used as outcome criteria. (c) 2012 by the American College of Rheumatology. Arthritis Care Res (Hoboken ) 2012;64:1699-1707. Impact factor: 3.731
17. Validation of the Dutch functional, communicative and critical health literacy scales.
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van der Vaart R, Drossaert CH, Taal E, Ten Klooster PM, Hilderink-Koertshuis RT, Klaase JM, van de Laar MA. Objective: While most existing health literacy (HL) measures focus primarily on reading comprehension, the functional, communicative and critical HL scales from Ishikawa et al. [19] aim to measure a broader HL spectrum. The objective of this study was to evaluate the validity of the Dutch translation of this instrument. Methods: Two survey studies (n=79 and n=209) and one cognitive interview study (n=18) were performed among samples of breast cancer patients and patients with rheumatic diseases. Results: Analyses showed the scales measured three distinct factors and convergent validity was satisfactory for communicative and critical HL. Nevertheless, the comprehension of the items and the suitability of the response options raised some problems. Conclusion: The HL scales seem promising to measure a broad definition of HL. By revising some of the items and response options as proposed in this article, the scale will become more understandable for people with low HL skills, which might increase the content validity and the distributional properties of the scale. Practice implications: The scale should be revised and revalidated. An improved version should be used in practice to gain insight into HL levels of patients. This will help to develop suitable education programs for people with low HL skills. Patient Educ Couns 2012;89:82-88. Impact factor: 2.305
18. Adherence to a treat-to-target strategy in early rheumatoid arthritis: results of the DREAM remission induction cohort. Vermeer M, Kuper HH, Bernelot Moens HJ, Hoekstra M, Posthumus MD, van Riel PL, van de Laar MA. Objective: Clinical trials have demonstrated that treatment-to-target (T2T) is effective in achieving remission in early rheumatoid arthritis (RA). However, the concept of T2T has not been fully implemented yet and the question is whether a T2T strategy is feasible in daily clinical practice. The objective of the study was to evaluate the adherence to a T2T strategy aiming at remission (disease activity score in 28 joints (DAS28) < 2.6) in early RA in daily practice. The recommendations regarding T2T included regular assessment of the DAS28 and an advice regarding DAS28-driven treatment adjustments. Methods: A medical chart review was performed among a random sample of 100 RA patients of the DREAM remission induction cohort. At all scheduled visits, it was determined whether the clinical decisions were compliant to the T2T recommendations. Results: The 100 patients contributed to a total of 1115 visits. The DAS28 was available in 97.9% (1092/1115) of the visits, of which the DAS28 was assessed at a frequency of at least every three months in 88.3% (964/1092). Adherence to the treatment advice was observed in 69.3% (757/1092) of the visits. In case of nonadherence when remission was present (19.5%, 108/553), most frequently
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medication was tapered or discontinued when it should have been continued (7.2%, 40/553) or treatment was continued when it should have been tapered or discontinued (6.2%, 34/553). In case of non-adherence when remission was absent (42.1%, 227/539), most frequently medication was not intensified when an intensification step should have been taken (34.9%, 188/539). The main reason for non-adherence was discordance between disease activity status according to the rheumatologist and DAS28. Conclusions: The recommendations regarding T2T were successfully implemented and high adherence was observed. This demonstrates that a T2T strategy is feasible in RA in daily clinical practice. Arthritis Res Ther 2012;14:R254 Impact factor: 4.302
19. The provisional ACR/EULAR definition of remission in RA: a comment on the patient global assessment criterion. Vermeer M, Kuper HH, van der Bijl AE, Baan H, Posthumus MD, Brus HL, van Riel PL, van de Laar MA. Objectives: The provisional ACR/European League Against Rheumatism (EULAR) definition of remission in RA requires a score of 1 despite fulfilment of the remaining criteria (TJC28, SJC28 and CRP in mg/dl 1. Receiver operating characteristic analysis showed moderate accuracy of the PGA to discriminate between fulfilment and no fulfilment of all remaining criteria. Conclusion: Frequently, patients did not meet the PGA criterion despite a good clinical disease state. Apparently the PGA is not solely influenced by RA disease activity. In patients with marked divergence between the PGA and objective clinical measurements, caution should be taken when applying the provisional ACR/EULAR definition of remission. Rheumatology (Oxford) 2012;51:1076-1080 Impact factor: 4.212
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20. Assessment of Helicobacter pylori eradication in patients on NSAID treatment. Vonkeman HH, de Leest HT, van de Laar MA, van Baarlen J, Steen KS, Lems WF, Bijlsma JW, Kuipers EJ, Houben HH, Janssen M, Dijkmans BA. Objectives: In this post-hoc analysis of a randomized, double blind, placebo controlled trial, we measured the sensitivity and specificity of Helicobacter pylori IgG-antibody titer changes, hematoxylin and eosin (H&E) stains, immunohistochemical (IHC) stains and culture results in NSAID using patients, following H. pylori eradication therapy or placebo. Methods: 347 NSAID using patients who were H. pylori positive on serological testing for H. pylori IgG-antibodies were randomized for H. pylori eradication therapy or placebo. Three months after randomization, gastric mucosal biopsies were taken for H. pylori culture and histological examination. At 3 and 12 months, blood samples were taken for repeated serological testing. The gold standard for H. pylori infection was based on a positive culture or both a positive histological examination and a positive serological test. Sensitivity, specificity and receiver operating curves (ROC) were calculated. Results: H. pylori eradication therapy was successful in 91 % of patients. Culture provided an overall sensitivity of 82 %, and 73 % after eradication, with a specificity of 100 %. Histological examination with either H&E or IHC stains provided sensitivities and specificities between 93 % and 100 %. Adding IHC to H&E stains did not improve these results. The ROC curve for percent change in H. pylori IgGantibody titers had good diagnostic power in identifying H. pylori negative patients, with an area under the ROC curve of 0.70 (95 % CI 0.59 to 0.79, P = 0.085) at 3 months and 0.83 (95 % CI 0.76 to 0.89, P < 0.0001) at 12 months. A cut-off point of at least 21 % decrease in H. pylori IgG-antibody titers at 3 months and 58 % at 12 months provided a sensitivity of 64 % and 87 % and a specificity of 81 % and 74 % respectively, for successful eradication of H. pylori. Conclusions: In NSAID using patients, following H. pylori eradication therapy or placebo, histological examination of gastric mucosal tissue biopsies provided good sensitivity and specificity ratios for evaluating success of H. pylori eradication therapy. A percentual H. pylori IgG-antibody titer change has better sensitivity and specificity than an absolute titer change or a predefined H. pylori IgG-antibody titer cut-off point for evaluating success of H. pylori eradication therapy. BMC Gastroenterol 2012;12:133. Impact factor: 2.110
21. Which dimensions of fatigue should be measured in patients with rheumatoid arthritis? A Delphi study. Nikolaus S, Bode C, Taal E, van de Laar MA. Objective: Rheumatoid arthritis (RA) patients experience fatigue as a multidimensional symptom. The aim of the present study was to use health professionals and patients alike to identify which dimensions of fatigue should be measured in RA.
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Methods: Twelve fatigue dimensions were constructed, based on items from traditional questionnaires and items generated from interviews. Health professionals and patients evaluated these dimensions, related to an initial pool of 294 items, in a Delphi procedure. Dimensions were selected if rated important by at least 80% of the participants. Results: Ten rheumatologists, 20 nurses and 15 patients participated. All fatigue dimensions were selected directly (severity, frequency, duration, changes in fatigue, perceived causes of fatigue, energy, sleep/rest, body feeling, cognition/concentration, coping, negative emotions/mood and consequences). No additional dimensions emerged from participants' comments and suggestions. Conclusions: This study revealed 12 fatigue dimensions. This underlines the multidimensionality of fatigue in RA and the need for comprehensive measurement. Musculoskeletal Care 2012;10:13-17. Impact factor: 0
Totale impact factor: 67.679 Gemiddelde impact factor: 3.223 Aantal artikelen 1e, 2e of laatste auteur: 18 Totale impact factor: 55.474 Gemiddelde impact factor: 3.082
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Revalidatiegeneeskunde 1. Comparison of shoulder load during power-assisted and purely hand-rim wheelchair propulsion. Kloosterman MG, Eising H, Schaake L, Buurke JH, Rietman JS. Background: Repetitive forces and moments are among the work requirements of hand-rim wheelchair propulsion that are related to shoulder injuries. No previous research has been published about the influence of power-assisted wheelchair propulsion on these work requirements. The purpose of our study was therefore to determine the influence of power-assisted propulsion on shoulder biomechanics and muscle activation patterns. We also explored the theoretical framework for the effectiveness of power-assisted propulsion in preventing shoulder injuries by decreasing the work requirements of hand-rim wheelchair propulsion. Methods: Nine non-wheelchair users propelled a hand-rim wheelchair on a treadmill at 0.9 m/s. Shoulder biomechanics, and muscle activation patterns, were compared between propulsion with and without power-assist. Findings: Propulsion frequency did not differ significantly between the two conditions (Wilcoxon Signed Rank test/significance level/effect size:4/.314/-.34). During power-assisted propulsion we found significantly decreased maximum shoulder flexion and internal rotation angles (1/.015/-.81 and 0/.008/-.89) and decreased peak force on the rim (0/.008/-.89). This resulted in decreased shoulder flexion, adduction and internal rotation moments (2/.021/-.77; 0/.008/-.89 and 1/.011/-.85) and decreased forces at the shoulder in the posterior, superior and lateral directions (2/.021/-.77; 2/.008/-.89 and 2/.024/-.75). Muscle activation in the pectoralis major, posterior deltoid and triceps brachii was also decreased (2/.038/.69; 1/.015/-.81 and 1/.021/-.77). Interpretation: Power-assist influenced the work requirements of hand-rim wheelchair propulsion by healthy subjects. It was primarily the kinetics at rim and shoulder which were influenced by power-assisted propulsion. Additional research with actual hand-rim wheelchair users is required before extrapolation to routine clinical practice. Clin Biomech 2012;27:428-435. Impact factor: 1.869
2. Vibro- and electrotactile user feedback on hand opening for myoelectric forearm prostheses. Witteveen HJ, Droog EA, Rietman JS, Veltink PH. Many of the currently available myoelectric forearm prostheses stay unused because of the lack of sensory feedback. Vibrotactile and electrotactile stimulation have high potential to provide this feedback. In this study, performance of a grasping task is investigated for different hand opening feedback conditions on 15 healthy subjects and validated on three patients. The opening of a virtual hand was controlled by a scroll wheel. Feedback about hand opening was given via an array of
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eight vibrotactile or electrotactile stimulators placed on the forearm, relating to eight hand opening positions. A longitudinal and transversal orientation of the array and four feedback conditions were investigated: no feedback, visual feedback, feedback through vibrotactile or electrotactile stimulation, and addition of an extra stimulator for touch feedback. No influence of array orientation was shown for all outcome parameters (duration of the task, the percentage of correct hand openings, the mean position error, and the percentage deviations up to one position). Vibrotactile stimulation enhances the performance compared to the nonfeedback conditions. The addition of touch feedback further increases the performance, but at the cost of an increased duration. The same effects were found for the patient group, but the task duration was around 25% larger. IEEE Trans Biomed Eng 2012;59:2219-2226. Impact factor: 2.278
3. Improving walking capacity by surgical correction of equinovarus foot deformity in adult patients with stroke or traumatic brain injury: a systematic review. Renzenbrink GJ, Buurke JH, Nene AV, Geurts AC, Kwakkel G, Rietman JS. Objective: Equinovarus foot deformity following stroke or traumatic brain injury compromises walking capacity, interfering with activities of daily living. In soft-tissue surgery the imbalanced muscles responsible for the deviant position of the ankle and foot are lengthened, released and/or transferred. However, knowledge about the effectiveness of surgical correction is limited. The aim of the present study was to carry out a systematic review of the literature to assess the effects of surgical correction of equinovarus foot deformity in patients with stroke or traumatic brain injury. Methods: A systematic search of full-length articles in the English, German or Dutch languages published from 1965 to March 2011 was performed in PubMed, EMBASE, CINAHL, Cochrane and CIRRIE. The identified studies were analysed following the International Classification of Functioning, Disability and Health criteria. Results: A total of 15 case series, case control and historically controlled studies (CEBM level 4) were identified, suggesting that surgical correction of equinovarus foot deformity is a safe procedure that is effective in terms of re-obtaining a balanced foot position, improving walking capacity and diminishing the need for orthotic use. Discussion: Further validation of surgical correction of equinovarus foot deformity following stroke or traumatic brain injury is required, using higher level study designs with validated assessment tools. Comparing surgical techniques with other interventions is necessary to generate evidence upon which treatment algorithms could be based. J Rehabil Med 2012;44:614-623. Impact factor: 2.134
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4. Influence of gravity compensation training on synergistic movement patterns of the upper extremity after stroke, a pilot study. Krabben T, Prange GB, Molier BI, Stienen AH, Jannink MJ, Buurke JH, Rietman JS. Background: The majority of stroke patients have to cope with impaired arm function. Gravity compensation of the arm instantaneously affects abnormal synergistic movement patterns. The goal of the present study is to examine whether gravity compensated training improves unsupported arm function. Methods: Seven chronic stroke patients received 18 half-hour sessions of gravity compensated reach training, in a period of six weeks. During training a motivating computer game was played. Before and after training arm function was assessed with the Fugl-Meyer assessment and a standardized, unsupported circle drawing task. Synergistic movement patterns were identified based on concurrent changes in shoulder elevation and elbow flexion/extension angles. Results: Median increase of Fugl-Meyer scores was 3 points after training. The training led to significantly increased work area of the hemiparetic arm, as indicated by the normalized circle area. Roundness of the drawn circles and the occurrence of synergistic movement patterns remained similar after the training. Conclusions: A decreased strength of involuntary coupling might contribute to the increased arm function after training. More research is needed to study working mechanisms involved in post stroke rehabilitation training. The used training setup is simple and affordable and is therefore suitable to use in clinical settings. J Neuroeng Rehabil 2012;9:44. Impact factor: 2.567
5. Intention detection of gait initiation using EMG and kinematic data. Wentink EC, Beijen SI, Hermens HJ, Rietman JS, Veltink PH. Gait initiation in transfemoral amputees (TFA) is different from non-amputees. This is mainly caused by the lack of stability and push-off from the prosthetic leg. Adding control and artificial push-off to the prosthesis may therefore be beneficial to TFA. In this study the feasibility of real-time intention detection of gait initiation was determined by mimicking the TFA situation in non-amputees. EMG and inertial sensor data was measured in 10 non-amputees. Only data available in TFA was used to determine if gait initiation can be predicted in time to control a transfemoral prosthesis to generate push-off and stability. Toe-off and heel-strike of the leading limb are important parameters to be detected, to control a prosthesis and to time push-off. The results show that toe-off and heel-strike of the leading limb can be detected using EMG and kinematic data in non-amputees 130-260 ms in advance. This leaves enough time to control a prosthesis. Based on these results we hypothesize that similar results can be found in TFA, allowing for adequate control of a prosthesis during gait initiation. Gait Posture 2013;37:223-228. Impact factor: 1.969
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6. A systematic review on the pros and cons of using a pushrim-activated power-assisted wheelchair Kloosterman MG, Snoek GJ, van der Woude LH, Buurke JH, Rietman JS. Objective: To determine the (dis)advantages of transition to a power-assisted wheelchair, and derive the clinical implications for its use or prescription. Data sources: Relevant articles published prior to May 2012 were identified using PubMed, Cochrane Library, REHABDATA, CIRRIE and CINAHL databases. Review methods: Clinical or (randomized) controlled trials, published in a peerreviewed journal, comparing power-assisted wheelchair use and hand-rim or powered wheelchair use were eligible. Data quality and validity were assessed by two reviewers independently using the Checklist for Measuring Quality developed by Downs and Black. Results: A systematic search yielded 15 cross-over trails with repeated measurement design and one qualitative interview. Methodological quality scored between 9 and 15 points out of the maximum score of 32. Ten studies measuring body function and structure reported reduced strain on the arm and cardiovascular system during power-assisted propulsion compared to hand-rim propulsion. Twelve studies measuring activities and social participation reported precision tasks easier to perform with a hand-rim wheelchair and tasks which require more torque were easier with a power-assisted wheelchair. Social participation was not altered significantly by the use of a hand-rim, powered or power-assisted wheelchair. Conclusion: Power-assisted propulsion might be beneficial for subjects in whom independent hand-rim wheelchair propulsion is endangered by arm injury, insufficient arm strength or low cardiopulmonary reserves. Also, subjects who have difficulty propelling a wheelchair in a challenging environment can benefit from power-assisted wheelchair use. Caution is warranted for the additional width and weight in relation to the usual mode of transportation and access to the home environment. Clin Rehabil 2013;27:299-313. Impact factor: 2.191
7. Variable stiffness actuated prosthetic knee to restore knee buckling during stance: a modeling study. Wentink EC, Koopman HF, Stramigioli S, Rietman JS, Veltink PH. Most modern intelligent knee prosthesis use dampers to modulate dynamic behavior and prevent excessive knee flexion, but they dissipate energy and do not assist in knee extension. Energy efficient variable stiffness control (VSA) can reduce the energy consumption yet effectively modulate the dynamic behavior and use stored energy during flexion to assist in subsequent extension. A principle design of energy efficient VSA in a prosthetic knee is proposed and analyzed for the specific case of rejection of a disturbed stance phase. The concept is based on the principle that the output stiffness of a spring can be changed without changing the energy stored in the elastic elements of the spring. The usability of this concept to control a prosthetic
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knee is evaluated using a model. Part of the stance phase of the human leg was modeled by a double pendulum. Specifically the rejection of a common disturbance of transfemoral prosthetic gait, an unlocked knee at heel strike, was evaluated. The ranges of spring stiffnesses were determined such that the angular characteristics of a normal stance phase were preserved, but disturbances could also be rejected. The simulations predicted that energy efficient VSA can be useful for the control of prosthetic knees. Med Eng Phys 2013;35:838-845. Impact factor: 1.779
8. Simulated bone remodeling around two types of osseointegrated implants for direct fixation of upper-leg prostheses. Tomaszewski PK, Verdonschot N, Bulstra SK, Rietman JS, Verkerke GJ. Direct attachment of an upper leg prosthesis to the skeletal system by a percutaneous implant is an alternative solution to the traditional socket fixation. In this study, we investigated long-term periprosthetic bone changes around two types of fixation implants using two different initial conditions, namely immediate postamputation implantation and the conventional implantation after considerable time of socket prosthesis use. We questioned the difference in bone modeling response the implants provoked and if it could lead to premature bone fracture. Generic CT-based finite element models of an intact femoral bone and amputated bone implanted with models of two existing direct-fixation implants, the OPRA system (Integrum AB) and the ISP Endo/Exo prosthesis (ESKA Implants AG) were created for this study. Adaptive bone-remodeling simulations used the heel-strike and toe-off loads from a normal walking cycle. The bone loss caused by prolonged use of socket prosthesis had more severe effects on the ultimate bone quality than adaptation induced by the direct-fixation implants. Both implants showed considerable bone remodeling; the titanium screw implant (OPRA system) provoked more bone loss than the porous coated CoCrMo stem (ISP implant). The chance of the peri-prosthetic bone fracture remained higher for the post-socket case as compared to the direct amputation cases. In conclusion, both direct-fixation implants lead to considerable bone loss and bone loss is more severe after a prolonged period of post-socket use. Hence, from a biomechanical perspective it is better to limit the post-socket time and to redesign direct fixation devices to reduce bone loss and the probability of periprosthetic bone fractures J Mech Behav Biomed Mater 2012;15:167-175. Impact factor: 2.368
9. Grasping force and slip feedback through vibrotactile stimulation to be used in myoelectric forearm prostheses. Witteveen HJ, Rietman JS, Veltink PH.
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User feedback about grasping force or slip of objects is lacking in current myoelectric forearm prostheses, resulting in a high number of prosthesis abandonment, because a high level of concentration is required to hold an object. Several approaches to provide force feedback to the user via vibrotactile stimulation have been described in literature, but none of them have investigated the optimal stimulation parameters. This study describes an evaluation of three modulation techniques to provide force feedback. Furthermore, the same modulation techniques to provide slip feedback were evaluated, which has not been described before. The performance in virtual object holding tasks was significantly improved in most cases compared to the non-feedback situation, but at the cost of an increased task duration Conf Proc IEEE Eng Med Biol Soc 2012;2012:2969-2972. Impact factor: 2.060
10. Hand-opening feedback for myoelectric forearm prostheses: performance in virtual grasping tasks influenced by different levels of distraction. Witteveen HJ, de Rond L, Rietman JS, Veltink PH. Sensory feedback and the required attentional demands are important aspects in prosthesis acceptance. In this study, hand-opening feedback is provided and the performance in a virtual grasping task is investigated. Simultaneously, a secondary task was performed to investigate the attentional demands. Ten nondisabled subjects performed the tasks with and without feedback about the hand opening through an array of eight vibrotactile stimulators on the forearm. Activation of one stimulator corresponded to one hand-opening position. For the dual-task experiments, subjects simultaneously performed a secondary auditory counting task. The addition of vibrotactile feedback increased the performance (expressed in percentages of correct hand positions, mean absolute errors in position, and percentages of deviations up to one hand-opening position), but the duration of the tasks was also increased. Three levels of distraction (no distraction, counting task, count and subtract task) were applied, which did not influence the performance in the grasping tasks except for the highest level of distraction. We concluded that the proposed method to provide hand-opening feedback through an array of eight vibrotactile stimulators is successful because the performance in a grasping task increases but it is not significantly attention demanding. J Rehabil Res Dev 2012;49:1517-1526. Impact factor: 1.708
11. Three-year follow-up results of a residential community reintegration program for patients with chronic acquired brain injury. Geurtsen GJ, van Heugten CM, Martina JD, Rietveld AC, Meijer R, Geurts AC. Three-year follow-up results of a residential community reintegration program for patients with chronic acquired brain injury.
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Objective: To evaluate outcomes of a residential community reintegration program 3 years after treatment on independent living, societal participation, emotional wellbeing, and quality of life in patients with chronic acquired brain injury and psychosocial problems hampering societal participation. Design: A follow-up assessment 3 years after treatment was compared with the 1year follow-up assessment in a prospective cohort study. Setting: A tertiary rehabilitation center for acquired brain injury. Participants: Of the 67 patients assessed at the 1-year follow-up, 63 subjects (94%; 42 men; mean age at admission to treatment 24.7y; mean time postonset 5.1y) were available at the 3-year follow-up and taken into account in the analyses. Intervention: A structured residential treatment program directed at improving independence in domestic life, work, leisure time, and social interactions. Main outcome measures: Community Integration Questionnaire, Employability Rating Scale, living situation, school, work situation, work hours, Center for Epidemiological Studies-Depression scale, and the World Health Organization Quality of Life Scale Abbreviated (5 scales). Results: There were no significant differences for any of the outcome measures between the 1-year and 3-year follow-up assessment. Conclusions: These results indicate that the established significant and clinically relevant improvements after a residential community reintegration program remain stable in the long term. Arch Phys Med Rehabil 2012;93:908-911 Impact factor: 2.358
Totale impact factor: 23.351 Gemiddelde impact factor: 2.123 Aantal artikelen 1e, 2e of laatste auteur: 5 Totale impact factor: 10.821 Gemiddelde impact factor: 2.164
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Thoraxchirurgie 1. Patients' satisfaction and wound-site complications after radial artery harvesting for coronary artery bypass. Arrigoni SC, Halbersma WB, Grandjean JG, Mariani MA. The aim of the study was to establish patients' satisfaction and the incidence of wound-site complications after radial artery (RA) harvesting for bypass surgery. A telephonic quality of life questionnaire was performed in 306 consecutive patients who had undergone coronary artery bypass grafting with the use of RA with the open technique. A psychometric Likert scale was used to define the degree of patients' satisfaction. The questionnaire concerned arm pain, cosmesis and mobility, sensory and neurological complications, and patients' general health state. The median values and the modal scores achieved the maximal value of satisfaction for all site-related complications and the mean scores were >4 out of 5. The median patients' general health state was 4. Cosmetic result of the wound was considered at least acceptable by 98% of patients. The incidence of impairing peripheral neurological complications was 16.7%. The degree of patients' satisfaction after RA harvesting was more than satisfactory and the incidence of wound-site complications was acceptable. The incidence of neurological injuries was lower than previously described. Interact Cardiovasc Thorac Surg 2012;14:324-326. Impact factor: 1.112
2. There is always hope after PCI and stenting. Giordano V, Grandjean JG Nowadays the introduction of intracoronary stents into clinical practice has totally changed the approach to the treatment of diffuse and obstructive coronary artery disease. Although optimal antiaggregant therapy has ensured a low incidence of subacute stent thrombosis, recurrent restenosis remains the major limitation of these intracoronary devices. In such circumstances, surgery may represent the only choice for definitive treatment of recurrent ischemic heart disease. We report an uncommon and challenging way to achieve a complete off-pump coronary revascularization of a seriously diseased, 'full metal jacket' left anterior descending artery (LAD), combining three different techniques at the same time: stent removal, endarterectomy and coronary artery bypass graft (CABG) J.Cardiovasc.Med. 2012;13:766-768. Impact factor: 2.657
3. Consequences of Delirium After Cardiac Operations. Koster S, Hensens AG, Schuurmans MJ, van der Palen J.
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Background: Delirium is a transient mental syndrome characterized by disturbances in consciousness, cognition, and perception. The risk that delirium will develop is increased in patients who undergo cardiac operations, especially the elderly. Generally, delirium during hospital admission is independently associated with many negative consequences, such as higher mortality, increased length of hospital stay, nursing home placement after admission, and cognitive and functional decline. Methods: This prospective follow-up study used the Short Form 36-Item questionnaire, the Cognitive Failure Questionnaire, and a purpose-designed questionnaire to assess 300 patients who underwent elective cardiac operations at 6 months after the procedure. Postoperative delirium developed in 52 patients (17%). Mortality and readmission were also assessed. Results: Delirium after cardiac procedures is associated with increased mortality (13.5% vs 2.0% in patients without), more hospital readmissions (45.7% vs 26.5%), and reduced quality of life. It is also associated with reduced cognitive functioning, including failures in attention, memory, perception, and motor function, and with functional dysfunction such as independency in activities of daily living and mobility. Conclusions: Postoperative delirium after cardiac operations is associated with many important consequences. These findings provide justification for intervention studies to evaluate whether delirium prevention, early recognition, or treatment strategies might improve postoperative functional and cognitive function. Ann Thorac Surg 2012;93:705-711. Impact factor: 3.741
Totale impact factor: 7.510 Gemiddelde impact factor: 2.503 Aantal artikelen 1e, 2e of laatste auteur: 3 Totale impact factor: 7.510 Gemiddelde impact factor: 2.503
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