A comparison of HPV DNA testing and liquid based cytology over three rounds of primary cervical screening: extended follow up in the ARTISTIC trial.

BACKGROUND: The additional sensitivity of HPV testing compared with cytology could permit extended cervical screening intervals. We wished to determine, through a further (third) round of screening in the ARTISTIC trial, the protection provided by a negative baseline HPV screen compared with that of cytology over a 6 year period. METHODS: Cumulative rates of CIN2 or worse (CIN2+) and CIN3 or worse (CIN3+) were correlated with baseline HPV status and cytology. HPV was detected using the Hybrid Capture 2 (Qiagen) assay for high risk types and genotyped using the Linear Array (Roche) and Papillocheck (Greiner) assays. LBC was performed using ThinPrep (Hologic). FINDINGS: Round 3 included 8,873 women of whom 6,337 had been screened in both rounds 1 and 2 and 2,536 had not been screened since round 1. The median duration of follow-up was 72.7 months. The cumulative rate of CIN2+ over three rounds was 3.88% (95%CI 3.59%, 4.17%) overall; 2.39% in round 1, 0.78% in round 2 and 0.74% in round 3. Cumulative rates by baseline status were 20.53% (95%CI 19.04%, 22.08%) for abnormal cytology, 20.12% (95%CI 18.68%, 21.61%) for HPV detection, 1.41% (95%CI 1.19%, 1.65%) for negative cytology and 0.87% (95%CI 0.70%, 1.06%) for a negative HPV test. In HPV negative women aged over 50 the cumulative rate was 0.16% (95%CI 0.07%, 0.34%). Women who were HPV positive/cytology negative at entry had a cumulative CIN2+ rate of 7.73% (95%CI 6.29%, 9.36%) over 6 years, twice the overall rate. INTERPRETATION: A negative HPV test was significantly more protective than normal cytology over three rounds. The findings of this extension of ARTISTIC suggest that the screening interval could be extended to 6 years if HPV testing replaced cytology as the primary screening test

The clinical effectiveness and cost-effectiveness of primary human papillomavirus cervical screening in England: extended follow-up of the ARTISTIC randomised trial cohort through three screening rounds.

BACKGROUND: The ARTISTIC (A Randomised Trial In Screening To Improve Cytology) trial originally reported after two rounds of primary cervical screening with human papillomavirus (HPV). Extended follow-up of the randomised trial cohort through a third round could provide valuable insight into the duration of protection of a negative HPV test, which could allow extended screening intervals. If HPV primary screening is to be considered in the national programme, then determining its cost-effectiveness is key, and a detailed economic analysis using ARTISTIC data is needed. AIMS/OBJECTIVES: (1) To determine the round 3 and cumulative rates of cervical intraepithelial neoplasia (CIN) grade 2 or worse (2+) and CIN grade 3 or worse (CIN3+) between the revealed and concealed arms of ARTISTIC after three screening rounds over 6 years. (2) To compare the cumulative incidence of CIN2+ over three screening rounds following negative screening cytology with that following negative baseline HPV. (3) To determine whether or not HPV screening could safely extend the screening interval from 3 to 6 years. (4) To study the potential clinical utility of an increased cut-off of 2 relative light unit/mean control (RLU/Co) for Hybrid Capture 2 (HC2) and HPV genotyping in primary cervical screening. (5) To determine the potential impact of HPV vaccination with Cervarix™ in terms of preventing abnormal cytology and CIN2+. (6) To determine the cost-effectiveness of HPV primary screening compared with current practice using cervical cytology in England. DESIGN: The ARTISTIC study cohort was recalled for a third round of screening 3 years after round 2 and 6 years following their enrolment to the study. Both arms of the original trial used a single protocol during round 3. SETTING: ARTISTIC study cohort undergoing cervical screening in primary care in Greater Manchester, UK. PARTICIPANTS: Between July 2007 and September 2009, 8873 women participated in round 3; 6337 had been screened in round 2 and 2536 had not been screened since round 1. INTERVENTIONS: All women underwent liquid-based cytology and HPV testing and genotyping. Colposcopy was offered to women with moderate dyskaryosis or worse and with HPV-positive mild dyskaryosis/borderline changes. Women with negative cytology or HPV-negative mild dyskaryosis/borderline changes were returned to routine recall. MAIN OUTCOME MEASURES: Principal outcomes were cumulative rates of CIN2+ over three screening rounds by cytology and HPV status at entry; HPV type specific rates of CIN2+; effect of age on outcomes correlated with cytology and HPV status; comparison of HC2 cut-off RLU/Co of both 1 and 2; and cost-effectiveness of HPV primary screening. RESULTS: The median duration of follow-up was 72.7 months in round 3. Over the three screening rounds, there was no significant difference in CIN2+ [odds ratio (OR): 1.06, 95% confidence interval (CI) 0.89 to 1.26, p = 0.5)] or CIN3+ (OR: 0.90, 95% CI 0.72 to 1.14, p = 0.4) rates between the trial arms (revealed vs. concealed). Overall, 16% of women were HC2 positive at entry, decreasing from 40% in women aged 20-24 years to around 7% in women aged over 50 years. Abnormal cytology rates at entry were 13% for borderline+ and 2% for moderate+ cytology. Following positive cytology at entry, the cumulative rate of CIN2+ was 20.5%, and was 20.1% following a HPV-positive result at baseline. The cumulative CIN2+ rate for women who were HPV negative at baseline was only 0.87% (95% CI 0.70% to 1.06%) after three rounds of screening, significantly lower than that for women with negative cytology, which was 1.41% (95% CI 1.19% to 1.65%). Women who were HPV negative at baseline had similar protection from CIN2+ after 6 years as women who were cytology negative at baseline after 3 years. Women who were HPV positive/cytology negative at baseline had a cumulative CIN2+ rate at 6 years of 7.7%, significantly higher than that for women who were cytology positive/HPV negative (3.2%). Women who were HPV type 16 positive at baseline had a cumulative CIN2+ rate over three rounds of 43.6% compared with 20.1% for any HPV-positive test. Using a HC2 cut-off of RLU/Co ≥ 2 would maintain acceptable sensitivity and result in 16% fewer HPV-positive results. Typing data suggested that around 55-60% of high-grade cytology and CIN2+, but less than 25% of low-grade cytology, would be prevented by HPV vaccine given current rates of coverage in the UK national programme. For the cost-effectiveness analysis, most of the primary HPV strategies examined where HPV was used as the sole primary test were cost saving in both unvaccinated and vaccinated cohorts under baseline cost assumptions, with a 7-18% reduction in annual screening-associated costs in unvaccinated cohorts and a 9-22% reduction for vaccinated cohorts. Utilising partial genotyping at the primary screening stage to identify women with HPV 16/18 and referring them to colposcopy was the most effective strategy (barring co-testing, which is significantly more costly than any other strategies considered), resulting in 83 additional life-years per 100,000 women for unvaccinated women when compared with current practice, and similar life-years saved compared with current practice for vaccinated women. In unvaccinated cohorts, however, this genotyping strategy is predicted to result in a 20% increase in the number of colposcopies performed in England, although in vaccinated cohorts the number of colposcopy referrals was predicted to be lower than in current practice. For all strategies in which HPV is used as the sole primary screening test, decreasing the follow-up interval for intermediate-risk women from 24 to 12 months increased the overall effectiveness of primary HPV screening. In exploratory analysis, strategies for which cytology screening was retained until either age 30 or 35 years, and for which HPV testing was used at older ages, were predicted to be of higher costs and intermediate effectiveness than those associated with full implementation of primary HPV screening from age 25 years. However, this finding should be interpreted with caution as it depends on assumptions made about screening behaviour and compliance with recommendations at the 'switch over' point. CONCLUSIONS: HPV testing as an initial screen was significantly more protective over three rounds (6 years) than the current practice of cytology and the use of primary HPV screening could allow a safe lengthening of the screening interval. A substantial decrease in high-grade cytology and CIN2+ can be expected as a consequence of the HPV vaccination programme. A HC2 cut-off of 2RLU/Co instead of the manufacturer's recommended cut-off of 1 would be clinically beneficial in terms of an optimal balance between sensitivity and specificity. Modelled analysis predicts that primary HPV screening would be both more effective and cost saving compared with current practice with cervical cytology for a number of potential strategies in both unvaccinated and vaccinated cohorts. Compliance with surveillance and optimal management of HPV-positive/cytology-negative women after primary HPV screening is of key importance. Limitations of the economic investigation included the need to make assumptions around compliance with screening attendance and follow-up for longer screening intervals in the future, assumptions regarding maintenance of current uptake vaccination in the future, and assumptions regarding the stability of cost of HPV and cytology tests in the future. Detailed sensitivity analysis across a range of possible assumptions was conducted to address these issues. This study and the economic evaluation lend support to convert from cytology to HPV-based screening. Future work should include researching (i) the attitudes of women who test HPV positive/cytology negative, (ii) the value of complementary biomarkers and (iii) activities relevant to primary HPV screening in unvaccinated and vaccinated populations from the point of view of QALY assessment. STUDY REGISTRATION: Current Controlled Trials ISRCTN25417821

The human RPS4 paralogue on Yq11.223 encodes a structurally conserved ribosomal protein and is preferentially expressed during spermatogenesis.

BACKGROUND: The Y chromosome of mammals is particularly prone to accumulate genes related to male fertility. However, the high rate of molecular evolution on this chromosome predicts reduced power to the across-species comparative approach in identifying male-specific genes that are essential for sperm production in humans. We performed a comprehensive analysis of expression of Y-linked transcripts and their X homologues in several human tissues, and in biopsies of infertile patients, in an attempt to identify new testis-specific genes involved in human spermatogenesis. RESULTS: We present evidence that one of the primate-specific Y-linked ribosomal protein genes, RPS4Y2, has restricted expression in testis and prostate, in contrast with its X-linked homologue, which is ubiquitously expressed. Moreover, we have determined by highly specific quantitative real time PCR that RPS4Y2 is more highly expressed in testis biopsies containing germ cells. The in silico analysis of the promoter region of RPS4Y2 revealed several differences relative to RPS4Y1, the more widely expressed paralogue from which Y2 has originated through duplication. Finally, through comparative modelling we obtained the three dimensional models of the human S4 proteins, revealing a conserved structure. Interestingly, RPS4Y2 shows different inter-domain contacts and the potential to establish specific interactions. CONCLUSIONS: These results suggest that one of the Y-linked copies of the ribosomal protein S4 is preferentially expressed during spermatogenesis and might be important for germ cell development. Even though RPS4Y2 has accumulated several amino acid changes following its duplication from RPS4Y1, approximately 35 million years ago, the evolution of the Y-encoded RPS4 proteins is structurally constrained. However, the exclusive expression pattern of RPS4Y2 and the novelties acquired at the C-terminus of the protein may indicate some degree of functional specialisation of this protein in spermatogenesis.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Transcriptional changes in response to X chromosome dosage in the mouse: implications for X inactivation and the molecular basis of Turner Syndrome.

BACKGROUND: X monosomic mice (39,XO) have a remarkably mild phenotype when compared to women with Turner syndrome (45,XO). The generally accepted hypothesis to explain this discrepancy is that the number of genes on the mouse X chromosome which escape X inactivation, and thus are expressed at higher levels in females, is very small. However this hypothesis has never been tested and only a small number of genes have been assayed for their X-inactivation status in the mouse. We performed a global expression analysis in four somatic tissues (brain, liver, kidney and muscle) of adult 40,XX and 39,XO mice using the Illumina Mouse WG-6 v1_1 Expression BeadChip and an extensive validation by quantitative real time PCR, in order to identify which genes are expressed from both X chromosomes. RESULTS: We identified several genes on the X chromosome which are overexpressed in XX females, including those previously reported as escaping X inactivation, as well as new candidates. However, the results obtained by microarray and qPCR were not fully concordant, illustrating the difficulty in ascertaining modest fold changes, such as those expected for genes escaping X inactivation. Remarkably, considerable variation was observed between tissues, suggesting that inactivation patterns may be tissue-dependent. Our analysis also exposed several autosomal genes involved in mitochondrial metabolism and in protein translation which are differentially expressed between XX and XO mice, revealing secondary transcriptional changes to the alteration in X chromosome dosage. CONCLUSIONS: Our results support the prediction that the mouse inactive X chromosome is largely silent, while providing a list of the genes potentially escaping X inactivation in rodents. Although the lower expression of X-linked genes in XO mice may not be relevant in the particular tissues/systems which are affected in human X chromosome monosomy, genes deregulated in XO mice are good candidates for further study in an involvement in Turner Syndrome phenotype.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

HPV testing compared with routine cytology in cervical screening: long-term follow-up of ARTISTIC RCT

Background: The National Screening Committee (NSC) based its recommendation that human papillomavirus (HPV) testing should replace cytology in primary cervical screening largely on the 2009 follow-up results of the ARTISTIC trial (A Randomised Trial In Screening To Improve Cytology). The NSC must now decide on screening intervals and triage policy. Options include extending the screening interval up to 10 years for human papillomavirus-negative (HPV–) women, delaying recall for human papillomavirus-positive (HPV+) women with normal cytology (as their infections are usually transient), and basing triage on full HPV typing. Methods: In ARTISTIC, 24,510 women were recruited who were attending routine cervical cytology in Greater Manchester in 2001–3. The women were randomly allocated between revealing and concealing their HPV test results and were recalled every 3 years. After 2009, the women returned to routine cytological screening with recall every 3 years for those aged 50 years. The 10-year cumulative CIN3+ risk following a new HPV infection at round 2 was 3.4% (95% CI 2.1% to 5.4%). The highest risks were associated with type-specific persistent infections that, overall, resulted in a 10-year cumulative CIN3+ risk of 20.4% (95% CI 15.6% to 26.4%). Conclusions: We found a similar level of protection 10 years after a negative HPV test and 3 years after negative cytology. These data support a considerably longer screening interval after a negative HPV test than after a negative cytology test. About three-quarters of women with HPV infection and normal cytology clear their infections within about 3 years. Their risk of CIN3+ within this time frame is low (1.5%), suggesting that the current policy of annual repeat testing and referral after 2 years may be unnecessarily cautious. Approximately 40% of women who remained HPV+ had cleared their initial infection and acquired a new HPV type. The cumulative CIN3+ risks in women with type-specific persistent infections are about six times higher than in women with new infections. Triage strategies based on HPV persistence would, therefore, reduce unnecessary referral of women with new (and largely transient) infections. HPV assays that identify HPV types 31, 33, 45, 52 and 58 in addition to 16 and 18 could be useful in triage as well as in primary HPV testing. Similar results in recent routine HPV screening suggest that our results are generalisable despite changes in cytology and HPV assay methods. We are continuing to follow the ARTISTIC cohort into the new era of primary HPV screening. Future work will focus on the implications of more sensitive HPV testing for primary HPV screening policy and triage of HPV-positive women. Our results suggest that a more sensitive test is needed to detect occult CIN3 at high risk of progression to cancer, butthis would substantially increase the overall HPV detection rate. Tests such as DNA (deoxyribonucleic acid) methylation for distinguishing HPV infection from neoplasia will be evaluated on stored samples and on further samples now being collected from women in the cohort who are still being screened

Visual Pathway Study Using In Vivo Diffusion Tensor Imaging Tractography to Complement Classic Anatomy

BACKGROUND: Knowledge of the individual course of the optic radiations (ORs) is important to avoid postoperative visual deficits. Cadaveric studies of the visual pathways are limited because it has not been possible to separate the OR from neighboring tracts accurately and results may not apply to individual patients. Diffusion tensor imaging studies may be able to demonstrate the relationships between the OR and neighboring fibers in vivo in individual subjects. OBJECTIVE: To use diffusion tensor imaging tractography to study the OR and the Meyer loop (ML) anatomy in vivo. METHODS: Ten healthy subjects underwent magnetic resonance imaging with diffusion imaging at 3 T. With the use of a fiducial-based diffusion tensor imaging tractography tool (Slicer 3.3), seeds were placed near the lateral geniculate nucleus to reconstruct individual visual pathways and neighboring tracts. Projections of the ORs onto 3-dimensional brain models were shown individually to quantify relationships to key landmarks. RESULTS: Two patterns of visual pathways were found. The OR ran more commonly deep in the whole superior and middle temporal gyri and superior temporal sulcus. The OR was closely surrounded in all cases by an inferior longitudinal fascicle and a parieto/occipito/temporo-pontine fascicle. The mean left and right distances between the tip of the OR and temporal pole were 39.8 ± 3.8 and 40.6 ± 5.7 mm, respectively. CONCLUSION: Diffusion tensor imaging tractography provides a practical complementary method to study the OR and the Meyer loop anatomy in vivo with reference to individual 3-dimensional brain anatomy

Simultaneous Measurements of Star Formation and Supermassive Black Hole Growth in Galaxies

Galaxies grow their supermassive black holes in concert with their stars, although the relationship between these major galactic components is poorly understood. Observations of the cosmic growth of stars and black holes in galaxies suffer from disjoint samples and the strong effects of dust attenuation. The thermal infrared holds incredible potential for simultaneously measuring both the star formation and black hole accretion rates in large samples of galaxies covering a wide range of physical conditions. Spitzer demonstrated this potential at low redshift, and by observing some of the most luminous galaxies at z~2. JWST will apply these methods to normal galaxies at these epochs, but will not be able to generate large spectroscopic samples or access the thermal infrared at high-redshift. An order of magnitude gap in our wavelength coverage will persist between JWST and ALMA. A large, cold infrared telescope can fill this gap to determine when (in cosmic time), and where (within the cosmic web), stars and black holes co-evolve, by measuring these processes simultaneously in statistically complete and unbiased samples of galaxies to z>8. A next-generation radio interferometer will have the resolution and sensitivity to measure star-formation and nuclear accretion in even the dustiest galaxies. Together, the thermal infrared and radio can uniquely determine how stars and supermassive blackholes co-evolve in galaxies over cosmic time

Health, education, and social care provision after diagnosis of childhood visual disability

Aim: To investigate the health, education, and social care provision for children newly diagnosed with visual disability.Method: This was a national prospective study, the British Childhood Visual Impairment and Blindness Study 2 (BCVIS2), ascertaining new diagnoses of visual impairment or severe visual impairment and blindness (SVIBL), or equivalent vi-sion. Data collection was performed by managing clinicians up to 1-year follow-up, and included health and developmental needs, and health, education, and social care provision.Results: BCVIS2 identified 784 children newly diagnosed with visual impairment/SVIBL (313 with visual impairment, 471 with SVIBL). Most children had associated systemic disorders (559 [71%], 167 [54%] with visual impairment, and 392 [84%] with SVIBL). Care from multidisciplinary teams was provided for 549 children (70%). Two-thirds (515) had not received an Education, Health, and Care Plan (EHCP). Fewer children with visual impairment had seen a specialist teacher (SVIBL 35%, visual impairment 28%, χ2p < 0.001), or had an EHCP (11% vs 7%, χ2p < 0 . 01).Interpretation: Families need additional support from managing clinicians to access recommended complex interventions such as the use of multidisciplinary teams and educational support. This need is pressing, as the population of children with visual impairment/SVIBL is expected to grow in size and complexity.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited