Invasive cervical cancer incidence following bivalent human papillomavirus vaccination: a population-based observational study of age at immunization, dose, and deprivation.

BACKGROUND: High-risk human papillomavirus causes cervical cancer. Vaccines have been developed that significantly reduce the incidence of preinvasive and invasive disease. This population-based observational study used linked screening, immunization, and cancer registry data from Scotland to assess the influence of age, number of doses, and deprivation on the incidence of invasive disease following administration of the bivalent vaccine. METHODS: Data for women born between January 1, 1988, and June 5, 1996, were extracted from the Scottish cervical cancer screening system in July 2020 and linked to cancer registry, immunization, and deprivation data. Incidence of invasive cervical cancer per 100 000 person-years and vaccine effectiveness were correlated with vaccination status, age at vaccination, and deprivation; Kaplan Meier curves were calculated. RESULTS: No cases of invasive cancer were recorded in women immunized at 12 or 13 years of age irrespective of the number of doses. Women vaccinated at 14 to 22 years of age and given 3 doses of the bivalent vaccine showed a significant reduction in incidence compared with all unvaccinated women (3.2/100 000 [95% confidence interval (CI) = 2.1 to 4.6] vs 8.4 [95% CI = 7.2 to 9.6]). Unadjusted incidence was significantly higher in women from most deprived (Scottish Index of Multiple Deprivation 1) than least deprived (Scottish Index of Multiple Deprivation 5) areas (10.1/100 000 [95% CI = 7.8 to 12.8] vs 3.9 [95% CI = 2.6 to 5.7]). Women from the most deprived areas showed a significant reduction in incidence following 3 doses of vaccine (13.1/100 000 [95% CI = 9.95 to 16.9] vs 2.29 [95% CI = 0.62 to 5.86]). CONCLUSION: Our findings confirm that the bivalent vaccine prevents the development of invasive cervical cancer and that even 1 or 2 doses 1 month apart confer benefit if given at 12-13 years of age. At older ages, 3 doses are required for statistically significant vaccine effectiveness. Women from more deprived areas benefit more from vaccination than those from less deprived areas.

Clinical Performance of Triage Strategies for Hr-HPV-Positive Women; A Longitudinal Evaluation of Cytology, p16/K-67 Dual Stain Cytology, and HPV16/18 Genotyping.

BACKGROUND: We evaluated the longitudinal performance of three options: HPV16/18 genotyping (HPV16/18), cytology (LBC), and p16/Ki-67 dual stain cytology (DS) for the triage of high-risk Human Papillomavirus-positive (Hr-HPV+) women within the cervical screening program in Scotland. METHODS: Data were derived from a cohort of Hr-HPV+ women (n = 385) who participated in PaVDaG (Papillomavirus Dumfries and Galloway) study. Performance of triage strategies for detecting high-grade disease was assessed at 3 (in women <50 years) or 5 years (in women >50 years). Sensitivity, specificity, PPV, and cNPV of each triage test were calculated for CIN2+ and CIN3+ when used singly or sequentially. RESULTS: The sensitivity of LBC (≥ borderline), DS, and HPV 16/18 genotyping for the detection of CIN2+ was 62.7% (50.7-73.3), 77.7% (63.1-83.7), and 62.7% (50.7-73.3) with corresponding cNPVs of 10.9%, 8.4%, and 11.9%. The option with the highest sensitivity and lowest cNPV was HPV 16/18 genotyping followed by LBC of Hr-HPV other+ and then DS of the LBC negatives. This yielded sensitivity of 94.7% (86.2-98.3) and cNPV 2.7% for CIN2+. Triage performance was similar if women had tested Hr-HPV+ positive by vaginal self-sampling. CONCLUSIONS: Two-step triage with HPV 16/18 genotyping before LBC (or DS) for Hr-HPV other+ women was associated with a lower risk of significant disease at follow-up compared with single triage approaches. IMPACT: This study provides longitudinal performance data on triage strategies in Hr-HPV+ women and will be informative for the evolution of cervical screening programs that increasingly rely on molecular technologies.

Clinical performance of DNA and RNA based HPV tests for test of cure (TOC) post treatment for cervical intraepithelial neoplasia (CIN) - a retrospective study.

HPV testing as a "test of cure" (TOC) of women treated for cervical high-grade lesions can support and inform appropriate clinical management pathways. However, there is a lack of studies that report the discrete performance of different HPV assays in this context, including HPV mRNA based assays. To address this, we performed an analysis of the clinical performance of two hrHPV assays in the (TOC) setting; the recently launched DNA based Alinity m HR HPV (Abbott Molecular) and RNA based Aptima HPV assay (Hologic). Using a retrospective case-control design, two panels of archived cervical liquid based cytology samples, originally taken as per routine TOC protocols in Scotland were assessed. Each panel contained 63 cases, where cervical intraepithelial neoplasia 2 or worse (CIN2+) was detected and 160 controls (women with no CIN2+ and two subsequent cytology negative results (minimum) 3 years apart or women who had histologically confirmed ≤CIN1). All samples were previously tested using the RealTime High Risk HPV assay (Abbott Molecular) as per national TOC protocol. Panel A and Panel B were tested using Alinity and Aptima assay respectively. Both assays showed similar performance to the original RealTime assay. Aptima had sensitivity for CIN2+ of 96.8% (95% CI: 89.0- 99.6) compared to RealTime (93.7% (95% CI: 84.5 - 98.2)). Alinity had sensitivity for CIN2+ of 92.1% (95% CI: 82.4- 97.4) compared to RealTime (98.4% (95% CI: 91.5- 99.95)). Both mRNA based and DNA based HPV tests show robust performance for the monitoring of residual disease post-treatment.

Long-term preservation of Hadean protocrust in Earth's mantle.

SignificanceDue to active plate tectonics, there are no direct rock archives covering the first ca. 500 million y of Earth's history. Therefore, insights into Hadean geodynamics rely on indirect observations from geochemistry. We present a high-precision 182W dataset for rocks from the Kaapvaal Craton, southern Africa, revealing the presence of Hadean protocrustal remnants in Earth's mantle. This has broad implications for geochemists, geophysicists, and modelers, as it bridges contrasting 182W isotope patterns in Archean and modern mantle-derived rocks. The data reveal the origin of seismically and isotopically anomalous domains in the deep mantle and also provide firm evidence for the operation of silicate differentiation processes during the first 60 million y of Earth's history.

Self-sampling as the principal modality for population based cervical screening: Five-year follow-up of the PaVDaG study.

Self-sampling provides a powerful means to engage women in cervical screening. In the original Papillomavirus Dumfries and Galloway study (PaVDaG), we demonstrated cross-sectional similarity of high-risk human papillomavirus (Hr-HPV) testing on self-taken vaginal vs clinician-taken samples for the detection of cervical intraepithelial neoplasia 2 or worse (CIN2+). Few data exist on the longitudinal performance of self-sampling; we present longitudinal outcomes of PaVDaG. Routinely screened women provided a self-taken and a clinician-collected sample. Ninety-one percent of 5136 women from the original cohort completed a further screening round. Sensitivity, specificity, positive predictive value and complement of the negative predictive value of the Hr-HPV test on self-samples for detection of CIN2+ and CIN3+ up-to 5 years after testing were determined. Additionally, clinical accuracy of Hr-HPV testing on vaginal and clinician-collected samples was assessed. A total of 183 CIN2+ and 102 CIN3+ lesions were diagnosed during follow-up. Risk of CIN2+ and CIN3+ following an Hr-HPV negative self-sample was 0.6% and 0.2%, respectively, for up to 5 years after testing. The relative sensitivity for CIN3+ and specificity for ≤CIN1 of Hr-HPV testing on self-taken specimens was slightly lower vs clinician-collected samples: 0.95 (95% CI: 0.90-0.99; PMcN = .0625) and 0.98 (95% CI: 0.95-1.00; PMcN = <.0000), respectively. The low risk of CIN2+ in women with Hr-HPV-self-sample(s) suggests, that the 3 to 5-year recall interval implemented in several cervical screening settings, based on clinician-taken samples, may be safe for self-samples. Future assessment will show if "universal" 5-year screening is appropriate for programs based on self-sampling.

The challenges of defining sample adequacy in an era of HPV based cervical screening.

BACKGROUND: The implementation of Human Papillomavirus based cervical screening continues apace on a global scale. Understanding the basis and burden of inadequate or invalid samples is important to ensure confidence in high quality laboratory results and inform the development of new technologies. Here we present population based data from Scotland and Denmark which detail the extent of invalid samples for HPV detection in both clinician-taken and self-taken samples. As a comparator we report on the rate of inadequate cytology preparations in both countries. METHODS: The proportion of samples with an invalid HPV test result was calculated by retrospective analysis of routine laboratory data associated with cervical screening programmes in the two countries. Two assays were in use for the programmes at the time (the Abbott RealTime High Risk HPV assay and the BD Onclarity); both have internal endogenous controls for human genes. In addition, acellular cytology samples were reported through a prospective audit (Scotland) and National quality reporting (Denmark). RESULTS: In total, 89,418 clinician samples and 14,677 self-taken samples were assessed. We observed low rates of invalid HPV tests in clinician taken samples (0.05-0.10 %), irrespective of sample collection media (ThinPrep or SurePath), HPV test system/endogenous control type or clinical indication for testing (primary screening, triage or test of cure). For self-taken samples, the number of invalid samples was 0.18 %. Complete absence of sample material (acellular) in clinician taken samples were observed at a level of 1 in approximately 16.5 thousand. CONCLUSIONS: Clinician and self-taken samples appear robust specimens for HPV testing and acellular samples are very rare. Efforts to develop endogenous controls for HPV assays that provide greater insight into true sample adequacy for cervical disease detection, beyond measuring the presence of human cells, will be welcome.

Deep hydrous mantle reservoir provides evidence for crustal recycling before 3.3 billion years ago.

Water strongly influences the physical properties of the mantle and enhances its ability to melt or convect. Its presence can also be used to trace recycling of surface reservoirs down to the deep mantle1, which makes knowledge of the water content in the Earth's interior and its evolution crucial for understanding global geodynamics. Komatiites (MgO-rich ultramafic magmas) result from a high degree of mantle melting at high pressures2 and thus are excellent probes of the chemical composition and water contents of the deep mantle. An excess of water over elements that show similar geochemical behaviour during mantle melting (for example, cerium) was recently found in melt inclusions in the most magnesium-rich olivine in 2.7-billion-year-old komatiites from Canada3 and Zimbabwe4. These data were taken as evidence for a deep hydrated mantle reservoir, probably the transition zone, in the Neoarchaean era (2.8 to 2.5 billion years ago). Here we confirm the mantle source of this water by measuring deuterium-to-hydrogen ratios in these melt inclusions and present similar data for 3.3-billion-year-old komatiites from the Barberton greenstone belt. From the hydrogen isotope ratios, we show that the mantle sources of these melts contained excess water, which implies that a deep hydrous mantle reservoir has been present in the Earth's interior since at least the Palaeoarchaean era (3.6 to 3.2 billion years ago). The reconstructed initial hydrogen isotope composition of komatiites is more depleted in deuterium than surface reservoirs or typical mantle but resembles that of oceanic crust that was initially altered by seawater and then dehydrated during subduction. Together with an excess of chlorine and depletion of lead in the mantle sources of komatiites, these results indicate that seawater-altered lithosphere recycling into the deep mantle, arguably by subduction, started before 3.3 billion years ago.

Defining Optimal Triage Strategies for hrHPV Screen-Positive Women-An Evaluation of HPV 16/18 Genotyping, Cytology, and p16/Ki-67 Cytoimmunochemistry.

Background: Several options for the triage of high-risk HPV screen-positive (hrHPV+) women were assessed.Methods: This study incorporated CIN2+ cases and controls, all of whom tested hrHPV+ and whose results of liquid-based cytology (LBC), HPV16/18 genotyping, and p16/Ki67 cytoimmunochemistry were available. Sensitivity and specificity for the CIN2+ of these triage tests were evaluated.Results: Absolute sensitivities of HPV 16/18 typing, LBC, and p16/Ki-67 cytoimmunochemistry for CIN2+ detection were 61.7%, 68.3%, and 85.0% for women with hrHPV+ clinician-taken samples. Respective specificities were 70.5%, 89.1%, and 76.7%. The absolute accuracy of the triage tests was similar for women with a hrHPV+ self-sample. P16/Ki-67 cyto-immunochemistry was significantly more sensitive than LBC although significantly less specific.Conclusions: All three single-test triage options, if positive, exceed the threshold of 20% risk at which colposcopy would be indicated. However, none of them conferred a post-test probability of CIN2+ <2%; which would permit routine recall. P16/Ki-67 cytoimmunochemistry on HPV16/18 negative women had a post-test probability of CIN2+ of 1.7% and 0.6% if also LBC negative.Impact: This is one of the few studies to directly compare the performance of triage strategies of hrHPV+ women, in isolation and combinations. It is the only study assessing triage strategies in women who test hrHPV+ in self-taken vaginal samples. A combined triage option that incorporated HPV 16/18 typing prior to p16/ki-67 cytoimmunochemistry in HPV 16/18-negative women yielded a post-test probability of CIN2+ of >20%, whereas women who tested negative had a probability of CIN2+ of <2%. Cancer Epidemiol Biomarkers Prev; 26(11); 1629-35. ©2017 AACR.

Clinical validation of hrHPV testing on vaginal and urine self-samples in primary cervical screening (cross-sectional results from the Papillomavirus Dumfries and Galloway-PaVDaG study).

OBJECTIVES: Papillomavirus Dumfries and Galloway (PaVDaG) assessed the performance of a high-risk human papillomavirus (hrHPV) PCR-based assay to detect high-grade cervical intraepithelial neoplasia (CIN2+) in self-collected vaginal and urine samples. SETTING: Women attending routine cervical screening in primary care. PARTICIPANTS: 5318 women aged 20-60 years provided self-collected random urine and vaginal samples for hrHPV testing and a clinician-collected liquid-based cytology (LBC) sample for cytology and hrHPV testing. INTERVENTIONS: HrHPV testing. All samples were tested for hrHPV using the PCR-based cobas 4800 assay. Colposcopy was offered to women with high-grade or repeated borderline/low-grade cytological abnormalities; also to those who were LBC negative but hrHPV 16/18 positive. PRIMARY AND SECONDARY OUTCOME MEASURES: The self-tests' absolute sensitivity and specificity for CIN2+ were assessed on all biospecimens; also, their relative sensitivity and specificity compared with clinician-taken samples. Interlaboratory and intralaboratory performance of the hrHPV assay in self-collected samples was also established. RESULTS: HrHPV prevalence was 14.7%, 16.6% and 11.6% in cervical, vaginal and urine samples, respectively. Sensitivity for detecting CIN2+ was 97.7% (95% to 100%), 94.6% (90.7% to 98.5%) and 63.1% (54.6% to 71.7%) for cervical, vaginal and urine hrHPV detection, respectively. The corresponding specificities were 87.3% (86.4% to 88.2%), 85.4% (84.4% to 86.3%) and 89.8% (89.0% to 90.7%). There was a 38% (24% to 57%) higher HPV detection rate in vaginal self-samples from women over 50 years compared with those ≤29 years. Relative sensitivity and specificity of hrHPV positivity for the detection of CIN2+ in vaginal versus cervical samples were 0.97 (0.94 to 1.00) and 0.98 (0.97 to 0.99); urine versus cervical comparisons were 0.53 (0.42 to 0.67) and 1.03 (1.02 to 1.04). The intralaboratory and interlaboratory agreement for hrHPV positivity in self-samples was high (κ values 0.98 (0.96 to 0.99) and 0.94 (0.92 to 0.97) for vaginal samples and 0.95 (0.93 to 0.98) and 0.90 (0.87 to 0.94) for urine samples). CONCLUSIONS: The sensitivity of self-collected vaginal samples for the detection of CIN2+ was similar to that of cervical samples and justifies consideration of this sample for primary screening.

ABRUPT CLINE FOR SEX CHROMOSOMES IN A HYBRID ZONE BETWEEN TWO SPECIES OF MICE.

We compared the patterns of movement of sex chromosomal and autosomal loci along a 160 km transect across a zone of hybridization between M. domesticus and M. musculus in southern Germany and western Austria using seven genetic markers. These included one Y-specific DNA sequence (YB10), two X-specific loci (DXWas68 and DXWas31), and four autosomal isozyme loci (Es-10, Es-1, Mpi-1, and Np-1). Random effects logistic regression analysis enabled us to examine the relationship between M. domesticus allele frequency and geographic distance from the western edge of the hybrid zone and allowed statistical evaluation of differences in cline midpoint and width among loci. More limited movement was observed for all three sex chromosomal markers across the zone compared with three of the four autosomal markers. If differential movement reflects fitness differences of specific alleles (or alleles at closely linked loci) on a hybrid background, then alleles that move to a limited extent across a hybrid zone may contribute to hybrid breakdown between two species. The limited flow of both X- and Y-specific alleles suggest that sex chromosomes have played an important role in Mus speciation.

MITOCHONDRIAL DNA DIVERSITY IN THE SEA URCHINS STRONGYLOCENTROTUS PURPURATUS AND S. DROEBACHIENSIS.

Restriction-fragment analysis was used to measure mitochondrial DNA (mtDNA) variability in 79 individuals of two species of temperate sea urchins. For the purple urchin Strongylocentrotus purpuratus, individuals were collected 1,500 km apart in 1985 and again from the same localities in 1988 (about one urchin generation). Twenty mtDNA genotypes belonging to four clades were found among 38 individuals. All four clades were found in both localities and in both years. Genetic structure was further tested by calculating the degree of interdeme genetic variation (GST ) and comparing this value to the GST 's from randomly shuffled data. No geographic structure was found. For S. droebachiensis, only six mtDNA genotypes were found among 41 individuals collected from the Pacific and Atlantic oceans. More than 80% of the individuals belonged to two genotypes. The genotype that dominated collections in the Pacific also occurred in the Atlantic; however, a common Atlantic genotype was never found in the Pacific. These two genotypes were identical at 64 of 65 restriction sites, and were only 0.2% divergent from each other. GST analysis confirmed that there were significant genetic differences between Atlantic and Pacific populations. The small divergence between genotypes suggests recent, but not continuous, migration. These marine species show smaller genotypic differences than terrestrial species over similar spatial and temporal scales. Both recruitment of adults from planktonic larval pools and the spread of sibling larvae over large distances from parents probably act as buffers to genetic differences in species with planktonic life-history phases.

EVOLUTIONARY INFERENCES FROM RESTRICTION MAPS OF MITOCHONDRIAL DNA FROM NINE TAXA OF XENOPUS FROGS.

Restriction endonuclease cleavage maps were prepared by the double digestion method for mitochondrial DNAs (mtDNAs) purified from Xenopus borealis, X. clivii, X. fraseri, X. muelleri, X. ruwenzoriensis, X. vestitus, X. laevis victorianus, X. l. laevis, and a variant of X. laevis designated X. laevis "davis." An average of 21 cleavage sites per genome were mapped with 11 restriction endonucleases. Among the four invariant sites found are three conserved not only among the Xenopus mtDNAs tested but also among nearly all vertebrate mtDNAs examined to date. Two of these are Sac II sites in the 12S and 16S ribosomal RNA genes, and one is a Hpa I site in the gene for asparagine transfer RNA. These three sites permit the alignment and comparison of mtDNAs from different vertebrate classes. Although most of the differences observed among the Xenopus maps are attributable to point mutations causing gain or loss of restriction sites, the maps also differ by three large length mutations in or near the displacement loop. Phylogenetic analysis of 30 informative sites suggests that those members of the laevis species-group that have 36 chromosomes per somatic cell can be divided into three subgroups: 1) X. borealis, X. clivii, and perhaps X. fraseri (the "borealis" subgroup), 2) X. muelleri, and 3) the subspecies of X, laevis. The mtDNA of the hexaploid (2n = 108) species, X. ruwenzoriensis, is most similar to that of taxa in the latter two subgroups, which contrasts with the morphological similarity of this species to X. fraseri. X. ruwenzoriensis may be an allopolyploid with a mother (the contributor of the cytoplasmic mtDNA genome) on the X. laevis or X. muelleri lineage and a father on the X. fraseri lineage. We present a model showing how mtDNA and nuclear genomes can yield contrasting phytogenies for species-groups that have undergone several rounds of interspecific hybridization. Comparison of mitochondrial and nuclear sequence divergences suggests that Xenopus mtDNA, like that of mammals and birds, evolves faster than nuclear DNA. Genetic distances among mtDNAs of Xenopus species are very large, generally approaching or exceeding one substitution per nucleotide.