Publications by authors named "Willem J G Melchers"

225 Publications

Commercialized Blood-, Urinary- and Tissue-Based Biomarker Tests for Prostate Cancer Diagnosis and Prognosis.

Cancers (Basel) 2020 Dec 16;12(12). Epub 2020 Dec 16.

Department of Urology, Radboud University Medical Centre, 6525 GA Nijmegen, The Netherlands.

In the diagnosis and prognosis of prostate cancer (PCa), the serum prostate-specific antigen test is widely used but is associated with low specificity. Therefore, blood-, urinary- and tissue-based biomarker tests have been developed, intended to be used in the diagnostic and prognostic setting of PCa. This review provides an overview of commercially available biomarker tests developed to be used in several clinical stages of PCa management. In the diagnostic setting, the following tests can help selecting the right patients for initial and/or repeat biopsy: PHI, 4K, MiPS, SelectMDx, ExoDx, Proclarix, ConfirmMDx, PCA3 and PCMT. In the prognostic setting, the Prolaris, OncotypeDx and Decipher test can help in risk-stratification of patients regarding treatment decisions. Following, an overview is provided of the studies available comparing the performance of biomarker tests. However, only a small number of recently published head-to-head comparison studies are available. In contrast, recent research has focused on the use of biomarker tests in relation to the (complementary) use of multiparametric magnetic resonance imaging in PCa diagnosis.
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http://dx.doi.org/10.3390/cancers12123790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765473PMC
December 2020

Gene Mutation Prevalence in Triazole-Resistant Clinical Isolates.

J Fungi (Basel) 2020 Oct 16;6(4). Epub 2020 Oct 16.

Department of Microbiology, Immunology and Transplantation, Laboratory of Clinical Bacteriology and Mycology, KU Leuven, 3000 Leuven, Belgium.

Recently, mutations in the -encoding gene (), a gene involved in ergosterol production, were associated with triazole-resistance in . In this study, we determined the prevalence and characteristics of mutations in a collection of clinical triazole-resistant isolates collected during 2001-2019 from two international mycology reference centers: the Belgian National Reference Center for Mycosis and the Center of Expertise in Mycology Radboudumc/CWZ. Clinical isolates with and without gene mutations and randomly selected wild-type (WT) controls were included. Isolates were characterized by in vitro susceptibility testing, and sequencing, and short tandem repeat typing. Available clinical records were analyzed for previous triazole exposure. In 23 isolates (24%) of the 95 triazole-resistant isolates, gene mutations were observed; including 5/23 (22%) isolates without gene mutations and 18/72 (25%) with mutations. Four previously described gene mutations (E105K, G307R/D, G466V, and S541G) and two novel mutations (W273S and L304P) were found; 4/23 (17%) in the sterol-sensing-domain region. No triazole-antifungal exposure was reported in 75% (9/12) of patients harboring an isolate with gene mutations. Three of 39 WT isolates (8%) contained a gene mutation; E105K (2-isolates) and S541G. gene mutations were predominantly found in with mutations with voriconazole MICs ≥ 8 mg/L.
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http://dx.doi.org/10.3390/jof6040227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711918PMC
October 2020

Benefit and burden in the Dutch cytology-based vs high-risk human papillomavirus-based cervical cancer screening program.

Am J Obstet Gynecol 2021 02 13;224(2):200.e1-200.e9. Epub 2020 Aug 13.

Department of Obstetrics and Gynaecology, Catharina Hospital, Eindhoven, the Netherlands; Department of Obstetrics and Gynaecology, GROW, School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands.

Background: In 2017, the Dutch cervical cancer screening program had replaced the primary cytology-based screening with primary high-risk human papillomavirus-based screening, including the opportunity to participate through self-sampling. Evaluation and balancing benefit (detection of high-grade cervical intraepithelial neoplasia) and burden of screening (unnecessary referrals, invasive diagnostics, and overtreatment) is needed.

Objective: This study aimed to compare the referral rates, detection of high-grade cervical intraepithelial neoplasia, overdiagnosis, and overtreatment in the new high-risk human papillomavirus-based screening program, including physician-sampled and self-sampled material, with the previous cytology-based screening program in the Netherlands.

Study Design: A retrospective cohort study was conducted within the Dutch population-based cervical cancer screening program. Screenees with referrals for colposcopy between 2014 and 2015 (cytology-based screening) and 2017 and 2018 (high-risk human papillomavirus-based screening) were included. Data were retrieved from the Dutch Pathology Registry (PALGA) and compared between the 2 screening programs. The main outcome measures were referral rate, detection of high-grade cervical intraepithelial neoplasia or worse, overdiagnosis (cervical intraepithelial neoplasia grade 1 or less in the histologic specimen), and overtreatment (cervical intraepithelial neoplasia grade 1 or less in the treatment specimen).

Results: Of the women included in the study, 19,109 received cytology-based screening, and 26,171 received high-risk human papillomavirus-based screening. Referral rates increased from 2.5% in cytology-based screening to 4.2% in high-risk human papillomavirus-based screening (+70.2%). Detection rates increased to 46.2% for cervical intraepithelial neoplasia grade 2 or worse, 32.2% for cervical intraepithelial neoplasia grade 3 or worse, and 31.0% for cervical cancer, and overdiagnosis increased to 143.4% with high-risk human papillomavirus-based screening. Overtreatment rates were similar in both screening periods. The positive predictive value of referral for detection of cervical intraepithelial neoplasia grade 2 or worse in high-risk human papillomavirus-based screening was 34.6% compared with 40.2% in cytology-based screening. Women screened through self-sampling were at higher risk of cervical intraepithelial neoplasia grade 2 or worse detection (odds ratio, 1.38; 95% confidence interval, 1.20-1.59) and receiving treatment (odds ratio, 1.31; 95% confidence interval, 1.16-1.48) than those screened through physician-sampling.

Conclusion: Compared with cytology-based screening, high-risk human papillomavirus-based screening increases detection of high-grade cervical intraepithelial neoplasia, with 462 more cervical intraepithelial neoplasia grade 2 or worse cases per 100,000 women but at the expense of 850 more cases per 100,000 women with invasive diagnostics indicating cervical intraepithelial neoplasia grade 1 or less.
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http://dx.doi.org/10.1016/j.ajog.2020.08.026DOI Listing
February 2021

Rapid, random-access, and quantification of hepatitis B virus using the Cepheid Xpert HBV viral load assay.

J Med Virol 2020 Aug 6. Epub 2020 Aug 6.

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

Background: Monitoring viral load (VL) is an essential part of the management of patients chronically infected with hepatitis B virus (HBV). The commercial HBV VL assays currently available are generally performed on high-throughput platforms for batch wise testing of plasma samples, with relatively long turn-around-times. Rapid VL testing could provide immediate input to clinical decision making.

Methods: One hundred two stored plasma samples from 102 patients who were previously tested for HBV VL by the Cobas Ampliprep/Taqman or Cobas 4800 (Roche, Pleasanton, CA), were analyzed by the recently introduced Cepheid Xpert HBV Viral Load Assay. Thirty-one of the 102 samples were negative for HBV DNA and 71 out of 102 samples had a detectable VL. HBV DNA loads ranged from <20 to 5E8 IU/mL. HBV genotypes (A, B, C, D, E, and G) were known for 52 of the VL positive samples. Correlation of VL results between both assays was determined by the Pearson correlation coefficient (r ). The level of concordance was assessed using the Bland-Altman analysis.

Results: HBV VLs correlated well between both assays, across all genotypes (Pearson correlation coefficient r  = 0.987). Six samples exceeded a 0.5  log difference between assays. Bland-Altman analysis demonstrated a mean of the difference of -0.107 log and a standard deviation of 0.271 log.

Conclusion: High correlation was observed between the Roche Cobas HBV Viral Load tests and the Xpert HBV Viral Load Assay, thus enabling rapid, random access, and accurate HBV VL assessment.
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http://dx.doi.org/10.1002/jmv.26392DOI Listing
August 2020

Paradoxal Trends in Azole-Resistant Aspergillus fumigatus in a National Multicenter Surveillance Program, the Netherlands, 2013-2018.

Emerg Infect Dis 2020 07;26(7):1447-1455

We investigated the prevalence of azole resistance of Aspergillus fumigatus isolates in the Netherlands by screening clinical A. fumigatus isolates for azole resistance during 2013-2018. We analyzed azole-resistant isolates phenotypically by in vitro susceptibility testing and for the presence of resistance mutations in the Cyp51A gene. Over the 6-year period, 508 (11%) of 4,496 culture-positive patients harbored an azole-resistant isolate. Resistance frequency increased from 7.6% (95% CI 5.9%-9.8%) in 2013 (58/760 patients) to 14.7% (95% CI 12.3%-17.4%) in 2018 (112/764 patients) (p = 0.0001). TR/L98H (69%) and TR/Y121F/T289A (17%) accounted for 86% of Cyp51A mutations. However, the mean voriconazole MIC of TR/L98H isolates decreased from 8 mg/L (2013) to 2 mg/L (2018), and the voriconazole-resistance frequency was 34% lower in 2018 than in 2013 (p = 0.0001). Our survey showed changing azole phenotypes in TR/L98H isolates, which hampers the use of current PCR-based resistance tests.
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http://dx.doi.org/10.3201/eid2607.200088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7323544PMC
July 2020

Evaluation of a New Culture Protocol for Enhancing Fungal Detection Rates in Respiratory Samples of Cystic Fibrosis Patients.

J Fungi (Basel) 2020 Jun 9;6(2). Epub 2020 Jun 9.

Department of Medical Microbiology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.

Cystic fibrosis (CF) can be complicated by fungal infection of the respiratory tract. Fungal detection rates in CF sputa are highly dependent on the culture protocol and incubation conditions and thus may lead to an underestimation of the true prevalence of fungal colonization. We conducted a prospective study to evaluate the additional value of mucolytic pre-treatment, increased inoculum (100 µL), additional fungal culture media (Sabouraud agar; SAB, Medium B+, selective agar; SceSel+ and Dichloran-Glycerol agar; DG18) and longer incubation time (3 weeks) compared with our current protocol. Using the new protocol, we prospectively analyzed 216 expectorated sputum samples from adult and pediatric CF patients ( = 77) and compared the culture yield to a three year retrospective cohort that used direct 10 µL loop inoculation on SAB with 5 days incubation (867 sputum samples/103 patients). Detection rates for molds increased from 42% to 76% ( < 0.0001). Twenty-six percent of cultures were polymicrobial in the prospective cohort as opposed to 4.7% in the retrospective cohort ( < 0.0001). Colonization rate with increased from 36% to 57%. SAB and DG18 showed the highest detection rates for all molds (SAB 58.6%; DG18 56.9%) and DG18 had the best performance for molds other than . The larger sample volume and longer incubation also contributed to the increased recovery of molds. The introduction of a modified fungal culture protocol leads to a major increase in detection rate and the diversity of molds, which influences fungal epidemiology and may have implications for treatment decisions.
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http://dx.doi.org/10.3390/jof6020082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7345163PMC
June 2020

Antifungal Activity of Antimicrobial Peptides and Proteins against .

J Fungi (Basel) 2020 May 18;6(2). Epub 2020 May 18.

Aberdeen Fungal Group, Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, UK.

Antimicrobial peptides and proteins (AMPs) provide an important line of defence against invading microorganisms. However, the activity of AMPs against the human fungal pathogen remains poorly understood. Therefore, the aim of this study was to characterise the anti- activity of specific human AMPs, and to determine whether can possess resistance to specific AMPs, as a result of in-host adaptation. AMPs were tested against a wide range of clinical isolates of various origins (including cystic fibrosis patients, as well as patients with chronic and acute aspergillosis). We also tested a series of isogenic isolates obtained from a single patient over a period of 2 years. A range of environmental isolates, obtained from soil in Scotland, was also included. Firstly, the activity of specific peptides was assessed against hyphae using a measure of fungal metabolic activity. Secondly, the activity of specific peptides was assessed against germinating conidia, using imaging flow cytometry as a measure of hyphal growth. We showed that lysozyme and histones inhibited hyphal metabolic activity in all the isolates tested in a dose-dependent fashion. In addition, imaging flow cytometry revealed that histones, β-defensin-1 and lactoferrin inhibited the germination of conidia.
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http://dx.doi.org/10.3390/jof6020065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7345740PMC
May 2020

Multicenter Evaluation of QIAstat-Dx Respiratory Panel V2 for Detection of Viral and Bacterial Respiratory Pathogens.

J Clin Microbiol 2020 05 26;58(6). Epub 2020 May 26.

Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands

QIAstat-Dx Respiratory Panel V2 (RP) is a novel molecular-method-based syndromic test for the simultaneous and rapid (∼70-min) detection of 18 viral and 3 bacterial pathogens causing respiratory infections. This report describes the first multicenter retrospective comparison of the performance of the QIAstat-Dx RP assay to the established ePlex Respiratory Pathogen Panel (RPP) assay, for which we used 287 respiratory samples from patients suspected with respiratory infections. The QIAstat-Dx RP assay detected 312 (92%) of the 338 respiratory targets that were detected by the ePlex RPP assay. Most of the discrepant results have been observed in the low-pathogen-load samples. In addition, the QIAstat-Dx RP assay detected 19 additional targets in 19 respiratory samples that were not detected by the ePlex RPP assay. Nine of these discordant targets were considered to represent true positives after discrepancy testing by a third method. The main advantage of the QIAstat-Dx system compared to other syndromic testing systems, including the ePlex RPP assay, is the ability to generate cycle threshold ( ) values, which could help with the interpretation of results. Taking the data together, this study showed good performance of the QIAstat-Dx RP assay in comparison to the ePlex RPP assay for the detection of respiratory pathogens. The QIAstat-Dx RP assay offers a new, rapid, and accurate sample-to-answer multiplex panel for the detection of the most common viral and bacterial respiratory pathogens and therefore has the potential to direct appropriate therapy and infection control precautions.
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http://dx.doi.org/10.1128/JCM.01793-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269373PMC
May 2020

Tumor control of cervical lymph node metastases of unknown primary origin: the impact of the radiotherapy target volume.

Eur Arch Otorhinolaryngol 2020 Jun 25;277(6):1753-1761. Epub 2020 Feb 25.

Department of Otorhinolaryngology and Head and Neck Surgery, Radboud University Medical Center Nijmegen, Geert Grooteplein-Zuid 22, 6525 GA, Nijmegen, The Netherlands.

Purpose: Debate on the extent of treatment of neck metastasis of cancer of unknown primary tumors (CUPs) is still ongoing. In two Dutch tertiary referral centers, the post-surgical radiation target volume changed from the bilateral neck including the pharyngeal axis to the unilateral neck only, in the course of the last decade. This study aims to investigate the outcome of patients with CUP before and after de-escalation of post-surgical radiotherapy.

Methods: Data of two Dutch tertiary referral centers were merged. Disease-free survival (DFS), overall survival (OS), and regional control rate (RCR) of 80 patients diagnosed with CUP (squamous cell and undifferentiated carcinomas) between 1990 and 2009 were retrospectively analyzed.

Results: Thirty patients received bilateral neck and pharyngeal axis radiotherapy and 42 patients ipsilateral radiotherapy only. In another eight patients, the postsurgical radiation target volume was expanded to the contralateral neck or to the pharyngeal axis, due to suspicious lesions on imaging. The 5-year DFS, OS and RCR were 60%, 51.2%, and 80%, respectively, in the total patient population. RCR did not differ in patients treated with ipsilateral as compared to bilateral radiotherapy nor did 5-year OS and DFS. No tumors occurred in the pharyngeal axis.

Conclusion: In this study, omitting elective treatment of the contralateral neck and pharyngeal axis did not lead to a decrease in locoregional control or survival rates when treating patients with CUP.
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http://dx.doi.org/10.1007/s00405-020-05867-2DOI Listing
June 2020

Impact of the BioFire FilmArray gastrointestinal panel on patient care and infection control.

PLoS One 2020 6;15(2):e0228596. Epub 2020 Feb 6.

Department of Medical Microbiology & Radboudumc Center for Infectious Diseases, Radboud university medical center, Nijmegen, The Netherlands.

Objectives: Conventional routine PCR testing for gastrointestinal infections is generally based on pathogen related panels specifically requested by clinicians and can be erroneous and time consuming. The BioFire FilmArray gastrointestinal (GI) panel combines 22 pathogens into a single cartridge-based test on a random-access system, thereby reducing the turnaround time to less than 2 hours. We described the clinical impact of implementing the BioFire FilmArray on patients with gastroenteritis in our hospital.

Methods: Patients attending a Dutch tertiary care center (Radboud University Medical Center), from whom stool samples were obtained, were eligible for inclusion. The clinicians selected one or a combination of different routinely performed PCR panels (bacterial panel, viral panel, clostridium testing, and three parasitic panels) based on clinical history and symptoms. All samples were in parallel tested with the FilmArray. We retrospectively collected patient data regarding infection control and patient management to assess the potential impact of implementing the FilmArray.

Results: In total 182 patients were included. Routine PCR detected one or more pathogens in 52 (28.6%) patients compared to 72 (39.6%) using the FilmArray. Turnaround time (including transport) decreased from median 53 hours for the routine PCR to 16 hours for the FilmArray. Twenty-six patients could have been removed from isolation 29 hours sooner, 3.6 antibiotic days could have been saved and in five patients additional imaging testing (including colonoscopies) could have been prevented.

Conclusion: The theoretical implementation of the BioFire FilmArray GI panel in patients with clinical suspicion of gastroenteritis resulted in a significant better patient management.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0228596PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004333PMC
May 2020

The risk of cervical cancer after cervical intraepithelial neoplasia grade 3: A population-based cohort study with 80,442 women.

Gynecol Oncol 2020 04 20;157(1):195-201. Epub 2020 Jan 20.

Department of Obstetrics and Gynecology, Catharina Hospital, PO Box 1350, 5602ZA Eindhoven, the Netherlands. Electronic address:

Objective: To estimate the risk of cervical cancer in women with a history of cervical intraepithelial neoplasia (CIN) grade 3 and to review the compliance with post-treatment follow-up.

Methods: A population-based retrospective cohort study including 80,442 women with a median follow-up of 15.8 years, and 1,278,297 person years. Women with CIN3 between 1990 and 2010 were identified from the Dutch Pathology Registry (PALGA) and linked to the general female population from the Netherlands Cancer Registry. Cases of recurrent CIN3 and cervical cancer, defined as occurrence minimally two years post-treatment, were identified until 2016. Standardized incidence ratios (SIRs) were calculated for the risk of cervical cancer.

Results: 1554 women (1.9%) developed recurrent CIN3 and 397 women (0.5%) cervical cancer. Women with CIN3 were associated with a twofold increased risk of cervical cancer (SIR 2.29; 95%CI 2.07-2.52) compared with the general female population. Women aged ≥50 years during CIN3 diagnosis had a sevenfold and women with recurrent CIN3 a ninefold increased risk of developing cervical cancer. The increased risk up to 20 years of follow-up seems to be mostly attributable to ageing. 37.0% of women who developed cervical cancer after CIN3 did not complete the advised post-treatment follow-up.

Conclusions: Women with CIN3 have a long-lasting twofold increased risk of developing cervical cancer, even when they complete the post-treatment follow-up and adhere to the regular screening program. This risk increases with CIN3 diagnosis at older age, further ageing during follow-up and in women with recurrent CIN3. Studies on optimizing follow-up strategies are warranted.
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http://dx.doi.org/10.1016/j.ygyno.2020.01.023DOI Listing
April 2020

Performance of the QIAstat-Dx Gastrointestinal Panel for Diagnosing Infectious Gastroenteritis.

J Clin Microbiol 2020 02 24;58(3). Epub 2020 Feb 24.

Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands

Detection and identification of enteropathogens that cause infectious gastroenteritis are essential steps for appropriate patient treatment and effective isolation precautions. Several syndrome-based tests have recently become available, with the gastrointestinal panel (GIP) assay on the QIAstat-Dx as the most recent addition to the syndromic testing landscape. The QIAstat-Dx GIP assay offers simultaneous testing for 24 bacterial, viral, and parasitic enteropathogens using a single test that reports the results in 70 min. In this study, we compared the performance of the GIP assay to laboratory-developed real-time PCR assays (LDTs), using 172 prospectively and retrospectively collected fecal samples from patients suspected to have infectious gastroenteritis. The GIP assay detected 97/107 enteropathogens (91%) that were detected by LDTs, and the overall agreement of results increased to 95% when excluding discrepant results with cycle threshold ( ) values of >35. Further, the GIP assay detected 42 additional enteropathogens that were not detected, or tested, by LDTs. These included 35 diarrheagenic targets for which the clinical relevance is unclear for most. The main advantage of the QIAstat-Dx system compared to other syndromic testing systems is the ability to generate values that could help with the interpretation of results. However, compared to LDTs, the GIP assay is limited by flexibility and high-throughput testing. In conclusion, the GIP assay offers an easy, sample-to-answer workflow with a rapid detection of the most common enteropathogens and therefore has the potential to direct appropriate therapy and infection control precautions.
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http://dx.doi.org/10.1128/JCM.01737-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041566PMC
February 2020

Introduction of primary screening using high-risk HPV DNA detection in the Dutch cervical cancer screening programme: a population-based cohort study.

BMC Med 2019 12 11;17(1):228. Epub 2019 Dec 11.

Department of Public Health, Erasmus MC University Medical Center, Dr. Molewaterplein 40, 3015 CN, Rotterdam, the Netherlands.

Background: In January 2017, the Dutch cervical cancer screening programme transitioned from cytomorphological to primary high-risk HPV (hrHPV) DNA screening, including the introduction of self-sampling, for women aged between 30 and 60 years. The Netherlands was the first country to switch to hrHPV screening at the national level. We investigated the health impact of this transition by comparing performance indicators from the new hrHPV-based programme with the previous cytology-based programme.

Methods: We obtained data from the Dutch nationwide network and registry of histo- and cytopathology (PALGA) for 454,573 women eligible for screening in 2017 who participated in the hrHPV-based programme between 1 January 2017 and 30 June 2018 (maximum follow-up of almost 21 months) and for 483,146 women eligible for screening in 2015 who participated in the cytology-based programme between 1 January 2015 and 31 March 2016 (maximum follow-up of 40 months). We compared indicators of participation (participation rate), referral (screen positivity; referral rate) and detection (cervical intraepithelial neoplasia (CIN) detection; number of referrals per detected CIN lesion).

Results: Participation in the hrHPV-based programme was significantly lower than that in the cytology-based programme (61% vs 64%). Screen positivity and direct referral rates were significantly higher in the hrHPV-based programme (positivity rate: 5% vs 9%; referral rate: 1% vs 3%). CIN2+ detection increased from 11 to 14 per 1000 women screened. Overall, approximately 2.2 times more clinical irrelevant findings (i.e. ≤CIN1) were found in the hrHPV-based programme, compared with approximately 1·3 times more clinically relevant findings (i.e. CIN2+); this difference was mostly due to a national policy change recommending colposcopy, rather than observation, of hrHPV-positive, ASC-US/LSIL results in the hrHPV-based programme.

Conclusions: This is the first time that comprehensive results of nationwide implementation of hrHPV-based screening have been reported using high-quality data with a long follow-up. We have shown that both benefits and potential harms are higher in one screening round of a well-implemented hrHPV-based screening programme than in an established cytology-based programme. Lower participation in the new hrHPV programme may be due to factors such as invitation policy changes and the phased roll-out of the new programme. Our findings add further to evidence from trials and modelling studies on the effectiveness of hrHPV-based screening.
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http://dx.doi.org/10.1186/s12916-019-1460-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6907114PMC
December 2019

Molecular Mechanisms of Conidial Germination in spp.

Microbiol Mol Biol Rev 2020 02 4;84(1). Epub 2019 Dec 4.

Department of Medical Microbiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.

Aspergilli produce conidia for reproduction or to survive hostile conditions, and they are highly effective in the distribution of conidia through the environment. In immunocompromised individuals, inhaled conidia can germinate inside the respiratory tract, which may result in invasive pulmonary aspergillosis. The management of invasive aspergillosis has become more complex, with new risk groups being identified and the emergence of antifungal resistance. Patient survival is threatened by these developments, stressing the need for alternative therapeutic strategies. As germination is crucial for infection, prevention of this process might be a feasible approach. A broader understanding of conidial germination is important to identify novel antigermination targets. In this review, we describe conidial resistance against various stresses, transition from dormant conidia to hyphal growth, the underlying molecular mechanisms involved in germination of the most common species, and promising antigermination targets. Germination of is characterized by three morphotypes: dormancy, isotropic growth, and polarized growth. Intra- and extracellular proteins play an important role in the protection against unfavorable environmental conditions. Isotropically expanding conidia remodel the cell wall, and biosynthetic machineries are needed for cellular growth. These biosynthetic machineries are also important during polarized growth, together with tip formation and the cell cycle machinery. Genes involved in isotropic and polarized growth could be effective antigermination targets. Transcriptomic and proteomic studies on specific morphotypes will improve our understanding of the germination process and allow discovery of novel antigermination targets and biomarkers for early diagnosis and therapy.
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http://dx.doi.org/10.1128/MMBR.00049-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6903801PMC
February 2020

Oral contraceptive and intrauterine device use and the risk of cervical intraepithelial neoplasia grade III or worse: a population-based study.

Eur J Cancer 2020 01 21;124:102-109. Epub 2019 Nov 21.

Department of Pathology, Radboud university medical center, PO Box 9101, 6500HB, Nijmegen, the Netherlands; PALGA, Randhoeve 225a, 3995 GA, Houten, the Netherlands. Electronic address:

Objective: Hormonal contraceptive use has been associated with the development of cervical cancer, although inconsistent results are reported on the association with intrauterine device (IUD) use. The aim of this study was to evaluate the association between the type of contraceptive use and the development of cervical intraepithelial neoplasia grade III or worse (CIN3+).

Methods: A retrospective population-based cohort study including women aged 29-44 years attending the cervical cancer screening program with normal cytology between 2005 and 2009 identified from the Dutch Pathology Registry. Subgroups with at least 5 years registered use of an oral contraceptive (OC) or IUD were compared with non-users. Risk ratios of CIN3+ were estimated per contraceptive type.

Results: 702,037 women were included with a median follow-up of 9.7 years, of which 6705 (0.96%) and 559 (0.08%) women developed CIN3 and cervical cancer, respectively. IUD use was associated with an increased risk of developing CIN3+ (risk ratio (RR) 1.51, 95% confidence interval (CI) 1.32-1.74), and OC use was associated with an increased risk of developing CIN3+ (RR 2.77, 95%CI 2.65-3.00) and cervical cancer (RR 2.06, 95%CI 1.52-2.79). The risk of developing CIN3+ and cervical cancer was higher for OC users compared with IUD users (RR 1.83, 95%CI 1.60-2.09 and RR 1.70, 95%CI 1.00-2.90, respectively).

Conclusions: Both OC use and IUD use were associated with an increased risk of developing CIN3+. However, for women with a contraceptive wish, an IUD seems safer than an OC as the risk of developing CIN3+ and cervical cancer was higher for OC users.
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http://dx.doi.org/10.1016/j.ejca.2019.10.009DOI Listing
January 2020

The Fungal PCR Initiative's evaluation of in-house and commercial Pneumocystis jirovecii qPCR assays: Toward a standard for a diagnostics assay.

Med Mycol 2020 Aug;58(6):779-788

Institut Pasteur, Molecular Mycology Unit, CNRS UMR2000, Paris, France.

Quantitative real-time PCR (qPCR) is increasingly used to detect Pneumocystis jirovecii for the diagnosis of Pneumocystis pneumonia (PCP), but there are differences in the nucleic acids targeted, DNA only versus whole nucleic acid (WNA), and also the target genes for amplification. Through the Fungal PCR Initiative, a working group of the International Society for Human and Animal Mycology, a multicenter and monocenter evaluation of PCP qPCR assays was performed. For the multicenter study, 16 reference laboratories from eight different countries, performing 20 assays analyzed a panel consisting of two negative and three PCP positive samples. Aliquots were prepared by pooling residual material from 20 negative or positive- P. jirovecii bronchoalveolar lavage fluids (BALFs). The positive pool was diluted to obtain three concentrations (pure 1:1; 1:100; and 1:1000 to mimic high, medium, and low fungal loads, respectively). The monocenter study compared five in-house and five commercial qPCR assays testing 19 individual BALFs on the same amplification platform. Across both evaluations and for all fungal loads, targeting WNA and the mitochondrial small sub-unit (mtSSU) provided the earliest Cq values, compared to only targeting DNA and the mitochondrial large subunit, the major surface glycoprotein or the beta-tubulin genes. Thus, reverse transcriptase-qPCR targeting the mtSSU gene could serve as a basis for standardizing the P. jirovecii load, which is essential if qPCR is to be incorporated into clinical care pathways as the reference method, accepting that additional parameters such as amplification platforms still need evaluation.
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http://dx.doi.org/10.1093/mmy/myz115DOI Listing
August 2020

Risk prediction of cervical abnormalities: The value of sociodemographic and lifestyle factors in addition to HPV status.

Prev Med 2020 01 19;130:105927. Epub 2019 Nov 19.

Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, the Netherlands; Dutch Expert Centre for Screening, Nijmegen, the Netherlands.

High-risk human papillomavirus (hrHPV) assessment as a primary screening test improves sensitivity but decreases specificity. Determining risk for cervical abnormalities and adapting policy accordingly may improve the balance between screening benefits and harms. Our aim is to assess the value of factors other than HPV in prediction of cervical abnormalities. Data from a Dutch prospective cohort were used. Women aged 18-29 years, not yet eligible for screening, were included in 2007. Data collection consisted of a questionnaire and a cervicovaginal self-sample. Linkage with PALGA (pathology database) was performed in 2017. The analyses included 1483 women. The full model, including sociodemographic and lifestyle factors, was compared to the null model, including baseline HPV only. The outcome of interest was cervical intraepithelial neoplasia 2 or worse (CIN2+). There were 86 women with CIN2+. Baseline hrHPV status was an important predictor (OR = 5.20, 95%CI = 3.27-8.27). The area under the ROC curve (AUC) of the null model was 0.67 (95%CI = 0.61-0.72). The full model had a slightly higher AUC of 0.73 (95%CI = 0.67-0.79). Bootstrap validation indicated that overfitting was present. This exploratory study has confirmed that a single hrHPV measurement is a strong predictor of cervical abnormalities, and additional risk factors in young women appeared to have limited added value. However, prediction based on hrHPV only does leave room for improvement. Future studies should therefore focus on women in the screening age range and search for other predictors to further enhance risk prediction. Adapting policy based on risk may eventually help optimise screening performance.
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http://dx.doi.org/10.1016/j.ypmed.2019.105927DOI Listing
January 2020

Clinical practice variation and overtreatment risk in women with abnormal cervical cytology in the Netherlands: two-step versus see-and-treat approach.

Am J Obstet Gynecol 2020 04 21;222(4):354.e1-354.e10. Epub 2019 Oct 21.

Department of Obstetrics and Gynecology, Catharina Hospital, Eindhoven, Netherlands.

Background: Only a few small studies have compared the 2-step method (biopsy followed by treatment) with a see-and-treat (immediate treatment) approach in women both low-grade or high-grade referral cytology. The clinical practice variation in the Netherlands has not been reviewed before.

Objectives: To determine overtreatment rates in the 2-step versus see-and-treat approach in women referred for colposcopy because of abnormal cytology results, and to evaluate clinical practice variation in the Netherlands.

Materials And Methods: This was a population-based retrospective cohort study including 36,581 women with a histologic result of the cervix identified from the Dutch Pathology Registry (PALGA) between 2016 and 2017. Odds ratios for overtreatment, defined primarily as cervical intraepithelial neoplasia grade 1 or less, were determined for the 2-step and see-and-treat approach in relation to age, high-risk human papillomavirus status, and referral cytology.

Results: Of the included women 10,713 women (29.3%) received the 2-step method; 6,851 women (18.7%) underwent see-and-treat; and 19,017 women (52.0%) received conservative management after colposcopy with histologic assessment with cytologic follow-up or another type of treatment. Despite the existence of a national guideline advising see-and-treat only in case of suspected high-grade disease in women who have completed their childbearing, there is a wide practice variation between the 2 strategies in the Netherlands, with 7.0-88.3% of the women receiving see-and-treat per laboratory. The median time between cytology and treatment was 1-2 months (range, 0-12 months) in women receiving see-and-treat and the 2-step method, respectively. A total of 4119 women (23.5%) were overtreated, with older women, high-risk human papillomavirus-negative women, and women with low-grade cytology results being more likely to be overtreated. Women with low-grade cytology results and see-and-treat were associated with a higher overtreatment rate than women receiving the 2-step method (65.0% [1414 of 2174] versus 32.1% [1161 of 3613], respectively; odds ratio, 3.34; 95% confidence interval, 2.92-3.82). However, in women with high-grade cytology results, see-and-treat was inversely associated with overtreatment (11.3% [529 of 4677] versus 14.3% [1015 of 7100], respectively; odds ratio, 0.68; 95% confidence interval, 0.58-0.81).

Conclusion: A see-and-treat approach is justified only in women with high-grade cytology results who have completed their childbearing. There is a wide practice variation between the 2 strategies in the Netherlands, and gynecologists should adhere to the guideline to prevent overtreatment.
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http://dx.doi.org/10.1016/j.ajog.2019.10.004DOI Listing
April 2020

Laryngeal Carcinoma in Patients With Inflammatory Bowel Disease: Clinical Outcomes and Risk Factors.

Inflamm Bowel Dis 2020 06;26(7):1060-1067

Department of Gastroenterology and Hepatology, Jeroen Bosch Hospital, 's-Hertogenbosch, the Netherlands.

Background: Inflammatory bowel disease (IBD) patients are at increased risk for developing extra-intestinal malignancies, mainly due to immunosuppressive medication. The risk of developing head and neck cancer in immunosuppressed transplant patients is increased. The relation between IBD patients and laryngeal cancer (LC) remains unclear. We aimed (1) to identify risk factors in IBD patients for LC development and (2) to compare clinical characteristics, outcome, and survival of LC in IBD patients with the general population.

Methods: All IBD patients with LC (1993-2011) were retrospectively identified using the Dutch Pathology Database. We performed 2 case-control studies: (1) to identify risk factors, we compared patients with IBD and LC (cases) with the general IBD population; (2) to analyze LC survival, we compared cases with controls from the general LC population.

Results: We included 55 cases, 1800 IBD controls, and 2018 LC controls. Cases were more frequently male compared with IBD controls (P < 0.001). For ulcerative colitis (UC), cases were older at IBD diagnosis (P < 0.001). Crohn's disease (CD) cases were more frequently tobacco users (P < 0.001) and more often had stricturing (P = 0.006) and penetrating (P = 0.008) disease. We found no survival difference. Immunosuppressive medication had no impact on survival.

Conclusions: Male sex was a risk factor for LC in IBD patients. Older age at IBD diagnosis was a risk factor for UC to develop LC. Tobacco use and stricturing and penetrating disease were risk factors for LC development in CD patients. Inflammatory bowel disease was not associated with impaired survival of LC. Immunosuppressive medication had no influence on survival.
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http://dx.doi.org/10.1093/ibd/izz210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7301406PMC
June 2020

RNA-based high-risk HPV genotyping and identification of high-risk HPV transcriptional activity in cervical tissues.

Mod Pathol 2020 04 19;33(4):748-757. Epub 2019 Sep 19.

Department of Biochemistry, Radboud Institute for Molecular Life Sciences, 6525 GA, Nijmegen, The Netherlands.

Nearly all cervical cancers are initiated by a persistent infection with one of the high-risk human papillomaviruses (high-risk HPV). High-risk HPV DNA testing is highly sensitive but cannot distinguish between active, productive infections and dormant infections or merely deposited virus. A solution for this shortcoming may be the detection of transcriptional activity of viral oncogenes instead of mere presence of high-risk HPVs. In this study, fresh-frozen cervical tissues (n = 22) were subjected to high-risk HPV DNA detection using the line probe assay and to targeted RNA next-generation sequencing using single-molecule molecular inversion probes. Targeted RNA sequencing was applied for (1) RNA-based genotyping of high-risk HPV, giving information on specific HPV-subtype (2) discrimination of E2, E6, and E7 transcripts and (3) discovery of possible non-HPV cancer biomarkers. Data were analyzed using computational biology. Targeted RNA sequencing enabled reliable genotyping of high-risk HPV subtypes and allowed quantitative detection of E2, E6, and E7 viral gene expression, thereby discriminating cervical lesions from normal cervical tissues. Moreover, targeted RNA sequencing identified possible cervical cancer biomarkers other than high-risk HPV. Interestingly, targeted RNA sequencing also provided high-quality transcription profiles from cervical scrape samples, even after 1 week of dry storage or storage in Preservcyt fixative. This proof of concept study shows that targeted RNA sequencing can be used for high-risk HPV genotyping and simultaneous detection of high-risk HPV gene activity. Future studies are warranted to investigate the potential of targeted RNA sequencing for risk assessment for the development of cervical lesions, based on molecular analysis of cervical scrapes.
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http://dx.doi.org/10.1038/s41379-019-0369-7DOI Listing
April 2020

The fading boundaries between patient and environmental routes of triazole resistance selection in Aspergillus fumigatus.

PLoS Pathog 2019 08 22;15(8):e1007858. Epub 2019 Aug 22.

Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, the Netherlands.

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http://dx.doi.org/10.1371/journal.ppat.1007858DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6705767PMC
August 2019

Environmental Hotspots for Azole Resistance Selection of Aspergillus fumigatus, the Netherlands.

Emerg Infect Dis 2019 07;25(7):1347-1353

Azole resistance is a major concern for treatment of infections with Aspergillus fumigatus. Environmental resistance selection is a main route for Aspergillus spp. to acquire azole resistance. We investigated the presence of environmental hotspots for resistance selection in the Netherlands on the basis of the ability of A. fumigatus to grow and reproduce in the presence of azole fungicide residues. We identified 3 hotspots: flower bulb waste, green waste material, and wood chippings. We recovered azole-resistant A. fumigatus from these sites; all fungi contained cyp51A tandem repeat-mediated resistance mechanisms identical to those found in clinical isolates. Tebuconazole, epoxiconazole, and prothioconazole were the most frequently found fungicide residues. Stockpiles of plant waste contained the highest levels of azole-resistant A. fumigatus, and active aerobic composting reduced Aspergillus colony counts. Preventing plant waste stockpiling or creating unfavorable conditions for A. fumigatus to grow in stockpiles might reduce environmental resistance burden.
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http://dx.doi.org/10.3201/eid2507.181625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6590754PMC
July 2019

Raw genome sequence data for 13 isogenic strains isolated over a 2 year period from a patient with chronic granulomatous disease.

Data Brief 2019 Aug 23;25:104021. Epub 2019 May 23.

Department of Medical Microbiology, Radboud University Medical Centre, Centre of Expertise in Mycology, Nijmegen, the Netherlands.

Azole-resistance in is an emerging worldwide threat as it precludes the use of one of the 3 major classes of antifungal drugs to treat chronic and invasive aspergillosis [1]. In addition to the well-known environmental emergence of azole-resistant strains, associated with the use of fungicides in agriculture [2], [3], the development of in-host resistance, facilitated by medical antifungal use, has been described [4]. Investigations involving linked sets of (isogenic) clinical isolates of sequentially recovered from individual patients, are extremely important in order to improve our understanding of how azole resistance develops in-host. Here we present the whole genome sequences of 13 clinical isogenic isolates. These isolates were cultured from a single patient suffering from invasive aspergillosis over a period of 2 years. This patient underwent a wide range of antifungal therapies and the resultant isolates acquired multiple azole resistance in-host during the course of infection. The data presented here is related to our research paper titled "In-host microevolution of : a phenotypic and genotypic analysis" which describes the phenotypic characterisation of these clinical isolates [5]. The raw sequence data was deposited in the NCBI Sequence Read Archive (https://www.ncbi.nlm.nih.gov/sra), under BioProject ID number PRJNA528395.
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http://dx.doi.org/10.1016/j.dib.2019.104021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6545414PMC
August 2019

Recreation of in-host acquired single nucleotide polymorphisms by CRISPR-Cas9 reveals an uncharacterised gene playing a role in Aspergillus fumigatus azole resistance via a non-cyp51A mediated resistance mechanism.

Fungal Genet Biol 2019 09 23;130:98-106. Epub 2019 May 23.

MRC Centre for Medical Mycology at the University of Aberdeen, Aberdeen Fungal Group, Institute of Medical Sciences, University of Aberdeen, UK. Electronic address:

The human host comprises a range of specific niche environments. In order to successfully persist, pathogens such as Aspergillus fumigatus must adapt to these environments. One key example of in-host adaptation is the development of resistance to azole antifungals. Azole resistance in A. fumigatus is increasingly reported worldwide and the most commonly reported mechanisms are cyp51A mediated. Using a unique series of A. fumigatus isolates, obtained from a patient suffering from persistent and recurrent invasive aspergillosis over 2 years, this study aimed to gain insight into the genetic basis of in-host adaptation. Single nucleotide polymorphisms (SNPs) unique to a single isolate in this series, which had developed multi-azole resistance in-host, were identified. Two nonsense SNPs were recreated using CRISPR-Cas9; these were 213 in svf1 and 167 in uncharacterised gene AFUA_7G01960. Phenotypic analyses including antifungal susceptibility testing, mycelial growth rate assessment, lipidomics analysis and statin susceptibility testing were performed to associate genotypes to phenotypes. This revealed a role for svf1 in A. fumigatus oxidative stress sensitivity. In contrast, recapitulation of 167 in AFUA_7G01960 resulted in increased itraconazole resistance. Comprehensive lipidomics analysis revealed decreased ergosterol levels in strains containing this SNP, providing insight to the observed itraconazole resistance. Decreases in ergosterol levels were reflected in increased resistance to lovastatin and nystatin. Importantly, this study has identified a SNP in an uncharacterised gene playing a role in azole resistance via a non-cyp51A mediated resistance mechanism. This mechanism is of clinical importance, as this SNP was identified in a clinical isolate, which acquired azole resistance in-host.
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http://dx.doi.org/10.1016/j.fgb.2019.05.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6876285PMC
September 2019

Relevance of heterokaryosis for adaptation and azole-resistance development in Aspergillus fumigatus.

Proc Biol Sci 2019 02;286(1896):20182886

1 Laboratory of Genetics, Wageningen University , Droevendaalsesteeg 1, 6708 PB Wageningen , The Netherlands.

Aspergillus fumigatus causes a range of diseases in humans, some of which are characterized by fungal persistence. Aspergillus fumigatus, being a generalist saprotroph, may initially establish lung colonization due to its physiological versatility and subsequently adapt through genetic changes to the human lung environment and antifungal treatments. Human lung-adapted genotypes can arise by spontaneous mutation and/or recombination and subsequent selection of the fittest genotypes. Sexual and asexual spores are considered crucial contributors to the genetic diversity and adaptive potential of aspergilli by recombination and mutation supply, respectively. However, in certain Aspergillus diseases, such as cystic fibrosis and chronic pulmonary aspergillosis, A. fumigatus may not sporulate but persist as a network of fungal mycelium. During azole therapy, such mycelia may develop patient-acquired resistance and become heterokaryotic by mutations in one of the nuclei. We investigated the relevance of heterokaryosis for azole-resistance development in A. fumigatus. We found evidence for heterokaryosis of A. fumigatus in patients with chronic Aspergillus diseases. Mycelium from patient-tissue biopsies segregated different homokaryons, from which heterokaryons could be reconstructed. Whereas all variant homokaryons recovered from the same patient were capable of forming a heterokaryon, those from different patients were heterokaryon-incompatible. We furthermore compared heterokaryons and heterozygous diploids constructed from environmental isolates with different levels of azole resistance. When exposed to azole, the heterokaryons revealed remarkable shifts in their nuclear ratio, and the resistance level of heterokaryons exceeded that of the corresponding heterozygous diploids.
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http://dx.doi.org/10.1098/rspb.2018.2886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6408600PMC
February 2019

Impact of molecular point-of-care testing on clinical management and in-hospital costs of patients suspected of influenza or RSV infection: a modeling study.

J Med Virol 2019 08 14;91(8):1408-1414. Epub 2019 Apr 14.

Department of Health Evidence, Radboud University Medical Center, Nijmegen, The Netherlands.

Background: At hospital admission, patients suspected of infection with influenza or respiratory syncytial virus (RSV) are placed in isolation, pending the outcome of diagnostics. In a significant number, isolated care proves unnecessary. We investigated the potential impact of molecular point-of-care (POC) diagnostics on patient management and in-hospital costs.

Method: Prospective collection of data on resource utilization within the hospital from consecutive patients 18 years or older presenting at our university medical center with symptoms of respiratory tract infection from December 2016 to April 2017. A cost analysis was conducted using Markov modeling comparing the actual course of events (on the basis of routine diagnostic tests) with two hypothetical scenarios: when POC would impact time to diagnosis only (scenario 1) or on discharge from the hospital, too (scenario 2).

Results: A total of 283 patients were included, of whom 217 (76.7%) were admitted. Influenza and RSV were detected in 31% and 7% of the patients, respectively. Fifty-four percent of patients tested negative, of which 79% were kept in isolated care waiting for test results, with a median duration of 24 hours. Median length of stay was 6.0 days. Mean total in-hospital costs per patient were € 5243. Introducing POC would lower mean costs per patient to € 4904 (scenario 1) and € 4206 (scenario 2). At the hospital level, this would result in a total cost reduction of € 95 937 to € 293 471 in a single influenza season.

Conclusions: Introducing POC testing for patients presenting with symptoms of viral respiratory tract infection can reduce time-to-diagnosis, hospital stay and, thereby, in-hospital costs.
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http://dx.doi.org/10.1002/jmv.25479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7166495PMC
August 2019

Aerosol Transmission of Aspergillus fumigatus in Cystic Fibrosis Patients in the Netherlands.

Emerg Infect Dis 2019 04;25(4):797-799

We collected sputum samples and cough plates from 15 cystic fibrosis patients in the Netherlands who were colonized with Aspergillus fumigatus; we recovered A. fumigatus of the same genotype in cough aerosols and sputum samples from 2 patients. The belief that transmission of A. fumigatus from cystic fibrosis patients does not occur should be reconsidered.
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http://dx.doi.org/10.3201/eid2504.181110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6433022PMC
April 2019

Post-Colposcopy Management and Progression Predictors of Biopsy-Proven CIN1 in Women Under 25 Years.

J Obstet Gynaecol Can 2019 Mar 27;41(3):292-299. Epub 2018 Oct 27.

Department of Obstetrics and Gynecology, Queen Elizabeth II Health Sciences Centre, Halifax, NS.

Objective: The post-colposcopy management and outcome of cervical intraepithelial neoplasia grade 1 (CIN1) in women under 25 years of age was reviewed, and potential predictors for progression were identified.

Methods: Women under 25 with biopsy-proven CIN1 between January 1, 2010, and December 31, 2012 who were seen in the colposcopy clinic at the Queen Elizabeth II Hospital in Halifax, Nova Scotia were retrospectively reviewed. The regression, persistence, and progression rates of CIN1 were evaluated, and the relevant behavioural and biologic factors were reviewed.

Results: Of the 326 women with a biopsy-proven CIN1, 234 (71.8%) women returned to the regular screening program, and 92 women remained in the colposcopy clinic during follow-up, with a median follow-up time of 26 months. Sixty-two percent of the women had no cervical abnormality, 23.6% of the women had persistent CIN1, and 14.4% of the women showed progression. Eight percent showed progression to CIN2 with a median time of 13 months, whereas 6.4% showed progression to CIN3+ within a median time of 17.5 months. The extent of the lesion (hazard ratio 2.33; 95% CI 1.17-4.64, P = 0.02) and the Pap test result at the initial visit (hazard ratio 2.16; 95% CI 1.22-3.82, P = 0.008) were significantly associated with progression to CIN2+.

Conclusion: On the basis of the 6% risk of CIN3+ and the median time to progression of 17.5 months, follow-up with cytology at 12 months seems acceptable. The extent of the lesion and the Pap test result at the initial visit were identified as risk factors for progression of CIN1.
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http://dx.doi.org/10.1016/j.jogc.2018.06.021DOI Listing
March 2019

Risk Factors and Clinical Outcomes of Head and Neck Cancer in Inflammatory Bowel Disease: A Nationwide Cohort Study.

Inflamm Bowel Dis 2018 08;24(9):2015-2026

Inflammatory Bowel Disease Centre, Department of Gastroenterology and Hepatology.

Background: Immunosuppressed inflammatory bowel disease (IBD) patients are at increased risk to develop extra-intestinal malignancies. Immunosuppressed transplant patients show increased incidence of head and neck cancer with impaired survival. This study aims to identify risk factors for oral cavity (OCC) and pharyngeal carcinoma (PC) development in IBD, to compare clinical characteristics in IBD with the general population, and to assess the influence of immunosuppressive medication on survival.

Methods: We retrospectively searched the Dutch Pathology Database to identify all IBD patients with OCC and PC between 1993 and 2011. Two case-control studies were performed: We compared cases with the general IBD population to identify risk factors, and we compared cases with non-IBD cancer patients for outcome analyses.

Results: We included 66 IBD patients and 2141 controls with OCC, 31 IBD patients and 1552 controls with PC, and 1800 IBD controls. Age at IBD diagnosis was a risk factor for OCC development, Crohn's disease (CD; odds ratio [OR], 1.04; 95% confidence interval [CI], 1.02-1.07), and ulcerative colitis (UC; OR, 1.03; 95% CI, 1.01-1.06). For PC, this applied to UC (OR, 1.05; 95% CI, 1.01-1.06). IBD OCC cases showed impaired survival (P = 0.018); in PC, survival was similar. There was no effect of immunosuppression on survival. Human papillomavirus (HPV) testing of IBD cases revealed 52.2% (12/23) HPV-positive oropharyngeal carcinomas (OPCs).

Conclusion: This study shows that IBD is associated with impaired OCC survival. Higher age at IBD diagnosis is a risk factor for OCC development. We found no influence of immunosuppression on survival; 52.2% of OPC in IBD contained HPV.
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http://dx.doi.org/10.1093/ibd/izy096DOI Listing
August 2018

Performance of human papillomavirus testing on self-collected versus clinician-collected samples for the detection of cervical intraepithelial neoplasia of grade 2 or worse: a randomised, paired screen-positive, non-inferiority trial.

Lancet Oncol 2019 02 15;20(2):229-238. Epub 2019 Jan 15.

Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Epidemiology and Biostatistics, Amsterdam Public Health, Amsterdam, Netherlands. Electronic address:

Background: Human papillomavirus (HPV) testing on self-collected samples is a potential alternative to HPV testing on clinician-collected samples, but non-inferiority of its clinical accuracy remains to be assessed in the regular screening population. The IMPROVE study was done to evaluate the clinical accuracy of primary HPV testing on self-collected samples within an organised screening setting.

Methods: In this randomised, non-inferiority trial, women aged 29-61 years were invited to participate in the study as part of their regular screening invitation in the Netherlands. Women who provided informed consent were randomly allocated (1:1, with a block size of ten stratified by age) to one of two groups: a self-sampling group, in which women were requested to collect their own cervicovaginal sample using an Evalyn Brush (Rovers Medical Devices BV, Oss, Netherlands); or a clinician-based sampling group, in which samples were collected by a general practitioner with a Cervex-Brush (Rovers Medical Devices BV). All samples were tested for HPV using the clinically validated GP5+/6+ PCR enzyme immunoassay (Labo Biomedical Products BV, Rijswijk, Netherlands). HPV-positive women in both groups were retested with the other collection method and triaged by cytology and repeat cytology in accordance with current Dutch screening guidelines. Primary endpoints were detection of cervical intraepithelial neoplasia (CIN) of grade 2 or worse (CIN2+) and grade 3 or worse (CIN3+). Non-inferiority of HPV testing on self-collected versus clinician-collected samples was evaluated against a margin of 90% for the relative sensitivity and 98% for the relative specificity. This study is registered at the Dutch Trial register (NTR5078) and has been completed.

Findings: Of the 187 473 women invited to participate, 8212 were randomly allocated to the self-sampling group and 8198 to the clinician-based sampling group. After exclusion of women who met the exclusion criteria or who did not return their sample, 7643 women were included in the self-sampling group and 6282 in the clinician-based sampling group. 569 (7·4%) self-collected samples and 451 (7·2%) clinician-collected samples tested positive for HPV (relative risk 1·04 [95% CI 0·92-1·17]). Median follow-up duration for HPV-positive women was 20 months (IQR 17-22). The CIN2+ sensitivity and specificity of HPV testing did not differ between self-sampling and clinician-based sampling (relative sensitivity 0·96 [0·90-1·03]; relative specificity 1·00 [0·99-1·01]). For the CIN3+ endpoint, relative sensitivity was 0·99 (0·91-1·08) and relative specificity was 1·00 (0·99-1·01).

Interpretation: HPV testing done with a clinically validated PCR-based assay had similar accuracy on self-collected and clinician-collected samples in terms of the detection of CIN2+ or CIN3+ lesions. These findings suggest that HPV self-sampling could be used as a primary screening method in routine screening.

Funding: Ministry of Health, Welfare, and Sport (Netherlands), and the European Commission.
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http://dx.doi.org/10.1016/S1470-2045(18)30763-0DOI Listing
February 2019