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Contains fulltext : 307355.pdf (Publisher’s version ) (Open Access)

01 januari 2023, Item does not contain fulltext, OBJECTIVE: Cytology performed directly on hrHPV-positive self-samples (reflex cytology) is feasible and for women with abnormal cytology, an additional cytology test at the general practitioner could be omitted. The aim of this study is to assess the added value of digital imaging (ThinPrep® Imaging System) on the clinical utility of reflex cytology by reducing screening error. DESIGN: A secondary analysis of a prospective cohort study. SETTING: One of five Dutch screening laboratories. POPULATION: Women tested hrHPV-positive on self-samples between December 2018 and August 2019. METHODS: Self-samples were used for reflex cytology with and without digital imaging. The follow-up data (cytological and histological results within 1 year of follow-up) were obtained through the Dutch Pathology Registry (PALGA). MAIN OUTCOME MEASURES: Test performance of the reflex cytology was determined by comparing it with physician-collected follow-up results. RESULTS: The sensitivity for detecting abnormal cells by reflex cytology on self-samples increased significantly from 26.3% (42/160; 95% confidence interval [CI] 19.6-33.8) without digital imaging to 35.4% (56/158; 95% CI 28-43.4) with digital imaging (P < 0.05) without compromising specificity. Importantly, 41.7% of women with ≥CIN2 (35/84) and 45.6% with ≥CIN3 (26/57) were detected by reflex cytology with digital imaging on hrHPV-positive self-samples. CONCLUSION: Digital imaging is of added value to reflex cytology on hrHPV-positive self-samples with a 9% increase in sensitivity. If reflex cytology on self-samples analysed with digital imaging had been implemented in the screening programme, 35.4% of the hrHPV-positive women with abnormal cytology on additional physician-collected samples could have been referred directly for colposcopy.

Item does not contain fulltext, BACKGROUND: The major goal of routine follow-up in oropharyngeal squamous cell carcinoma (OPSCC) patients is the asymptomatic detection of new disease in order to improve survival. This study evaluated the effect of routine follow-up on overall survival (OS). METHODS: A retrospective cohort of 307 consecutive OPSCC patients treated with curative intent between 2006 and 2012 was analyzed. The effectiveness of routine follow-up was studied by comparing treatment-intent and OS in patients with asymptomatically versus symptomatically detected new disease. RESULTS: Three- and five-year risks of new disease were 29% (95% CI: 24-34) and 33% (95% CI: 27-39). Of the 81 patients with locoregional recurrence or second primary head and neck cancer, 8 (10%) were detected asymptomatically with no difference in OS with those detected with symptoms. CONCLUSIONS: Asymptomatic detection of new disease during routine visits was not associated with improved OS. The focus of follow-up should be on providing psychosocial care and rehabilitation.

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Radboud University, 31 maart 2023, Promotores : Wertheim, H.F.L., Huijnen, M.A. Co-promotores : Melchers, W.J.G., Cremers, A.J.H., Item does not contain fulltext

Radboud University, 21 juni 2023, Promotor : Verweij, P.E. Co-promotor : Melchers, W.J.G., Item does not contain fulltext

Item does not contain fulltext, The opportunistic fungal pathogen Aspergillus fumigatus utilizes two high-affinity iron uptake mechanisms, termed reductive iron assimilation (RIA) and siderophore-mediated iron acquisition (SIA). The latter has been shown to be crucial for virulence of this fungus and is a target for development of novel strategies for diagnosis and treatment of fungal infections. So far, research on SIA in this mold focused mainly on the hyphal stage, revealing the importance of extracellular fusarinine-type siderophores in iron acquisition as well as of the siderophore ferricrocin in intracellular iron handling. The current study aimed to characterize iron acquisition during germination. High expression of genes involved in biosynthesis and uptake of ferricrocin in conidia and during germination, independent of iron availability, suggested a role of ferricrocin in iron acquisition during germination. In agreement, (i) bioassays indicated secretion of ferricrocin during growth on solid media during both iron sufficiency and limitation, (ii) ferricrocin was identified in the supernatant of conidia germinating in liquid media during both iron sufficiency and limitation, (iii) in contrast to mutants lacking all siderophores, mutants synthesizing ferricrocin but lacking fusarinine-type siderophores were able to grow under iron limitation in the absence of RIA, and (iv) genetic inactivation of the ferricrocin transporter Sit1 decreased germination in the absence of RIA. Taken together, this study revealed that ferricrocin has not only an intracellular role but also functions as an extracellular siderophore to support iron acquisition. The iron availability-independent ferricrocin secretion and uptake during early germination indicate developmental, rather than iron regulation. IMPORTANCE Aspergillus fumigatus is one of the most common airborne fungal pathogens for humans. Low-molecular-mass iron chelators, termed siderophores, have been shown to play a central role in iron homeostasis

Item does not contain fulltext, The detection and accurate identification of bacterial species in clinical samples are crucial for diagnosis and appropriate antibiotic treatment. To date, sequencing of the 16S rRNA gene has been widely used as a complementary molecular approach when identification by culture fails. The accuracy and sensitivity of this method are highly affected by the selection of the 16S rRNA gene region targeted. In this study, we assessed the clinical utility of 16S rRNA reverse complement PCR (16S RC-PCR), a novel method based on next-generation sequencing (NGS), for the identification of bacterial species. We investigated the performance of 16S RC-PCR on 11 bacterial isolates, 2 polymicrobial community samples, and 59 clinical samples from patients suspected of having a bacterial infection. The results were compared to culture results, if available, and to the results of Sanger sequencing of the 16S rRNA gene (16S Sanger sequencing). By 16S RC-PCR, all bacterial isolates were accurately identified to the species level. Furthermore, in culture-negative clinical samples, the rate of identification increased from 17.1% (7/41) to 46.3% (19/41) when comparing 16S Sanger sequencing to 16S RC-PCR. We conclude that the use of 16S RC-PCR in the clinical setting leads to an increased sensitivity of detection of bacterial pathogens, resulting in a higher number of diagnosed bacterial infections, and thereby can improve patient care. IMPORTANCE The identification of the causative infectious pathogen in patients suspected of having a bacterial infection is essential for diagnosis and the start of appropriate treatment. Over the past 2 decades, molecular diagnostics have improved the ability to detect and identify bacteria. However, novel techniques that can accurately detect and identify bacteria in clinical samples and that can be implemented in clinical diagnostics are needed. Here, we demonstrate the clinical utility of bacterial identification in clinical samples by a novel method cal

Item does not contain fulltext, Currently, nontuberculous mycobacteria (NTM) are identified using small genomic regions, and species-level identification is often not possible. We introduce a next-generation sequencing (NGS) workflow that identifies mycobacteria to (sub)species level on the basis of the whole genome extracted from enriched shotgun metagenomic data. This technique is used to study the association between genotypes and clinical manifestations to pave the way to more personalized health care. Two sets of clinical isolates (explorative set [n = 212] and validation set [n = 235]) were included. All data were analyzed using a custom pipeline called MyCodentifier. Sequences were matched against a custom hsp65 database (NGS-hsp65) and whole-genome database (NGS-WG) created based on the phylogeny presented by Tortoli et al. (E. Tortoli, T. Fedrizzi, C. J. Meehan, A. Trovato, et al., Infect Genet Evol 56:19-25, 2017, https://doi.org/10.1016/j.meegid.2017.10.013). Lastly, phylogenetic analysis was performed and correlated with clinical manifestation. In the explorative set, we observed 98.6% agreement between the line probe assay and the NGS-hsp65 database. In the validation set, 99.1% agreement between the NGS-WG and NGS-hsp65 databases was seen on the complex level. We identified a cluster of Mycobacterium marinum isolates not represented by the Tortoli et al. phylogeny. Phylogenetic analysis of M. avium complex isolates confirmed misclassification of M. timonense and M. bouchedurhonense and identified subclusters within M. avium although no correlation with clinical manifestation was observed. We performed routine NGS to identify NTM from MGIT enriched shotgun metagenomic data. Phylogenetic analyses identified subtypes of M. avium, but in our set of isolates no correlation with clinical manifestation was found. However, this NGS workflow paves a way for more personalized health care in the future.

Contains fulltext : 296047.pdf (Publisher’s version ) (Open Access), The opportunistic pathogen Aspergillus fumigatus is found on all continents and thrives in soil and agricultural environments. Its ability to readily adapt to novel environments and to produce billions of spores led to the spread of azole-resistant A. fumigatus across the globe, posing a threat to many immunocompromised patients, including critically ill patients with severe influenza or COVID-19. In our study, we sought to compare the adaptational response to azoles from A. fumigatus isolates that differ in azole susceptibility and genetic background. To gain more insight into how short-term adaptation to stressful azole compounds is managed through gene expression, we conducted an RNA-sequencing study on the response of A. fumigatus to itraconazole and the newest clinically approved azole, isavuconazole. We observed many similarities in ergosterol biosynthesis up-regulation across isolates, with the exception of the pan-azole-resistant isolate, which showed very little differential regulation in comparison to other isolates. Additionally, we found differential regulation of membrane efflux transporters, secondary metabolites, iron metabolism, and various stress response and cell signaling mechanisms.

Contains fulltext : 296139.pdf (Publisher’s version ) (Open Access), Germination of inhaled Aspergillus fumigatus conidia is a necessary sequitur for infection. Germination of conidia starts with the breaking of dormancy, which is initiated by an increase of the cellular perimeter in a process termed isotropic growth. This swelling phase is followed by polarized growth, resulting in the formation of a germ tube. The multinucleate tubular cells exhibit tip growth from the hyphae, after which lateral branches emerge to form the mycelial network. The regulatory mechanisms governing conidial germination are not well defined. In this study, we identified a novel role for the transcription factor SltA in the orchestration of germination and hyphal development. Conidia lacking sltA fail to appropriately regulate isotropic growth and begin to swell earlier and subsequently switch to polarized growth faster. Additionally, hyphal development is distorted in a ∆sltA isolate as hyphae are hyper-branching and wider, and show branching at the apical tip. ∆sltA conidia are more tolerant to cell wall stressors on minimal medium compared to the wild-type (WT) strain. A transcriptome analysis of different stages of early growth was carried out to assess the regulatory role of SltA. Null mutants generated for three of the most dysregulated genes showed rapid germ tube emergence. Distinct from the phenotype observed for ∆sltA, conidia from these strains lacked defects in isotropic growth, but switched to polarized growth faster. Here, we characterize and describe several genes in the regulon of SltA, highlighting the complex nature of germination.IMPORTANCEAspergillus fumigatus is the main human fungal pathogen causing aspergillosis. For this fungus, azoles are the most commonly used antifungal drugs for treatment of aspergillosis. However, the prevalence of azole resistance is alarmingly increasing and linked with elevated mortality. Germination of conidia is crucial within its asexual life cycle and plays a critical role during the infection in the hu

Item does not contain fulltext, BACKGROUND: Compared to the previous cytology-based program, the introduction of primary high-risk human papillomavirus (hrHPV) based screening in 2017 has led to an increased number of referrals. To counter this, triage of hrHPV-positive women in cervical cancer screening can potentially be optimized by taking sociodemographic and lifestyle risk factors for cervical abnormalities into account. Therefore, it is essential to gain knowledge of the views of women (30-60 years) eligible for cervical cancer screening. OBJECTIVE: The main goal of this qualitative study was to gain insight in the aspects that influence acceptability of risk-based triage in cervical cancer screening. DESIGN: A focus group study in which participants were recruited via four general medical practices, and purposive sampling was used to maximize heterogeneity with regards to age, education level, and cervical cancer screening experiences. APPROACH: The focus group discussions were transcribed verbatim and analyzed using reflexive thematic analysis. PARTICIPANTS: A total of 28 women (average age: 45.2 years) eligible for cervical cancer screening in The Netherlands participated in seven online focus group discussions. Half of the participants was higher educated, and the participants differed in previous cervical cancer screening participation and screening result. KEY RESULTS: In total, 5 main themes and 17 subthemes were identified that determine the acceptability of risk-stratified triage. The main themes are: 1) adequacy of the screening program: an evidence-based program that is able to minimize cancer incidence and reduce unnecessary referrals; 2) personal information (e.g., sensitive topics and stigma); 3) emotional impact: fear and reassurance; 4) communication (e.g., transparency); and 5) autonomy (e.g., prevention). CONCLUSION: The current study highlights several challenges regarding the development and implementation of risk-based triage that need attention in order to be accepted b

Radboud University, 15 september 2023, Promotor : Verweij, P.E. Co-promotor : Melchers, W.J.G., Item does not contain fulltext

Item does not contain fulltext, The cervicovaginal microbiome (CVM) is a dynamic continuous microenvironment that can be clustered in microbial community state types (CSTs) and is associated with women's cervical health. Lactobacillus-depleted communities particularly associate with an increased susceptibility for persistence of high-risk human papillomavirus (hrHPV) infections and progression of disease, but the long-term ecological dynamics of CSTs after hrHPV infection diagnosis remain poorly understood. To determine such dynamics, we examined the CVM of our longitudinal cohort of 141 women diagnosed with hrHPV infection at baseline with collected cervical smears at two timepoints six-months apart. Here we describe that the long-term microbiome dissimilarity has a positive correlation with microbial diversity at both visits and that women with high abundance and dominance for Lactobacillus iners at baseline exhibit more similar microbiome composition at second visit than women with Lactobacillus-depleted communities at baseline. We further show that the species Lactobacillus acidophilus and Megasphaera genomosp type 1 associate with CST changes between both visits. Lastly, we also observe that Gardnerella vaginalis is associated with the stability of Lactobacillus-depleted communities while L. iners is associated with the instability of Megasphaera genomosp type 1-dominated communities. Our data suggest dynamic patterns of cervicovaginal CSTs during hrHPV infection, which could be potentially used to develop microbiome-based therapies against infection progression towards disease.

01 juli 2023, Contains fulltext : 294344.pdf (Publisher’s version ) (Open Access), BACKGROUND: Host-cell DNA methylation analysis can be used to triage women with high-risk human papillomavirus (HPV)-positive self-collected cervicovaginal samples, but current data are restricted to under-/never-screened women and referral populations. This study evaluated triage performance in women who were offered primary HPV self-sampling for cervical cancer screening. METHODS: Self-collected samples from 593 HPV-positive women who participated in a primary HPV self-sampling trial (IMPROVE study; NTR5078), were tested for the DNA methylation markers ASCL1 and LHX8 using quantitative multiplex methylation-specific PCR (qMSP). The diagnostic performance for CIN3 and cervical cancer (CIN3 + ) was evaluated and compared with that of paired HPV-positive clinician-collected cervical samples. RESULTS: Significantly higher methylation levels were found in HPV-positive self-collected samples of women with CIN3 + than control women with no evidence of disease (P values <0.0001). The marker panel ASCL1/LHX8 yielded a sensitivity for CIN3 + detection of 73.3% (63/86; 95% CI 63.9-82.6%), with a corresponding specificity of 61.1% (310/507; 95% CI 56.9-65.4%). The relative sensitivity for detecting CIN3+ was 0.95 (95% CI 0.82-1.10) for self-collection versus clinician-collection, and the relative specificity was 0.82 (95% CI 0.75-0.90). CONCLUSIONS: The ASCL1/LHX8 methylation marker panel constitutes a feasible direct triage method for the detection of CIN3 + in HPV-positive women participating in routine screening by self-sampling.

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Contains fulltext : 248162.pdf (Publisher’s version ) (Open Access)

Item does not contain fulltext, Methylation of host-cell deoxyribonucleic acid (DNA) has been proposed as a promising biomarker for triage of high-risk (hr) human papillomavirus (HPV) positive women at screening. Our study aims to validate recently identified host-cell DNA methylation markers for triage in an hrHPV-positive cohort derived from primary HPV-based cervical screening in The Netherlands. Methylation markers ASCL1, LHX8, ST6GALNAC5, GHSR, ZIC1 and SST were evaluated relative to the ACTB reference gene by multiplex quantitative methylation-specific PCR (qMSP) in clinician-collected cervical samples (n = 715) from hrHPV-positive women (age 29-60 years), who were enrolled in the Dutch IMPROVE screening trial (NTR5078). Primary clinical end-point was cervical intraepithelial neoplasia grade 3 (CIN3) or cancer (CIN3+). The single-marker and bi-marker methylation classifiers developed for CIN3 detection in a previous series of hrHPV-positive clinician-collected cervical samples were applied. The diagnostic accuracy was visualised using receiver operating characteristic (ROC) curves and assessed through area under the ROC curve (AUC). The performance of the methylation markers to detect CIN3+ was determined using the predefined threshold calibrated at 70% clinical specificity. Individual methylation makers showed good performance for CIN3+ detection, with highest AUC for ASCL1 (0.844) and LHX8 (0.830). Combined as a bi-marker panel with predefined threshold, ASCL1/LHX8 yielded a CIN3+ sensitivity of 76.9% (70/91; 95% CI 68.3-85.6%) at a specificity of 74.5% (465/624; 95% CI 71.1-77.9%). In conclusion, our study shows that the individual host-cell DNA methylation classifiers and the bi-marker panel ASCL1/LHX8 have clinical utility for the detection of CIN3+ in hrHPV-positive women invited for routine screening.

Item does not contain fulltext, Most medical microbiology laboratories in the Netherlands have switched from direct potassium hydroxide microscopy and culture to polymerase chain reaction (PCR) testing when diagnosing dermato- and onychomycoses and Candida species in human dander, hair and nails. The predictive value of a PCR test is in most cases higher than the predictive value of KOH microscopy and culture in diagnosing or ruling out a fungal infection and should therefore replace traditional diagnostics in routine care. KOH microscopy and culture should be reserved in cases of therapy failure and suspected false negative PCR testing. An application for a PCR should be performed if there is any doubt about the clinical diagnosis. The application must be accompanied by sufficient clinical information from the patient to enable the microbiologist to determine whether the PCR test used is appropriate.

Contains fulltext : 252112.pdf (Publisher’s version ) (Open Access), A sexual cycle was described in 2009 for the opportunistic fungal pathogen Aspergillus fumigatus, opening up for the first time the possibility of using techniques reliant on sexual crossing for genetic analysis. The present study was undertaken to evaluate whether the technique 'bulk segregant analysis' (BSA), which involves detection of differences between pools of progeny varying in a particular trait, could be applied in conjunction with next-generation sequencing to investigate the underlying basis of monogenic traits in A. fumigatus. Resistance to the azole antifungal itraconazole was chosen as a model, with a dedicated bioinformatic pipeline developed to allow identification of SNPs that differed between the resistant progeny pool and resistant parent compared to the sensitive progeny pool and parent. A clinical isolate exhibiting monogenic resistance to itraconazole of unknown basis was crossed to a sensitive parent and F1 progeny used in BSA. In addition, the use of backcrossing and increasing the number in progeny pools was evaluated as ways to enhance the efficiency of BSA. Use of F1 pools of 40 progeny led to the identification of 123 candidate genes with SNPs distributed over several contigs when aligned to an A1163 reference genome. Successive rounds of backcrossing enhanced the ability to identify specific genes and a genomic region, with BSA of progeny (using 40 per pool) from a third backcross identifying 46 genes with SNPs, and BSA of progeny from a sixth backcross identifying 20 genes with SNPs in a single 292 kb region of the genome. The use of an increased number of 80 progeny per pool also increased the resolution of BSA, with 29 genes demonstrating SNPs between the different sensitive and resistant groupings detected using progeny from just the second backcross with the majority of variants located on the same 292 kb region. Further bioinformatic analysis of the 292 kb region identified the presence of a cyp51A gene variant resulting in a meth

Item does not contain fulltext, INTRODUCTION: Immunostaining with p16(INK4a) (p16), a tumor-suppressor surrogate protein biomarker for high-risk human papillomavirus (hrHPV) oncogenic activity, may complement standard hematoxylin and eosin (H&E) histology review, and provide more objective criteria to support the cervical intraepithelial neoplasia (CIN) diagnosis. With this study we assessed the impact of p16 immunohistochemistry on CIN grading in an hrHPV-based screening setting. MATERIAL AND METHODS: In this post-hoc analysis, 326 histology follow-up samples from a group of hrHPV-positive women were stained with p16 immunohistochemistry. All H&E samples were centrally revised. The pathologists reported their level of confidence in classifying the CIN lesion. RESULTS: Combining H&E and p16 staining resulted in a change of diagnosis in 27.3% (n = 89) of cases compared with the revised H&E samples, with a decrease of 34.5% (n = 18) in CIN1 and 22.7% (n = 15) in CIN2 classifications, and an increase of 18.3% (n = 19) in no CIN and 20.7% (n = 19) in CIN3 diagnoses. The level of confidence in CIN grading by the pathologist increased with adjunctive use of p16 immunohistochemistry to standard H&E. CONCLUSIONS: This study shows that adjunctive use of p16 immunohistochemistry to H&E morphology reduces the number of CIN1 and CIN2 classifications with a proportional increase in no CIN and CIN3 diagnoses, compared with standard H&E-based CIN diagnosis alone. The pathologists felt more confident in classifying the material with H&E and p16 immunohistochemistry than by using H&E alone, particularly during assessment of small biopsies. Adjunctive use of p16 immunohistochemistry to standard H&E assessment of CIN would be valuable for the diagnostic accuracy, thereby optimizing CIN management and possibly decreasing overtreatment.

Radboud University, 07 oktober 2022, Promotor : Verweij, P.E. Co-promotores : Melchers, W.J.G., Meis, J.F.G.M., Contains fulltext : 281785.pdf (Publisher’s version ) (Open Access)

Contains fulltext : 282758.pdf (Publisher’s version ) (Open Access)

Contains fulltext : 282501.pdf (Publisher’s version ) (Open Access), Aspergillus fumigatus is the major filamentous fungal pathogen in humans. The gold standard treatment of A. fumigatus is based on azole drug use, but the appearance of azole-resistant isolates is increasing at an alarming rate. The cyp51A gene encodes the enzymatic target of azole drugs, and azole-resistant alleles of cyp51A often have an unusual genetic structure containing a duplication of a 34- or 46-bp region in the promoter causing enhanced gene transcription. These tandem repeats are called TR34 and TR46 and produce duplicated binding sites for the SrbA and AtrR transcription factors. Using site-directed mutagenesis, we demonstrate that both the SrbA (sterol response element [SRE]) and AtrR binding sites (AtrR response element [ATRE]) are required for normal cyp51A gene expression. Loss of either the SRE or ATRE from the distal 34-bp repeat of the TR34 promoter (further 5' from the transcription start site) caused loss of expression of cyp51A and decreased voriconazole resistance. Surprisingly, loss of these same binding sites from the proximal 34- or 46-bp repeat led to increased cyp51A expression and voriconazole resistance. These data indicate that these duplicated regions in the cyp51A promoter function differently. Our findings suggest that the proximal 34- or 46-bp repeat in cyp51A recruits a corepressor that requires multiple factors to act while the distal repeat is free of this repression and provides the elevated cyp51A expression caused by these promoter duplications. IMPORTANCE Aspergillus fumigatus is the most common human filamentous fungal pathogen. Azole drugs are the current therapy of choice for A. fumigatus, but the prevalence of azole resistance is increasing. The main genetic alteration causing azole resistance is a change in the cyp51A gene, which encodes the target of these drugs. Azole-resistant cyp51A alleles routinely contain duplications in their promoter regions that cause increased gene transcription. Here, we demonstrate that clin

Item does not contain fulltext, Cervical cancer is the third leading cause of female cancers globally, resulting in more than 300,000 deaths every year. The majority of all cervical cancers are caused by persistent infections with high-risk human papillomaviruses (hrHPV) that can progress to cancer via a series of premalignant lesions. Most women, however, clear this infection within a year, concomitant with disease regression. Both hrHPV clearance and disease regression have been associated with the composition of the cervicovaginal microenvironment, which is defined by the host immune system and the cervicovaginal microbiome (CVM). A healthy microbiome is generally characterized by a high abundance of Lactobacillus species, and a change in the composition may cause bacterial vaginosis (BV), which is associated with an increased susceptibility to persistent hrHPV infections and disease. In this review, the composition of the CVM is discussed, with emphasis on the possible causes that drive changes in the cervicovaginal microbiota in relation to hrHPV infections, disease progression, and disease regression. The literature search focused on the composition of the CVM and its correlation with hrHPV infections and neoplastic lesions as well as the current efforts to adjust the microbiome against adverse viral outcomes.

Contains fulltext : 251134.pdf (Publisher’s version ) (Open Access)

Contains fulltext : 282373.pdf (Publisher’s version ) (Open Access), BACKGROUND: Molecular biomarker tests are developed as diagnostic tools for prostate cancer (PCa) diagnosis. The SelectMDx (MDxHealth, Nijmegen, The Netherlands) test is a urinary-based biomarker test intended to be used to predict presence of high-grade PCa upon biopsy in men with elevated serum prostate-specific antigen (PSA) levels. Previous validation of the SelectMDx test revealed that 53% of the unnecessary biopsies (biopsies indicating no- or GG1 PCa) could be avoided using the SelectMDx test as a decision-tool to select men for prostate biopsy. The objective of this study is to examine the use of the commercially available SelectMDx test under routine, real-life practice. METHODS: Men that underwent a SelectMDx test between May 2019 and December 2020 and that were originating from countries that perform the SelectMDx test on a regular basis were included in this study, resulting in 5157 cases from 10 European countries. Clinical parameters, urinary RNA scores, and test outcomes were compared between PSA groups, age groups, countries, and the validation cohort (described previously [4]) using the Mann-Whitney U test, Chi-Square test, Benjamini-Hochberg and Kruskal-Wallis tests. RESULTS: 40.72% of the cases received a negative SelectMDx result. The test is also used in patients outside the intended-use population (PSA < 3 and >10 ng/mL). Clinical parameters (age, PSA density, DRE outcome) varied between patient population from individual countries and the validation cohort, resulting in differences in the potential number of saved biopsies using the test. CONCLUSIONS: The potential number of reduced biopsies in clinical use was 40,72% using the SelectMDx test, assuming a negative SelectMDx test resulted in the decision not to biopsy the patient. This is higher compared to the validation cohort, which is explained by differences in patient population.

Contains fulltext : 244041.pdf (Publisher’s version ) (Open Access), Effective management and treatment of fungal diseases is hampered by poor diagnosis, limited options for antifungal therapy, and the emergence of antifungal drug resistance. An understanding of molecular mechanisms contributing to resistance is essential to optimize the efficacy of currently available antifungals. In this perspective, one of the oldest antifungals, 5-fluorocytosine (5-FC), has been the focus of recent studies applying advanced genomic and transcriptomic techniques to decipher the order of events at the molecular level that lead to resistance. These studies have highlighted the complexity of resistance and provided new insights that are reviewed in the present paper.

Item does not contain fulltext, Molecular diagnosis; Viral infection; Chemokines; Disease prognosis; CXCL10; CXCL11; CCL3; CCL4; CCL5; Random forest.

Contains fulltext : 242613.pdf (Publisher’s version ) (Open Access)

Contains fulltext : 242774.pdf (Publisher’s version ) (Open Access)

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Radboud University, 17 december 2021, Promotores : Verweij, P.E., Melchers, W.J.G. Co-promotores : Merkus, P.J.F.M., Meis, J.F.G.M., Contains fulltext : 240235.pdf (Publisher’s version ) (Open Access)