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Screening for human papillomavirus (HPV) infection is more effective in reducing the incidence of cervical cancer than screening using Pap smears. Moreover, HPV testing can be done on a vaginal sample self-taken by a woman, which offers an opportunity to improve screening coverage. However, the clinical accuracy of HPV testing on self-samples is not well-known. We assessed whether HPV testing on self-collected samples is equivalent to HPV testing on samples collected by clinicians. We identified relevant studies through a search of PubMed, Embase, and CENTRAL. Studies were eligible for inclusion if they fulfilled all of the following selection criteria: a cervical cell sample was self-collected by a woman followed by a sample taken by a clinician; a high-risk HPV test was done on the self-sample (index test) and HPV-testing or cytological interpretation was done on the specimen collected by the clinician (comparator tests); and the presence or absence of cervical intraepithelial neoplasia grade 2 (CIN2) or worse was verified by colposcopy and biopsy in all enrolled women or in women with one or more positive tests. The absolute accuracy for finding CIN2 or worse, or CIN grade 3 (CIN3) or worse of the index and comparator tests as well as the relative accuracy of the index versus the comparator tests were pooled using bivariate normal models and random effect models. We included data from 36 studies, which altogether enrolled 154 556 women. The absolute accuracy varied by clinical setting. In the context of screening, HPV testing on self-samples detected, on average, 76% (95% CI 69–82) of CIN2 or worse and 84% (72–92) of CIN3 or worse. The pooled absolute specificity to exclude CIN2 or worse was 86% (83–89) and 87% (84–90) to exclude CIN3 or worse. The variation of the relative accuracy of HPV testing on self-samples compared with tests on clinician-taken samples was low across settings, enabling pooling of the relative accuracy over all studies. The pooled sensitivity of HPV testing on self-samples was lower than HPV testing on a clinician-taken sample (ratio 0·88 [95% CI 0·85–0·91] for CIN2 or worse and 0·89 [0·83–0·96] for CIN3 or worse). Also specificity was lower in self-samples versus clinician-taken samples (ratio 0·96 [0·95–0·97] for CIN2 or worse and 0·96 [0·93–0·99] for CIN3 or worse). HPV testing with signal-based assays on self-samples was less sensitive and specific than testing on clinician-based samples. By contrast, some PCR-based HPV tests generally showed similar sensitivity on both self-samples and clinician-based samples. In screening programmes using signal-based assays, sampling by a clinician should be recommended. However, HPV testing on a self-sample can be suggested as an additional strategy to reach women not participating in the regular screening programme. Some PCR-based HPV tests could be considered for routine screening after careful piloting assessing feasibility, logistics, population compliance, and costs. The 7th Framework Programme of the European Commission, the Belgian Foundation against Cancer, the International Agency for Research on Cancer, and the German Guideline Program in Oncology.

The earthworm is particularly fascinating to biologists because of its strong regenerative capacity. However, many aspects of its regeneration in nature remain elusive. Here we report chromosome-level genome, large-scale transcriptome and single-cell RNA-sequencing data during earthworm ( Eisenia andrei ) regeneration. We observe expansion of LINE2 transposable elements and gene families functionally related to regeneration (for example, EGFR , epidermal growth factor receptor) particularly for genes exhibiting differential expression during earthworm regeneration. Temporal gene expression trajectories identify transcriptional regulatory factors that are potentially crucial for initiating cell proliferation and differentiation during regeneration. Furthermore, early growth response genes related to regeneration are transcriptionally activated in both the earthworm and planarian. Meanwhile, single-cell RNA-sequencing provides insight into the regenerative process at a cellular level and finds that the largest proportion of cells present during regeneration are stem cells. The mechanisms regulating regeneration of the earthworm are unclear. Here, the authors use genomic and transcriptomic analysis of the earthworm Eisenia andrei together with Hi-C analysis to identify genes involved and show activation of LINE2 transposable elements on regeneration.

The human papillomavirus (HPV) vaccine is the first vaccine developed specifically targeting the prevention of cervical cancer. For more than 15 years, China has expedited a series of efforts on research and development of the domestically manufactured HPV vaccines, producing local population-based evidence, promoting free HPV vaccination from pilots, and launching action plans to tackle barriers in the scale-up of HPV vaccination. To further roll out the HPV vaccination program in China, several challenges should be addressed to support the steps forward. The availability of more locally manufactured HPV vaccines, pricing negotiation and local evidence supporting the efficacy of one-dose schedule would greatly alleviate the continued supply and financial constraints in China. Meanwhile, more attention should be paid to girls living in low-resource areas and males to ensure equal access to the HPV vaccination. Furthermore, linkage to secondary prevention and further real-world monitoring and evaluation are warranted to inform effective cervical cancer prevention strategies in the post-vaccine era. Graphical Abstract

This Escherichia coli-produced bivalent HPV 16 and 18 vaccine was well tolerated and effective against HPV 16 and 18 associated high-grade genital lesions and persistent infection in interim analysis of this phase 3 trial. We now report data on long-term efficacy and safety after 66 months of follow-up. This phase 3, double-blind, randomised, controlled trial was done in five study sites in China. Eligible participants were women aged 18–45 years, with intact cervix and 1–4 lifetime sexual partners. Women who were pregnant or breastfeeding, had chronic disease or immunodeficiency, or had HPV vaccination history were excluded. Women were stratified by age (18–26 and 27–45 years) and randomly (1:1) allocated by software (block randomisation with 12 codes to a block) to receive three doses of the E coli-produced HPV 16 and 18 vaccine or hepatitis E vaccine (control) and followed-up for 66 months. The primary outcomes were high-grade genital lesions and persistent infection (longer than 6 months) associated with HPV 16 or 18 in the per-protocol susceptible population. This trial was registered with ClinicalTrials.gov, NCT01735006. Between Nov 22, 2012, and April 1, 2013, 8827 women were assessed for eligibility. 1455 women were excluded, and 7372 women were enrolled and randomly assigned to receive the HPV vaccine (n=3689) or control (n=3683). Vaccine efficacy was 100·0% (95% CI 67·2–100·0) against high-grade genital lesions (0 [0%] of 3310 participants in the vaccine group and 13 [0·4%] of 3302 participants in the control group) and 97·3% (89·9–99·7) against persistent infection (2 [0·1%] of 3262 participants in the vaccine group and 73 [2·2%] of 3271 participants in the control group) in the per-protocol population. Serious adverse events occurred at a similar rate between vaccine (267 [7·2%] of 3691 participants) and control groups (290 [7·9%] of 3681); none were considered related to vaccination. The E coli-produced HPV 16 and 18 vaccine was well tolerated and highly efficacious against HPV 16 and 18 associated high-grade genital lesions and persistent infection and would supplement the global HPV vaccine availability and accessibility for cervical cancer prevention. National Natural Science Foundation of China, National Key R&D Program of China, Fujian Provincial Project, Fundamental Funds for the Central Universities, Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, and Xiamen Innovax.

Background Self-sampling HPV test and thermal ablation are effective tools to increase screening coverage and treatment compliance for accelerating cervical cancer elimination. We assessed the cost-effectiveness of their combined strategies to inform accessible, affordable, and acceptable cervical cancer prevention strategies. Methods We developed a hybrid model to evaluate costs, health outcomes, and incremental cost-effectiveness ratios (ICER) of six screen-and-treat strategies combining HPV testing (self-sampling or physician-sampling), triage modalities (HPV genotyping, colposcopy or none) and thermal ablation, from a societal perspective. A designated initial cohort of 100,000 females born in 2015 was considered. Strategies with an ICER less than the Chinese gross domestic product (GDP) per capita ($10,350) were considered highly cost-effective. Results Compared with current strategies in China (physician-HPV with genotype or cytology triage), all screen-and-treat strategies are cost-effective and self-HPV without triage is optimal with the most incremental quality-adjusted life-years (QALYs) gained (220 to 440) in rural and urban China. Each screen-and-treat strategy based on self-collected samples is cost-saving compared with current strategies (−$818,430 to −$3540) whereas more costs are incurred using physician-collected samples compared with current physician-HPV with genotype triage (+$20,840 to +$182,840). For screen-and-treat strategies without triage, more costs (+$9404 to +$380,217) would be invested in the screening and treatment of precancerous lesions rather than the cancer treatment compared with the current screening strategies. Notably, however, more than 81.6% of HPV-positive women would be overtreated. If triaged with HPV 7 types or HPV16/18 genotypes, 79.1% or 67.2% (respectively) of HPV-positive women would be overtreated with fewer cancer cases avoided (19 cases or 69 cases). Conclusions Screen-and-treat strategy using self-sampling HPV test linked to thermal ablation could be the most cost-effective for cervical cancer prevention in China. Additional triage with quality-assured performance could reduce overtreatment and remains highly cost-effective compared with current strategies.

A new test ( careHPV; QIAGEN, Gaithersburg, MD, USA) has been developed to detect 14 high-risk types of carcinogenic human papillomavirus (HPV) in about 2·5 h, to screen women in developing regions for cervical intraepithelial neoplasia (CIN). We did a cross-sectional study to assess the clinical accuracy of careHPV as a rapid screening test in two county hospitals in rural China. From May 10 to June 15, 2007, the careHPV test was done locally by use of self-obtained vaginal and provider-obtained cervical specimens from a screening population-based set of 2530 women aged 30 to 54 years in Shanxi province, China. All women were assessed by visual inspection with acetic acid (VIA), Digene High-Risk HPV HC2 DNA Test (HC2), liquid-based cytology, and colposcopy with directed biopsy and endocervical curettage as necessary. In 2388 women with complete data, 441 women with negative colposcopy, but unsatisfactory or abnormal cytology or who were positive on HC2 or the new careHPV test, were recalled for a second colposcopy, four-quadrant cervical biopsies, and endocervical curettage. An absence of independence between the tests was not adjusted for and the Bonferroni correction was used for multiple comparisons. Complete data were available for 2388 (94·4%) women. 70 women had CIN2+ (moderate or severe CIN or cancer), of whom 23 had CIN3+. By use of CIN2+ as the reference standard and area-under-the-curve analysis with a two-sided alpha error level of 0·0083, the sensitivities and specificities of the careHPV test for a cut-off ratio cut-point of 0·5 relative light units, were 90·0% (95% CI 83·0–97·0) and 84·2% (82·7–85·7), respectively, on cervical specimens, and 81·4% (72·3–90·5) and 82·4% (80·8–83·9), respectively, on vaginal specimens (areas under the curve not significantly different, p=0·0596), compared with 41·4% (29·9–53·0) and 94·5% (93·6–95·4) for VIA (areas under the curve significantly different, p=0·0001 and p=0·0031, for cervical and vaginal-specimen comparisons for the careHPV test, respectively). The sensitivity and specificity of HC2 for cervical specimens were 97·1% (93·2–100) and 85·6% (84·2–87·1), respectively (areas under the curve not significantly different from the careHPV test on cervical specimens, p=0·0163). The careHPV test is promising as a primary screening method for cervical-cancer prevention in low-resource regions. Bill & Melinda Gates Foundation.

Abstract Background/Aims: To investigate the potential therapeutic effect of novel polysaccharide H-1-2 from pseudostellaria heterophylla against type 2 Diabetes Mellitus (T2DM) and elucidate the underling molecular mechanisms. Methods: Relative expression of HIF1α and Sirt1 in T2DM patients was determined via real-time PCR. The direct binding of HIF1α on Sirt1 promoter was validated by ChIP assay. The inhibitory regulation of Sirt1 by HIF1α was analyzed using luciferase reporter assay. The endogenous protein of HIF1α and Sirt1 in response to H-1-2 treatment was quantified by western blotting. The blood glucose, secreted insulin and serous lipid profiles were measured with ELISA kits. Results: We consolidated that HIF1α and Sirt1 was dysregulated in T2DM patients and subjected to H-1-2 modulation. H-1-2 significantly inhibited hypoxia and up-regulated Sirt1 expression in EndoC-βH1 cells. Accordingly, H-1-2 enhanced glucose-stimulation insulin secretion and improved blood glucose and lipid profiles in T2DM cells, and elevated the glucose and insulin tolerance simultaneously. Furthermore, we demonstrated that H-1-2 alleviated T2DM via inhibition of hypoxia and up-regulation of Sirt1 in isolated pancreatic β-cells from T2DM rats. Conclusion: Our data unambiguously demonstrated H-1-2 administration alleviated T2DM by enhancing Sirt1 expression through inhibition of hypoxia.

Deep learning (DL) enabled liquid-based cytology has potential for cervical cancer screening or triage. Here, we develop a DL model using whole cytology slides from 17,397 women and test it on 10,826 additional cases through a three-stage process. The DL model achieves robust performance across nine hospitals. In a multi-reader, multi-case study, it outperforms cytopathologists’ sensitivity by 9%. Reading time significantly decreases with DL assistance (218s vs 30s; p  < 0.0001). In community-based organized screening, the DL model’s sensitivity matches that of senior cytopathologists (0.878 vs 0.854; p  > 0.999), yet it has reduced specificity (0.831 vs 0.901; p  < 0.0001). Notably, hospital-based opportunistic screening shows that junior cytopathologists with DL assistance significantly improve both their sensitivity and specificity (0.857 vs 0.657, 0.840 vs 0.737; both p  < 0.0001). When triaging human papillomavirus-positive cases, DL assistance exhibits better performance than junior cytopathologists alone. These findings support using the DL model as an assistance tool in cervical screening and case triage. Cytology is commonly used for cervical cancer screening or triage. Here, the authors used deep learning to develop a liquid-based cytology screening approach to detect cervical cancer in both community and hospital-based settings.

Shenzhu Tiaopi granule (STG) has antidiabetic functions. Data-independent acquisition proteomic technology is an integral part of systems biology. Herein, proteomics was used to analyse the effects of STG on type 2 diabetes mellitus (T2DM) and the mechanism by which STG normalizes glucose metabolism. Goto-Kakizaki (GK) T2DM model (Mod) rats, aged 15-16 weeks and with a fasting blood glucose (FBG) level of ≥11.1 mmol/L, were treated with metformin or STG for 12 weeks. Wistar rats aged 15-16 weeks were included in the control (Con) group. Body weight, FBG, total cholesterol (TC), total triglyceride (TG) levels and low-density lipoprotein (LDL-C) levels were measured, and pathological observation, Western blot analysis and data-independent acquisition proteomics of the liver were performed. Significant differences in FBG, TC, TG, LDL-C (p < 0.01) and pathological liver morphology were observed between the Mod group and Con group, whereas both metformin and STG normalized the glucose and lipid metabolism indicators (p < 0.05 or p < 0.01). In total, 5856 proteins were identified via proteomic analysis, 97 of which were significantly differentially expressed in the liver and affected fatty acid metabolism, unsaturated fatty acid biosynthesis, the peroxisome proliferator-activated receptor (PPAR) signalling pathway, pyruvate metabolism, and terpenoid backbone biosynthesis. Screening identified 10 target proteins, including perilipin-2 (Plin2), pyruvate dehydrogenase kinase 4, farnesyl diphosphate synthase (Fdps) and farnesyl-diphosphate farnesyltransferase 1. Among these proteins, the key proteins were Plin2 and Fdps, which were found to be associated with the PPAR signalling pathway and terpenoid backbone biosynthesis via relationship networks. Plin2 and Fdps are closely related to hyperglycaemia. STG can downregulate Plin2 and upregulate Fdps (p < 0.01). STG ameliorated hyperglycaemia by significantly altering the expression of different proteins, especially Fdps and Plin2, in the livers of GK rats. These findings may reveal the potential of traditional Chinese medicine for treating T2DM.

Background The cost-effectiveness of human papillomavirus (HPV) vaccination in women pre-sexual debut has been demonstrated in many countries. This study aimed to estimate the cost-effectiveness of a 3-dose bivalent HPV vaccination at ages 12 to 55 year in both rural and urban settings in China. Methods The Markov cohort model simulated the natural history of HPV infection and included the effect of screening and HPV vaccination over the lifetime of a 100,000 female cohort. Transition probabilities and utilities were obtained from published literature. Cost data were estimated by Delphi panel using healthcare payers’ perspective. Vaccine cost was assumed Hong Kong listed price. Vaccine efficacy (VE) was based on the PATRICIA trial data assuming VE irrespective of HPV type at all ages on incident HPV. Costs and outcomes were discounted at 3 %. Cervical cancer cases and incremental cost-effectiveness ratio (ICER) for vaccination and screening compared with screening alone were estimated for each vaccination age. Reduced VE in women post-sexual debut were investigated in scenario analyses. Results With 70 % vaccination coverage, a reduction of cancer cases varying from 585 to 33 in rural and 691 to 32 in urban were estimated at ages 12 to 55, respectively. The discounted ICERs of vaccination at any age under 23 years in rural and any age under 25 years in urban were lower than the current threshold. Scenario analyses with lower VE post-sexual debut confirmed the results with age 20 in rural and 21 in urban had consistent lower ICERs. The more ‘catch-up’ cohorts vaccinated at the start of a program, the more cancer lesions are avoided in the long-term. Conclusions Vaccination at any age under 23 years old in rural and any age under 25 years old in urban were cost-effective. Catch-up to the age of 25 years in rural and urban could still be cost-effective.