Radboud Institute for Health science

Nijmegen, Netherlands

Radboud Institute for Health science

Nijmegen, Netherlands
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Hanskamp-Sebregts M.,Instituut voor Kwaliteit en Veiligheid | Zegers M.,Instituut voor Kwaliteit en Veiligheid | Van Gurp P.J.,Radboud Institute for Health science | De Veten Hub Wollersheim H.C.W.,EMGO Instituut voor Onderzoek naar Gezondheid en Zorg EMGO
Nederlands Tijdschrift voor Geneeskunde | Year: 2017

Objectives: Record review is the most used method to quantify patient safety. We systematically reviewed the reliability and validity of adverse event detection with record review. Design: A systematic review of the literature. Methods: We searched PubMed, EMBASE, CINAHL, PsycINFO and the Cochrane Library and from their inception through February 2015. We included all studies that aimed to describe the reliability and/or validity of record review. Two reviewers conducted data extraction. We pooled κ values (κ) and analysed the differences in subgroups according to number of reviewers, reviewer experience and training level, adjusted for the prevalence of adverse events. Results: In 25 studies, the psychometric data of the Global Trigger Tool (GTT) and the Harvard Medical Practice Study (HMPS) were reported and 24 studies were included for statistical pooling. The inter-raterreliability of the GTT and HMPS showed a pooled κ of 0.65 and 0.55, respectively. The inter-rater agreement was statistically significantly higher when the group of reviewers within a study consisted of a maximum five reviewers. We found no studies reporting on the validity of the GTT and HMPS. Conclusions: The reliability of record review is moderate to substantial and improved when a small group of reviewers carried out record review. The validity of the record review method has never been evaluated, while clinical data registries, autopsy or direct observations of patient care are methods that can be used to test concurrent validity.

Lempers V.J.C.,Radboud University Nijmegen | Lempers V.J.C.,Radboud Institute for Health science | Martial L.C.,Radboud University Nijmegen | Martial L.C.,Radboud Institute for Health science | And 9 more authors.
Current Opinion in Pharmacology | Year: 2015

The management of drug-drug interactions (DDIs) between azole antifungals (fluconazole, itraconazole, posaconazole and voriconazole) and immunosuppressants (cyclosporine, tacrolimus, everolimus and sirolimus) in transplant patients remains challenging, as the impact of altered immunosuppressant concentrations puts the patient at high risk for either toxicity or transplant rejection. As a result, it is a complex task for the clinician to maintain immunosuppressant concentrations within the desired therapeutic range and this requires a highly individualized patient approach. We provide important tools for adequate assessment of the drug interactions that cause this pharmacokinetic variability of immunosuppressants. A stepwise approach for the evaluation and subsequent management options, including a decision flow chart, are provided for optimal handling of these clinically relevant DDIs. © 2015 Elsevier Ltd.

Tanniou J.,Julius Center for Health science and Primary Care | van der Tweel I.,Julius Center for Health science and Primary Care | Teerenstra S.,Radboud Institute for Health science | Roes K.C.,Julius Center for Health science and Primary Care
Pharmaceutical Statistics | Year: 2017

In drug development, it sometimes occurs that a new drug does not demonstrate effectiveness for the full study population but appears to be beneficial in a relevant subgroup. In case the subgroup of interest was not part of a confirmatory testing strategy, the inflation of the overall type I error is substantial and therefore such a subgroup analysis finding can only be seen as exploratory at best. To support such exploratory findings, an appropriate replication of the subgroup finding should be undertaken in a new trial. We should, however, be reasonably confident in the observed treatment effect size to be able to use this estimate in a replication trial in the subpopulation of interest. We were therefore interested in evaluating the bias of the estimate of the subgroup treatment effect, after selection based on significance for the subgroup in an overall "failed" trial. Different scenarios, involving continuous as well as dichotomous outcomes, were investigated via simulation studies. It is shown that the bias associated with subgroup findings in overall nonsignificant clinical trials is on average large and varies substantially across plausible scenarios. This renders the subgroup treatment estimate from the original trial of limited value to design the replication trial. An empirical Bayesian shrinkage method is suggested to minimize this overestimation. The proposed estimator appears to offer either a good or a conservative correction to the observed subgroup treatment effect hence provides a more reliable subgroup treatment effect estimate for adequate planning of future studies. Copyright © 2017 John Wiley & Sons, Ltd.

Smits M.,Radboud Institute for Health science | Hanssen S.,Radboud Institute for Health science | Huibers L.,Radboud Institute for Health science | Giesen P.,University of Aarhus
Nederlands Tijdschrift voor Geneeskunde | Year: 2016

Objective To assess the organisation and appropriateness of telephone triage in general practices in the Netherlands. Design Cross-sectional observational study. Methods Via email we invited all members of the Dutch Association of practice assistants to complete an online survey. The questionnaire included questions about practice assistants' background characteristics and the practices' triage organisation. Furthermore, they were asked to assess the indicated type of care for a number of fictive case scenarios involving a variety of health problems and levels of urgency. To determine the appropriateness of the respondents' assessments, each was compared to a reference standard agreed by experts. In addition, the association between practice assistants' background characteristics and organizational setup of the triage organisation with the appropriateness of triage was examined. Results The response rate was 41.1% (N=973). The required care was assessed appropriately in 63.6% of the cases, overestimated in 19.3% and underestimated in 17.1% of cases. The sensitivity of identifying patients with a highly urgent problem was 76.7%, whereas the specificity was 94.0%. The appropriateness of the assessments of the required care was higher for more experienced assistants and assistants with regular daily work meetings with the GP. Triage training, use of a triage tool and authorization of advice provision were not associated with appropriateness of triage. Conclusion Triage by practice assistants in general practices is efficient, but potentially unsafe in highly urgent cases. It is therefore important to train practice assistants in the identification of highly urgent cases.

PubMed | Radboud Institute for Molecular Life science, Montpellier University, Grupo de Investigacion en Biomedicina Molecular, Donders Institute for Brain and 2 more.
Type: | Journal: Molecular therapy. Nucleic acids | Year: 2017

Usher syndrome (USH) is the most common cause of combined deaf-blindness in man. The hearing loss can be partly compensated by providing patients with hearing aids or cochlear implants, but the loss of vision is currently untreatable. In general, mutations in the USH2A gene are the most frequent cause of USH explaining up to 50% of all patients worldwide. The first deep-intronic mutation in the USH2A gene (c.7595-2144A>G) was reported in 2012, leading to the insertion of a pseudoexon (PE40) into the mature USH2A transcript. When translated, this PE40-containing transcript is predicted to result in a truncated non-functional USH2A protein. In this study, we explored the potential of antisense oligonucleotides (AONs) to prevent aberrant splicing of USH2A pre-mRNA as a consequence of the c.7595-2144A>G mutation. Engineered 2-O-methylphosphorothioate AONs targeting the PE40 splice acceptor site and/or exonic splice enhancer regions displayed significant splice correction potential in both patient derived fibroblasts and a minigene splice assay for USH2A c.7595-2144A>G, whereas a non-binding sense oligonucleotide had no effect on splicing. Altogether, AON-based splice correction could be a promising approach for the development of a future treatment for USH2A-associated retinitis pigmentosa caused by the deep-intronic c.7595-2144A>G mutation.

Ezinga M.,Radboud University Nijmegen | Ezinga M.,Radboud Institute for Health science | Wetzels J.F.M.,Radboud University Nijmegen | Bosch M.E.W.,Radboud University Nijmegen | And 4 more authors.
Antiviral Therapy | Year: 2014

Background: Monitoring of side effects of long-term HIV treatment has become increasingly important. Tenofovir disoproxil fumarate (TDF), a first-line treatment option, is associated with kidney tubular dysfunction (KTD). Our objective was to further investigate the prevalence and risk factors of KTD, in particular its association with TDF plasma concentration in HIV-infected patients treated with TDF for at least one year. Methods: An observational cross-sectional single-centre study was conducted. KTD was defined as the presence of at least two of the following criteria: urinary α1-microglobulin/creatinine ratio >15 mg/10 mmol; fractional excretion (FE) of phosphate >20% in the presence of hypophosphataemia; FE of uric acid >10% in the presence of hypouricaemia and glucosuria. Multivariate logistic regression was used to study which variable was associated with KTD. Results: A total of 161 HIV patients were included. Abnormalities in tubular function were observed in 101 patients (62.7%), while 17 patients (10.6%) fulfilled the definition of KTD. Urinary α1-microglobulin/creatinine ratio was the most sensitive parameter to detect KTD. Multivariate logistic regression showed TDF plasma concentration to be the only variable associated with KTD. Post hoc analysis showed a stronger association between the product of TDF plasma concentration and TDF exposure and KTD. Conclusions: Parameters of KTD are frequently observed in patients on long-term TDF-containing combination antiretroviral therapy. KTD is associated with higher TDF plasma concentrations. A stronger association between the product of TDF plasma concentration and TDF exposure and KTD could suggest cumulative toxicity. A causative role for elevated TDF plasma concentration in development of KTD cannot be demonstrated in this cross-sectional analysis. Longitudinal research is needed to investigate the development and clinical relevance of KTD. ©2014 International Medical Press

Van Kempen J.A.L.,Radboud University Nijmegen | Melis R.J.F.,Radboud University Nijmegen | Perry M.,Radboud University Nijmegen | Schers H.J.,Radboud Institute for Health science | Olde Rikkert M.G.M.,Radboud University Nijmegen
Journal of the American Board of Family Medicine | Year: 2015

Background: To compare the outcomes of Comprehensive Geriatric Assessments by family physicians and geriatricians. Methods: An explorative observational study was conducted in six family practices (12 ambulatory family practitioners) and 1 geriatric department (4 hospital-based geriatricians) from a university medical center in Nijmegen (the Netherlands). As participants, we included 587 patients aged 70 years and older and registered in the six family practices. The main outcome measures were the judgment on the following: 1) absence or presence of frailty and 2) the state (good-fair-poor) on 8 underlying domains (physical, medication, cognition, sensory, instrumental activities of daily living scale, mobility, mental, and social) according to family practitioners and geriatricians based on a Comprehensive Geriatric Assessment. Results: Family physicians and geriatricians agreed on frailty absence/presence in 76% of cases. Geriatricians considered elderly more often frail than family physicians did (n = 294, 50% vs n = 213, 36%). Disagreement on frailty status was notably found in the patients who had less distinct, either poor or good, health states. Discordant frailty judgments, in which the geriatrician rated a person as frail and the family physicians did not, were related to geriatricians more often rating physical health as impaired. Further, geriatricians' judgments of frailty were more strongly related to impaired scores on the domains cognition, sensory, mobility, and mental compared with family physicians judgments: odds ratios 79.3 versus 9.3, 7.6 versus 2.0, 25.0 versus 3.0, and 18.0 versus 2.2, respectively. Impaired physical health and problematic medication use had equally strong associations with frailty in geriatricians and family physicians: odds ratios of 11.5 versus 10.4 and 2.4 versus 2.5, respectively. Conclusions: Geriatricians more often judge patients as frail compared with family physicians and seem to evaluate the available information differently. With increasing collaboration between primary and secondary care, understanding these differences becomes increasingly relevant. © 2015, American Board of Family Medicine. All rights reserved.

Bruggemann R.J.M.,Radboud University Nijmegen | Bruggemann R.J.M.,Radboud Institute for Health science | Aarnoutse R.E.,Radboud University Nijmegen | Aarnoutse R.E.,Radboud Institute for Health science
Current Fungal Infection Reports | Year: 2015

Therapeutic drug monitoring (TDM) involves the measurement of plasma or serum drug concentration to adapt dosages to achieve predefined target concentrations that are associated with optimal clinical response while minimizing the chance of encountering toxicity. Many papers in the field of antifungal drugs have focused on the evidence that supports the use of TDMthereby emphasizing the breakpoints or target concentrations in general literature. This review focuses on the process of TDM to inform health care workers on the fundaments and prerequisites that safeguard the good application of TDM. Knowledge on the complete process of TDMincluding pharmacokinetics (and relevant covariates), pharmacodynamic aspects, trials that are necessary to provide uswith evidence, translation of knowledge to other populations and pathogens, and implications for the pre-analytical, analytical, and postanalytical phases (the process of TDM) are discussed in relevant detail. For each individual step, recommendations are made for the readers. We believe this will be a valuable resource and to be of added value to the many papers that focus on relations between exposure and efficacy or toxicity. It will help to achieve greater benefit of TDM. © The Author(s) 2015.

Lempers V.J.,Radboud University Nijmegen | Lempers V.J.,Radboud Institute for Health science | Bruggemann R.J.,Radboud University Nijmegen | Bruggemann R.J.,Radboud Institute for Health science
Journal of Antimicrobial Chemotherapy | Year: 2016

The Information Age has revolutionized the ability of healthcare professionals (HCPs) to oversee a substantial body of clinically relevant information literally at one's fingertips. In the field of clinical pharmacology, this may be particularly useful for managing drug-drug interactions (DDIs). A thorough understanding of the underlying mechanisms of DDIs allows the HCP to predict such interactions and avoid those of greatest clinical significance. Specifically, successful treatment with antifungal agents is complicated by the high potential to interact with other concomitant medications. We describe here the development of a real-time knowledge base of DDIs with antifungal agents, providing expert recommendations to HCPs on how to handle DDIs with these drugs. This new resource will facilitate rapid identification, quantification and classification of these DDIs by clinicians with varying levels of experience and resources worldwide, ultimately improving patient safety and strengthening health systems. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.

Van De Loo K.F.E.,Radboudumc Amalia Childrens Hospital | Van Gelder M.H.J.,Radboud Institute for Health science | Roukema J.,Radboudumc Amalia Childrens Hospital | Roeleveld N.,Radboud Institute for Health science | And 3 more authors.
European Respiratory Journal | Year: 2016

The aim of this study was to systematically review and meta-analyse observational studies on prenatal maternal psychological stress and the subsequent development of asthma and wheezing in early childhood. All available published literature from 1960 until November 2013 was systematically searched through electronic databases (PubMed, Embase, PsycInfo and Web of Science). All observational studies assessing associations between any form of prenatal maternal psychological stress and respiratory morbidity in the child were included. Data extraction, quality assessment and meta-analyses were performed. The overall meta-analysis included 10 studies and showed that the prevalence of wheezing, asthma and other respiratory symptoms is higher in children of mothers who were exposed to or experienced some form of psychological stress during pregnancy than in mothers who did not (pooled OR 1.56 (95% CI 1.36-1.80)). Comparable results were observed in subgroup analyses of stress exposure, perceived stress, asthma and wheezing. This study demonstrates that prenatal maternal psychological stress is associated with respiratory morbidity, including asthma and wheezing in the child. Future studies examining the early origins of asthma and wheezing need to account for the impact of prenatal maternal stress. © ERS 2016.

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