Reply to comment on Peto et al. (2020): Weekly COVID-19 testing with household quarantine and contact tracing is feasible and would probably end the epidemic.

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Weekly population testing could stop this pandemic and prevent the next

The rapid spread of the SARS-COV-2 delta variant in the UK despite high vaccination coverage will inevitably accelerate when social restrictions end unless testing and contact tracing become much more effective. To minimize further social and economic damage, the effect on R of introducing weekly population testing as social restrictions are relaxed should be evaluated. The large increase in testing capacity required can be achieved with self-taken saliva samples analysed by RT-LAMP in local testing facilities. The costs and effectiveness can be evaluated in whole-city demonstration studies. A local population register in each city or district is essential to issue weekly invitations, manage sample collection, monitor results and achieve rapid notification of households and other contacts when a test is positive. In the UK, weekly test invitations should be managed, like vaccination invitations, by the NHS, with social and financial support for quarantined households to make self-isolation acceptable. A framework for effective population testing that had been established and evaluated during this pandemic could be rapidly reinstated to suppress the next pandemic while vaccines for a new and perhaps more deadly virus are developed and rolled out

Cohabitation, infection and breast cancer risk.

For 50 years, the effect of age at first birth (AFB) has been thought to explain the strong association between breast cancer risk and age at first marriage (AFM), which was first reported in 1926. The independent effects of AFM, AFB and number of sexual partners adjusted for parity and other risk factors were estimated in reanalysis of a large international case-control study conducted in 1979 to 1982 (2274 breast cancers, 18209 controls) by unconditional logistic regression. Respective AFB and AFM breast cancer odds ratios (ORs) for ≥31 years relative to ≤18 years were 3.01 (95% CI 2.44-3.71; P(trend) < .0001) and 3.24 (95% CI 2.62-4.01; P(trend) < .0001) in univariate analyses. Among married parous women, these ORs fell to 1.38 (95% CI 0.98-1.95; P(trend) < .03) for AFB and 1.70 (95% CI 1.17-2.46; P(trend) < .002) for AFM when fitted together in multivariate analysis including other risk factors. A similar adjusted OR for AFM ≥ 31 years relative to ≤18 years was seen among married nulliparous women (OR 1.71, 95% CI 0.98-2.98; P(trend) < .001). AFM (a surrogate for age at starting prolonged cohabitation) is thus strongly associated with breast cancer risk. This suggests an effect of close contact. Identifying the (probably infective) mechanism might lead to effective prevention of breast cancer. The independent effect of AFB is smaller and could be due to residual confounding

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

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

Certified causes of death in patients with mesothelioma in South East England

Background: Mesothelioma is a highly fatal cancer that is caused by exposure to asbestos fibres. In many populations, the occurrence of mesothelioma is monitored with the use of mortality data from death certification. We examine certified causes of death of patients who have been diagnosed with mesothelioma, and assess the validity of death certification data as a proxy for mesothelioma incidence.Methods: We extracted mesothelioma registrations in the South East of England area between 2000 and 2004 from the Thames Cancer Registry database. We retained for analysis 2200 patients who had died at the time of analysis, after having excluded seven dead cases where the causes of death were not known to the cancer registry. The 2200 deaths were classified hierarchically to identify (1) mesothelioma deaths, (2) deaths certified as lung cancer deaths or (3) deaths from unspecified cancer, and (4) deaths from other causes.Results: 87% of the patients had mesothelioma mentioned on the death certificate. 6% had no mention of mesothelioma but included lung cancer as a cause of death. Another 6% had no mention of mesothelioma or lung cancer, but included an unspecified cancer as a cause of death. Lastly, 2% had other causes of death specified on the death certificate.Conclusion: This analysis suggests that official mortality data may underestimate the true occurrence of mesothelioma by around 10%