Publications by authors named "Nicolaas P A Zuithoff"

67 Publications

Maximum bite force in children with juvenile idiopathic arthritis with and without clinical established temporomandibular joint involvement and in healthy children: a cross-sectional study.

J Oral Rehabil 2021 Mar 29. Epub 2021 Mar 29.

Department of Oral and Maxillofacial Surgery and Special Dental Care, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Background: In children with juvenile idiopathic arthritis (JIA), the temporomandibular joint (TMJ) can be involved, resulting in dysfunction of the masticatory system. Bite force is one of the variables that reflects the function of the masticatory system. The aim of this study was to compare maximum bite force in children with JIA, with and without TMJ involvement and with healthy children.

Methods: Children with JIA and healthy children between the ages 6 and 18 were included in this cross-sectional study. The clinical examination consisted of measuring the anterior maximum voluntary bite force (AMVBF), assessment of the TMJ screening protocol items and TMJ, masseter and temporal muscle palpation pain. Unadjusted linear regression analyses were performed to evaluate the explanatory factors for AMVBF. Two adjusted models were constructed with corrections for age and gender differences: model 1 to compare children with JIA and healthy children and model 2 to compare children with JIA with and without TMJ involvement.

Results: In this cross-sectional study, 298 children with JIA and 169 healthy children participated. AMVBF was 24 Newton (N) lower in children with JIA, when compared with healthy children (95%CI: -35.5--12.4, p = .000). When children with JIA also had clinically established TMJ involvement, AMVBF was reduced 42 N (component JIA:-16.78, 95% CI -28.96--4.59, p = .007 and component TMJ involvement:-25.36, 95% CI -40.08--10.63, p = .001). Age and male gender increased AMVBF.

Conclusion: Children with JIA had a reduction in the AMVBF compared with healthy children. In children with JIA and clinically established TMJ involvement, AMVBF was more reduced.
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http://dx.doi.org/10.1111/joor.13172DOI Listing
March 2021

Association between Oncostatin M Expression and Inflammatory Phenotype in Experimental Arthritis Models and Osteoarthritis Patients.

Cells 2021 Feb 27;10(3). Epub 2021 Feb 27.

Department of Orthopedics, University Medical Centre Utrecht, 3584 CX Utrecht, The Netherlands.

Pro-inflammatory cytokines are considered to play a major role in osteoarthritis (OA), yet so far, the specific cytokines involved in the pathology of OA have not been identified. Oncostatin M (OSM) is a cytokine from the interleukin 6 (IL-6) family that has been shown to be elevated in synovial fluid of most rheumatoid arthritis (RA) patients, but only in a limited subset of OA patients. Little is known about OSM in the different joint tissues during OA and how its expression correlates with hallmarks of disease. Here, we mapped OSM expression in the joint tissues of two rat models of arthritis: an acute inflammatory model and an instability-induced osteoarthritic model. OSM expression was correlated with hallmarks of OA, namely cartilage damage, synovitis, and osteophyte formation. Reanalysis of an existing dataset on cytokine profiling of OA synovial fluid was performed to assess pattern differences between patients positive and negative for OSM. In the inflammatory model, OSM expression correlated with synovitis and osteophyte formation but not with cartilage damage. On the contrary, in the instability model of OA, an increase in synovitis, cartilage damage, and osteophyte formation was observed without changes in OSM expression. In line with these findings, synovial fluid of OA patients with detectable OSM contained higher levels of other inflammatory cytokines, namely interferon gamma (IFN-γ), IL-1α and tumor necrosis factor alpha (TNF-α), likely indicating a more inflammatory state. Taken together these data indicate OSM might play a prominent role in inflammatory phenotypes of OA.
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http://dx.doi.org/10.3390/cells10030508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997294PMC
February 2021

Cerebrospinal fluid leakage after cranial surgery in the pediatric population-a systematic review and meta-analysis.

Childs Nerv Syst 2021 May 4;37(5):1439-1447. Epub 2021 Feb 4.

Department of Neurology and Neurosurgery, University Medical Center Utrecht, Utrecht, The Netherlands.

Background: Cerebrospinal fluid (CSF) leakage is a common complication after neurosurgical intervention. It is associated with substantial morbidity and increased healthcare costs. The current systematic review and meta-analysis aim to quantify the incidence of cerebrospinal fluid leakage in the pediatric population and identify its risk factors.

Methods: The authors followed the PRISMA guidelines. The Embase, PubMed, and Cochrane database were searched for studies reporting CSF leakage after intradural cranial surgery in patients up to 18 years old. Meta-analysis of incidences was performed using a generalized linear mixed model.

Results: Twenty-six articles were included in this systematic review. Data were retrieved of 2929 patients who underwent a total of 3034 intradural cranial surgeries. Surprisingly, only four of the included articles reported their definition of CSF leakage. The overall CSF leakage rate was 4.4% (95% CI 2.6 to 7.3%). The odds of CSF leakage were significantly greater for craniectomy as opposed to craniotomy (OR 4.7, 95% CI 1.7 to 13.4) and infratentorial as opposed to supratentorial surgery (OR 5.9, 95% CI 1.7 to 20.6). The odds of CSF leakage were significantly lower for duraplasty use versus no duraplasty (OR 0.41 95% CI 0.2 to 0.9).

Conclusion: The overall CSF leakage rate after intradural cranial surgery in the pediatric population is 4.4%. Risk factors are craniectomy and infratentorial surgery. Duraplasty use is negatively associated with CSF leak. We suggest defining a CSF leak as "leakage of CSF through the skin," as an unambiguous definition is fundamental for future research.
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http://dx.doi.org/10.1007/s00381-021-05036-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084768PMC
May 2021

Postpartum hemorrhage in Suriname: A national descriptive study of hospital births and an audit of case management.

PLoS One 2020 18;15(12):e0244087. Epub 2020 Dec 18.

Board of Doctoral Graduations and Honorary Doctorate Awards, Anton de Kom University, Paramaribo, Suriname, South Africa.

Background: Postpartum hemorrhage (PPH) is the leading cause of direct maternal mortality globally and in Suriname. We aimed to study the prevalence, risk indicators, causes, and management of PPH to identify opportunities for PPH reduction.

Methods: A nationwide retrospective descriptive study of all hospital deliveries in Suriname in 2017 was performed. Logistic regression analysis was applied to identify risk indicators for PPH (≥ 500ml blood loss). Management of severe PPH (blood loss ≥1,000ml or ≥500ml with hypotension or at least three transfusions) was evaluated via a criteria-based audit using the national guideline.

Results: In 2017, the prevalence of PPH and severe PPH in Suriname was 9.2% (n = 808/8,747) and 2.5% (n = 220/8,747), respectively. PPH varied from 5.8% to 15.8% across the hospitals. Risk indicators associated with severe PPH included being of African descent (Maroon aOR 2.1[95%CI 1.3-3.3], Creole aOR 1.8[95%CI 1.1-3.0]), multiple pregnancy (aOR 3.4[95%CI 1.7-7.1]), delivery in Hospital D (aOR 2.4[95%CI 1.7-3.4]), cesarean section (aOR 3.9[95%CI 2.9-5.3]), stillbirth (aOR 6.4 [95%CI 3.4-12.2]), preterm birth (aOR 2.1[95%CI 1.3-3.2]), and macrosomia (aOR 2.8 [95%CI 1.5-5.0]). Uterine atony (56.7%, n = 102/180[missing 40]) and retained placenta (19.4%, n = 35/180[missing 40]), were the main causes of severe PPH. A criteria-based audit revealed that women with severe PPH received prophylactic oxytocin in 61.3% (n = 95/155[missing 65]), oxytocin treatment in 68.8% (n = 106/154[missing 66]), and tranexamic acid in 4.9% (n = 5/103[missing 117]).

Conclusions: PPH prevalence and risk indicators in Suriname were similar to international and regional reports. Inconsistent blood loss measurement, varied maternal and perinatal characteristics, and variable guideline adherence contributed to interhospital prevalence variation. PPH reduction in Suriname can be achieved through prevention by practicing active management of the third stage of labor in every birth and considering risk factors, early recognition by objective and consistent blood loss measurement, and prompt treatment by adequate administration of oxytocin and tranexamic acid according to national guidelines.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244087PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7748130PMC
March 2021

Bumetanide for Core Symptoms of Autism Spectrum Disorder (BAMBI): A Single Center, Double-Blinded, Participant-Randomized, Placebo-Controlled, Phase-2 Superiority Trial.

J Am Acad Child Adolesc Psychiatry 2020 Jul 27. Epub 2020 Jul 27.

UMC Utrecht Brain Centre, University Medical Centre Utrecht, the Netherlands; Amsterdam UMC, Vrije Universiteit Amsterdam, N=You centre, Amsterdam Neuroscience, Amsterdam Reproduction and Development, the Netherlands. Electronic address:

Objective: Recent trials have indicated positive effects of bumetanide in autism spectrum disorder (ASD). We tested efficacy of bumetanide on core symptom domains using a single center, parallel-group, participant-randomized, double-blind, placebo-controlled phase-2 superiority trial in a tertiary hospital in the Netherlands.

Method: Unmedicated children aged 7 to 15 years with ASD and IQ ≥55 were block-randomized 1:1 to oral-solution bumetanide versus placebo, titrated to a maximum of 1.0 mg twice daily for 91 days (D91), followed by a 28-day wash-out period. The primary outcome was difference in Social Responsiveness Scale-2 (SRS-2) total score at D91, analyzed by modified intention-to-treat with linear mixed models.

Results: A total of 92 participants (mean age 10.5 [SD 2.4] years) enrolled between June 2016 and December 2018. In all, 47 children were allocated to bumetanide and 45 to placebo. Two participants dropped out per treatment arm. After 91 days, bumetanide was not superior to placebo on the primary outcome, the SRS-2 (mean difference -3.16, 95% CI = -9.68 to 3.37, p = .338). A superior effect was found on one of the secondary outcomes, the Repetitive Behavior Scale-Revised (mean difference -4.16, 95% CI = -8.06 to -0.25, p = .0375), but not on the Sensory Profile (mean difference 5.64, 95% CI = -11.30 to 22.57, p = .508) or the Aberrant Behavior Checklist Irritability Subscale (mean difference -0.65, 95% CI = -2.83 to 1.52, p = .552). No significant wash-out effect was observed. Significant adverse effects were predominantly diuretic effects (orthostatic hypotension (17 [36%] versus 5 [11%], p = .007); hypokalemia (24 [51%] versus 0 [0%], p < .0001), the occurrence of which did not statistically influence treatment outcome.

Conclusion: The trial outcome was negative in terms of no superior effect on the primary outcome. The secondary outcomes suggest efficacy on repetitive behavior symptoms for a subset of patients.

Clinical Trial Registration Information: Bumetanide in Autism Medication and Biomarker Study (BAMBI); https://www.clinicaltrialsregister.eu/; 2014-001560-35.
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http://dx.doi.org/10.1016/j.jaac.2020.07.888DOI Listing
July 2020

Effect of tailoring anticoagulant treatment duration by applying a recurrence risk prediction model in patients with venous thromboembolism compared to usual care: A randomized controlled trial.

PLoS Med 2020 06 26;17(6):e1003142. Epub 2020 Jun 26.

Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.

Background: Patients with unprovoked (i.e., without the presence of apparent transient risk factors such as recent surgery) venous thromboembolism (VTE) are at risk of recurrence if anticoagulants are stopped after 3-6 months, yet their risk remains heterogeneous. Thus, prolonging anticoagulant treatment should be considered in high-risk patients, whereas stopping is likely preferred in those with a low predicted risk. The Vienna Prediction Model (VPM) could aid clinicians in estimating this risk, yet its clinical effects and external validity are currently unknown. The aim of this study was to investigate the clinical impact of this model on reducing recurrence risk in patients with unprovoked VTE, compared to usual care.

Methods And Findings: In a randomized controlled trial, the decision to prolong or stop anticoagulant treatment was guided by predicted recurrence risk using the VPM (n = 441), which was compared with usual care (n = 442). Patients with unprovoked VTE were recruited from local thrombosis services in the Netherlands (in Utrecht, Harderwijk, Ede, Amersfoort, Zwolle, Hilversum, Rotterdam, Deventer, and Enschede) between 22 July 2011 and 30 November 2015, with 24-month follow-up complete for all patients by early 2018. The primary outcome was recurrent VTE during 24 months of follow-up. Secondary outcomes included major bleeding and clinically relevant non-major (CRNM) bleeding. In the total study population of 883 patients, mean age was 55 years, and 507 (57.4%) were men. A total of 96 recurrent VTE events (10.9%) were observed, 46 in the intervention arm and 50 in the control arm (risk ratio 0.92, 95% CI 0.63-1.35, p = 0.67). Major bleeding occurred in 4 patients, 2 in each treatment arm, whereas CRNM bleeding occurred in 20 patients (12 in intervention arm versus 8 in control arm). The VPM showed good discriminative power (c-statistic 0.76, 95% CI 0.69-0.83) and moderate to good calibration, notably at the lower spectrum of predicted risk. For instance, in 284 patients with a predicted risk of >2% to 4%, the observed rate of recurrence was 2.5% (95% CI 0.7% to 4.3%). The main limitation of this study is that it did not enroll the preplanned number of 750 patients in each study arm due to declining recruitment rate.

Conclusions: Our results show that application of the VPM in all patients with unprovoked VTE is unlikely to reduce overall recurrence risk. Yet, in those with a low predicted risk of recurrence, the observed rate was also low, suggesting that it might be safe to stop anticoagulant treatment in these patients.

Trial Registration: Netherlands Trial Register NTR2680.
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http://dx.doi.org/10.1371/journal.pmed.1003142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319277PMC
June 2020

Prostate-specific membrane antigen (PSMA) expression in adenoid cystic carcinoma of the head and neck.

BMC Cancer 2020 Jun 5;20(1):519. Epub 2020 Jun 5.

Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.

Background: Treatment options for advanced head and neck adenoid cystic carcinoma (AdCC) are limited. Prostate-Specific Membrane Antigen (PSMA), a transmembrane protein that is known for its use in diagnostics and targeted therapy in prostate cancer, is also expressed by AdCC. This study aimed to analyse PSMA expression in a large cohort of primary, recurrent and metastasized AdCC of the head and neck.

Methods: One hundred ten consecutive patients with histologically confirmed AdCC in the period 1990-2017 were included. An analysis was made of clinical details, revised pathology and semiquantitative immunohistochemical expression of PSMA on tissue microarray and whole slides. Associations of PSMA expression with clinicopathological parameters were explored and survival was analysed by multivariate Cox-proportional Hazard analysis.

Results: PSMA expression was present in 94% of the 110 primary tumours, with a median of 31% positive cells (IQR 15-60%). Primary tumours (n = 18) that recurred (n = 15) and/or had metastases (n = 10) demonstrated 40, 60 and 23% expression respectively. Expression was not independently related to increased pathological stage, tumour grade, and the occurrence of locoregional recurrence or metastasis. After dichotomization, only primary tumour PSMA expression ≤10% appeared to be associated with reduced 10-years recurrence-free survival (HR 3.0, 95% CI 1.1-8.5, p = .04).

Conclusions: PSMA is highly expressed in primary, recurrent and metastatic AdCC of the salivary and seromucous glands. PSMA expression has no value in predicting clinical behaviour of AdCC although low expression may indicate a reduced recurrence-free survival. This study provides supporting results to consider using PSMA as target for imaging and therapy when other diagnostic and palliative treatment options fail.
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http://dx.doi.org/10.1186/s12885-020-06847-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275445PMC
June 2020

The course of cerebrospinal fluid parameters ≤ 20 days after aneurysmal subarachnoid hemorrhage.

J Neurol Sci 2020 Aug 19;415:116899. Epub 2020 May 19.

Department of Neurology and Neurosurgery, University Medical Center Utrecht Brain Center, Utrecht University, Utrecht, the Netherlands.

Background: Aneurysmal subarachnoid hemorrhage (aSAH) patients have an inflammatory response in the cerebrospinal fluid (CSF). We determined CSF cell counts, erythrocyte/leukocyte ratio, and glucose- and protein concentrations in patients ≤20 days after aSAH without bacterial meningitis. Such knowledge may help to interpret CSF parameters in patients with an external drain if nosocomial bacterial meningitis or ventriculitis is suspected.

Methods: Patients with aSAH admitted between 2010 and 2017 with at least one CSF sample ≤ 20 days after ictus were included from a prospectively collected database. CSF samples were excluded if the patient used antibiotics or if the CSF culture was positive. We calculated estimated marginal means with 95% confidence intervals (CIs) with linear mixed models for CSF cell counts, glucose- and protein concentrations.

Results: We included 209 patients with 306 CSF samples. Highest estimated median leukocyte count was 305 (95%CI:225-412) x10^6/L, and the lowest estimated median erythrocyte/leukocyte ratio was 109 (95%CI:73-163). Estimated mean glucose concentrations remained within the normal range. The estimated median protein concentration decreased from 3.3 g/L (95%CI:2.5-4.2) on day 0 to 1.0 g/L (95%CI:0.8-1.2) on day 14.

Conclusion: The limits we found for the inflammatory reaction in aSAH patients may help physicians to interpret CSF parameters in aSAH patients with an external CSF drain. Future studies are needed to compare CSF parameters in aSAH patients with and without bacterial meningitis or ventriculitis.
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http://dx.doi.org/10.1016/j.jns.2020.116899DOI Listing
August 2020

Quality of intrapartum care: direct observations in a low-resource tertiary hospital.

Reprod Health 2020 Mar 14;17(1):36. Epub 2020 Mar 14.

Division Woman and Baby, University Medical Centre Utrecht, Utrecht, Netherlands.

Background: The majority of the world's perinatal deaths occur in low- and middle-income countries. A substantial proportion occurs intrapartum and is avoidable with better care. At a low-resource tertiary hospital, this study assessed the quality of intrapartum care and adherence to locally-tailored clinical guidelines.

Methods: A non-participatory, structured, direct observation study was held at Mnazi Mmoja Hospital, Zanzibar, Tanzania, between October and November 2016. Women in active labour were followed and structure, processes of labour care and outcomes of care systematically recorded. Descriptive analyses were performed on the labour observations and compared to local guidelines and supplemented by qualitative findings. A Poisson regression analysis assessed factors affecting foetal heart rate monitoring (FHRM) guidelines adherence.

Results: 161 labouring women were observed. The nurse/midwife-to-labouring-women ratio of 1:4, resulted in doctors providing a significant part of intrapartum monitoring. Care during labour and two-thirds of deliveries was provided in a one-room labour ward with shared beds. Screening for privacy and communication of examination findings were done in 50 and 34%, respectively. For the majority, there was delayed recognition of labour progress and insufficient support in second stage of labour. While FHRM was generally performed suboptimally with a median interval of 105 (interquartile range 57-160) minutes, occurrence of an intrapartum risk event (non-reassuring FHR, oxytocin use or poor progress) increased assessment frequency significantly (rate ratio 1.32 (CI 1.09-1.58)).

Conclusions: Neither international nor locally-adapted standards of intrapartum routine care were optimally achieved. This was most likely due to a grossly inadequate capacity of birth attendants; without whom innovative interventions at birth are unlikely to succeed. This calls for international and local stakeholders to address the root causes of unsafe intrafacility care in low-resource settings, including the number of skilled birth attendants required for safe and respectful births.
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http://dx.doi.org/10.1186/s12978-020-0849-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7071714PMC
March 2020

Consumption of a diet high in dairy leads to higher 15:0 in cholesteryl esters of healthy people when compared to diets high in meat and grain.

Nutr Metab Cardiovasc Dis 2020 05 25;30(5):804-809. Epub 2020 Jan 25.

Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands. Electronic address:

Background And Aims: A higher dairy product intake has been associated to higher blood concentrations of 15:0 (pentadecanoic acid), 17:0 (margaric acid), and 14:0 (myristic acid). This study investigates whether a diet high in dairy products influences cholesteryl ester fatty acid concentrations of these specific fatty acids (FA).

Methods And Results: In a randomized multiple cross-over study, 13 men and 17 women aged 22 ± 4 years with a BMI of 21.6 ± 2.2 kg/m received 3 isocaloric intervention diets (dairy, meat or grain) in random order. For this post-hoc analysis, FA in plasma cholesteryl esters were measured using gas chromatography. We performed a linear mixed model per centered log-ratio transformed FA, adjusting for period, and the interaction between diet and period. Consumed total fat intake per controlled intervention diet was 31.0 ± 0.9 en%/day (dairy), 31.5 ± 0.6 en%/day (meat), and 28.4 ± 1.2 en%/day (grain), respectively. The dairy diet led to higher relative concentrations of 15:0 when compared to diets high in meat and grain, (β; 0.27, 95%CI: 0.18,0.37; p = 1.2 × 10, and β: 0.15; 95%CI: 0.06,0.24; p = 1.2 × 10, respectively). The dairy diet also led to higher 14:0 when compared to the meat diet (β: 0.34; 95%CI: 0.21,0.46; p = 6.0 × 10), but not when compared to the grain diet. 17:0 did not differ between diets.

Conclusion: The plasma cholesteryl ester fraction after a diet high in dairy was characterized by higher 15:0 levels. Concentrations of 14:0 were only higher when comparing the FA profile after a diet high in dairy when compared to a diet high in meat.

Clinical Trial Registration: ClinicalTrials.gov, NCT01314040.
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http://dx.doi.org/10.1016/j.numecd.2020.01.006DOI Listing
May 2020

Valuing Healthcare Goods and Services: A Systematic Review and Meta-Analysis on the WTA-WTP Disparity.

Pharmacoeconomics 2020 05;38(5):443-458

Centre for Nutrition, Prevention and Health Services, National Institute for Public Health and the Environment (RIVM), PO Box 1, 3720 BA, Bilthoven, The Netherlands.

Objective: The objective of this systematic review was to review the available evidence on the disparity between willingness to accept (WTA) and willingness to pay (WTP) for healthcare goods and services.

Methods: A tiered approach consisting of (1) a systematic review, (2) an aggregate data meta-analysis, and (3) an individual participant data meta-analysis was used. MEDLINE, EMBASE, Scopus, Scisearch, and Econlit were searched for articles reporting both WTA and WTP for healthcare goods and services. Individual participant data were requested from the authors of the included studies.

Results: Thirteen papers, reporting WTA and WTP from 19 experiments/subgroups, were included in the review. The WTA/WTP ratios reported in these papers, varied from 0.60 to 4.01, with means of 1.73 (median 1.31) for 15 estimates of the mean and 1.58 (median 1.00) for nine estimates of the median. Individual data obtained from six papers, covering 71.2% of the subjects included in the review, yielded an unadjusted WTA/WTP ratio of 1.86 (95% confidence interval 1.52-2.28) and a WTA/WTP ratio adjusted for age, sex, and income of 1.70 (95% confidence interval 1.42-2.02). Income category and age had a statistically significant effect on the WTA/WTP ratio. The approach to handling zero WTA and WTP values has a considerable impact on the WTA/WTP ratio found.

Conclusions And Implications: The results of this study imply that losses in healthcare goods and services are valued differently from gains (ratio > 1), but that the degree of disparity found depends on the method used to obtain the WTA/WTP ratio, including the approach to zero responses. Irrespective of the method used, the ratios found in our meta-analysis are smaller than the ratios found in previous meta-analyses.
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http://dx.doi.org/10.1007/s40273-020-00890-xDOI Listing
May 2020

High CXCR4 expression in adenoid cystic carcinoma of the head and neck is associated with increased risk of locoregional recurrence.

J Clin Pathol 2020 Aug 16;73(8):476-482. Epub 2020 Jan 16.

Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.

Aim: Treatment options for head and neck adenoid cystic carcinoma (AdCC) are limited in advanced disease. Chemokine receptor type 4 (CXCR4) is present in various tumour types, including AdCC. Upregulation is associated with tumour recurrence and metastasis. New CXCR4-specific diagnostic and therapeutic target agents have recently been available. This study aimed to analyse CXCR4 expression in a cohort of primary head and neck AdCC.

Methods: After histopathological revision, tumour tissues of 73 consecutive patients with AdCC over 1990-2016 were sampled on a tissue microarray. Slides were immunohistochemically stained for CXCR4 and semiquantitatively scored. Associations between protein expression and cliniopathological parameters were tested. HRs were calculated using a Cox proportional hazard model.

Results: Sixty-six tumours could be analysed. CXCR4 expression was present in 81% of the tumours with a median of 29% (IQR 1-70) positive cells. Expression was univariately correlated to perineural growth (Spearman ρ .26, p=0.04) and bone invasion (Spearman ρ .32, p=0.01), but not with tumour grade.CXCR4 expression in the primary tumour was significantly higher in tumours that recurred as compared with those that did not recur (median 60%, IQR 33-72 vs 12%, IQR 1-70, Kruskal-Wallis p=0.01). After dichotomisation, >25% of CXCR4 expressions proved an independent prognosticator for a reduced recurrence-free survival (RFS) (HR 7.2, 95% CI 1.5 to 72.4, p=0.04).

Conclusion: CXCR4 is expressed in the majority of primary AdCCs and independently correlated to worse RFS, suggesting CXCR4 as a target for imaging and therapy purposes in patients with advanced AdCC.
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http://dx.doi.org/10.1136/jclinpath-2019-206273DOI Listing
August 2020

The effect of an mHealth clinical decision-making support system on neonatal mortality in a low resource setting: A cluster-randomized controlled trial.

EClinicalMedicine 2019 Jul 4;12:31-42. Epub 2019 Jul 4.

University of Allied Sciences, Ho, Ghana.

Background: MHealth interventions promise to bridge gaps in clinical care but documentation of their effectiveness is limited. We evaluated the utilization and effect of an mhealth clinical decision-making support intervention that aimed to improve neonatal mortality in Ghana by providing access to emergency neonatal protocols for frontline health workers.

Methods: In the Eastern Region of Ghana, sixteen districts were randomized into two study arms (8 intervention and 8 control clusters) in a cluster-randomized controlled trial. Institutional neonatal mortality data were extracted from the District Health Information System-2 during an 18-month intervention period. We performed an intention-to-treat analysis and estimated the effect of the intervention on institutional neonatal mortality (primary outcome measure) using grouped binomial logistic regression with a random intercept per cluster. This trial is registered at ClinicalTrials.gov ( and Pan African Clinical Trials Registry (

Findings: There were 65,831 institutional deliveries and 348 institutional neonatal deaths during the study period. Overall, 47 ∙ 3% of deliveries and 56 ∙ 9% of neonatal deaths occurred in the intervention arm. During the intervention period, neonatal deaths increased from 4 ∙ 5 to 6 ∙ 4 deaths and, from 3 ∙ 9 to 4 ∙ 3 deaths per 1000 deliveries in the intervention arm and control arm respectively. The odds of neonatal death was 2⋅09 (95% CI (1 ∙ 00;4 ∙ 38); p = 0 ∙ 051) times higher in the intervention arm compared to the control arm (adjusted odds ratio). The correlation between the number of protocol requests and the number of deliveries per intervention cluster was 0 ∙ 71 (p = 0 ∙ 05).

Interpretation: The higher risk of institutional neonatal death observed in intervention clusters may be due to problems with birth and death registration, unmeasured and unadjusted confounding, and unintended use of the intervention. The findings underpin the need for careful and rigorous evaluation of mHealth intervention implementation and effects.

Funding: Netherlands Foundation for Scientific Research - WOTRO, Science for Global Development; Utrecht University.
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http://dx.doi.org/10.1016/j.eclinm.2019.05.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6677648PMC
July 2019

Effects of shared medical appointments compared to individual appointments in children with atopic dermatitis: A pragmatic randomized controlled trial.

Clin Exp Allergy 2019 08 17;49(8):1095-1106. Epub 2019 Jul 17.

Department of Dermatology and Allergology, University Medical Centre Utrecht, Utrecht, The Netherlands.

Background: Atopic dermatitis (AD) needs intensive treatment and has a negative impact on quality of life. Shared medical appointments (SMAs) showed to be effective in clinical outcomes of chronic diseases, but little is known about the effects on children and families.

Objective: To evaluate the effects of SMAs compared to individual appointments (IA) for children with AD and their parents on coping and clinical outcomes.

Methods: In a pragmatic randomized controlled trial, new patients in UMC Utrecht with AD, younger than 18 years, and their parents were assigned to the SMA group or the IA group using a covariate adaptive randomization method, controlled for age. Before the intervention, 2 months (primary time-point) and 6 months thereafter, we assessed parental emotional coping (primary outcome), quality of life, anxiety about corticosteroids and patient disease activity. Patients, parents and healthcare professionals could not be blinded to group assignment.

Results: Of 140 patients, enrolled in the trial, 69 patients were assigned to the SMA and 71 to the IA intervention of whom 114 completed the intervention (SMA: 49; IA: 65). After 2 months, there were no differences between SMAs and IAs in effects on emotional coping: b 0.66, 95% CI -0.7 to 2.03; P = 0.33 (mean difference: 0.30; 95% CI -1.56 to 2.16; N SMA: 11; IA: 24), quality of life, anxiety about corticosteroids and disease activity. From the initial appointment to long-term follow-up, both groups showed substantial improvements, but not significant in disease activity and significant reduction in anxiety about corticosteroids. This study is limited by a low response rate; therefore, linear mixed models and dropout analyses were performed. No serious adverse events were reported.

Conclusion And Clinical Relevance: For children with AD and their parents, there were no additional benefits of GMAs in parental emotional coping, anxiety about corticosteroids, quality of life and disease activity.

Trial Registration: www.ISRCTN.org, ISRCTN08506572.
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http://dx.doi.org/10.1111/cea.13416DOI Listing
August 2019

Trends in Risk of Limitations in Instrumental Activities of Daily Living Over Age in Older Persons With and Without Multiple Chronic Conditions.

J Gerontol A Biol Sci Med Sci 2020 01;75(1):197-203

Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht (UMC Utrecht).

Background: To investigate trends over age by comorbidity status for the risk of limitations in individual activities of daily living for community-living older persons.

Methods: A longitudinal population-based study was conducted in 9,319 community-living Dutch persons aged 60 years and older. Self-reported multiple chronic conditions (MCC) and nine instrumental activities of daily livings (IADLs) were assessed in 15 studies of the Dutch National Care for the Elderly Program (TOPICS-MDS). Risks of limitations in IADLs, odds ratios (per 5 years), and rate ratios (per 5 years) were calculated with mixed logistic and negative binomial regression models with age as the underlying timescale, stratified by number of MCC (no, 1-2, ≥ 3 MCC), and corrected for confounders.

Results: At inclusion, the number of IADL limitations was highest for the "≥3 MCC" group (2.00 interquartile range [1.00-4.00]) and equal for "no MCC" or "1-2 MCC" (1.00 interquartile range [0.00-2.00]). Trends of individual IADLs depicted a higher risk in IADL limitation with increasing age over 2 years of follow-up, except for handling finances for the "no MCC" group. The longitudinal age effect on IADL limitations varied subject to MCC, being strongest for the "no MCC" group for most IADLs; grooming and telephone use were almost unaltered by age and MCC.

Conclusion: We observed a decline in IADL functioning with increasing age over 2 years of follow-up in persons with and without MCC. The impact of MCC on IADL decline varied per IADL activity.
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http://dx.doi.org/10.1093/gerona/glz049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6909894PMC
January 2020

Concordance in Aneurysm Size at Time of Rupture in Familial Intracranial Aneurysms.

Stroke 2019 02;50(2):504-506

Brain Center Rudolf Magnus, Neurology and Neurosurgery, University Medical Center Utrecht, the Netherlands (E.M.H.S., L.M., A.A., G.J.E.R., Y.R.).

Background and Purpose- Intracranial aneurysm (IA) size and location are important determinants of aneurysm rupture risk. In familial IAs there is concordance of location; however, if such concordance exists for size is unknown. We analyzed the concordance of aneurysm size at time of rupture in familial IAs. Methods- In pairs of affected relatives with aneurysmal subarachnoid hemorrhage, the ratio between the largest and the smallest aneurysm size at time of rupture was calculated. We also compared the proportion of families in which both IAs ruptured at a size < or ≥7 mm with the proportion of families in which one IA ruptured at <7 mm and another ≥7 mm. We calculated the repeatability with corresponding 95% CI for aneurysm size at time of rupture. Results- About 130 patients from 64 families were included. Of the 68 affected pairs 18 (26%) had a ratio ≤1.2, 38 (57%) had a ratio >1.2, and 12 (17%) had a ratio ≥3. We found no difference between the proportion of families (n=31; 49%) who both had IA at time of rupture <7 mm (n=20; 31%) or both ≥7 mm (n=11; 18%) and the proportion of those families with one patient with an IA <7 mm and another with an IA ≥7 mm (n=33; 51%; P=0.86). Overall, the repeatability in aneurysm size at rupture within familial IAs was 0.10 (95% CI, 0-0.35). Conclusions- There is no good concordance in aneurysm size at rupture within familial IAs. These data suggest that size of a ruptured IA in a family member should not significantly impact on the management of a familial unruptured IA in a relative.
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http://dx.doi.org/10.1161/STROKEAHA.118.021911DOI Listing
February 2019

Efficacy of individual and group hypnotherapy in irritable bowel syndrome (IMAGINE): a multicentre randomised controlled trial.

Lancet Gastroenterol Hepatol 2019 Jan 23;4(1):20-31. Epub 2018 Nov 23.

Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht, Netherlands.

Background: Hypnotherapy for irritable bowel syndrome (IBS) has been used primarily in patients with refractory symptoms in specialised departments and delivered on an individual basis. We aimed to test the hypothesis that hypnotherapy would be more effective than educational supportive therapy, and that group hypnotherapy would be non-inferior to individual hypnotherapy for patients with IBS referred from primary and secondary care.

Methods: We did a multicentre randomised controlled trial (IMAGINE) in 11 hospitals in the Netherlands. Patients with IBS, aged 18-65 years, who were referred from primary or secondary care were randomly allocated (3:3:1) in blocks of six using a computer-based random number table procedure by staff not involved in the treatment to receive six sessions of individual or group hypnotherapy or group educational supportive therapy (control group). The primary outcome was adequate relief of IBS symptoms, with responders defined as patients who reported adequate relief when asked once weekly on three or four occasions in 4 consecutive weeks. We compared hypnotherapy (both groups) with control in the intention-to-treat population (excluding individuals subsequently found to be ineligible for enrolment), and assessed non-inferiority of group hypnotherapy versus individual hypnotherapy in the per-protocol population (with a non-inferiority margin of 15%) at 3 months and 12 months. This trial is registered with ISRCTN, number ISRCTN22888906, and is completed.

Findings: Between May 31, 2011, and April 6, 2016, 494 patients referred for psychological treatment for IBS were assessed for eligibility, of whom 354 were randomly allocated to the three groups: 150 to individual hypnotherapy, 150 to group hypnotherapy, and 54 to educational supportive therapy. After exclusion of individuals subsequently found to be ineligible for enrolment, 142 patients in the individual hypnotherapy group, 146 in the group hypnotherapy group, and 54 in the control group were included in the intention-to-treat population. Of these, 22 (15%) patients in the individual hypnotherapy group, 22 (15%) in the group hypnotherapy group, and 11 (20%) in the control group dropped out before or during therapy. In the intention-to-treat analysis, the adequate response rate was 40·8% (95% CI 31·7-50·5) in the individual hypnotherapy group, 33·2% (24·3-43·5) in the group hypnotherapy group, and 16·7% (7·6-32·6) in the control group at 3 months. At 12 months, 40·8% (31·3-51·1) of patients in the individual hypnotherapy group, 49·5% (38·8-60·0) of patients in the group hypnotherapy group, and 22.6% (11·5-39·5) of patients in the control group reported adequate relief. Hypnotherapy was more effective than control at 3 months (odds ratio 2·9, 95% CI 1·2-7·4, p=0·0240) and 12 months (2·8, 1·2-6·7, p=0·0185). In the per-protocol analysis, 49·9% (39·2-60·6) in the individual hypnotherapy group and 42·7% (32·3-53·8) in the group hypnotherapy group had adequate relief at 3 months, and 55·5% (43·4-67·1) of individual and 51·7% (40·2-63·0) of group hypnotherapy patients reported adequate relief at 12 months. Group hypnotherapy was therefore non-inferior to individual hypnotherapy. Eight unexpected serious adverse reactions (six in the individual hypnotherapy group and two in the group hypnotherapy group) were reported, most of which were cancer or inflammatory bowel disease, and were judged by the medical ethics committee as not being related to the therapy.

Interpretation: Hypnotherapy should be considered as a possible treatment for patients with IBS in primary and secondary care. Furthermore, group therapy could allow many more patients to be treated for the same cost.

Funding: None.
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http://dx.doi.org/10.1016/S2468-1253(18)30310-8DOI Listing
January 2019

Trajectories of Limitations in Instrumental Activities of Daily Living in Frail Older Adults With Vision, Hearing, or Dual Sensory Loss.

J Gerontol A Biol Sci Med Sci 2019 05;74(6):936-942

Julius Center for Health Sciences and Primary Care, University Medical Center (UMC) Utrecht.

Background: This study investigated the trajectories of decline in individual instrumental activities of daily living (IADL) with aging and the effect of hearing loss, vision loss, or dual sensory loss on these trajectories in community-living frail older persons.

Method: This longitudinal population-based study was conducted in 9,319 community-living frail Dutch persons aged 60 years and older. Self-reported hearing loss, vision loss, or dual sensory loss and nine IADL were assessed in 15 studies of the Dutch National Care for the Elderly Program (The Older Persons and Informal Caregivers Survey Minimum Dataset). Probabilities of limitations in IADL, odds ratios (per 5 years) for binary, and rate ratios (per 5 years) for score outcomes were calculated using mixed logistic and negative binomial models with age as the underlying timescale, stratified by sensory loss, and corrected for confounders.

Results: At baseline, the number of IADL limitations was higher in dual sensory loss (2.00 [interquartile range 1.00-4.00]) and vision loss (2.00 [interquartile range 1.00-4.00]) compared to no sensory loss (1.00 [interquartile range 0.00-2.00]) or hearing loss (1.00 [interquartile range 0.00-3.00]). Trajectories of individual IADL showed an increase in limitations in all IADL with age. Household tasks, traveling, shopping, preparing a meal, and walking showed the most rapid decline. Handling finances, traveling, and walking followed a different pattern of decline based on sensory loss status.

Conclusions: The age effect on limitations in IADL appears to be similar across all types of sensory loss, with the exception of handling finances, traveling, and walking. At baseline, persons with self-reported sensory loss had higher levels of self-reported functional limitations. Trajectories depict a decline in IADL competence with age.
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http://dx.doi.org/10.1093/gerona/gly155DOI Listing
May 2019

Effectiveness of general practitioner online training and an information booklet for parents on antibiotic prescribing for children with respiratory tract infection in primary care: a cluster randomized controlled trial.

J Antimicrob Chemother 2018 05;73(5):1416-1422

Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.

Objectives: Antibiotics are too often prescribed in childhood respiratory tract infection (RTI), despite limited effectiveness, potential side effects and bacterial resistance. We aimed to reduce antibiotic prescribing for children with RTI by online training for general practitioners (GPs) and information for parents.

Methods: A pragmatic cluster randomized controlled trial in primary care. The intervention consisted of online training for GPs and an information booklet for parents. The primary outcome was the antibiotic prescription rate for children presenting with RTI symptoms, as registered by GPs. Secondary outcomes were number of reconsultations within the same disease episode, consultations for new episodes, hospital referrals and pharmacy-dispensed antibiotic courses for children. This trial was registered at the Dutch Trial Register (NTR), registration number: NTR4240.

Results: After randomization, GPs from a total of 32 general practices registered 1009 consultations. An antibiotic was prescribed in 21% of consultations in the intervention group, compared with 33% in the usual care group, controlled for baseline prescribing (rate ratio 0.65, 95% CI 0.46-0.91). The probability of reconsulting during the same RTI episode did not differ significantly between the intervention and control groups, and nor did the numbers of consultations for new episodes and hospital referrals. In the intervention group antibiotic dispensing was 32 courses per 1000 children/year lower than the control group, adjusted for baseline prescribing (rate ratio 0.78, 95% CI 0.66-0.92). The numbers and proportion of second-choice antibiotics did not differ significantly.

Conclusions: Concise, feasible, online GP training, with an information booklet for parents, showed a relevant reduction in antibiotic prescribing for children with RTI.
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http://dx.doi.org/10.1093/jac/dkx542DOI Listing
May 2018

Prognostic value of circulating microRNAs on heart failure-related morbidity and mortality in two large diverse cohorts of general heart failure patients.

Eur J Heart Fail 2018 01 26;20(1):67-75. Epub 2017 Sep 26.

ACS Biomarker BV, Amsterdam, The Netherlands.

Aims: Small studies suggested circulating microRNAs (miRNAs) as biomarkers for heart failure (HF). However, standardized approaches and quality assessment for measuring circulating miRNAs are not uniformly established, and most studies have been small, so that results are inconsistent. We used a standardized data handling protocol, optimized for circulating miRNA qPCRs to remove noise and used it to assess which circulating miRNAs robustly add prognostic information in patients with HF.

Methods And Results: We measured 12 miRNAs in two independent cohorts totalling 2203 subjects. Cohort I (Barcelona) comprised 834 chronic HF patients. Cohort II (Detroit) comprised 1369 chronic HF patients. Each sample was measured in duplicate, and normalized to a very abundant and stable miRNA (miR-486-5p). We used a multistep algorithm to distinguish false amplification signals and thus classify each miRNA measurement as 'valid', 'undetectable' or 'invalid'. Higher levels of miR-1254 and miR-1306-5p were significantly associated with risk of the combined endpoint of all-cause mortality and HF hospitalization in both cohorts, with hazard ratios ranging from 1.11 to 1.21 per log increase (P-values 0.004 to 0.009). However, adding these miRNAs to established predictors (age, sex, haemoglobin, renal function, and NT-proBNP) did not further augment the c-statistic beyond 0.69 (cohort I) or 0.70 (cohort II).

Conclusion: We used a stringent quality assessment for miRNA testing, and were able to replicate the association of miR-1254 and miR-1306-5p with risk of death and HF hospitalization in HF patients of two independent cohorts. However, these two circulating miRNAs failed to improve prognostication over established predictors.
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http://dx.doi.org/10.1002/ejhf.984DOI Listing
January 2018

What determines treatment satisfaction of patients with type 2 diabetes on insulin therapy? An observational study in eight European countries.

BMJ Open 2017 Jul 11;7(7):e016180. Epub 2017 Jul 11.

Department of General Practice, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.

Objective: Patients with type 2 diabetes (T2DM) on insulin therapy are less satisfied with their diabetes treatment than those on oral hypoglycaemic therapies or lifestyle advice only. Determinants of satisfaction in patients with T2DM on insulin therapy are not clearly known. The aim of this study was to determine the association of treatment satisfaction with demographic and clinical characteristics of patients with T2DM.

Design: For this study we used data from the GUIDANCE (Guideline Adherence to Enhance Care) study, a cross-sectional study among 7597 patients with T2DM patients from Belgium, France, Germany, Ireland, Italy, Sweden, the Netherlands and the UK. The majority of patients were recruited from primary care. Treatment satisfaction was assessed by the Diabetes Treatment Satisfaction Questionnaire (DTSQ, score 0-36; higher scores reflecting higher satisfaction). To determine which patient characteristics and laboratory values were independently associated with treatment satisfaction, a linear mixed model analysis was used.

Participants: In total, 1984 patients on insulin were analysed; the number of included patients per country ranged from 166 (the Netherlands) to 384 (Italy).

Results: The mean DTSQ score was 28.50±7.52 and ranged from 25.93±6.57 (France) to 30.11±5.09 (the Netherlands). Higher DTSQ scores were associated with having received diabetes education (β 1.64, 95% CI 0.95 to 2.32), presence of macrovascular complications (β 0.76, 95% CI 0.21 to 1.31) and better health status (β 0.08 for every one unit increase on a 0-100 scale, 95% CI 0.07 to 0.10). Lower DTSQ scores were associated with more frequently perceived hyperglycaemia (β -0.32 for every 1 unit increase on a seven-point Likert scale, 95% CI -0.50 to -0.13), and higher glycated haemoglobin (β -0.52 for every percentage increase, 95% CI -0.75 to -0.29).

Conclusions: A number of factors including diabetes education, perceived and actual hyperglycaemia and macrovascular complications are associated with treatment satisfaction. Self-management education programmes should incorporate these factors for ongoing support in patients with T2DM.
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http://dx.doi.org/10.1136/bmjopen-2017-016180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5541515PMC
July 2017

Clinical Predictors of Future Nonadherence in Inflammatory Bowel Disease.

Inflamm Bowel Dis 2017 09;23(9):1568-1576

1Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, the Netherlands; 2Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands; 3Center for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, the Netherlands; 4Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, the Netherlands; 5Department of Gastroenterology and Hepatology (Co-MIK), Zuyderland Medical Center, Heerlen, Sittard, Geleen, the Netherlands; 6Department of Gastroenterology and Hepatology, Diaconessenhuis, Leiden, the Netherlands; 7Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, the Netherlands; 8Department of Gastroenterology and Hepatology, Onze Lieve Vrouwe Gasthuis, Amsterdam, the Netherlands; 9Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands; 10Department of Gastroenterology and Hepatology, Antonius Hospital, Nieuwegein, the Netherlands; 11Department of Gastroenterology and Hepatology, Slingeland Hospital, Doetinchem, the Netherlands; 12Department of Gastroenterology and Hepatology, Leiden University Medical Center, the Netherlands; 13Department of Gastroenterology and Hepatology, Maastricht University Medical Center, the Netherlands; 14Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, the Netherlands; 15Department of Gastroenterology and Hepatology, Meander Medical Center, Amersfoort, the Netherlands; and 16Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands.

Background: Nonadherence to medical therapy is frequently encountered in patients with inflammatory bowel disease (IBD). We aimed to identify predictors for future (non)adherence in IBD.

Methods: We conducted a multicenter prospective cohort study with adult patients with Crohn's disease (CD) and ulcerative colitis (UC). Data were collected by means of 3-monthly questionnaires on the course of disease and healthcare utilization. Medication adherence was assessed using a visual analogue scale, ranging from 0% to 100%. Levels <80% were considered to indicate nonadherence. The Brief Illness Perception Questionnaire was used to identify illness perceptions. We used a logistic regression analysis to identify patient- and disease-related factors predictive of nonadherence 3 months after the assessment of predictors.

Results: In total, 1558 patients with CD and 1054 patients with UC were included and followed for 2.5 years. On average, 12.1% of patients with CD and 13.3% of patients with UC using IBD-specific medication were nonadherent. Nonadherence was most frequently observed in patients using mesalazine (CD), budesonide (UC) and rectally administrated therapy (both CD and UC). A higher perceived treatment control and understanding of the disease were associated with adherence to medical therapy. Independent predictors of future nonadherence were age at diagnosis (odds ratio [OR]: 0.99 per year), nonadherence (OR: 26.91), a current flare (OR: 1.30) and feelings of anxiety/depression (OR: 1.17), together with an area under the receiver-operating-characteristics curve of 0.74.

Conclusions: Lower age at diagnosis, flares, feelings of anxiety or depression, and nonadherence are associated with future nonadherence in patients with IBD. Altering illness perceptions could be an approach to improve adherence behavior.
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http://dx.doi.org/10.1097/MIB.0000000000001201DOI Listing
September 2017

A computationally simple central monitoring procedure, effectively applied to empirical trial data with known fraud.

J Clin Epidemiol 2017 Jul 12;87:59-69. Epub 2017 Apr 12.

Julius Clinical Ltd., Broederplein 41-43, 3703 CD Zeist, The Netherlands; Julius Center for Health Sciences and Primary Care, UMC Utrecht, P.O. Box 85500, 3508 GA Utrecht, The Netherlands.

Objectives: Central monitoring of multicenter clinical trials becomes an ever more feasible quality assurance tool, in particular for the detection of data fabrication. More widespread application, across both industry sponsored as well as academic clinical trials, requires central monitoring methodologies that are both effective and relatively simple in implementation.

Study Design And Setting: We describe a computationally simple fraud detection procedure intended to be applied repeatedly and (semi-)automatically to accumulating baseline data and to detect data fabrication in multicenter trials as early as possible. The procedure is based on anticipated characteristics of fabricated data. It consists of seven analyses, each of which flags approximately 10% of the centers. Centers that are flagged three or more times are considered "potentially fraudulent" and require additional investigation. The procedure is illustrated using empirical trial data with known fraud.

Results: In the illustration data, the fraudulent center is detected in most repeated applications to the accumulating trial data, while keeping the proportion of false-positive results at sufficiently low levels.

Conclusion: The proposed procedure is computationally simple and appears to be effective in detecting center-level data fabrication. However, assessment of the procedure on independent trial data sets with known data fabrication is required.
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http://dx.doi.org/10.1016/j.jclinepi.2017.03.018DOI Listing
July 2017

Magnetic Resonance Imaging and Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage: A Systematic Review and Meta-Analysis.

Stroke 2017 01 6;48(1):239-245. Epub 2016 Dec 6.

From the Department of Radiology (L.A.v.d.K., J.B.D.V., J.H.), Julius Center for Health Sciences and Primary Care (N.P.A.Z.), and Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus (G.J.E.R., M.D.I.V.), University Medical Center Utrecht, The Netherlands; and Department of Neurology (J.M.O., L.C.) and Department of Radiology (C.C.), University of Toulouse, France.

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http://dx.doi.org/10.1161/STROKEAHA.116.011707DOI Listing
January 2017

Effectiveness of a Proactive Primary Care Program on Preserving Daily Functioning of Older People: A Cluster Randomized Controlled Trial.

J Am Geriatr Soc 2016 09 26;64(9):1779-88. Epub 2016 Jul 26.

Department of General Practice, Nursing Science and Sports Medicine, University Medical Center Utrecht, the Netherlands.

Objectives: To determine the effectiveness of a proactive primary care program on the daily functioning of older people in primary care.

Design: Single-blind, three-arm, cluster-randomized controlled trial with 1-year follow-up.

Setting: Primary care setting, 39 general practices in the Netherlands.

Participants: Community-dwelling people aged 60 and older (N = 3,092).

Interventions: A frailty screening intervention using routine electronic medical record data to identify older people at risk of adverse events followed by usual care from a general practitioner; after the screening intervention, a nurse-led care program consisting of a comprehensive geriatric assessment, evidence-based care planning, care coordination, and follow-up; usual care.

Measurements: Primary outcome was daily functioning measured using the Katz-15 (6 activities of daily living (ADLs), 8 instrumental activities of daily living (IADLs), one mobility item (range 0-15)); higher scores indicate greater dependence. Secondary outcomes included quality of life, primary care consultations, hospital admissions, emergency department visits, nursing home admissions, and mortality.

Results: The participants in both intervention arms had less decline in daily functioning than those in the usual care arm at 12 months (mean Katz-15 score: screening arm, 1.87, 95% confidence interval (CI) = 1.77-1.97; screening and nurse-led care arm, 1.88, 95% CI = 1.80-1.96; control group, 2.03, 95% CI = 1.92-2.13; P = .03). No differences in quality of life were observed.

Conclusion: Participants in both intervention groups had less decline than those in the control group at 1-year follow-up. Despite the statistically significant effect, the clinical relevance is uncertain at this point because of the small differences. Greater customizing of the intervention combined with prolonged follow-up may lead to more-robust results.
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http://dx.doi.org/10.1111/jgs.14325DOI Listing
September 2016

Client Factors Affect Provider Adherence to Clinical Guidelines during First Antenatal Care.

PLoS One 2016 20;11(6):e0157542. Epub 2016 Jun 20.

Research and Development Division, Ghana Health Service, Accra, Ghana.

Background: The first antenatal clinic (ANC) visit helps to distinguish pregnant women who require standard care, from those with specific problems and so require special attention. There are protocols to guide care providers to provide optimal care to women during ANC. Our objectives were to determine the level of provider adherence to first antenatal visit guidelines in the Safe Motherhood Protocol (SMP), and assess patient factors that determine complete provider adherence.

Methods: This cross-sectional study is part of a cohort study that recruited women who delivered in eleven health facilities and who had utilized antenatal care services during their pregnancy in the Greater Accra region of Ghana. A record review of the first antenatal visit of participants was carried out to assess the level of adherence to the SMP, using a thirteen-point checklist. Information on their socio-demographic characteristics and previous pregnancy history was collected using a questionnaire. Percentages of adherence levels and baseline characteristics were estimated and cluster-adjusted odds ratios (OR) calculated to identify determinants.

Results: A total of 948 women who had delivered in eleven public facilities were recruited with a mean age (SD) of 28.2 (5.4) years. Overall, complete adherence to guidelines pertained to only 48.1% of pregnant women. Providers were significantly more likely to completely adhere to guidelines when caring for multiparous women [OR = 5.43 (1.69-17.44), p<0.01] but less likely to do so when attending to women with history of previous pregnancy complications [OR = 0.50 (0.33-0.75), p<0.01].

Conclusion: Complete provider adherence to first antenatal visit guidelines is low across different facility types in the Greater Accra region of Ghana and is determined by parity and history of previous pregnancy complication. Providers should be trained and supported to adhere to the guidelines during provision of care to all pregnant women.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0157542PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4913935PMC
July 2017

The natural course of elevated levels of depressive symptoms in patients with vascular disease over eight years of follow-up. The SMART-Medea study.

J Affect Disord 2016 Sep 24;202:95-101. Epub 2016 May 24.

Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, The Netherlands. Electronic address:

Background: Patients with cardiovascular disease have an increased risk for depression, and depression predicts poor prognosis in these patients, but the long-term course of depression is not known. We studied the natural course of elevated levels of depressive symptoms in patients with cardiovascular disease over eight years follow-up.

Methods: Within the Second Manifestations of ARTerial disease - Memory, depression and aging (SMART-Medea) study, depressive symptoms were assessed with the Patient Health Questionnaire-9 (PHQ-9) in 690 patients (62±10 years) at baseline and bi-annually during 8 years follow-up. Natural course was described for symptom severity and course type (never, single episode, intermittent, and chronic) based on the cut-off point of ≥6 on the PHQ-9. Using multinomial regression analysis (reference: never depressed) we estimated age- and sex-adjusted odds ratios (OR) for the associations of demographic factors and vascular disease categories with course type.

Results: Of the 690 patients, 60% was never depressed, 10% had a single episode, 19% had an intermittent and 11% a chronic course of depression. Increased risk for chronic course was observed for women (OR=3.42; 95% CI=1.98-5.90), those with younger age (OR=3.20; 95% CI=1.73-5.94), and for patients with cerebrovascular disease when compared to patients with coronary artery disease (OR=2.50; 95% CI=1.31-4.78).

Limitations: No information was available on clinical diagnosed major depressive disorder and/or clinical events during follow-up.

Conclusions: In patients with cardiovascular disease, an intermittent or chronic course of elevated levels of depressive symptoms is very common. Patients with cardiovascular disease may require more careful clinical monitoring and management of depressive symptoms.
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http://dx.doi.org/10.1016/j.jad.2016.05.050DOI Listing
September 2016

Five-year efficacy of pulmonary vein antrum isolation as a primary ablation strategy for atrial fibrillation: a single-centre cohort study.

Europace 2016 Sep 2;18(9):1335-42. Epub 2016 Feb 2.

Division of Heart and Lungs, Department of Cardiology, University Medical Center Utrecht, Heidelberglaan 100, 3584CX Utrecht, The Netherlands

Aims: Pulmonary vein antrum isolation (PVAI) is the cornerstone of atrial fibrillation (AF) ablation. There is an ongoing discussion on whether and when to add substrate modification to PVAI. This study evaluates (1) long-term efficacy of PVAI as a primary ablation strategy in all patients independently from AF type and (2) predictors of arrhythmia recurrence.

Methods And Results: A total of 509 consecutive patients (mean age 57 years, 38.9% non-paroxysmal AF) with AF underwent PVAI. In redo procedures, ablation was restricted to re-pulmonary vein (PV) isolation in case of PV reconnection. If the PVs were found to be isolated, substrate modification was performed. In total, 774 procedures were performed. Mean follow-up duration after the first and last ablation was, respectively, 66 ± 23 and 55 ± 25 months. A single PVAI was sufficient in restoring and maintaining long-term sinus rhythm in 41.3% (n = 210) of patients. Multiple procedures (mean 1.5) with re-PV isolation increased long-term success to 58.3% (n = 297). Additional substrate modification (n = 70) increased success to 62.5% (n = 318). After the last ablation, 87.5% of patients experienced success or significant clinical improvement on or off antiarrhythmic drugs. The incidence of left-sided atrial flutter or atrial tachycardia was 5% after PVAI and increased to 32% after additional substrate modification. Independent predictors for arrhythmia recurrence after the last ablation were non-paroxysmal AF, female sex, body mass index, hypertension, and AF duration.

Conclusion: Five-year freedom of atrial tachyarrhythmia could be achieved by PVAI as primary ablation strategy in 58.3% of patients. Additional substrate modification only moderately increased overall success.
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http://dx.doi.org/10.1093/europace/euv439DOI Listing
September 2016

No Added Value of Novel Biomarkers in the Diagnostic Assessment of Patients Suspected of Acute Coronary Syndrome.

PLoS One 2015 15;10(7):e0132000. Epub 2015 Jul 15.

Julius Center for Health Sciences and Primary Care, University Medical Center, Universiteitsweg 100, 3584 CG, Utrecht, the Netherlands.

Background: Despite the availability of high-sensitive troponin (hs-cTnT), there is still room for improvement in the diagnostic assessment of patients suspected of acute coronary syndrome (ACS). Apart from serial biomarker testing, which is time-consuming, novel biomarkers like copeptin have been proposed to expedite the early diagnosis of suspected ACS in addition to hs-cTnT. We determined whether placenta derived growth factor (PlGF), soluble Fms-like tyrosine kinase 1 (sFlt-1), myoglobin, N-terminal prohormone B-type Natriuretic Peptide (NT-proBNP), growth-differentiation factor 15 (GDF-15) and copeptin improved early assessment of chest pain patients.

Methods: This prospective, single centre diagnostic FAME-ER study included patients presenting to the ED with symptoms suggestive of ACS. Blood was collected to measure biomarkers, notably, hs-cTnT was retrospectively assessed. Added value of markers was judged by increase in AUC using multivariable logistic regression.

Results: Of 453 patients enrolled, 149 (33%) received a final diagnosis of ACS. Hs-cTnT had the highest diagnostic value in both univariable and multivariable analysis. PPVs of the biomarkers ranged from 23.5% (PlGF) to 77.9% (hs-cTnT), NPVs from 67.0% (PlGF) to 86.4% (hs-cTnT). Only myoglobin yielded diagnostic value in addition to clinical symptoms and electrocardiography (ECG) (AUC of clinical model 0.80) with AUC of 0.84 (p<0.001). However, addition of hs-cTnT was superior (AUC 0.89, p<0.001). Addition of the biomarkers to our clinical model and hs-cTnT did not or only marginally (GDF-15) improved diagnostic performance.

Conclusion: When assessing patients suspected of ACS, only myoglobin had added diagnostic value beyond clinical symptoms and ECG. However, when combined with hs-cTnT, it yields no additional diagnostic value. PlGF, sFlt-1, NT-proBNP, GDF-15 and copeptin had no added value to the clinical model or hs-cTnT.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0132000PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4503345PMC
April 2016