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Persistent symptoms among some individuals who develop COVID-19 have led to the hypothesis that SARS-CoV-2 might, in some form or location, persist for long periods following acute infection.1,2 Studies on SARS-CoV-2 persistence to date, however, have been limited by small and non-representative study populations, short durations since acute infection, unclear documentation of vaccination and reinfection histories, and the absence of a true negative comparator group to assess assay specificity (appendix p 2). Coupled with a 2024 study of replication-competent virus in blood during acute infection,6 our findings suggest that SARS-CoV-2 might seed distal sites through the bloodstream and establish protected reservoirs in some sites. Because our measurement of SARS-CoV-2 is via immunoreactivity, it cannot be assumed that every signal is specific for SARS-CoV-2 antigen. Antigens from related pathogens or the host can theoretically cross-react, differing from the detection of nucleic acid for which specificity is typically complete and direct analyte evaluation by sequencing is possible. [...]understanding the specificity of any immune-based assay purporting to detect SARS-CoV-2 antigens is crucial and requires a large true negative group to precisely estimate false positivity.

Time, number, and space may be represented in the brain by a common set of cognitive/neural mechanisms. In support of this conjecture, Schwarz and Eiselt ( Journal of Experimental Psychology: Human Perception and Performance, 35 , 989–1004, 2009 ) found that numerically smaller digits were perceived to occur earlier than larger digits, and they concluded that this difference reflected faster processing of smaller numbers. This difference, however, could have been related to a response bias, whereby participants map responses of “which first” onto the “first” number along the mental number line. In Experiment 1 , participants made temporal order judgements between digits presented to the left or to the right. The point of subjective simultaneity was shifted so that the 9 had to be presented before the 2 in order for simultaneity to be perceived. This difference could reflect either faster processing of the 2 or a response bias. Experiments 2a and 2b eliminated response biases by using simultaneity judgements, which have no logical stimulus mapping. Both of the latter experiments established that the 2 was not processed faster than the 9. Although the present results relate specifically to numerical magnitude and temporal order associations, they also have broader implications. Other studies have reported associations between dimensions such as size, duration, and number and have attributed these to parietal mechanisms. Such associations, however, may also be an artefact of response biases.

Cervical screening and human papillomavirus (HPV) vaccination have been implemented in most high-income countries; however, coverage is low in low-income and middle-income countries (LMICs). In 2018, the Director-General of WHO announced a call to action for the elimination of cervical cancer as a public health problem. WHO has called for global action to scale-up vaccination, screening, and treatment of precancer, early detection and prompt treatment of early invasive cancers, and palliative care. An elimination threshold in terms of cervical cancer incidence has not yet been defined, but an absolute rate of cervical cancer incidence could be chosen for such a threshold. In this study, we aimed to quantify the potential cumulative effect of scaled up global vaccination and screening coverage on the number of cervical cancer cases averted over the 50 years from 2020 to 2069, and to predict outcomes beyond 2070 to identify the earliest years by which cervical cancer rates could drop below two absolute levels that could be considered as possible elimination thresholds—the rare cancer threshold (six new cases per 100 000 women per year, which has been observed in only a few countries), and a lower threshold of four new cases per 100 000 women per year. In this statistical trends analysis and modelling study, we did a statistical analysis of existing trends in cervical cancer worldwide using high-quality cancer registry data included in the Cancer Incidence in Five Continents series published by the International Agency for Research on Cancer. We then used a comprehensive and extensively validated simulation platform, Policy1-Cervix, to do a dynamic multicohort modelled analysis of the impact of potential scale-up scenarios for cervical cancer prevention, in order to predict the future incidence rates and burden of cervical cancer. Data are presented globally, by Human Development Index (HDI) category, and at the individual country level. In the absence of further intervention, there would be 44·4 million cervical cancer cases diagnosed globally over the period 2020–69, with almost two-thirds of cases occurring in low-HDI or medium-HDI countries. Rapid vaccination scale-up to 80–100% coverage globally by 2020 with a broad-spectrum HPV vaccine could avert 6·7–7·7 million cases in this period, but more than half of these cases will be averted after 2060. Implementation of HPV-based screening twice per lifetime at age 35 years and 45 years in all LMICs with 70% coverage globally will bring forward the effects of prevention and avert a total of 12·5–13·4 million cases in the next 50 years. Rapid scale-up of combined high-coverage screening and vaccination from 2020 onwards would result in average annual cervical cancer incidence declining to less than six new cases per 100 000 individuals by 2045–49 for very-high-HDI countries, 2055–59 for high-HDI countries, 2065–69 for medium-HDI countries, and 2085–89 for low-HDI countries, and to less than four cases per 100 000 by 2055–59 for very-high-HDI countries, 2065–69 for high-HDI countries, 2070–79 for medium-HDI countries, and 2090–2100 or beyond for low-HDI countries. However, rates of less than four new cases per 100 000 would not be achieved in all individual low-HDI countries by the end of the century. If delivery of vaccination and screening is more gradually scaled up over the period 2020–50 (eg, 20–45% vaccination coverage and 25–70% once-per-lifetime screening coverage by 2030, increasing to 40–90% vaccination coverage and 90% once-per-lifetime screening coverage by 2050, when considered as average coverage rates across HDI categories), end of the century incidence rates will be reduced by a lesser amount. In this scenario, average cervical cancer incidence rates will decline to 0·8 cases per 100 000 for very-high-HDI countries, 1·3 per 100 000 for high-HDI countries, 4·4 per 100 000 for medium-HDI countries, and 14 per 100 000 for low-HDI countries, by the end of the century. More than 44 million women will be diagnosed with cervical cancer in the next 50 years if primary and secondary prevention programmes are not implemented in LMICs. If high coverage vaccination can be implemented quickly, a substantial effect on the burden of disease will be seen after three to four decades, but nearer-term impact will require delivery of cervical screening to older cohorts who will not benefit from HPV vaccination. Widespread coverage of both HPV vaccination and cervical screening from 2020 onwards has the potential to avert up to 12·5–13·4 million cervical cancer cases by 2069, and could achieve average cervical cancer incidence of around four per 100 000 women per year or less, for all country HDI categories, by the end of the century. A draft global strategy to accelerate cervical cancer elimination, with goals and targets for the period 2020–30, will be considered at the World Health Assembly in 2020. The findings presented here have helped inform initial discussions of elimination targets, and ongoing comparative modelling with other groups is supporting the development of the final goals and targets for cervical cancer elimination. National Health and Medical Research Council (NHMRC) Australia, part-funded via the NHMRC Centre of Excellence for Cervical Cancer Control (C4; APP1135172).

Many countries are transitioning from cytology-based to longer-interval HPV screening. Trials comparing HPV-based screening to cytology report an increase in CIN2/3 detection at the first screen, and longer-term reductions in CIN3+; however, population level year-to-year transitional impacts are poorly understood. We undertook a comprehensive evaluation of switching to longer-interval primary HPV screening in the context of HPV vaccination. We used Australia as an example setting, since Australia will make this transition in December 2017. Using a model of HPV vaccination, transmission, natural history and cervical screening, Policy1-Cervix, we simulated the planned transition from recommending cytology every two years for sexually-active women aged 18-20 to 69, to recommending HPV screening every five years for women aged 25-74 years. We estimated rates of CIN2/3, cervical cancer incidence, and mortality for each year from 2005 to 2035, considering ranges for HPV test accuracy and screening compliance in the context of HPV vaccination (current coverage ~82% in females; ~76% in males). Transient increases are predicted to occur in rates of CIN2/3 detection and invasive cervical cancer in the first two to three years following the screening transition (of 16-24% and 11-14% in respectively, compared to 2017 rates). However, by 2035, CIN2/3 and invasive cervical cancer rates are predicted to fall by 40-44% and 42-51%, respectively, compared to 2017 rates. Cervical cancer mortality rates are predicted to remain unchanged until ~2020, then decline by 34-45% by 2035. Over the period 2018-2035, switching to primary HPV screening in Australia is expected to avert 2,006 cases of invasive cervical cancer and save 587 lives. Transient increases in detected CIN2/3 and invasive cancer, which may be detectable at the population level, are predicted following a change to primary HPV screening. This is due to improved test sensitivity bringing forward diagnoses, resulting in longer term reductions in both cervical cancer incidence and mortality. Fluctuations in health outcomes due to the transition to a longer screening interval are predicted to occur for 10-15 years, but cervical cancer rates will be significantly reduced thereafter due to the impact of HPV vaccination and HPV screening. In order to maintain confidence in primary HPV screening through the transitional phase, it is important to widely communicate that an initial increase in CIN2/3 and perhaps even invasive cervical cancer is expected after a national transition to primary HPV screening, that this phenomenon is due to increased prevalent disease detection, and that this effect represents a marker of screening success.

Several countries are implementing a transition to HPV testing for cervical screening in response to the introduction of HPV vaccination and evidence indicating that HPV screening is more effective than cytology. In Australia, a 2017 transition from 2-yearly conventional cytology in 18-20 to 69 years to 5-yearly primary HPV screening in 25 to 74 years will involve partial genotyping for HPV 16/18 with direct referral to colposcopy for this higher risk group. The objective of this study was to determine the optimal management of women positive for other high-risk HPV types (not 16/18) ('OHR HPV'). We used a dynamic model of HPV transmission, vaccination, natural history and cervical screening to determine the optimal management of women positive for OHR HPV. We assumed cytology triage testing was used to inform management in this group and that those with high-grade cytology would be referred to colposcopy and those with negative cytology would receive 12-month surveillance. For those with OHR HPV and low-grade cytology (considered to be a single low-grade category in Australia incorporating ASC-US and LSIL), we evaluated (1) the 20-year risk of invasive cervical cancer assuming this group are referred for 12-month follow-up vs. colposcopy, and compared this to the risk in women with low-grade cytology under the current program (i.e. an accepted benchmark risk for 12-month follow-up in Australia); (2) the population-level impact of the whole program, assuming this group are referred to 12-month surveillance vs. colposcopy; and (3) the cost-effectiveness of immediate colposcopy compared to 12-month follow-up. Evaluation was performed both for HPV-unvaccinated cohorts and cohorts offered vaccination (coverage ~72%). The estimated 20-year risk of cervical cancer is ≤1.0% at all ages if this group are referred to colposcopy vs. ≤1.2% if followed-up in 12 months, both of which are lower than the ≤2.6% benchmark risk in women with low-grade cytology in the current program (who are returned for 12-month follow-up). At the population level, immediate colposcopy referral provides an incremental 1-3% reduction in cervical cancer incidence and mortality compared with 12-month follow-up, but this is in the context of a predicted 24-36% reduction associated with the new HPV screening program compared to the current cytology-based program. Furthermore, immediate colposcopy substantially increases the predicted number of colposcopies, with >650 additional colposcopies required to avert each additional case of cervical cancer compared to 12-month follow-up. Compared to 12-month follow-up, immediate colposcopy has an incremental cost-effectiveness ratio (ICER) of A$104,600/LYS (95%CrI:A$100,100-109,100) in unvaccinated women and A$117,100/LYS (95%CrI:A$112,300-122,000) in cohorts offered vaccination [Indicative willingness-to-pay threshold: A$50,000/LYS]. In primary HPV screening programs, partial genotyping for HPV16/18 or high-grade triage cytology in OHR HPV positive women can be used to refer the highest risk group to colposcopy, but 12-month follow-up for women with OHR HPV and low-grade cytology is associated with a low risk of developing cervical cancer. Direct referral to colposcopy for this group would be associated with a substantial increase in colposcopy referrals and the associated harms, and is also cost-ineffective; thus, 12-month surveillance for women with OHR HPV and low-grade cytology provides the best balance between benefits, harms and cost-effectiveness.

Background Intimate partner violence (IPV) against women in the United States (US) remains a complex public health crisis. Women who experience IPV are among the most vulnerable patients seen in primary care. Screening increases the detection of IPV and, when paired with appropriate response interventions, can mitigate the health effects of IPV. The Department of Veterans Affairs (VA) has encouraged evidence-based IPV screening programs since 2014, yet adoption is modest and questions remain regarding the optimal ways to implement these practices, which are not yet available within the majority of VA primary care clinics. Methods/design This paper describes the planned evaluation of VA’s nationwide implementation of IPV screening programs in primary care clinics through a randomized implementation-effectiveness hybrid type 2 trial. With the support of our VA operational partners, we propose a stepped wedge design to compare the impact of two implementation strategies of differing intensities (toolkit + implementation as usual vs. toolkit + implementation facilitation) and investigate the clinical effectiveness of IPV screening programs. Using balanced randomization, 16–20 VA Medical Centers will be assigned to receive implementation facilitation in one of three waves, with implementation support lasting 6 months. Implementation facilitation in this effort consists of the coordinated efforts of the two types of facilitators, external and internal. Implementation facilitation is compared to dissemination of a toolkit plus implementation as usual. We propose a mixed methods approach to collect quantitative (clinical records data) and qualitative (key informant interviews) implementation outcomes, as well as quantitative (clinical records data) clinical effectiveness outcomes. We will supplement these data collection methods with provider surveys to assess discrete implementation strategies used before, during, and following implementation facilitation. The integrated-Promoting Action on Research Implementation in Health Services (i-PARIHS) framework will guide the qualitative data collection and analysis. Summative data will be analyzed using the Reach Effectiveness Adoption Implementation Maintenance (RE-AIM) framework. Discussion This research will advance national VHA efforts by identifying the practices and strategies useful for enhancing the implementation of IPV screening programs, thereby ultimately improving services for and health of women seen in primary care. Trial registration NCT04106193 . Registered on 23 September 2019.

Constructs, calibrates and validates a complex model of human papillomavirus (HPV) vaccination and cervical screening in NZ. Determines, in collaboration with the NZ National Cervical Screening Programme (NCSP), a set of possible strategies (i.e. clinical management pathways) suitable to the NZ context using HPV as the primary screening test. Evaluates the lifetime effects and costs associated with each of these strategies, in relation to current practice for cervical screening, in both vaccinated and unvaccinated cohorts, taking into account the levels of vaccine coverage achieved in NZ. Identifies optimal future screening approaches in NZ in both vaccinated and unvaccinated women. Source: National Library of New Zealand Te Puna Matauranga o Aotearoa, licensed by the Department of Internal Affairs for re-use under the Creative Commons Attribution 3.0 New Zealand Licence.

•Cervical cancer rates are higher in Māori vs other women in New Zealand.•Both HPV vaccination and HPV screening are predicted to reduce this disparity.•Increased vaccine and screening coverage could further reduce but may not close gap.•Multiple approaches will be required, including beyond vaccination and screening.•These potentially include access to cervical cancer treatment, and tobacco control. Cervical cancer rates are over twice as high, and screening coverage is lower, in Māori women compared to other women in New Zealand, whereas uptake of HPV vaccine is higher in Maori females. We aimed to assess the impact of HPV vaccination and the proposed transition to 5-yearly primary HPV screening in Māori and other women in New Zealand, at current participation levels; and additionally to investigate which improvements to participation in Māori females (in vaccination, screening, or surveillance for screening-defined higher-risk women) would have the greatest impact on cervical cancer incidence/mortality. An established model of HPV vaccination and cervical screening in New Zealand was adapted to fit observed ethnicity-specific data. Ethnicity-specific models were used to estimate the long-term impact of vaccination and screening (vaccination coverage 63% vs 47%; five-year screening coverage 68% vs 81% in Maori vs European/Other women, respectively). Shifting from cytology to HPV-based screening is predicted to reduce cervical cancer incidence by 17% (14%) in Maori (European/Other) women, respectively. The corresponding reductions due to vaccination and HPV-based screening combined were 58% (44%), but at current participation levels long-term incidence would remain almost twice as high in Māori women (6.1/100,000 compared to 3.1/100,00 in European/Other women). Among strategies we examined, the greatest impact came from high vaccine coverage and achieving higher attendance by Māori women under surveillance for screen-detected abnormalities. Relative reductions in cervical cancer due to vaccination and HPV-based screening are predicted to be greater in Maori than in European/Other women. While these interventions have the potential to substantially reduce between-group differences, cervical cancer incidence would remain higher in Maori women. These findings highlight the importance of multiple approaches and the potential influence of factors beyond HPV prevention.

Background The mitochondrial unfolded protein response (mitoUPR) is a stress response pathway activated by disruption of proteostasis in the mitochondria. This pathway has been proposed to influence lifespan, with studies suggesting that mitoUPR activation has complex effects on longevity. Results Here, we examined the contribution of the mitoUPR to the survival and lifespan of three long-lived mitochondrial mutants in Caenorhabditis elegans by modulating the levels of ATFS-1, the central transcription factor that mediates the mitoUPR. We found that clk-1 , isp-1 , and nuo-6 worms all exhibit an ATFS-1-dependent activation of the mitoUPR. While loss of atfs-1 during adulthood does not affect lifespan in any of these strains, absence of atfs-1 during development prevents clk-1 and isp-1 worms from reaching adulthood and reduces the lifespan of nuo-6 mutants. Examining the mechanism by which deletion of atfs-1 reverts nuo-6 lifespan to wild-type, we find that many of the transcriptional changes present in nuo-6 worms are mediated by ATFS-1. Genes exhibiting an ATFS-1-dependent upregulation in nuo-6 worms are enriched for transcripts that function in stress response and metabolism. Consistent, with this finding, loss of atfs-1 abolishes the enhanced stress resistance observed in nuo-6 mutants and prevents upregulation of multiple stress response pathways including the HIF-1-mediated hypoxia response, SKN-1-mediated oxidative stress response and DAF-16-mediated stress response. Conclusions Our results suggest that in the long-lived mitochondrial mutant nuo-6 activation of the mitoUPR causes atfs-1- dependent changes in the expression of genes involved in stress response and metabolism, which contributes to the extended longevity observed in this mutant. This work demonstrates that the mitoUPR can modulate multiple stress response pathways and suggests that it is crucial for the development and lifespan of long-lived mitochondrial mutants.