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Objectives: Organisation of a screening programme influences programme resilience to a disruption as COVID-19. Due to COVID-19, the Dutch human papillomavirus-based cervical screening programme was temporarily suspended. Afterwards, multiple measures have been taken to catch-up participation. This study aimed to investigate programme resilience by examining the effect of COVID-19 and programme measures taken on participation in cervical screening., Study Design: Observational cohort study., Methods: Data from the national screening registry and Dutch nationwide pathology databank (Palga) were used on invitations and follow-up in 2018/2019 (pre-COVID) and 2020 (COVID). Sending invitations, reminders and self-sampling kits were suspended from March to July 2020. Main outcome measures include distribution of participant characteristics (age, region and screening history), participation rates by age and region, time between invitation and participation (i.e. response time) and self-sampling use per month., Results: Participation rate was significantly lower in 2020 (49.8%) compared to 2018/19 (56.8%, P < 0.001), in all ages and regions. Compared to 2018/19, participation rates decreased most in women invited from January to March 2020 (-6.7%, -9.1% and -10.4%, respectively). From August, participation rates started to recover (difference between -0.8% and -2.7%). Median response time was longer in February and March (2020: 143 and 173 days; 2018/19: 53 and 55 days) and comparable from July onwards (median difference 0-6 days). Self-sampling use was higher in 2020 (16.3%) compared to 2018/19 (7.6%)., Conclusions: The pandemic impacted participation rates in the Dutch cervical screening programme, especially of women invited before the programme pause. Implementation of self-sampling in national cervical screening programmes could increase participation rates and could serve as an alternative screening method in times of exceptional health care circumstances, such as a pandemic. Due to the well-organised programme and measures taken to catch-up participation, the impact of COVID-19 on the screening programme remained small., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: The aim was to evaluate the cross-sectional and long-term triage performance of FAM19A4/miR124-2 methylation analysis in human papillomavirus (HPV)-based cervical screening., Methods: We conducted a post hoc analysis within a Dutch population-based HPV-positive study cohort of women aged 30-60 years (n = 979). Cross-sectional cervical intraepithelial neoplasia (CIN) 3+ sensitivity, specificity, positive predictive value and negative predictive value as well as cumulative CIN3+ or cervical cancer risks after 9 and 14 years were compared for three baseline triage strategies: (1) cytology, (2) FAM19A4/miR124-2 methylation analysis and (3) combined FAM19A4/miR124-2 methylation with cytology., Results: CIN3+ sensitivity of FAM19A4/miR124-2 methylation analysis was similar to that of cytology (71.3% vs 76.0%, ratio 0.94, 95% CI 0.84 to 1.05), at a lower specificity (78.3% vs 87.0%, ratio 0.90, 95% CI 0.86 to 0.94). Combining FAM19A4/miR124-2 methylation analysis with cytology resulted in a CIN3+ sensitivity of 84.6% (95% CI 78.3 to 90.8) at a specificity of 69.6% (95% CI 66.5 to 72.7). Similar 9- and 14-year CIN3+ risks for baseline cytology-negative women and baseline FAM19A4/miR124-2 methylation-negative women were observed, with risk differences of -0.42% (95% CI -2.1 to 1.4) and -0.07% (95% CI -1.9 to 1.9), respectively. The 14-year cumulative cervical cancer incidence was significantly lower for methylation-negative women compared to cytology-negative women (risk difference 0.98%, 95% CI 0.26 to 2.0)., Discussion: FAM19A4/miR124-2 methylation analysis has a good triage performance on baseline screening samples, with a cross-sectional CIN3+ sensitivity and long-term triage-negative CIN3+ risk equalling cytology triage. Therefore, FAM19A4/miR124-2 methylation analysis appears to be a good and objective alternative to cytology in triage scenarios in HPV-based cervical screening., (Copyright © 2020 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Tests for the DNA of high-risk types of human papillomavirus (HPV) have a higher sensitivity for cervical intraepithelial neoplasia grade 3 or worse (CIN3+) than does cytological testing, but the necessity of such testing in cervical screening has been debated. Our aim was to determine whether the effectiveness of cervical screening improves when HPV DNA testing is implemented., Methods: Women aged 29-56 years who were participating in the regular cervical screening programme in the Netherlands were randomly assigned to combined cytological and HPV DNA testing or to conventional cytological testing only. After 5 years, combined cytological and HPV DNA testing were done in both groups. The primary outcome measure was the number of CIN3+ lesions detected. Analyses were done by intention to treat. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN20781131., Findings: 8575 women in the intervention group and 8580 in the control group were recruited, followed up for sufficient time (> or =6.5 years), and met eligibility criteria for our analyses. More CIN3+ lesions were detected at baseline in the intervention group than in the control group (68/8575 vs 40/8580, 70% increase, 95% CI 15-151; p=0.007). The number of CIN3+ lesions detected in the subsequent round was lower in the intervention group than in the control group (24/8413 vs 54/8456, 55% decrease, 95% CI 28-72; p=0.001). The number of CIN3+ lesions over the two rounds did not differ between groups., Interpretation: The implementation of HPV DNA testing in cervical screening leads to earlier detection of CIN3+ lesions. Earlier detection of such lesions could permit an extension of the screening interval.

Background: Ischaemic renal dysfunction is present in many clinical settings, including cardiovascular surgery. Renal hypoperfusion seems to be the most important pathophysiologic mechanism. Arginine plasma levels are rate limiting for NO synthesis, and low arginine plasma levels are seen after major vascular surgery., Objective: to establish the effects of low arginine plasma levels on renal blood flow after renal ischaemia/reperfusion., Design: Wistar rats were used in this unilateral renal ischaemia/reperfusion model. After 70 min of ischaemia, the kidney was reperfused for 150 min. Arginase infusion was used to lower arginine plasma levels. Blood flow measurement was performed at the end of the experiment using radiolabelled microspheres. Additional experiments were performed for histopathology., Results: Arginase efficiently decreased arginine plasma levels to about 50% of normal. There was a lower blood flow in the ischaemic kidney than the contralateral (non-ischaemic) kidney. Lowering arginine plasma levels did not reduce renal blood flow in the ischaemic kidney. Renal histopathology was not influenced by lowered arginine plasma levels., Conclusions: Lowering arginine plasma levels did not affect blood flow or histology following renal ischaemia and reperfusion.

Polycomb-group (PcG) proteins, such as BMI-1 and EZH2, form multimeric gene-repressing complexes involved in axial patterning, hematopoiesis, and cell cycle regulation. In addition, BMI-1 is involved in experimental lymphomagenesis. Little is known about its role in human lymphomagenesis. Here, BMI-1 and EZH2 expression patterns are analyzed in a variety of B-cell non-Hodgkin lymphomas (B-NHLs), including small lymphocytic lymphoma, follicular lymphoma, large B-cell lymphoma, mantle-cell lymphoma, and Burkitt lymphoma. In contrast to the mutually exclusive pattern of BMI-1 and EZH2 in reactive follicles, the neoplastic cells in B-NHLs of intermediate- and high-grade malignancy showed strong coexpression of BMI-1 and EZH2. This pattern overlapped with the expression of Mib-1/Ki-67, a marker for proliferation. Neoplastic cells in B-NHL of low-grade malignancy were either BMI-1(low)/EZH2(+) (neoplastic centroblasts) or BMI-1(low)EZH2(-) (neoplastic centrocytes). These observations show that low-, intermediate-, and high grade B-NHLs are associated with increased coexpression of the BMI-1 and EZH2 PcG proteins, whose normal expression pattern is mutually exclusive. This expression pattern is probably caused by a failure to down-regulate BMI-1 in dividing neoplastic cells, because BMI-1 expression is absent from normal dividing B cells. These observations are in agreement with findings in studies of Bmi-1 transgenic mice. The extent of BMI-1/EZH2 coexpression correlated with clinical grade and the presence of Mib-1/Ki-67 expression, suggesting that the irregular expression of BMI-1 and EZH2 is an early event in the formation of B-NHL. This points to a role for abnormal PcG expression in human lymphomagenesis. (Blood. 2001;97:3896-3901)

Background: The blood vessels of a transplanted organ are the interface between donor and recipient. The endothelium in the blood vessels is thought to be the major target for graft rejection. Endothelial cells of a transplanted organ are believed to remain of donor origin after transplantation. We aimed to verify this concept., Methods: We studied biopsy samples from 12 renal transplants for the presence of endothelial cells of recipient origin. We used three different techniques: immunohistochemistry for MHC class-I antigens, immunohistochemistry for ABO-blood-group antigens, and in-situ hybridisation for X and Y chromosomes. After we had confirmed that these techniques did identify endothelial cells of recipient origin, tests were done in a second group of 26 patients to find out whether endothelial chimerism correlated with graft rejection., Findings: We found a strong correlation between the percentage of recipient endothelial cells in the peritubular capillaries and the type of graft rejection (r = 0.71, p < 0.0001). These cells were found mainly in grafts of patients who had had rejection, especially among patients with vascular rejection. In grafts of patients without rejection only sporadically recipient endothelial cells were detectable., Interpretation: Our data show that endothelial cells of the recipient can replace those of the donor. This replacement is associated with graft rejection. We postulate that endothelium that is damaged by vascular rejection is repaired by endothelial cells of the recipient.

The human BMI-1 and EZH2 polycomb group (PcG) proteins are constituents of two distinct complexes of PcG proteins with gene regulatory activity. PcG proteins ensure correct embryonic development by suppressing homeobox genes, and they also contribute to regulation of lymphopoiesis. The two PcG complexes are thought to regulate different target genes and probably have different tissue distributions. Altered expression of PcG genes is linked to transformation in cell lines and induction of tumors in mutant mice, but the role of PcG genes in human cancers is relatively unexplored. Using antisera specific for human PcG proteins, we used immunohistochemistry and immunofluorescence to detect BMI-1 and EZH2 PcG proteins in Reed-Sternberg cells of Hodgkin's disease (HRS). The expression patterns were compared to those in follicular lymphocytes of the lymph node, the normal counterparts of HRS cells. In the germinal center, expression of BMI-1 is restricted to resting Mib-1/Ki-67(-) centrocytes, whereas EZH2 expression is associated with dividing Mib-1/Ki-67(+) centroblasts. By contrast, HRS cells coexpress BMI-1, EZH2, and Mib-1/Ki-67. Because HRS cells are thought to originate from germinal center lymphocytes, these observations suggests that Hodgkin's disease is associated with coexpression of BMI-1 and EZH2 in HRS cells.

Background: Renal transplant loss from chronic rejection remains substantial. To increase our understanding of this syndrome, we identified risk factors predicting late graft loss, with a special emphasis on the impact of human lymphocyte antigen (HLA) matching., Methods: We studied all 654 cadaveric kidney transplants performed in our center between 1983 and 1996 that had survived for more than six months. Eighty-two transplants, lost because of chronic rejection, were used as the outcome variable. The influence of HLA mismatches and shares on long-term graft survival was evaluated at the level of private antigens and cross-reactive groups (CREG) of multiple histocompatibility complex (MHC) class I. HLA and other recipient, donors and transplant parameters were studied using univariate and multivariate Cox regression analysis., Results: The cohort had a mean number of 1.9 HLA mismatches. Because of the homozygosity of HLA antigens, HLA mismatches were not reciprocal to shares. CREG and HLA-A-B mismatches had a relative risk for graft loss of 1.19 (95% CI, 0.97 to 1.45) and 1.05 (0.84 to 1.32) per mismatch. In contrast, the relative risk per shared CREG and broad HLA-A-B antigen was 0.76 (0.63 to 0.92) and 0.79 (0.61 to 1.03). Multivariate analysis revealed that individuals sharing less than four CREGs had a relative risk of 2.13 (1.29 to 3.75) for late graft loss. Other independent predictors were a recipient age of less than 50 years, relative risk 1.95 (1.02 to 3.71); a donor age of more than 50 years, relative risk 1.68 (1.01 to 2.80); acute rejection (vascular vs. no rejection), relative risk 3.52 (1.72 to 7.18); proteinuria (dipstick > 1+ vs. negative), relative risk 2.86 (1.29 to 6.35); and a serum creatinine concentration of more than 150 micromol/liter at six months, relative risk 3.41 (1.96 to 5.94)., Conclusion: We identified several coexisting recipient-, donor-, and transplant-related risk factors for graft loss from chronic rejection. In this well-matched group of renal transplants, HLA mismatches and shares had a nonreciprocal relationship. Sharing of HLA antigens, especially CREG of MHC class I, was associated with improved long-term survival.