Triage Test Research Articles

The outcome of colposcopy in women attending with persistent postcoital bleeding and negative HPV-DNA test

Objective: Women with postcoital bleeding (PCB) are recommended to be evaluated by colposcopy even if cytology is negative. Human papillomavirus (HPV) testing increases the detection of cervical intraepithelial neoplasia or worse compared to the Pap smear test. We aimed to determine the incidence of cervical pathology among women with persistent PCB with a negative Pap smear or HPV-DNA test. Our study, therefore, questions the place of HPV DNA test in women with PCB.
 Material and Methods: The clinical data of 212 women with persistent PCB and negative cytology or negative HPV DNA test referred to colposcopy, between January 2010 and June 2019, were retrospectively evaluated.
 Results: Among the 212 PCB patients, 161 (75.9%) were cytology negative and 51 (24.1%) were HPV DNA test (n=40) or co-test (n=11) (negative for HPV DNA test and cytology) negative. There were no cases of invasive cancer. The women referred with negative cytology were more likely than those with negative HPV DNA to have CIN (21/161 (13%), 1/51 (1.9%) p=0.042. Seven women (4.3%) were diagnosed with high-grade cervical dysplasia in the negative cytology group. None of the patients in the HPV DNA negative group was diagnosed with high-grade cervical dysplasia.
 Conclusion: Our data show that a normal Pap smear cytology in women with PCB does not rule out the possibility of HSIL. HPV DNA testing is a useful triage test to determine if colposcopy referral is required in the context of post-coital bleeding with negative smear test.

Host Blood RNA Transcript and Protein Signatures for Sputum-Independent Diagnostics of Tuberculosis in Adults.

To achieve the ambitious targets for tuberculosis (TB) prevention, care, and control stated by the End TB Strategy, new health care strategies, diagnostic tools are warranted. Host-derived biosignatures are explored for their TB diagnostic potential in accordance with the WHO target product profiles (TPPs) for point-of-care (POC) testing. We aimed to identify sputum-independent TB diagnostic signatures in newly diagnosed adult pulmonary-TB (PTB) patients recruited in the context of a prospective household contact cohort study conducted in Andhra Pradesh, India. Whole-blood mRNA samples from 158 subjects (PTB, n = 109; age-matched household controls, n = 49) were examined by dual-color Reverse-Transcriptase Multiplex Ligation-dependent Probe-Amplification (dcRT-MLPA) for the expression of 198 pre-defined genes and a Mesoscale discovery assay for the concentration of 18 cytokines/chemokines in TB-antigen stimulated QuantiFERON supernatants. To identify signatures, we applied a two-step approach; in the first step, univariate filtering was used to identify and shortlist potentially predictive biomarkers; this step may be seen as removing redundant biomarkers. In the second step, a logistic regression approach was used such that group membership (PTB vs. household controls) became the binary response in a Lasso regression model. We identified an 11-gene signature that distinguished PTB from household controls with AUCs of ≥0.98 (95% CIs: 0.94–1.00), and a 4-protein signature (IFNγ, GMCSF, IL7 and IL15) that differentiated PTB from household controls with AUCs of ≥0.87 (95% CIs: 0.75–1.00), in our discovery cohort. Subsequently, we evaluated the performance of the 11-gene signature in two external validation data sets viz, an independent cohort at the Glenfield Hospital, University Hospitals of Leicester NHS Trust, Leicester, UK (GSE107994 data set), and the Catalysis treatment response cohort (GSE89403 data set) from South Africa. The 11-gene signature validated and distinguished PTB from healthy and asymptomatic M. tuberculosis infected household controls in the GSE107994 data set, with an AUC of 0.95 (95% CI: 0.91–0.98) and 0.94 (95% CI: 0.89–0.98). More interestingly in the GSE89403 data set, the 11-gene signature distinguished PTB from household controls and patients with other lung diseases with an AUC of 0.93 (95% CI: 0.87–0.99) and 0.73 (95% CI: 0.56–0.89). These criteria meet the WHO TTP benchmarks for a non–sputum-based triage test for TB diagnosis. We suggest that further validation is required before clinical implementation of the 11-gene signature we have identified markers will be possible.

The comparative effectiveness of mpMRI and MRI-guided biopsy vs regular biopsy in a population-based PSA testing: a modeling study

The benefit of prostate cancer screening is counterbalanced by the risk of overdiagnosis and overtreatment. The use of a multi-parametric magnetic resonance imaging (mpMRI) test after a positive prostate-specific antigen (PSA) test followed by magnetic resonance imaging-guided biopsy (MRIGB) may reduce these harms. The aim of this study was to determine the effects of mpMRI and MRIGB vs the regular screening pathway in a population-based prostate cancer screening setting. A micro-simulation model was used to predict the effects of regular PSA screening (men with elevated PSA followed by TRUSGB) and MRI based screening (men with elevated PSA followed by mpMRI and MRIGB). We predicted reduction of overdiagnosis, harm-benefit ratio (overdiagnosis per cancer death averted), reduction in number of biopsies, detection of clinically significant cancer, prostate cancer death averted, life-years gained (LYG), and quality adjusted life years (QALYs) gained for both strategies. A univariate sensitivity analysis and threshold analysis were performed to assess uncertainty around the test sensitivity parameters used in the MRI strategy.In the MRI pathway, we predicted a 43% reduction in the risk of overdiagnosis, compared to the regular pathway. Similarly a lower harm-benefit ratio (overdiagnosis per cancer death averted) was predicted for this strategy compared to the regular screening pathway (1.0 vs 1.8 respectively). Prostate cancer mortality reduction, LY and QALYs gained were also slightly increased in the MRI pathway than the regular screening pathway. Furthermore, 30% of men with a positive PSA test could avoid a biopsy as compared to the regular screening pathway. Compared to regular PSA screening, the use of mpMRI as a triage test followed by MRIGB can substantially reduce the risk of overdiagnosis and improve the harm-benefit balance, while maximizing prostate cancer mortality reduction and QALYs gained.

Análise do desenvolvimento neuropsicomotor de pré-termos em ambulatório multidisciplinar: um olhar da fisioterapia

INTRODUÇÃO: Desde a gestação até o nascimento o desenvolvimento neuropsicomotor é influenciado por diversos fatores biopsicossociais. Tal influência pode ser ainda mais acentuada em recém-nascidos pré-termo devido a internação na Unidade de Terapia Intensiva Neonatal, por isto bebês pré-termos estão mais susceptíveis a essas influências. OBJETIVO: Analisar sob a ótica do fisioterapeuta o desenvolvimento neuropsicomotor de pré-termos em ambulatório multidisciplinar de um hospital público. METODOLOGIA: Estudo observacional e longitudinal, ambispectivo, de 19 crianças nascidas prematuras de 0 a 12 meses de idade corrigida, sendo critério de exclusão crianças com alterações cognitivas e/ou genéticas ou não terem assinado o termo de consentimento. Os dados foram coletados por meio da análise de prontuários entre agosto de 2017 e dezembro de 2018, o desenvolvimento avaliado por meio do Teste Triagem Denver II , em dois momentos: A1 e A2, em sua admissão e retorno ao serviço após a alta da Unidade de Terapia Intensiva Neonatal e para análise da relação entre mãe e bebê foi utilizada a Avaliação Vínculo Mãe/filho apenas em A1. As estimulações eram realizadas por meio de orientações e folder educativo para os pais e responsáveis. Os dados foram analisados, por meio de média, desvio-padrão, frequência absoluta e relativa, mediana, minimo e máximo e Teste de Wilcoxon para os domínios do Teste Denver II A1 em comparação a A2, utilizando o programa SPSS versão 20.0. RESULTADOS: Foram acompanhadas 19 crianças, destas 79% foram classificadas com desenvolvimento normal no A1. As crianças que apresentaram déficits no A1 (10,5%), superaram no A2. Porém, no segundo atendimento, algumas passaram a apresentar dificuldade em novas tarefas/domínio (motor, motor fino e pessoal-social), de modo que 31,5% apresentaram desenvolvimento geral anormal em A2. Foi encontrada diferença significativa (p=0,02) ao comparar as classificações gerais de Denver II nos dois momentos de avaliação. O vínculo mãe-filho foi classificado como fraco (média de 5,8 pontos). CONCLUSÃO: Observou-se que os bebês superaram os atrasos identificados na primeira avaliação, embora os resultados no Denver tiveram variações ao longo do tempo. Dessa forma, acredita-se que o perfil familiar identificado nesta pesquisa somada a abordagem multiprofissional possa ter favorecido o desenvolvimento neuropsicomotor dos bebês prematuros com até 12 meses de idade corrigida.

Reducing unnecessary referrals for colposcopy in hrHPV-positive women within the Dutch cervical cancer screening programme: A modelling study

BackgroundWith the implementation of primary high-risk human papillomavirus (hrHPV) screening in the Netherlands, an increase was observed in the number of unnecessary referrals (≤Cervical Intraepithelial Neoplasia (CIN) 1) to colposcopy. We aimed to investigate which alternative triage strategies safely reduce unnecessary referrals in HPV-based cervical cancer screening programmes. MethodsMicrosimulation model MISCAN was used to simulate an unvaccinated cohort of ten million 30-year old Dutch women. We calculated unnecessary referrals, cervical cancer incidence, mortality, costs and QALYs for 24 triage strategies. Condition for direct referral (atypical squamous cells of undetermined significance (ASC-US), low-grade squamous intraepithelial lesions (LSIL), high-grade squamous intraepithelial lesions (HSIL), conditional on HPV-genotype 16/18/other high risk (OHR)), type of triage test (cytology alone or combined with hrHPV) and time to triage test (6 or 12 months) was varied. ResultsThe 24 triage strategies had varying effects on the number of unnecessary referrals ranging from −72% to +35%. Adjusting conditions for referral to ‘HPV16/18+ and ASC-US+’ and ‘HPVOHR+ and HSIL+’ and extending the interval between tests to 12 months resulted in a reduction in unnecessary referrals of 40% (incidence +0%, mortality −1%). Reduction in unnecessary referrals without genotyping was achieved by adjusting conditions for direct referral to LSIL (12 months to repeat test) (unnecessary referrals −37%, incidence +2%, mortality +0%). ConclusionsTo reduce the number of unnecessary referrals without increasing incidence and mortality by more than 2% in the Dutch cervical cancer screening programme, genotyping for HPV16 or HPV16/18 should be implemented with 12 months to repeat testing.

Cervical cancer prevention in El Salvador: A prospective evaluation of screening and triage strategies incorporating high-resolution microendoscopy to detect cervical precancer.

Cervical cancer remains a leading cause of cancer death for women in low- and middle-income countries. The goal of our study was to evaluate screening and triage strategies, including high-resolution microendoscopy (HRME), to detect cervical abnormalities concerning for precancer at the point of care. Women (n = 1824) were enrolled at the Instituto de Cáncer de El Salvador. All underwent screening by both human papillomavirus (HPV) testing using careHPV and visual inspection with acetic acid (VIA). Screen-positives, along with 10% of screen-negatives, were invited to return for a follow-up examination that included triage with VIA, colposcopy and HRME imaging. Biopsies were taken of any abnormalities identified. If no abnormalities were identified, then the worst scoring site by HRME was biopsied. The sensitivities of HPV testing and VIA to screen for cervical intraepithelial neoplasia Grade 2 or more severe diagnoses (CIN2+) were 82.1% and 75% (P = .77), while the specificities were 90.4% and 80.9% (P < .001), respectively. The sensitivities of VIA, colposcopy and HRME as triage tests for CIN2+ were 82.1%, 82.1% and 71.4%, respectively (P ≥ .38). HRME had a significantly higher specificity (66.7%) than VIA (51.9%) (P < .001) and colposcopy (53.3%) (P < .001). When evaluating different theoretical screening and triage strategies, screening with HPV testing followed by triage with HRME would result in more women receiving appropriate care (97%) compared to screening with VIA (75%) or HPV alone (90%). Our findings demonstrate that screening with HPV is superior to VIA, and that triage with HRME imaging increases the specificity of detecting CIN2+ at the point of care in a low-resource setting.

Rochelle Walensky: new Director of the US CDC

Rochelle Walensky: new Director of the US CDC

DNA methylation markers as triage test for the early identification of cervical lesions in a Chinese population.

Objective strategies are required in cervical cancer screening. We have identified several DNA methylation markers with high sensitivity and specificity to detect cervical intraepithelial neoplasia 2 or worse (CIN2+) in Dutch women. Our study aims to analyze the diagnostic characteristics of these markers in a Chinese cohort. A total of 246 liquid‐based cytology samples were included, of which 205 women underwent colposcopy due to an abnormal cytology result (atypical squamous cells of undetermined significance [ASCUS] or worse), while 227 were tested high‐risk human papillomavirus (hrHPV) positive. All six individual markers (ANKRD18CP, C13ORF18, EPB41L3, JAM3, SOX1 and ZSCAN1) showed enhanced methylation levels and frequency with increasing severity of the underlying lesion (P ≤ .001). In cytological abnormal women, sensitivity to detect CIN2+ was 79%, 76% and 72% for the three panels (C13ORF18/EBP41L3/JAM3, C13ORF18/ANKRD18CP/JAM3 and ZSCAN1/SOX1, respectively), with a specificity of 57%, 65% and 68%. For the first two panels, these diagnostic characteristics were similar to the Dutch cohort, while for ZSCAN1/SOX1 the sensitivity was higher in the Chinese cohort, but with a lower specificity (both P < .05). In hrHPV‐positive samples, similar sensitivity and specificity for the detection of CIN2+ were found as for the abnormal cytology cohort, which were now all similar between both cohorts and non‐inferior to HPV16/18 genotyping. Our analysis reveals that the diagnostic performances are highly comparable for C13ORF18/EBP41L3/JAM3 and C13ORF18/ANKRD18CP/JAM3 methylation marker panels in both Chinese and Dutch cohorts. In conclusion, methylation panels identified in a Dutch population are also applicable for triage testing in cervical cancer screening in China.

C-Reactive Protein Testing for Active Tuberculosis among Inpatients without HIV in Uganda: a Diagnostic Accuracy Study.

The objective of this prospective cross-sectional study, conducted at a national referral hospital in Kampala, Uganda, was to determine diagnostic performance of serum C-reactive protein (CRP) as a triage test for tuberculosis (TB) among HIV-seronegative inpatients. We calculated the sensitivity, specificity, positive and negative likelihood ratios, and positive and negative predictive values to determine the diagnostic performance of a CRP enzyme-linked immunosorbent assay (ELISA) (Eurolyser) in comparison to that of a reference standard of Mycobacterium tuberculosis culture on two sputum samples. We constructed receiver operating curves and reported performance in reference to the manufacturer's cutoff and also to a threshold chosen to achieve sensitivity of >90%, in accordance with the WHO's target-product profile for a triage test. Among 119 HIV-seronegative inpatients, 46 (39%) had culture-positive pulmonary TB. In reference to M. tuberculosis culture, CRP had a sensitivity of 78% (95% confidence interval [CI], 64 to 89%) and a specificity of 52% (95% CI, 40 to 64%) at the manufacturer's threshold of 10 mg/liter. At a threshold of 1.5 mg/liter, the sensitivity was 91% (95% CI, 79 to 98%) but the specificity was only 21% (95% CI, 12 to 32%). Performance did not differ when stratified by illness severity at either threshold. In conclusion, among HIV-seronegative inpatients, CRP testing performed substantially below targets for a TB triage test. Additional studies among HIV-seronegative individuals in clinics and community settings are needed to assess the utility of CRP for TB screening.

Soluble Vascular Biomarkers in Rheumatoid Arthritis and Ankylosing Spondylitis: Effects of 1-year Antitumor Necrosis Factor-α Therapy.

Rheumatoid arthritis (RA) and ankylosing spondylitis (AS) have been associated with cardiovascular disease. The treatment of arthritis by tumor necrosis factor-α (TNF-α) inhibitors may decrease the serum concentrations of vascular biomarkers. We determined circulating levels of oxidized low-density lipoprotein (oxLDL)/β2 glycoprotein I (β2-GPI) complexes, antibodies to 60 kDa heat shock protein (anti-Hsp60), soluble urokinase plasminogen activator receptor (suPAR), and B-type natriuretic peptide (BNP) fragment in sera of RA and AS patients undergoing anti-TNF treatment. Fifty-three patients with RA/AS were treated with etanercept or certolizumab pegol for 1 year. Circulating oxLDL/β2-GPI complex (AtherOx), anti-Hsp60 IgG, and BNP8-29 fragment levels were assessed by ELISA. suPAR levels were determined by suPARnostic Quick Triage test. Flow-mediated vasodilation (FMD), carotid intima-media thickness (CIMT), and arterial pulse wave velocity (PWV) were determined by ultrasound. One-year anti-TNF treatment significantly decreased oxLDL/β2-GPI levels, as well as suPAR levels in patients with critically high suPAR levels at baseline. In RA, BNP levels were higher in seropositive vs seronegative patients. Serum levels of these vascular biomarkers variably correlated with lipids, anticitrullinated protein antibodies, rheumatoid factor, and C-reactive protein. CIMT positively correlated with BNP, and PWV with suPAR and anti-Hsp60, whereas FMD inversely associated with anti-Hsp60. In repeated measures ANOVA analysis, disease activity supported the effects of anti-TNF treatment on 12-month changes in oxLDL/β2-GPI. CIMT supported the effects of therapy on changes in anti-Hsp60 and suPAR. These biomarkers may be involved in the pathogenesis of atherosclerosis underlying RA/AS. TNF inhibition variably affects the serum levels of oxLDL/β2-GPI, suPAR, and BNP.

Diagnostic accuracy of 18F-fluciclovine PET/CT in primary lymph node staging of prostate cancer.

To determine preoperative diagnostic accuracy of 18F-fluciclovine PET/CT-scan in detection (or exclusion) of lymph node metastases (LNM) in men with prostate cancer (PCa) in comparison to the histopathological results of the extended pelvic lymph node dissection (e-PLND). A retrospective medical records-based cohort study, including 47 men with primary PCa who received 18F-fluciclovine PET/CT and subsequent e-PLND for lymph node staging. Incidence and number of visualized LNM, their locations and diameters on 18F-fluciclovine PET/CT were recorded in comparison to the histopathological results of the e-PLND as reference. Positive predictive value (PPV), negative predictive value (NPV), sensitivity, specificity and diagnostic accuracy of 18F-fluciclovine PET/CT were calculated on the basis of histopathology results after e-PLND. Forty-seven men were eligible for analysis. Median lymph node yield was 19 (range 10-70). A total of 996 lymph nodes were removed, and 59 metastases were found in 21 cases (45%). Preoperative PET was issued 'positive' in 11 men and in 9 of them (82%) this was histopathologically confirmed resulting in a PPV of 82% (95% CI, 51-96). On the contrary, PET was issued 'negative' in 36 cases, but in 12 of them (33%) metastases were detected in the e-PLND specimen, resulting in an NPV of 67% (95% CI, 50-80). The patient-based sensitivity was 43% (95% CI, 24-64) and the patient-based specificity rate was 92% (95% CI, 75-99), whereas overall diagnostic accuracy was established to be 70% in the present cohort. 18F-Fluciclovine PET/CT has a high specificity and positive predicted value for the presence of LNM in men with prostate cancer. However, the sensitivity and NPV seem to be limited to exclude the absence of LNM at a clinically acceptable level. Prospective evaluation is necessary to define patients who may benefit from 18F-fluciclovine PET/CT as a triage test for the indication for e-PLND.

Diagnostic performance of the modified Korean Thyroid Imaging Reporting and Data System for thyroid malignancy according to nodule size: a comparison with five society guidelines

PurposeThe aim of this study was to evaluate the diagnostic performance of the modified Korean Thyroid Imaging Reporting and Data System (K-TIRADS) compared with five society risk stratification systems (RSSs) according to nodule size.MethodsIn total, 3,826 consecutive thyroid nodules (≥1 cm) with final diagnoses in 3,088 patients were classified according to five RSSs. The K-TIRADS was modified by raising the biopsy size threshold for low-suspicion nodules and subcategorizing intermediate-suspicion nodules. We assessed the performance of the RSSs as triage tests and their diagnostic accuracy according to nodule size (with a threshold of 2 cm).ResultsOf all nodules, 3,277 (85.7%) were benign and 549 (14.3%) were malignant. In small thyroid nodules (≤2 cm), the American College of Radiology Thyroid Imaging Reporting and Data System (ACR TI-RADS) had the highest reduction rate of unnecessary biopsies (76.3%) and the lowest sensitivity (76.1%). The modified K-TIRADS had the second highest reduction rate of unnecessary biopsies (67.6%) and sensitivity (86.6%). The modified K-TIRADS and ACR TI-RADS had the highest diagnostic odds ratios (P=0.165) and the highest areas under the curve (P=0.315). In large nodules (>2 cm), the sensitivity of the ACR TI-RADS for malignancy was significantly lower (88.8%) than the sensitivities of the modified K-TIRADS and other RSSs, which were very high (98.7%-99.3%) (P<0.001).ConclusionThe modified K-TIRADS allows a large proportion of unnecessary biopsies to be avoided, while maintaining high sensitivity and diagnostic accuracy for small malignant tumors and very high sensitivity for large malignant tumors.

ZNF671 Methylation as a Potential Biomarker to Identify Women with Cervical Intraepithelial Neoplasms Type 3 and Worse

Background: Cervical screening aims to identify women with cervical intraepithelial neoplasia 3 (CIN3) and squamous cell carcinoma (SCC), termed as CIN3+. Identification of women with CIN3+ ensure that they can receive optimal treatment and prevent overtreatment. Studies have suggested that the higher degree of cervical lesions, the more accumulation of DNA methylation (SCC > CIN3 > CIN2 > CIN1). DNA methylation analysis as a triage for women in cervical scrapings is feasible, but finding novel biomarkers with high sensitivity and high specificity is still a challenge. Zinc finger protein 671 (ZNF671), a member of the KRAB-ZFP family of mammalian transcriptional repressors, was hypermethylation of its promoter and downregulated in SCC. Methods: We investigated methylation of PAX1 or ZNF671 and genotyping of high-risk human papillomavirus (hrHPV) for detection of CIN3+ in 1006 women underwent Thinprep Cytologic test (TCT) and biopsy under colposcopy. Real-time methylation-specific PCR (qMSP) was used to detect the level of PAX1m and ZNF671m. Bisulfite pyrosequencing, the gold standard for detecting DNA methylation, was also used to measure the level of ZNF671m in 532 subjects. Findings: Sensitivities and specificities for CIN3+ were respectively, 75.69% and 77.54% for PAX1m, 79.52% and 85.76% for ZNF671m. High sensitivity (89.39%) but low specificity (60.63%) was observed for hrHPV. The sensitivities and specificities of PAX1m or hrHPV were 90.28% and 59.09%, of ZNF671m or hrHPV were 93.13% and 63.19%, of PAX1m or ZNF671m were 77.44% and 75.93%, respectively. The sensitivities and specificities of PAX1m(Algorithm 1) or ZNF671m (Algorithm 2) combined with hrHPV for CIN3+ were 98.61% and 51.57%, 76.77% and 88.42%, respectively. Interpretation: Compared with PAX1m, the level of ZNF671m could separate women more accurately into high risk groups either combined hrHPV genotyping or analysis alone. ZNF671mmay serve as a potential biomarker to identify women with CIN3+. And we propose that ZNF671m might be applied as a triage test alone or combined hrHPV genotyping and contribute to the globalization of cervical cancer screening. Funding Statement: This research was supported by Chinese National Major Project for New Drug Innovation (2019ZX09201-002-006), the National Natural Science Foundation (NNSF) of China (81973401) and the Natural Science Foundation for Young Scientist of Hunan Province, China (2018JJ3829). Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: This study was undertaken in accordance with the Declaration of Helsinki, and the protocol was approved by the Ethical Committee of Xiangya Hospital of Central South University, China. All patients gave written informed consent before participation in this study.

Routine laboratory testing to determine if a patient has COVID-19.

Routine laboratory testing to determine if a patient has COVID-19.

The optimal HPV-screening protocol in Eastern-Europe: The example of Slovenia

ObjectiveEastern European countries are contemplating to introduce the high-risk Human Papillomavirus (HPV)-test as the primary screening test for their cervical cancer screening programme, but its optimal protocol is yet unknown. The aim of this study was to compare the costs, effects and cost-effectiveness of different primary HPV-screening protocols in Eastern Europe, using Slovenia as an example and with respect of local preferences for screening. MethodsWe evaluated 968 HPV-screening protocols, which varied by screening ages, triage tests (i.e. cytology, repeat HPV and/or genotyping) and strategy for women under 35 years old, using the microsimulation model MISCAN-Cervix. ResultsWithin the subset of strategies that would be acceptable for Slovenian women, the optimal HPV-screening protocol is to start with two cytology tests at age 25 and 28 and switch to 5-yearly HPV screening from age 30 to 65. When also other protocols were considered, the optimal screening strategy would be 5-yearly HPV screening from age 30 to 65 only, improving the cost-effectiveness with 5%. Adding genotyping in the triage algorithm consistently improved cost-effectiveness. Sensitivity analyses showed the robustness of the results for other situations in Eastern Europe. ConclusionsDespite differences in cervical cancer epidemiology between Eastern and Western European regions where HPV screening was evaluated, the optimal screening protocol was found to be very similar. Furthermore, strategies that were considered socially acceptable to the population were found to be almost as cost-effective as less acceptable strategies and can therefore be considered a viable alternative to prevent opportunistic screening.

Adherence to triage among women with HPV-positive self-collection: a study in a middle-low income population in Argentina.

IntroductionScreening for cervical cancer (CC) prevention has substantially changed with the introduction of human papillomavirus (HPV) tests. This technology compared to cytology has increased the detection of pre-malignant and malignant cervical lesions in real-world programmes in different settings. Very importantly, through self-collection, HPV testing can reduce barriers to screening and increase coverage. However, when using HPV self-collection, triage tests are a key step in the CC prevention process, and high adherence to triage has been difficult to obtain in low-middle income settings. The aim of this study was to measure adherence to triage among women with HPV+ self-collection and analysed factors associated with this adherence in a middle-low resource setting in Argentina. We also evaluated key indicators related to the implementation of the HPV self-collection strategy.MethodsWe analysed data on screening/triage/diagnosis/treatment from women aged 30+ who performed self-collection between 2015 and 2017 (n = 15,763), in the public health system in Tucuman, Argentina. We analysed secondary data from the national screening information system. The primary outcomes were: 1) adherence to cytology triage within the recommended timeframe (120 days) and 2) overall adherence to cytology triage including data at 18 months after screening. Multivariable regression was used to examine the association between age group, year of the screening test, record of the previous Pap-based screening and health insurance status with adherence to triage test as a primary outcome. We reported odds ratios, 95% confidence intervals and p-value of 0.05, which was considered the threshold for p-values).ResultsWe analysed data of 2,389 HPV+ women. The overall adherence to triage at 18 months was 42.9%. The percentage of women completing cytology triage within the recommended timeframe of 120 days was lower (25.2%). Women with the record of a previous Pap-based screening had 1.86 times the odds of having a triage compared to women without a record of a previous Pap-based screening (95% CI: 1.64–2.64, p <0.001). Furthermore, the probability of having triage at the recommended timeframe was higher among women who were older and women with public health insurance.ConclusionsOur results showed that adherence to triage in the recommended timeframe was low. In addition, the probability of having triage at the recommended timeframe was higher among women with a record of a previous Pap-based screening, a proxy of the use of health services. Our results showed that adherence to triage in the context of the HPV-self-collection strategy is challenging. The implementation of alternative approaches that might facilitate adherence to triage should be further investigated.

A clinical score for identifying active tuberculosis while awaiting microbiological results: Development and validation of a multivariable prediction model in sub-Saharan Africa.

In highly resource-limited settings, many clinics lack same-day microbiological testing for active tuberculosis (TB). In these contexts, risk of pretreatment loss to follow-up is high, and a simple, easy-to-use clinical risk score could be useful. We analyzed data from adults tested for TB with Xpert MTB/RIF across 28 primary health clinics in rural South Africa (between July 2016 and January 2018). We used least absolute shrinkage and selection operator regression to identify characteristics associated with Xpert-confirmed TB and converted coefficients into a simple score. We assessed discrimination using receiver operating characteristic (ROC) curves, calibration using Cox linear logistic regression, and clinical utility using decision curves. We validated the score externally in a population of adults tested for TB across 4 primary health clinics in urban Uganda (between May 2018 and December 2019). Model development was repeated de novo with the Ugandan population to compare clinical scores. The South African and Ugandan cohorts included 701 and 106 individuals who tested positive for TB, respectively, and 686 and 281 randomly selected individuals who tested negative. Compared to the Ugandan cohort, the South African cohort was older (41% versus 19% aged 45 years or older), had similar breakdown of biological sex (48% versus 50% female), and had higher HIV prevalence (45% versus 34%). The final prediction model, scored from 0 to 10, included 6 characteristics: age, sex, HIV (2 points), diabetes, number of classical TB symptoms (cough, fever, weight loss, and night sweats; 1 point each), and >14-day symptom duration. Discrimination was moderate in the derivation (c-statistic = 0.82, 95% CI = 0.81 to 0.82) and validation (c-statistic = 0.75, 95% CI = 0.69 to 0.80) populations. A patient with 10% pretest probability of TB would have a posttest probability of 4% with a score of 3/10 versus 43% with a score of 7/10. The de novo Ugandan model contained similar characteristics and performed equally well. Our study may be subject to spectrum bias as we only included a random sample of people without TB from each cohort. This score is only meant to guide management while awaiting microbiological results, not intended as a community-based triage test (i.e., to identify individuals who should receive further testing). In this study, we observed that a simple clinical risk score reasonably distinguished individuals with and without TB among those submitting sputum for diagnosis. Subject to prospective validation, this score might be useful in settings with constrained diagnostic resources where concern for pretreatment loss to follow-up is high.

The Diagnostic Value of p16/Ki67 Dual Immunostaining for Anal Intraepithelial Neoplasia: A Meta-Analysis.

The p16/Ki67 dual immunostaining was performed on anal cytology specimens; this is an anal cancer screening method. A literature search was performed in the BioMed Central, Cochrane Library, Embase, Google Scholar, and PubMed electronic databases for relevant articles. We included studies that discussed the efficacy of p16/Ki67 dual immunostaining for detecting anal intraepithelial neoplasia (AIN). Studies that calculated the diagnostic efficacy on a per-patient basis were included. We excluded review articles, case series, and studies that did not provide sufficient information. We extracted data on true positive, true negative, false positive, and false negative from the included studies to generate pooled sensitivity, specificity, and diagnostic odds ratio (DOR). All analyses were performed with a random-effects model using MetaDiSc 1.4 and MetaDTA. The meta-analysis produced a pooled sensitivity of 0.63 (95% CI: 0.34, 0.86) and specificity of 0.65 (95% CI: 0.46, 0.81) for p16/Ki67 dual immunostaining in detecting AIN. The pooled DOR was 3.26 (95% CI: −0.29, 6.82). A subgroup analysis of HIV-infected men who have sex with men (MSM) demonstrated a pooled sensitivity of 0.75 (95% CI: 0.28, 0.96). p16/Ki67 dual immunostaining might have a higher sensitivity for detecting AIN in HIV-infected MSM. p16/Ki67 dual immunostaining might be more sensitive in HIV-infected MSM and has higher specificity compared to human papillomavirus testing among this high-risk group. p16/Ki67 dual immunostaining might be an adjuvant and potential triage test for anal cytology in anal cancer screening.

Prioritizing Health Care and Employment Resources During COVID-19: Roles of Benevolent and Hostile Ageism.

Background and ObjectivesBenevolent and hostile ageism are subtypes of ageism that characterize older adults as incompetent. With benevolent ageism, older adults are also viewed as warm. The COVID-19 pandemic has strained resources and prompted debates about priority for older adults versus other groups.Research Design and MethodsCollege students completed an online survey of how much priority should be given to older adults in three relevant healthcare-related scenarios and three relevant employment scenarios.ResultsBenevolent ageism significantly predicted higher priority for older adults to receive healthcare (triage, COVID-19 vaccine, COVID-19 testing) and employment resources (retention of job, working from home) while greater endorsement of hostile ageism significantly predicted lower priority ratings.Discussion and ImplicationsThese findings replicate and extend past work. As the COVID-19 pandemic continues to wreak havoc on healthcare and employment resources, this study sheds light on one factor -- benevolent and hostile ageism -- that contributes to a greater understanding of prioritization views toward a vulnerable segment of the population.

Worldwide Performance of a Methylation Biomarker for Cervical Precancer and Cancer Diagnosis

The shift towards primary HPV-based screening has roused the search for a secondary triage test that provides a sufficient sensitivity to detect high grade cervical intraepithelial neoplasia (CIN) and cancer, but also brings a high specificity to avoid unnecessary clinical work and colposcopy referrals. The S5 DNA-methylation classifier based on target CpG sites of the host gene EPB41L3, and viral gene regions of HPV16, 18, 31 and 33 has demonstrated an improved performance for detecting CIN2+ compared to either HPV16/18 genotyping, cytology or combination.In this study, we tested for the first time the performance of the S5 DNA-methylation classifier in detecting CIN3 and invasive cervical cancer from diverse geographic settings using the cut-off of 0·80 and the exploratory cut-offs of 2·62 and 3·70. Assays were performed using exfoliated cervical specimens (n=808) and formalin-fixed biopsies (n=160) from women diagnosed with cytology negative results (n=220), CIN3 (n=204) and cervical cancer (n=544). Methylation increased proportionally with disease severity in all geographical regions tested (Cuzick test for trend, p<0·0001). S5 separated women with negative histology from those with CIN3 or cervical cancer (p<0·0001). At the 0.80 cut-off, a total of 543/544 cervical cancers were correctly identified as S5 positive (99·81%, 95%CI 98·34-99·96) while at 3·70 the classifier showed a positivity of 95·77% (95%CI 92·39- 97·40). The S5 odds ratios when negative for cervical disease versus CIN3+ were significantly higher than for HPV16/18 genotyping at all cut-offs. Notably, at the 0·80 cut-off, cervical cancers which were consistently hrHPV-negative when tested with multiple hrHPV genotyping assays were 96·15% (95%CI 94·38-98·25) identified by the S5 classifier. These cancers would have been missed in the current primary hrHPV screening programme. EPB41L3 methylation had a stronger association with disease severity F=367·50 than age F=81·00 (p<0·0001), indicating that methylation on EPB41L3 might have a strong potential to predict CIN progression, independent of natural epigenetic methylation that occurs with age. The S5-classifier can accurately detect high-grade CIN and malignancy irrespective of geographic context and setting. The classifier has the potential to be used in clinics as a screening and triage tool. Adjustment of the S5 cut-off can be performed taking into account the relative importance given to sensitivity versus specificity, thus reflecting local triage modality needed. Funding Statement: Cancer research UK who funded part of this study (Cancer Prevention programme Grant C569/A10404/CRUK_/Cancer Research UK/United Kingdom Declaration of Interests: The authors declare no conflict of Interest. Ethics Approval Statement: The samples used for this study have received ethical and research approvals from: i) The International Agency for Research on Cancer (IARC) of the World Health Organization (WHO) for all samples from Bhutan, Colombia, Georgia, India and Philippines, South Africa and Spain; ii) The Scottish HPV Archive, MRC Centre for Reproductive Health, The University of Edinburgh for all samples from the United Kingdom; iii) Department of Microbial, Cellular and Molecular Biology, Addis Ababa University for all samples from Ethiopia; iv) University of New Mexico Human Research Review Committee for all samples from USA – New Mexico. The study protocol has been approved by Queen Mary University of London’s Ethical Committee (MTA-2018-ICE-0426, MTA-2018-ICE-1353, 11/06/2018).