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1. The Aptima HPV Assay Fulfills the Cross-Sectional Clinical and Reproducibility Criteria of International Guidelines for Human Papillomavirus Test Requirements for Cervical Screening

Author

Heideman, DAM, Hesselink, AT, van Kemenade, FJ, Iftner, T, Berkhof, J, Topal, F, Agard, D, Meijer, CJLM, and Snijders, PJF

Subjects
Cervical Cancer, Cancer, Sexually Transmitted Infections, Biotechnology, Infectious Diseases, Clinical Research, Genetics, Adult, Early Detection of Cancer, Female, Humans, Middle Aged, Molecular Diagnostic Techniques, Papillomaviridae, Papillomavirus Infections, Reproducibility of Results, Sensitivity and Specificity, Uterine Cervical Dysplasia, Biological Sciences, Agricultural and Veterinary Sciences, Medical and Health Sciences, Microbiology
Abstract

The Aptima HPV assay (Hologic Gen-Probe, San Diego, CA) is an FDA-approved assay for detecting human papillomavirus (HPV) E6/E7 mRNA from 14 high-risk HPV types. This study evaluated the clinical performance of the Aptima HPV assay for cervical intraepithelial neoplasia of grade 2 or worse (CIN2+), relative to the high-risk HPV GP5+/GP6+ PCR, in a cross-sectional clinical equivalence analysis using the noninferiority score test with cervical samples from population-based screening, i.e., 69 cervical scraping samples from women with CIN2+ and 843 from women without evidence of CIN2+. In addition, intralaboratory reproducibility over time and interlaboratory agreement of the Aptima HPV assay results were assessed with another set of 548 cervical samples. The Aptima HPV assay showed a clinical sensitivity for CIN2+ of 94.2% (95% confidence interval [CI], 85.5 to 97.8%) and a clinical specificity for CIN2+ of 94.5% (95% CI, 92.8 to 95.9%); by comparison, these figures were 97.1% (95% CI, 89.1 to 99.3%) (67/69 samples) and 93.6% (95% CI, 91.7 to 95.0%) (785/839 samples), respectively, for GP5+/GP6+ PCR. The clinical sensitivity and specificity of the Aptima HPV assay were noninferior to those of GP5+/GP6+ PCR (P = 0.039 and 0.00016, respectively). In addition, high reproducibility of the Aptima HPV assay, as reflected by the intralaboratory reproducibility over time of 96.0% (95% CI, 94.4 to 97.3%) (526/548 samples; kappa = 0.89) and interlaboratory agreement of 96.7% (95% CI, 95.4 to 98.1%) (531/548 samples; kappa = 0.91), was found. Altogether, these data show that the Aptima HPV assay meets the cross-sectional clinical and reproducibility criteria of the international guidelines for HPV test requirements for cervical screening. Longitudinal data are needed to ensure that the long-term negative predictive value of this mRNA assay is similar to those of validated HPV DNA tests.

Published
2013

6. Comparing the performance of FAM19A4 methylation analysis, cytology and HPV16/18 genotyping for the detection of cervical (pre)cancer in high-risk HPV-positive women of a gynecologic outpatient population (COMETH study)

Author

Luttmer, R, De Strooper, LMA, Berkhof, J, Snijders, PJF, Dijkstra, MG, Uijterwaal, MH, Steenbergen, RDM, van Kemenade, Folkert, Rozendaal, L, Helmerhorst, Verheijen, RHM, ter Harmsel, WA, van Baal, WM, Graziosi, PGCM, Quint, WGV, Heideman, DAM, Meijer, CJLM, Pathology, and Obstetrics & Gynecology

Subjects
SDG 3 - Good Health and Well-being, female genital diseases and pregnancy complications
Abstract

Recently, DNA methylation analysis of FAM19A4 in cervical scrapes has been shown to adequately detect high-grade cervical intraepithelial neoplasia and cervical cancer (>= CIN3) in high-risk HPV (hrHPV)-positive women. Here, we compared the clinical performance of FAM19A4 methylation analysis to cytology and HPV16/18 genotyping, separately and in combination, for >= CIN3 detection in hrHPV-positive women participating in a prospective observational multi-center cohort study. The study population comprised hrHPV-positive women aged 18-66 years, visiting a gynecological outpatient clinic. From these women, cervical scrapes and colposcopy-directed biopsies (for histological confirmation) were obtained. Cervical scrapes were analyzed for FAM19A4 gene promoter methylation, cytology and HPV16/18 genotyping. Methylation analysis was performed by quantitative methylation-specific PCR (qMSP). Sensitivities and specificities for >= CIN3 were compared between tests. Stratified analyses were performed for variables that potentially influence marker performance. Of all 508 hrHPV-positive women, the sensitivities for >= CIN3 of cytology, FAM19A4 methylation analysis, and cytology combined with HPV16/18 genotyping were 85.6, 75.6 and 92.2%, respectively, with corresponding specificities of 49.8, 71.1 and 29.4%, respectively. Both sensitivity and specificity of FAM19A4 methylation analysis were associated with age (p = 30 years (n=287), >= CIN3 sensitivity of FAM19A4 methylation analysis was 88.3% (95% CI: 80.2-96.5) which was noninferior to that of cytology [85.5% (95% CI: 76.0-94.0)], at a significantly higher specificity [62.1% (95% CI: 55.8-68.4) compared to 47.6% (95% CI: 41.1-54.1)]. In conclusion, among hrHPV-positive women from an outpatient population aged >= 30 years, methylation analysis of FAM19A4 is an attractive marker for the identification of women with >= CIN3.

Published
2016

7. The clinical value of HPV genotyping in triage of women with high-risk-HPV-positive self-samples

Author

Ebisch, RMF, de Kuyper-de Ridder, GM, Bosgraaf, RP, Massuger, LFAG, IntHout, J, Verhoef, VMJ, Heideman, DAM, Snijders, PJF, Meijer, CJLM, van Kemenade, Folkert, Bulten, J, Siebers, AG, Bekkers, RLM, Melchers, WJG, and Pathology

Subjects
SDG 3 - Good Health and Well-being, female genital diseases and pregnancy complications
Abstract

Cytology alone, or combined with HPV16/18 genotyping, might be an acceptable method for triage in hrHPV-cervical cancer screening. Previously studied HPV-genotype based triage algorithms are based on cytology performed without knowledge of hrHPV status. The aim of this study was to explore the value of hrHPV genotyping combined with cytology as triage tool for hrHPV-positive women. 520 hrHPV-positive women were included from a randomised controlled self-sampling trial on screening non-attendees (PROHTECT-3B). Eighteen baseline triage strategies were evaluated for cytology and hrHPV genotyping (Roche Cobas 4800) on physician-sampled triage material. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), referral rate, and number of referrals needed to diagnose (NRND) were calculated for CIN2+ and CIN3+. A triage strategy was considered acceptable if the NPV for CIN3+ was >98%, combined with maintenance or improvement of sensitivity and an increase in specificity in reference to the comparator, being cytology with a threshold of atypical cells of undetermined significance (ASC-US). Three triage strategies met the criteria: HPV16+ and/or >LSIL; HPV16+ and/or >HSIL; (HPV16+ and/or HPV18+) and/or >HSIL. Combining HPV16+ and/or >HSIL yielded the highest specificity (74.9%, 95% CI 70.5-78.9), with a sensitivity (94.4%, 95% CI 89.0-97.7) similar to the comparator (93.5%, 95% CI 87.7-97.1), and a decrease in referral rate from 52.2% to 39.5%. In case of prior knowledge of hrHPV presence, triage by cytology testing can be improved by adjusting its threshold, and combining it with HPV16/18 genotyping. These strategies improve the referral rate and specificity for detecting CIN3+ lesions, while maintaining adequate sensitivity.

Published
2016

8. Comparative performance of novel self-sampling methods in detecting high-risk human papillomavirus in 30,130 women not attending cervical screening

Author

Bosgraaf, RP, Verhoef, VMJ, Massuger, LFAG, Siebers, AG, Bulten, J, de Kuyper-de Ridder, GM, Meijer, CJM, Snijders, PJF, Heideman, DAM, IntHout, J, van Kemenade, Folkert, Melchers, WJG, Bekkers, RLM, and Pathology

Subjects
SDG 3 - Good Health and Well-being, female genital diseases and pregnancy complications
Abstract

We determined whether the participation rate for a brush-based cervicovaginal self-sampling device is noninferior to the participation rate for a lavage-based one for testing for hrHPV (high-risk human papillomavirus). Additionally, positivity rates for hrHPV, the detection rates for cervical intraepithelial neoplasia grades 2 and 3 or worse (CIN2+/3+), and user comfort were compared. A total of 35,477 non-responders of the regular cervical screening program aged 33-63 years were invited to participate. Eligible women (n=30,130) were randomly assigned to receive either a brush-based or a lavage-based device, and a questionnaire for reporting user convenience. Self-sampling responders testing hrHPV-positive were invited for a physician-taken sample for cytology; triage-positive women were referred for colposcopy. A total of 5,218 women participated in the brush-based sampling group (34.6%) and 4809 women in the lavage-based group (31.9%), i.e. an absolute difference of 2.7% (95%CI 1.8-4.2). The hrHPV-positivity rates in the two groups were identical (8.3%, relative risk (RR) 0.99, 95%CI 0.87-1.13). The detection of CIN2+ and CIN3+ in the brush group (2.0% for CIN2+; 1.3% for CIN3+) was similar to that in the lavage group (1.9% for CIN2+; 1.0% for CIN3+) with a cumulative RR of 1.01, 95%CI 0.83-1.24 for CIN2+ and 1.25, 95%CI 0.92-1.70 for CIN3+. The two self-sampling devices performed similarly in user comfort. In conclusion, offering a brush-based device to non-responders is noninferior to offering a lavage-based device in terms of participation. The two self-sampling methods are equally effective in detecting hrHPV, CIN2+/CIN3+ and are both well accepted. What's new? If people won't come into the clinic to get tested for HPV, send the test to them: that's the public health strategy the Netherlands will employ beginning in 2016. This study compared two methods of self-sampling for HPV, one brush based and one lavage based. The authors measured participation rates, user comfort, how often each method detected the virus, and how often neoplasias were detected. They found non-inferiority in the participation rates, and in all other measures the two methods performed equally well.

Published
2015

9. Validation of the FAM19A4/mir124-2 DNA methylation test for both lavage- and brush-based self-samples to detect cervical (pre)cancer in HPV-positive women

Author

De Strooper, LMA, Verhoef, VMJ, Berkhof, J, Hesselink, AT, de Bruin, HME, van Kemenade, Folkert, Bosgraaf, RP, Bekkers, RLM, Massuger, LFAG, Melchers, WJG, Steenbergen, RDM, Snijders, PJF, Meijer, CJLM, Heideman, DAM, De Strooper, LMA, Verhoef, VMJ, Berkhof, J, Hesselink, AT, de Bruin, HME, van Kemenade, Folkert, Bosgraaf, RP, Bekkers, RLM, Massuger, LFAG, Melchers, WJG, Steenbergen, RDM, Snijders, PJF, Meijer, CJLM, and Heideman, DAM

Abstract

Objectives. DNA methylation analysis of cancer-related genes is a promising tool for HPV-positive women to identify those with cervical (pre)cancer (CIN3+) in need of treatment. However, clinical performance of methylation markers can be influenced by the sample type utilized. We describe a multiplex quantitative methylation-specific PCR that targets FAM19A4 and mir124-2 loci, to detect CIN3+ using both HPV-positive lavage- and brush self-samples. Methods. We determined methylation thresholds for clinical classification using HPV-positive training sets comprising lavage self-samples of 182 women (including 40 with CIN3+) and brush self-samples of 224 women (including 61 with CIN3+). Subsequently, independent HPV-positive validation sets of 389 lavage self-samples (including 78 with CIN3+), and 254 brush self-samples (including 72 with CIN3+) were tested using the preset thresholds. Furthermore, the clinical performance of combined methylation analysis and HPV16/18 genotyping was determined. Results. Training set analysis revealed similar FAM19A4 and mir124-2 thresholds for both self-sample types to yield highest CIN3+ sensitivity at 70% specificity. Validation set analysis resulted in a CIN3+ sensitivity of 70.5% (95%CI: 60.4-80.6) at a specificity of 67.8% (95%CI: 62.7-73.0) for lavage self-samples, and a CIN3+ sensitivity of 69.4% (95%CI: 58.8-80.1) at a 76.4% (95%CI: 70.2-82.6) specificity for brush self-samples. In combination with HPV16/18 genotyping, CIN3+ sensitivity and specificity were 88.5% (95%CI: 81.4-95.6) and 46.0% (95%CI: 40.4-51.5) for lavage self-samples, and 84.7% (95%CI: 76.4-93.0) and 54.9% (95%CI: 47.7-62.2) for brush self-samples. Conclusions. FAM19A4/mir124-2 methylation analysis performs equally well in HPV-positive lavage- and brush self-samples to identify women with CIN3+. In combination with HPV16/18 genotyping, significantly higher CIN3+ sensitivities are obtained, at decreased specificity. (C) 2016 The Authors. Published by Elsevier Inc

Published
2016

10. FAM19A4 methylation analysis in self-samples compared with cervical scrapes for detecting cervical (pre)cancer in HPV-positive women

Author

Luttmer, R, De Strooper, LMA, Dijkstra, MG, Berkhof, J, Snijders, PJF, Steenbergen, RDM, van Kemenade, Folkert, Rozendaal, L, Helmerhorst, Verheijen, RHM, ter Harmsel, WA, van Baal, WM, Graziosi, PGCM, Quint, WGV, Spruijt, JWM, van Dijken, DKE, Heideman, DAM, Meijer, CJLM, Luttmer, R, De Strooper, LMA, Dijkstra, MG, Berkhof, J, Snijders, PJF, Steenbergen, RDM, van Kemenade, Folkert, Rozendaal, L, Helmerhorst, Verheijen, RHM, ter Harmsel, WA, van Baal, WM, Graziosi, PGCM, Quint, WGV, Spruijt, JWM, van Dijken, DKE, Heideman, DAM, and Meijer, CJLM

Abstract

Background: High-risk human papillomavirus (hrHPV)-positive women require triage to identify those with cervical high-grade intraepithelial neoplasia and cancer (>= CIN3 (cervical intraepithelial neoplasia grade 3)). FAM19A4 methylation analysis, which detects advanced CIN and cancer, is applicable to different sample types. However, studies comparing the performance of FAM19A4 methylation analysis in hrHPV-positive self-samples and paired physician-taken scrapes are lacking. Methods: We compared the performance of FAM19A4 methylation analysis (and/or HPV16/18 genotyping) in self-samples and paired physician-taken scrapes for >= CIN3 detection in hrHPV-positive women (n = 450,18-66 years). Results: Overall FAM19A4 methylation levels between sample types were significantly correlated, with strongest correlation in women with >= CIN3 (Spearman's rho 0.697, P<0.001). The performance of FAM19A4 methylation analysis and/or HPV16/18 genotyping did not differ significantly between sample types. In women >= 30 years, >= CIN3 sensitivity of FAM19A4 methylation analysis was 78.4% in self-samples and 88.2% in scrapes (ratio 0.89; CI: 0.75-1.05). In women <30 years, >= CIN3 sensitivities were 37.5% and 45.8%, respectively (ratio 0.82; CI: 0.55-1.21). In both groups, >= CIN3 specificity of FAM19A4 methylation analysis was significantly higher in self-samples compared with scrapes. Conclusions: FAM19A4 methylation analysis in hrHPV-positive self-samples had a slightly lower sensitivity and a higher specificity for >= CIN3 compared with paired physician-taken scrapes. With a similarly good clinical performance in both sample types, combined FAM19A4 methylation analysis and HPV16/18 genotyping provides a feasible triage strategy for hrHPV-positive women, with direct applicability on self-samples.

Published
2016

11. A beneficial tumor microenvironment in oropharyngeal squamous cell carcinoma is characterized by a high T cell and low IL-17(+) cell frequency

Author

Punt, S, Dronkers, Emilie, Welters, MJP, Goedemans, R, Koljenovic, Senada, Bloemena, E, Snijders, PJF, Gorter, A, van der Burg, SH, Baatenburg de Jong, R.J., Jordanova, ES, Punt, S, Dronkers, Emilie, Welters, MJP, Goedemans, R, Koljenovic, Senada, Bloemena, E, Snijders, PJF, Gorter, A, van der Burg, SH, Baatenburg de Jong, R.J., and Jordanova, ES

Abstract

Patients with HPV-positive oropharyngeal squamous cell carcinomas (OPSCCs) have a better prognosis than patients with non-HPV-induced OPSCC. The role of the immune response in this phenomenon is yet unclear. We studied the number of T cells, regulatory T cells (Tregs), T helper 17 (Th17) cells and IL-17(+) non-T cells (mainly granulocytes) in matched HPV-positive and HPV-negative OPSCC cases (n = 162). Furthermore, the production of IFN-gamma and IL-17 by tumor-infiltrating T cells was analyzed. The number of tumor-infiltrating T cells and Tregs was higher in HPV-positive than HPV-negative OPSCC (p < 0.0001). In contrast, HPV-negative OPSCC contained significantly higher numbers of IL-17(+) non-T cells (p < 0.0001). Although a high number of intra-tumoral T cells showed a trend toward improved survival of all OPSCC patients, their prognostic effect in patients with a low number of intra-tumoral IL-17(+) non-T cells was significant with regard to disease-specific (p = 0.033) and disease-free survival (p = 0.012). This suggests that a high frequency of IL-17(+) non-T cells was related to a poor immune response, which was further supported by the observation that a high number of T cells was correlated with improved disease-free survival in the HPV-positive OPSCC (p = 0.008). In addition, we detected a minor Th17 cell population. However, T cells obtained from HPV-positive OPSCC produced significantly more IL-17 than those from HPV-negative tumors (p = 0.006). The improved prognosis of HPV-positive OPSCC is thus correlated with higher numbers of tumor-infiltrating T cells, more active Th17 cells and lower numbers of IL-17(+) non-T cells.

Published
2016

12. Agreement between colposcopic impression and histological diagnosis among human papillomavirus type 16-positive women: a clinical trial using dynamic spectral imaging colposcopy

Author

Zaal, A, Louwers, Jacqueline, Berkhof, J, Kocken, Marielle, ter Harmsel, WA, Graziosi, GCM, Spruijt, JWM, Balas, C, Papagiannakis, E, Snijders, PJF, Meijer, CJLM, van Kemenade, Folkert, Verheijen, RHM, Obstetrics & Gynecology, and Erasmus MC other

Subjects
SDG 3 - Good Health and Well-being, female genital diseases and pregnancy complications
Abstract

Objective To investigate the agreement between conventional colposcopic impression, dynamic spectral imaging (DSI) colposcopy and histology, for human papillomavirus type 16-positive (HPV16(+)) and non-16 high-risk (hr) HPV + women. Design Prospective, comparative, multicentre clinical trial. Setting Three colposcopy clinics in the Netherlands. Population Women (n = 177) aged 18 years or over with an intact cervix, referred for colposcopy. Methods The colposcopist graded the lesion by using the DSI colposcope as a regular video colposcope. Subsequently the DSI impression was displayed and biopsies were taken from all abnormal areas as well as from a random (normal) site. A cervical smear was taken for HPV typing. Main outcome measures Histologically confirmed high-grade cervical intraepithelial neoplasia or cancer (CIN2(+)), positive for HPV16 or for any other hrHPV type. Results The DSI colposcope identified more CIN2(+) cervical lesions among HPV16(+) women than in non-16 hrHPV(+) women (P = 0.032 regardless of final histology and P = 0.009 among women with CIN2(+)). Consequently, the sensitivity of the DSI colposcope for detecting CIN2(+) lesions was higher in HPV16(+) women than in non-16 hrHPV(+) women (97% versus 74%, P = 0.009). No such differences were seen for the colposcopist impression. In addition, mainly smaller cervical lesions are missed by the col Conclusions The sensitivity of DSI colposcopy for CIN2(+) is higher in HPV16(+) than in non-16 hrHPV(+) women. Furthermore, regardless of HPV16 status, the sensitivity of DSI for CIN2(+) is higher than that of the colposcopist, probably because colposcopists tend to miss smaller cervical lesions.

Published
2012

13. KRAS and BRAF Mutation Analysis in Routine Molecular Diagnostics Comparison of Three Testing Methods on Formalin-Fixed, Paraffin-Embedded Tumor-Derived DNA

Author

Heideman, DAM, Lurkin, Irene, Doeleman, M, Smit, EF, Verheul, HM, Meijer, GA, Snijders, PJF, Thunnissen, E, Zwarthoff, Ellen, and Pathology

Subjects
SDG 3 - Good Health and Well-being
Abstract

Accurate mutation detection assays are strongly needed for use in routine molecular pathology analyses to aid in the selection of patients with cancer for targeted therapy. The high-resolution melting (HRM) assay is an ideal prescreening tool, and SNaPshot analysis offers a straightforward genotyping system. Our present study was determined to compare these mutation testing methods on formalin-fixed, paraffin-embedded (FFPE) tumor derived DNA. We compared the performance of HRM, followed by cycle sequencing (HRM-sequencing); multiplex PCR assay, followed by SNaPshot analysis (multiplex mutation assay); and a successor assay using HRM, followed by SNaPshot (HRM-SNaPshot) for mutation analysis of both KRAS (codon 12/13/61) and BRAF (codon 600/601). In a series of 195 FFPE-derived DNA specimens, a high genotypic concordance between HRM-sequencing and multiplex mutation assay was found (kappa, 0.98; 95% CI, 0.94 to 1), underlining the potential of a combined HRM-SNaPshot approach. In reconstruction experiments, the analytical sensitivity of HRM-SNaPshot was twofold to fourfold higher than HRM-sequencing and multiplex mutation assay, respectively. In addition, HRM-SNaPshot had a good performance rate (99%) on FFPE tumor derived DNA, and mutation detection was highly concordant with the predecessor assays (K for both, 0.98). The occurrence of BRAF and KRAS mutations is mutually exclusive. HRM-SNaPshot is an attractive method for mutation analysis in pathology, given its good performance rate on FFPE-derived DNA, high analytical sensitivity, and prescreening approach. (J Mol Diagn 2012, 14:247-255; DOI: 10.1016/j.jmoldx.2012.01.011)

Published
2012

14. Dynamic spectral imaging colposcopy: higher sensitivity for detection of premalignant cervical lesions

Author

Louwers, JA, Zaal, A, Kocken, Marielle, ter Harmsel, WA, Graziosi, GCM, Spruijt, JWM, Berkhof, J, Balas, C, Papagiannakis, E, Snijders, PJF, Meijer, CJLM, van Kemenade, Folkert, Verheijen, RHM, Obstetrics & Gynecology, and Erasmus MC other

Abstract

Objective To validate the dynamic spectral imaging (DSI) colposcope's colour-coded map in discriminating high- from low-grade cervical lesions and non-neoplastic tissue. Design Prospective, comparative, multicentre clinical trial. Setting The colposcopy clinics of three Dutch hospitals. Population Women of 18 years or over with an intact cervix, referred for colposcopy. Methods During a 3-minute image acquisition phase, the DSI colposcope was used as a regular video colposcope: the colposcopist located and graded potential lesions based on conventional colposcopic criteria. Subsequently, a colour-coded map was calculated and displayed, representing localisation and severity of the cervical lesion. Biopsies were collected from all atypical sites, as identified by digital mapping and/or conventional colposcopy. Furthermore, one additional biopsy was taken. Main outcome measures Histologically confirmed high-grade cervical disease (CIN2+). Results In total 275 women were included in the study: 183 women were analysed in the 'according-to-protocol' (ATP) cohort and 239 women in the 'intention-to-treat' (ITT) cohort. In the ATP cohort, the sensitivity of DSI colposcopy to identify women with high-grade (CIN2+) lesions was 79% (95% CI 70-88) and the sensitivity of conventional colposcopy was 55% (95% CI 44-65) (P = 0.0006, asymptotic McNemar test). When the DSI colour-coded map was combined with conventional colposcopy, the sensitivity was 88% (95% CI 82-95). Conclusions DSI colposcopy has a significantly higher sensitivity to detect cervical lesions than conventional colposcopy. If the colour-coded map is combined with conventional colposcopic examination, the sensitivity increases further.

Published
2011

15. Triaging borderline/mild dyskaryotic Pap cytology with p16/Ki-67 dual-stained cytology testing: cross-sectional and longitudinal outcome study

Author

Uijterwaal, MH, Witte, BI, van Kemenade, Folkert, Rijkaart, D, de Ridder, R, Berkhof, J, Balfoort-van de Meij, GAMA, Bleeker, MCG, Snijders, PJF, Meijer, CJLM, Uijterwaal, MH, Witte, BI, van Kemenade, Folkert, Rijkaart, D, de Ridder, R, Berkhof, J, Balfoort-van de Meij, GAMA, Bleeker, MCG, Snijders, PJF, and Meijer, CJLM

Abstract

Background: Women with borderline/mildly dyskaryotic (BMD) cytology smears are currently followed up with repeat testing at 6 and 18 months. The objective of this study is to analyse the cross-sectional and longitudinal performance of p16/Ki-67 dual-stained cytology for the detection of cervical intraepithelial neoplasia (CIN) grade 3 or worse (CIN3+) and CIN2+ in women with BMD, and to compare the results with baseline human papillomavirus (HPV) testing. Methods: Conventional Pap cytology specimens of 256 women with BMD were dual stained for p16/Ki-67 retrospectively, and compared with baseline HPV results and long-term follow-up results. Results: p16/Ki-67 dual-stained cytology showed a sensitivity of 100%, a specificity of 64.4% and a negative predictive value (NPV) of 100.% for CIN3+. Human papillomavirus testing demonstrated similar sensitivity (96.3%), and NPV (99.1%), but a significantly lower specificity (57.6%; P = 0.024) for CIN3+. Sensitivity, specificity and NPV for CIN2+ of dual-stained cytology were 89.7%, 73.1% and 95.1%, respectively, which was similar when compared with HPV testing. Dual-stained cytology showed a significant lower referral rate than HPV testing (43.6% vs 49.1%; P = 0.043). During long-term follow-up, no CIN3+ lesions developed in HPV-positive, dual-stained negative women. Conclusions: Comparable sensitivity and NPV of dual-stained cytology for CIN3+, combined with a significantly higher specificity, makes p16/Ki-67 dual-stained cytology a viable alternative to HPV testing for triaging BMD.

Published
2014

16. Surveillance van pathogenen in Nederland - Detailkarakterisering van pathogenen die relevant zijn voor de openbare gezondheidszorg

Author

Avoort HGAM van der, Binnendijk RS van, Boer J den, Boxman ILA, Bruisten S, Duizer E, Duynhoven YTHP, Ende A van de, Erkens CGM, Giessen AW van de, Giessen J van der, Godeke GJ, Greeff SC de, Hahne S, Herremans MMPT, Heuvelink A, Hof S van, Kimman TG, Koopmans MPG, Kortbeek L, Kremer K, Kuijper EJ, Laar MJW van de, Loon AJM van, Luytjes W, Meijer A, Meijer CJLM, Mooi FR, Neeling H de, Notermans DW, Op de Coul ELM, Peeters MF, Pelt W van, Pinelli E, Plas SM van der, Reimerink J, Reubsaet F, Schouls LM, Schuurman R, Snijders PJF, Soolingen D van, Vennema H, Wannet WJB, Wielinga P, Wijngaard CC van den, Wilbrink B, Wolf F de, Zaaijer HL, Boot H, LTR, LIS, and VTV

Subjects
infectious deseases control, kiemsurveillance, prevention, preventie, pathogenen, detailkarakterisering, pathogen surveillance, charaterisation, bestrijding
Abstract

Increased surveillance of pathogens may for strengthen the prevention and control of infectious diseases. Infectious diseases cause a considerable burden of disease the Netherlands. Detailed characterization of pathogens will yield insight in changes of the pathogen itself, in changes in transmission patterns, and in changes in virulence and resistance. Therefore it is necessary to determine which pathogens should be studied, to what level of detail, and how they should be collected. In this report , the bacteria, viruses and parasites that give the the greatest burden of disease or present the greatest risk for the public health have been described in a standardized way. Several pathogens emerge from this study for which an increase in collection and characterization is desirable. Examples are: 1) Human papillomavirus, to improve assessment of the potential vaccine efficacy. 2) Influenza virus, to better characterize resistance to antiviral drugs. 3) Bordetella pertusis (whooping cough), to detect population changes that can influence vaccine efficacy. 4) Meticillin-resistance Staphylococcus aureus (MRSA), to reduce delays in contact-source tracing and containment. The pathogen surveillance in the Netherlands will be intensified on basis of this report. This enhanced surveillance will be executed in close co-operation with the peripheral microbiological laboratories.

Published
2007

17. Vaccin ter voorkoming van baarmoederhalskanker?

Author

Kocken, Marielle, Louwers, Jacqueline, ter Harmsel, WA, Meijer, CJLM, Quint, WGV (Wim), Snijders, PJF, Verheijen, RHM, Helmerhorst, Obstetrics & Gynecology, and Virology

Subjects
SDG 3 - Good Health and Well-being
Published
2006

18. Vaccinatie ter preventie van cervixcarcinoom

Author

Kocken, Marielle, Louwers, Jacqueline, Helmerhorst, Meijer, CJLM, Quint, WGV (Wim), Snijders, PJF, Verheijen, RHM, ter Harmsel, WA, Obstetrics & Gynecology, and Virology

Subjects
SDG 3 - Good Health and Well-being
Published
2006

19. Prevalence of human papillomavirus infection in women in Busan, South Korea

Author

Shin, Hr, Lee, Dh, Herrero, R, Smith, Js, Vaccarella, S, Hong, Sh, Jung, Ky, Kim, Hh, Park, Ud, Cha, Hs, Park, S, Touzé, Antoine, Munoz, N, Snijders, Pjf, Meijer, Cjlm, Coursaget, Pierre, Franceschi, S, Inconnu, and ProdInra, Migration

Subjects
[SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio]
Published
2003

21. Long-term CIN3+risk in women with abnormal cytology; role of hrHPV testing

Author

Kocken, Marielle, Berkhof, J, van Kemenade, Folkert, Louwers, Jacqueline, Zaal, A, Nobbenhuis, MAE, Kenter, G, Snijders, PJF, Meijer, CJLM, Helmerhorst, Kocken, Marielle, Berkhof, J, van Kemenade, Folkert, Louwers, Jacqueline, Zaal, A, Nobbenhuis, MAE, Kenter, G, Snijders, PJF, Meijer, CJLM, and Helmerhorst

Abstract

BACKGROUND: Many studies have examined the short-term value of high-risk human papillomavirus (hrHPV) testing in predicting cumulative risk of cervical intraepithelial neoplasia grade 3 or cancer (CIN3+). This study focuses on long-term CIN3+ risk after initial wait and see policy. METHODS: A total of 342 women with abnormal cytology of borderline/mild dyskaryosis (BMD) or worse (>BMD), included between 1990 and 1992, were followed-up by cytology and hrHPV testing until 1996 and monitored by cytology thereafter. Primary endpoint was cumulative CIN3+ risk by December 2009. RESULTS: Women with BMD had a 5-year CIN3+ risk of 22.5% (95% confidence interval (CI) 17.0-29.1) and of 0.7% (0.1-4.5) in the subsequent 5 years. High-risk human papillomavirus-negative women with BMD had a 5-year risk of <0.01% (95% CI 0.0-5.1) and of <0.01% (0.0-5.7) in the following 5 years, while for hrHPV-positive women these risks were 37.5% (29.0-46.9) and 1.6% (0.2-9.5), respectively. Women with >BMD had a 5-year risk of 45.1% (36.4-54.1) and of 3.5% (0.9-12.2) in the subsequent 5 years CONCLUSION: Women with BMD have an elevated CIN3+ risk for 5 years only; afterwards their risk is similar to the general population. High-risk human papillomavirus-negative women with BMD may return to regular screening directly. All other women with >= BMD should be referred for additional testing and/or colposcopy. British Journal of Cancer (2012) 106, 817-825. doi:10.1038/bjc.2012.5 www.bjcancer.com Published online 14 February 2012 (C) 2012 Cancer Research UK

Published
2012

25. Surveillance van pathogenen in Nederland - Detailkarakterisering van pathogenen die relevant zijn voor de openbare gezondheidszorg

Author

Boot H, LTR, LIS, VTV, Avoort HGAM van der, Binnendijk RS van, Boer J den, Boxman ILA, Bruisten S, Duizer E, Duynhoven YTHP, Ende A van de, Erkens CGM, Giessen AW van de, Giessen J van der, Godeke GJ, Greeff SC de, Hahne S, Herremans MMPT, Heuvelink A, Hof S van, Kimman TG, Koopmans MPG, Kortbeek L, Kremer K, Kuijper EJ, Laar MJW van de, Loon AJM van, Luytjes W, Meijer A, Meijer CJLM, Mooi FR, Neeling H de, Notermans DW, Op de Coul ELM, Peeters MF, Pelt W van, Pinelli E, Plas SM van der, Reimerink J, Reubsaet F, Schouls LM, Schuurman R, Snijders PJF, Soolingen D van, Vennema H, Wannet WJB, Wielinga P, Wijngaard CC van den, Wilbrink B, Wolf F de, Zaaijer HL, Boot H, LTR, LIS, VTV, Avoort HGAM van der, Binnendijk RS van, Boer J den, Boxman ILA, Bruisten S, Duizer E, Duynhoven YTHP, Ende A van de, Erkens CGM, Giessen AW van de, Giessen J van der, Godeke GJ, Greeff SC de, Hahne S, Herremans MMPT, Heuvelink A, Hof S van, Kimman TG, Koopmans MPG, Kortbeek L, Kremer K, Kuijper EJ, Laar MJW van de, Loon AJM van, Luytjes W, Meijer A, Meijer CJLM, Mooi FR, Neeling H de, Notermans DW, Op de Coul ELM, Peeters MF, Pelt W van, Pinelli E, Plas SM van der, Reimerink J, Reubsaet F, Schouls LM, Schuurman R, Snijders PJF, Soolingen D van, Vennema H, Wannet WJB, Wielinga P, Wijngaard CC van den, Wilbrink B, Wolf F de, and Zaaijer HL

Abstract

RIVM rapport:Increased surveillance of pathogens may for strengthen the prevention and control of infectious diseases. Infectious diseases cause a considerable burden of disease the Netherlands. Detailed characterization of pathogens will yield insight in changes of the pathogen itself, in changes in transmission patterns, and in changes in virulence and resistance. Therefore it is necessary to determine which pathogens should be studied, to what level of detail, and how they should be collected. In this report , the bacteria, viruses and parasites that give the the greatest burden of disease or present the greatest risk for the public health have been described in a standardized way. Several pathogens emerge from this study for which an increase in collection and characterization is desirable. Examples are: 1) Human papillomavirus, to improve assessment of the potential vaccine efficacy. 2) Influenza virus, to better characterize resistance to antiviral drugs. 3) Bordetella pertusis (whooping cough), to detect population changes that can influence vaccine efficacy. 4) Meticillin-resistance Staphylococcus aureus (MRSA), to reduce delays in contact-source tracing and containment. The pathogen surveillance in the Netherlands will be intensified on basis of this report. This enhanced surveillance will be executed in close co-operation with the peripheral microbiological laboratories., Verdere intensivering van de analyse van pathogenen in Nederland is nodig om preventie en bestrijding van infectieziekten te verbeteren. Infectieziekten veroorzaken een aanzienlijke ziektelast in Nederland. Daarnaast gaat van infectieziekten ook een grote dreiging uit voor de openbare gezondheidszorg. Detailkarakterisering van pathogenen geeft inzicht in mogelijke veranderingen van de pathogeen zelf, zoals veranderde virulentie of resistentie. Daarnaast levert het ook inzicht in mogelijk veranderde transmissieroutes. Wel is het noodzakelijk om goed af te wegen welke pathogenen gekarakteriseerd moeten worden, tot welk detailniveau, en hoe groot de steekproef van een bepaalde pathogeen moet zijn om een representatief beeld te krijgen. In dit rapport zijn de bacterien, virussen en parasieten die de grootste ziektelast veroorzaken of de grootste bedreiging vormen voor de openbare gezondheidszorg op een gestandariseerde manier beschreven. In deze beschrijving is in het bijzonder aandacht besteed aan de relevantie van de pathogenen voor de openbare gezondheidszorg. Uit deze inventariserende studie komen een aantal pathogenen naar voren waarvan het wenselijk is om die intensiever te verzamelen en te karateriseren. Voorbeelden hiervan zijn: 1) Humaan papillomavirus, om de potentiele vaccineffectiviteit beter te kunnen inschatten. 2) Influenzavirus, om resistentie tegen antivirale middelen beter in kaart te brengen. 3) Bordetella pertusis (kinkhoest), om populatieveranderingen, die mogelijk de vaccineffectiviteit verlagen, beter te kunnen waarnemen. 4) Meticilline resistente Staphylococcus aureus (MRSA), om bron-en-contact opsporing en inperkingsmaatregelen te versnellen. Dit rapport zal als basis dienen voor de intensivering van de kiemsurveillance van pathogenen in Nederland, die in samenwerking met de perifere microbiologische laboratoria uitgevoerd zal gaan worden.

Published
2007

27. A genome-wide search for genes involed in type 2 diabetes in a recently genetically isolated population from the Netherlands

Author

Aoultchenko, IS, Vaessen, Norbert, Heutink, P, Pullen, J, Snijders, PJF, Hofman, Bert, Ayuningtyas, Wireni, Houwing-Duistermaat, JJ, Edwards, M, Bennett, S, Oostra, Ben, Duijn, Cornelia, Aoultchenko, IS, Vaessen, Norbert, Heutink, P, Pullen, J, Snijders, PJF, Hofman, Bert, Ayuningtyas, Wireni, Houwing-Duistermaat, JJ, Edwards, M, Bennett, S, Oostra, Ben, and Duijn, Cornelia

Published
2003

32. Reliable high risk HPV DNA testing by polymerase chain reaction: an intermethod and intramethod comparison

Author

Jacobs, MV, Snijders, PJF, Voorhorst, FJ, Dillner, J, Forslund, O, Johansson, B, von Knebel Doeberitz, M, Meijer, CJML, Meyer, T, Nindl, I, Pfister, H, Stockfleth, E, Strand, A, Wadell, G, Walboomers, JMM, Jacobs, MV, Snijders, PJF, Voorhorst, FJ, Dillner, J, Forslund, O, Johansson, B, von Knebel Doeberitz, M, Meijer, CJML, Meyer, T, Nindl, I, Pfister, H, Stockfleth, E, Strand, A, Wadell, G, and Walboomers, JMM

Published
1999

34. TP53 mutation and human papilloma virus status of oral squamous cell carcinomas in young adult patients.

Author

Braakhuis, BJM, Rietbergen, MM, Buijze, M, Snijders, PJF, Bloemena, E, Brakenhoff, RH, and Leemans, CR

Subjects
MOUTH tumors, ANALYSIS of variance, FISHER exact test, GENES, GENETIC mutation, PAPILLOMAVIRUS diseases, DATA analysis software, SEQUENCE analysis, GENETICS
Abstract

Objective Little is known about the molecular carcinogenesis of oral squamous cell carcinoma ( OSCC) in young adult patients. The aim of this study was to investigate the detailed TP53 mutation and human papilloma virus ( HPV) status of OSCC in patients, younger than 45 years. Methods TP53 mutations were determined with direct sequencing on paraffin-embedded carcinoma tissue from 31 young patients and compared with two older age OSCC reference groups: one from the same institute ( N = 87) and an independent one ( N = 675). Biologically active tumour HPV was detected by p16-immunohistochemistry followed by a HPV- DNA GP5 + /6 + - PCR. Results HPV16 was present in one OSCC (3%). TP53 mutations were found in 14 (45%) OSCC: five were missense and nine resulted in a truncated protein. Six of these latter were insertions or deletions of one or more nucleotides leading to frameshift, one was at a splice site and two resulted in a stop codon. The percentage of truncating mutations (64% of all mutations) was higher than that observed in the institute's reference group (44%, P = 0.23) and in the independent reference group (24%, P = 0.002). Conclusions This study shows that TP53 mutations are common in OSCC of young adult patients; infection with biologically active HPV is rare. [ABSTRACT FROM AUTHOR]

Published
2014
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43. The influence of fluticasone inhalation on markers of carcinogenesis in bronchial epithelium.

Author

van den Berg RM, van Tinteren H, van Zandwijk N, Visser C, Pasic A, Kooi C, Sutedja TG, Baas P, Grünberg K, Mooi WJ, Snijders PJF, Postmus PE, and Smit EF

Abstract

Rationale: Bronchial epithelium exposed to cigarette smoke undergoes a series of histologic changes that may ultimately lead to invasive cancer. Inhaled corticosteroids reduce the number of lung tumors developing in rats exposed to cigarette smoke. Objectives: We studied the effect of inhaled fluticasone on premalignant lesions in smokers and patients curatively treated for head and neck cancer or lung cancer. Methods: Participants were screened for premalignant lesions by bronchoscopy. Biopsies were taken from three to five locations and classified using WHO criteria. In case of a metaplasia index of > 15%, participants were randomized to receive a powder inhalation device containing either fluticasone 500 mug or a placebo, to be used twice a day. After 6 months, biopsies were obtained from the same locations as previously sampled. Efficacy of treatment was assessed by reversal of metaplasia/dysplasia; secondary endpoints were reversal of increased p53 and KI-67 immunoreactivity and expression of human telomerase reverse transcriptase. Measurements and Main Results: Of the 201 subjects that were screened, 108 were included. Mean age was 53 yr (35-71), mean number of pack-years 48 (18-99), mean metaplasia index 48%, and 32% had some degree of dysplasia at baseline. The two treatment arms did not differ with respect to response or change in either metaplasia index or the expression of the markers p53, KI-67, or human telomerase reverse transcriptase. Conclusions: Inhaled fluticasone in a dose of 500 mug twice a day does not affect the natural course of premalignant lesions in the central airways. [ABSTRACT FROM AUTHOR]

Published
2007
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45. Human papillomavirus and oral cancer: the International Agency for Research on Cancer multicenter study.

Author

Herrero R, Castellsagué X, Pawlita M, Lissowska J, Kee F, Balaram P, Rajkumar T, Sridhar H, Rose B, Pintos J, Fernández L, Idris A, Sánchez MJ, Nieto A, Talamini R, Tavani A, Bosch FX, Reidel U, Snijders PJF, and Meijer CJL

Abstract

Background: Human papillomavirus (HPV), the causal agent of cervical cancer, appears to be involved in the etiology of cancer of the oral cavity and oropharynx. To investigate these associations, we conducted a multicenter case-control study of cancer of the oral cavity and oropharynx in nine countries.Methods: We recruited 1670 case patients (1415 with cancer of the oral cavity and 255 with cancer of the oropharynx) and 1732 control subjects and obtained an interview, oral exfoliated cells, and blood from all participants and fresh biopsy specimens from case patients. HPV DNA was detected by polymerase chain reaction (PCR). Antibodies against HPV16 L1, E6, and E7 proteins in plasma were detected with enzyme-linked immunosorbent assays. Multivariable models were used for case-control and case-case comparisons.Results: HPV DNA was detected in biopsy specimens of 3.9% (95% confidence interval [CI] = 2.5% to 5.3%) of 766 cancers of the oral cavity with valid PCR results and 18.3% (95% CI = 12.0% to 24.7%) of 142 cancers of the oropharynx (oropharynx and tonsil combined) with valid PCR results. HPV DNA in cancer biopsy specimens was detected less frequently among tobacco smokers and paan chewers and more frequently among subjects who reported more than one sexual partner or who practiced oral sex. HPV16 DNA was found in 94.7% of HPV DNA-positive case patients. HPV DNA in exfoliated cells was not associated with cancer risk or with HPV DNA detection in biopsy specimens. Antibodies against HPV16 L1 were associated with risk for cancers of the oral cavity (odds ratio [OR] = 1.5, 95% CI = 1.1 to 2.1) and the oropharynx (OR = 3.5, 95% CI = 2.1 to 5.9). Antibodies against HPV16 E6 or E7 were also associated with risk for cancers of the oral cavity (OR = 2.9, 95% CI = 1.7 to 4.8) and the oropharynx (OR = 9.2, 95% CI = 4.8 to 17.7).Conclusions: HPV appears to play an etiologic role in many cancers of the oropharynx and possibly a small subgroup of cancers of the oral cavity. The most common HPV type in genital cancers (HPV16) was also the most common in these tumors. The mechanism of transmission of HPV to the oral cavity warrants further investigation. [ABSTRACT FROM AUTHOR]

Published
2003

49. Management of HPV-positive women in cervical screening using results from two consecutive screening rounds.

Author

Polman NJ, Veldhuijzen NJ, Heideman DAM, Snijders PJF, Meijer CJLM, and Berkhof J

Subjects
Adult, Algorithms, Colposcopy, Female, Genotype, Human papillomavirus 16 genetics, Human papillomavirus 18 genetics, Humans, Mass Screening methods, Papillomavirus Infections virology, Uterine Cervical Neoplasms virology, Uterine Cervical Dysplasia virology, Early Detection of Cancer methods, Human papillomavirus 16 isolation & purification, Human papillomavirus 18 isolation & purification, Papillomavirus Infections diagnosis, Precancerous Conditions diagnosis, Uterine Cervical Neoplasms diagnosis, Uterine Cervical Dysplasia diagnosis
Abstract

We studied whether triage of human papillomavirus (HPV)-positive women participating in an HPV-based screening programme can be improved by including the HPV result at the previous screen in the triage algorithm. We analyzed data of a subgroup of 366 women from the POBASCAM trial, screened by cytology and HPV cotesting. Women were included if they tested HPV-positive in the second HPV-based screening round. We evaluated the clinical performance of 16 strategies, consisting of cytology, HPV genotyping, and/or previous screen HPV result. The clinical endpoint was cervical precancer or cancer (CIN3+). The current Dutch triage testing policy for HPV-positive women is to refer women for colposcopy if they have abnormal cytology at baseline or after 6-18 months. In the second HPV-based screening round, this strategy yielded a negative predictive value (NPV) of 95.8% (95% confidence interval: 91.9-98.2) and colposcopy referral rate of 37.6% (32.3-43.2%). Replacing repeat cytology by the previous screen HPV result yielded a similar NPV (96.9%, 93.3-98.9) and colposcopy referral rate (38.8%, 33.4-44.4). A higher NPV (99.2%, 96.3-100%) at the cost of a higher colposcopy referral rate (49.2%, 43.6-54.8) was achieved when cytology was combined with HPV16/18 genotyping. The other 13 triage strategies yielded a lower NPV, a higher colposcopy referral rate or performed similarly but required additional testing. HPV-positive women in the second HPV-based screening round can be suitably managed by cytology, HPV16/18 genotyping and the HPV result at the previous screen, obviating the need for repeat testing of HPV-positive, cytology negative women., (© 2018 UICC.)

Published
2019
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50. Virological and Serological Predictors of Anal High-grade Squamous Intraepithelial Lesions Among Human Immunodeficiency Virus-positive Men Who Have Sex With Men.

Author

Marra E, Siegenbeek van Heukelom ML, Leeman A, Waterboer T, Meijer CJLM, Snijders PJF, King AJ, Cairo I, van Eeden A, Brokking W, van der Weele P, Quint W, Prins JM, de Vries HJC, and Schim van der Loeff MF

Subjects
Adult, Anus Diseases pathology, Homosexuality, Male, Humans, Longitudinal Studies, Male, Middle Aged, Viral Load, Anus Diseases blood, Anus Diseases virology, HIV Seropositivity, Papillomavirus Infections blood, Papillomavirus Infections virology, Squamous Intraepithelial Lesions blood, Squamous Intraepithelial Lesions virology
Abstract

Background: Our objective was to identify virological and serological predictors of anal high-grade squamous intraepithelial lesions (HSIL) in human immunodeficiency virus (HIV)-positive men who have sex with men (MSM)., Methods: HIV-positive MSM were recruited from a longitudinal study during which anal self-swabs and serum were collected at up to 5 bi-annual visits. Swabs were human papillomavirus (HPV) genotyped, and the type-specific HPV viral load in the anal swabs was determined. Serum antibodies to the E6, E7, E1, E2, and L1 proteins of 7 high-risk HPV (hrHPV) types and HPV6 and 11 were analyzed. The participants who had a high-resolution anoscopy after the last study visit were included in the current analysis. Anal HSIL was diagnosed by histopathological examinations of anal biopsies. The causative HPV type of anal HSIL was determined in whole tissue sections (WTS) and by laser capture micro-dissection if more than one HPV-type was found in WTS. Multivariable logistic regression was used to study whether persistent anal HPV infections, HPV viral loads, and seropositivity for HPV were predictors of anal HSIL, either in general or caused by the concordant HPV type., Results: Of 193 HIV-positive MSM, 50 (26%) were diagnosed with anal HSIL. HrHPV persistence in anal swabs was common, varying by hrHPV type between 3-21%. Anal HPV persistence was the only determinant independently associated with anal HSIL, both in general and by concordant, causative HPV type., Conclusions: Persistent HPV infections were strongly associated with anal HSIL, in general as well as for the concordant HPV type., (© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Published
2019
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