Field experience with the 8-HPV-type oncoprotein test for cervical cancer screening among HPV-positive women living with and without HIV in LMICs.

Overexpression of HPV-oncoproteins E6 and E7 is necessary for HPV-driven cervical carcinogenesis. Hence, these oncoproteins are promising disease-specific biomarkers. We assessed the technical and operational characteristics of the 8-HPV-type OncoE6/E7 Cervical Test in different laboratories using cervical samples from HPV-positive women living with (WLWH) and without HIV. The 8-HPV-type OncoE6/E7 Test (for short: "OncoE6/E7 test") was performed in 2833 HIV-negative women and 241 WLWH attending multicentric studies in Latin America (ESTAMPA study), and in Africa (CESTA study). Oncoprotein positivity were evaluated at each testing site, according to HIV status as well as type-specific agreement with HPV-DNA results. A feedback questionnaire was given to the operators performing the oncoprotein test to evaluate their impression and acceptability regarding the test. The OncoE6/E7 test revealed a high positivity rate heterogeneity across all testing sites (I2: 95.8%, p < .01) with significant lower positivity in WLWH compared to HIV-negative women (12% vs 25%, p < .01). A similar HPV-type distribution was found between HPV DNA genotyping and oncoprotein testing except for HPV31 and 33 (moderate agreement, k = 0.57). Twenty-one laboratory technicians were trained on oncoprotein testing. Despite operators' concerns about the time-consuming procedure and perceived need for moderate laboratory experience, they reported the OncoE6/E7 test as easy to perform and user-friendly for deployment in resource-limited settings. The high positivity rate variability found across studies and subjectivity in test outcome interpretation could potentially results in oncoprotein false positive/negative, and thus the need for further refinements before implementation of the oncoprotein testing in screen-triage-and-treat approaches is warranted.

Global evaluation of lineage-specific human papillomavirus capsid antigenicity using antibodies elicited by natural infection.

Human Papillomavirus (HPV) type variants have been classified into lineages and sublineages based upon their whole genome sequence. Here we have examined the specificity of antibodies generated following natural infection with lineage variants of oncogenic types (HPV16, 18, 31, 33, 45, 52 and 58) by testing serum samples assembled from existing archives from women residing in Africa, The Americas, Asia or Europe against representative lineage-specific pseudoviruses for each genotype. We have subjected the resulting neutralizing antibody data to antigenic clustering methods and created relational antigenic profiles for each genotype to inform the delineation of lineage-specific serotypes. For most genotypes, there was evidence of differential recognition of lineage-specific antigens and in some cases of a sufficient magnitude to suggest that some lineages should be considered antigenically distinct within their respective genotypes. These data provide compelling evidence for a degree of lineage specificity within the humoral immune response following natural infection with oncogenic HPV.

Prevalencia y determinantes de la infección por virus de papiloma humano en mujeres jóvenes de Guanacaste y Puntarenas, Costa Rica, 2004-2005.

OBJETIVO: Estimar la prevalencia e identificar determinantes de la infección por el virus del papiloma humano (VPH) en mujeres jóvenes (18-25 años). Material y métodos. Se analizaron datos de 5 871 mujeres sexualmente activas a quienes se les realizó una entrevista y toma de muestras cervicouterinas para detección de VPH y citología durante la visita de reclutamiento del Ensayo de Vacunación contra VPH16/18 en Costa Rica. Se calculó la prevalencia total para cualquier tipo de VPH y tipos oncogénicos, no oncogénicos y específicos, con intervalos de confianza al 95% (IC95%). Se utilizó regresión logística múltiple paso-a-paso para identificar determinantes asociados con la infección. RESULTADOS: La prevalencia total de VPH fue 50.0% (IC95% 48.8,51.3) y por tipos oncogénicos fue 33.8% (IC95% 32.6,35.0). El VPH-16 fue el tipo más prevalente (8.3%, IC95% 7.6,9.0). Los determinantes asociados con un alto riesgo de infección prevalente por VPH oncogénicos fueron no estar casada/unión libre, >1 compañero sexual, infección concomitante por Chlamydia trachomatis, y entre aquéllas con un único compañero sexual en su vida, un compañero con antecedente de múltiples compañeras sexuales. Conclusión. Se confirma la asociación de las infecciones por VPH oncogénicos con el comportamiento sexual de la mujer y se destacan los comportamientos del compañero sexual.

Cohort profile: evaluation of immune response and household transmission of SARS-CoV-2 in Costa Rica: the RESPIRA study.

PURPOSE: The RESPIRA cohort aims to describe the nature, magnitude, time course and efficacy of the immune response to SARS-CoV-2 infection and vaccination, population prevalence, and household transmission of COVID-19. PARTICIPANTS: From November 2020, we selected age-stratified random samples of COVID-19 cases from Costa Rica confirmed by PCR. For each case, two population-based controls, matched on age, sex and census tract were recruited, supplemented with hospitalised cases and household contacts. Participants were interviewed and blood and saliva collected for antibodies and PCR tests. Participants will be followed for 2 years to assess antibody response and infection incidence. FINDINGS TO DATE: Recruitment included 3860 individuals: 1150 COVID-19 cases, 1999 population controls and 719 household contacts from 304 index cases. The age and regional distribution of cases was as planned, including four age strata, 30% rural and 70% urban. The control cohort had similar sex, age and regional distribution as the cases according to the study design. Among the 1999 controls recruited, 6.8% reported at enrolment having had COVID-19 and an additional 12.5% had antibodies against SARS-CoV-2. Compliance with visits and specimens has been close to 70% during the first 18 months of follow-up. During the study, national vaccination was implemented and nearly 90% of our cohort participants were vaccinated during follow-up. FUTURE PLANS: RESPIRA will enable multiple analyses, including population prevalence of infection, clinical, behavioural, immunological and genetic risk factors for SARS-CoV-2 acquisition and severity, and determinants of household transmission. We are conducting retrospective and prospective assessment of antibody levels, their determinants and their protective efficacy after infection and vaccination, the impact of long-COVID and a series of ancillary studies. Follow-up continues with bimonthly saliva collection for PCR testing and biannual blood collection for immune response analyses. Follow-up will be completed in early 2024. TRIAL REGISTRATION NUMBER: NCT04537338.

Reproducible and clinically translatable deep neural networks for cervical screening.

Cervical cancer is a leading cause of cancer mortality, with approximately 90% of the 250,000 deaths per year occurring in low- and middle-income countries (LMIC). Secondary prevention with cervical screening involves detecting and treating precursor lesions; however, scaling screening efforts in LMIC has been hampered by infrastructure and cost constraints. Recent work has supported the development of an artificial intelligence (AI) pipeline on digital images of the cervix to achieve an accurate and reliable diagnosis of treatable precancerous lesions. In particular, WHO guidelines emphasize visual triage of women testing positive for human papillomavirus (HPV) as the primary screen, and AI could assist in this triage task. In this work, we implemented a comprehensive deep-learning model selection and optimization study on a large, collated, multi-geography, multi-institution, and multi-device dataset of 9462 women (17,013 images). We evaluated relative portability, repeatability, and classification performance. The top performing model, when combined with HPV type, achieved an area under the Receiver Operating Characteristics (ROC) curve (AUC) of 0.89 within our study population of interest, and a limited total extreme misclassification rate of 3.4%, on held-aside test sets. Our model also produced reliable and consistent predictions, achieving a strong quadratic weighted kappa (QWK) of 0.86 and a minimal %2-class disagreement (% 2-Cl. D.) of 0.69%, between image pairs across women. Our work is among the first efforts at designing a robust, repeatable, accurate and clinically translatable deep-learning model for cervical screening.

Randomised clinical trial: efficacy and safety of H. pylori eradication treatment with and without Saccharomyces boulardii supplementation.

BACKGROUND: Standard triple therapy is commonly prescribed Helicobacter pylori eradication regimen in Europe. However, the world is witnessing declines in eradication success. It is crucial to find better treatment options. AIMS: To evaluate efficacy, compliance and side effects of H. pylori eradication treatment by adding Saccharomyces boulardii. METHODS: We conducted a randomized clinical trial within the GISTAR cohort, consisting of healthy individuals aged 40-64 years. Participants were administered clarithromycin-containing triple therapy (clarithromycin 500 mg, amoxicillin 1000 mg, esomeprazole 40 mg) twice daily. Randomization was applied based on two factors: 1)addition of Saccharomyces boulardii CNCM I-745 500 mg BID or not; 2)treatment duration of 10 or 14 days. Treatment completion and adverse events were assessed via telephone interview 21-28 days after medication delivery. The efficacy was evaluated using a 13C-urea breath test (UBT) six months after treatment. RESULTS: Altogether 404 participants were enrolled; data on adverse events were available from 391. Overall, 286 participants received follow-up UBT. Intention-to-treat analysis revealed higher eradication rates for 10-day probiotic treatment (70.8% vs. 54.6%, P = 0.022), but not for 14-day. Probiotic subgroups combined showed non-significantly higher efficacy in per-protocol analysis (90.6% vs. 85.0%, P = 0.183). S. boulardii reduced the frequency of adverse events (P = 0.033) in 14-day regimen, particularly treatment-associated diarrhea (P = 0.032). However, after the adjustment to control Type I error, results lost their significance. CONCLUSION: Addition of S. boulardii to 14-day clarithromycin-containing triple regimen non-significantly lowers the likelihood of diarrhea and does not increase the eradication rate.

Cervical Cancer Screening and Treatment algorithms using Human Papillomavirus testing - lessons learnt from a South African pilot randomized controlled trial.

BACKGROUND: To report quantitative and qualitative results on cervical cancer (CC) HPV-based screening and treatment algorithms, with/out triage with visual inspection after acetic acid (VIA), followed by ablative treatment (AT). METHODS: Women 30-54 years-old from Durban, South Africa were recruited, regardless of HIV status, randomized into one of two study arms and screened for HPV. VIA-triage arm: HPV-positive women were triaged using VIA, biopsied and received AT if VIA-positive and eligible; no-triage arm: eligible HPV-positive women received AT. Women ineligible for AT were referred to colposcopy. Women were asked about side effects immediately and one week after AT. Retention to screening and treatment algorithms was compared between arms. RESULTS: 350 women (275 HIV-uninfected and 75 women living with HIV, (WLWH)) were allocated to receive HPV testing with VIA-triage (n=175) or no-triage (n=175). HPV prevalence was 28% (95%CI=23-33); WLWH: 52% (95%CI=40-64) vs HIV-uninfected: 21% (95%CI=17-27) (p<0.05). Among women who underwent VIA triage with histological diagnosis, 3/17 were VIA negative with CIN2+; 14/18 were VIA positive with

Estimating the cumulative incidence of SARS-CoV-2 infection in Costa Rica: modelling seroprevalence data in a population-based cohort.

Background: The true incidence of SARS-CoV-2 infection in Costa Rica was likely much higher than officially reported, because infection is often associated with mild symptoms and testing was limited by official guidelines and socio-economic factors. Methods: Using serology to define natural infection, we developed a statistical model to estimate the true cumulative incidence of SARS-CoV-2 in Costa Rica early in the pandemic. We estimated seroprevalence from 2223 blood samples collected from November 2020 to October 2021 from 1976 population-based controls from the RESPIRA study. Samples were tested for antibodies against SARS-CoV-2 nucleocapsid and the receptor-binding-domain of the spike proteins. Using a generalized linear model, we estimated the ratio of true infections to officially reported cases. Applying these ratios to officially reported totals by age, sex, and geographic area, we estimated the true number of infections in the study area, where 70% of Costa Ricans reside. We adjusted the seroprevalence estimates for antibody decay over time, estimated from 1562 blood samples from 996 PCR-confirmed COVID-19 cases. Findings: The estimated total proportion infected (ETPI) was 4.0 times higher than the officially reported total proportion infected (OTPI). By December 16th, 2021, the ETPI was 47% [42-52] while the OTPI was 12%. In children and adolescents, the ETPI was 11.0 times higher than the OTPI. Interpretation: Our findings suggest that nearly half the population had been infected by the end of 2021. By the end of 2022, it is likely that a large majority of the population had been infected. Funding: This work was sponsored and funded by the National Institute of Allergy and Infectious Diseases through the National Cancer Institute, the Science, Innovation, Technology and Telecommunications Ministry of Costa Rica, and Costa Rican Biomedical Research Agency-Fundacion INCIENSA (grant N/A).

Latin America and the Caribbean Code Against Cancer 1st Edition: 17 cancer prevention recommendations to the public and to policy-makers (World Code Against Cancer Framework).

Preventable risk factors are responsible of at least 40% of cases and almost 45% of all cancer deaths worldwide. Cancer is already the leading cause of death in almost half of the Latin American and the Caribbean countries constituting a public health problem. Cost-effective measures to reduce exposures through primary prevention and screening of certain types of cancers are critical in the fight against cancer but need to be tailored to the local needs and scenarios. The Latin America and the Caribbean (LAC) Code Against Cancer, 1st edition, consists of 17 evidence-based recommendations for the general public, based on the most recent solid evidence on lifestyle, environmental, occupational, and infectious risk factors, and medical interventions. Each recommendation is accompanied by recommendations for policymakers to guide governments establishing the infrastructure needed to enable the public adopting the recommendations. The LAC Code Against Cancer has been developed in a collaborative effort by a large number of experts from the region, under the umbrella strategy and authoritative methodology of the World Code Against Cancer Framework. The Code is a structured instrument ideal for cancer prevention and control that aims to raise awareness and educate the public, while building capacity and competencies to policymakers, health professionals, stakeholders, to contribute to reduce the burden of cancer in LAC.

Latin American and the Caribbean Code Against Cancer 1st edition: Infections and cancer.

About 13% of all cancers around the world are associated with infectious agents, particularly in low-resource settings. The main infectious agents associated with cancer are Helicobacter pylori (H. pylori), that causes gastric cancer, human papillomavirus (HPV) that causes cervical, vulvar, vaginal, penile, anal, and oropharyngeal cancer, hepatitis B and C viruses that cause liver cancer, and human immunodeficiency virus (HIV), associated with cancers of the cervix, Kaposi sarcoma (KS) and non-Hodgkin´s lymphoma. In Latin America and the Caribbean (LAC), about 150,000 cancer cases are caused annually by infections. The LAC Cancer Code Against Cancer consists of a set of 17 evidence-based and individual-level cancer prevention recommendations targeted to the general population, suited to the epidemiological, socioeconomic, and cultural conditions of the region, and tailored to the availability and accessibility of health-care systems. The recommendations with respect to infection-driven malignancies include testing and treating for H. pylori in the context of specific public health programs, vaccination against HPV and Hepatitis B Virus (HBV) and detection and treatment of chronic infections with HBV, Hepatitis C virus (HCV) and HIV, in addition to the promotion of safe sex and use of condoms to prevent sexually transmitted infections (STI). Countries, policy makers, health care systems and individuals should consider the adoption of these recommendations to help reduce the incidence and mortality of infection-related cancers in LAC, to improve quality of life of individuals and reduce the costs of cancer care in the region.

Performance of cervical cytology and HPV testing for primary cervical cancer screening in Latin America: an analysis within the ESTAMPA study.

Background: Cervical cytology remains widely used as the initial tool in cervical cancer screening worldwide. WHO guidelines recommend replacing cytology with primary HPV testing to reach cervical cancer elimination goals. We assessed the performance of cytology and high-risk HPV testing to detect cervical precancer, cervical intraepithelial neoplasia (CIN) grade 3 or worse (CIN3+) among women aged 30-64 years participating in the ESTAMPA study. Methods: Women were screened with cytology and HPV across ESTAMPA study centres in Latin America. Screen-positives were referred to colposcopy with biopsy collection and treatment as needed. Those with no evident precancer were recalled at 18-months for a second HPV test to complete disease ascertainment. Performance indicators for cytology and HPV to detect CIN3+ were estimated. Findings: 30,606 participants with available cytology and HPV results were included in the analysis. A total of 440 histologically confirmed CIN3s and 30 cancers were diagnosed. Cytology sensitivity for CIN3+ was 48.5% (95% CI: 44.0-53.0), whereas HPV testing had a sensitivity of 98.1% (95% CI: 96.3-96.7). Specificity was 96.5% (95% CI: 96.3-96.7) using cytology and 88.7% (95% CI: 88.3-89.0) with HPV. Performance estimates varied substantially by study centre for cytology (ranging from 32.1% to 87.5% for sensitivity and from 89.2% to 99.5% for specificity) while for HPV results were more consistent across sites (96.7%-100% and 83.6-90.8%, respectively). Interpretation: The limited and highly variable sensitivity of cytology strongly supports transition to the more robust and reproducible HPV-based cervical screening to ensure progress towards global cervical cancer elimination targets in Latin America. Funding: IARC/WHO, UNDP, HRP/WHO, NCI and local funders.

Behavioral factors and SARS-CoV-2 transmission heterogeneity within a household cohort in Costa Rica.

INTRODUCTION: Variability in household secondary attack rates and transmission risks factors of SARS-CoV-2 remain poorly understood. METHODS: We conducted a household transmission study of SARS-CoV-2 in Costa Rica, with SARS-CoV-2 index cases selected from a larger prospective cohort study and their household contacts were enrolled. A total of 719 household contacts of 304 household index cases were enrolled from November 21, 2020, through July 31, 2021. Blood specimens were collected from contacts within 30-60 days of index case diagnosis; and serum was tested for presence of spike and nucleocapsid SARS-CoV-2 IgG antibodies. Evidence of SARS-CoV-2 prior infections among household contacts was defined based on the presence of both spike and nucleocapsid antibodies. We fitted a chain binomial model to the serologic data, to account for exogenous community infection risk and potential multi-generational transmissions within the household. RESULTS: Overall seroprevalence was 53% (95% confidence interval (CI) 48-58%) among household contacts. The estimated household secondary attack rate is 34% (95% CI 5-75%). Mask wearing by the index case is associated with the household transmission risk reduction by 67% (adjusted odds ratio = 0.33 with 95% CI: 0.09-0.75) and not sharing bedroom with the index case is associated with the risk reduction of household transmission by 78% (adjusted odds ratio = 0.22 with 95% CI 0.10-0.41). The estimated distribution of household secondary attack rates is highly heterogeneous across index cases, with 30% of index cases being the source for 80% of secondary cases. CONCLUSIONS: Modeling analysis suggests that behavioral factors are important drivers of the observed SARS-CoV-2 transmission heterogeneity within the household.

When living in the same house with known SARS-CoV-2 cases, household members may change their behavior and adopt preventive measures to reduce the spread of SARS-CoV-2. To understand how behavioral factors affect SARS-CoV-2 spreading in household settings, we focused on household members of individuals with laboratory-confirmed SARS-CoV-2 infections and followed the way SARS-CoV-2 spread within the household, by looking at who had antibodies against the virus, which means they were infected. We also asked participants detailed questions about their behavior and applied mathematical modeling to evaluate its impact on SARS-CoV-2 transmission. We found that mask-wearing by the SARS-CoV-2 cases, and avoiding sharing a bedroom with the infected individuals, reduces SARS-CoV-2 transmission. However, caring for SARS-CoV-2 cases, and prolonged interaction with infected individuals facilitate SARS-CoV-2 spreading. Our study helps inform what behaviors can help reduce SARS-CoV-2 transmission within a household.

Estimating human papillomavirus vaccine efficacy from a single-arm trial: proof-of-principle in the Costa Rica Vaccine Trial.

BACKGROUND: The World Health Organization recommends a 1- or 2-dose human papillomavirus (HPV) vaccination schedule for females aged 9 to 20 years. Studies confirming the efficacy of a single dose and vaccine modifications are needed, but randomized controlled trials are costly and face logistical and ethical challenges. We propose a resource-efficient single-arm trial design that uses untargeted and unaffected HPV types as controls. METHODS: We estimated HPV vaccine efficacy (VE) from a single arm by comparing 2 ratios: the ratio of the rate of persistent incident infection with vaccine-targeted HPV 16 and 18 (HPV 16/18) and cross-protected types HPV 31, 33, and 45 (HPV 31/33/45) to vaccine-unaffected types HPV 35, 39, 51, 52, 56, 58, 59, and 66 (HPV 35/39/51/52/56/58/59/66) vs the ratio of prevalence of these types at the time of trial enrollment. We compare VE estimates using only data from the bivalent HPV 16/18 vaccine arm of the Costa Rica Vaccine Trial with published VE estimates that used both the vaccine and control arms. RESULTS: Our single-arm approach among 3727 women yielded VE estimates against persistent HPV 16/18 infections similar to published 2-arm estimates from the trial (according-to-protocol cohort: 91.0% , 95% CI = 82.9% to 95.3% [single-arm] vs 90.9% , 95% CI = 82.0% to 95.9% [2-arm]; intention-to-treat cohort: 41.7%, 95% CI = 32.4% to 49.8% [single-arm] vs 49.0% , 95% CI = 38.1% to 58.1% [2-arm]). VE estimates were also similar in analytic subgroups (number of doses received; baseline HPV serology status). CONCLUSIONS: We demonstrate that a single-arm design yields valid VE estimates with similar precision to a randomized controlled trial. Single-arm studies can reduce the sample size and costs of future HPV vaccine trials while avoiding concerns related to unvaccinated control groups. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00128661.

REPRODUCIBLE AND CLINICALLY TRANSLATABLE DEEP NEURAL NETWORKS FOR CANCER SCREENING.

Cervical cancer is a leading cause of cancer mortality, with approximately 90% of the 250,000 deaths per year occurring in low- and middle-income countries (LMIC). Secondary prevention with cervical screening involves detecting and treating precursor lesions; however, scaling screening efforts in LMIC has been hampered by infrastructure and cost constraints. Recent work has supported the development of an artificial intelligence (AI) pipeline on digital images of the cervix to achieve an accurate and reliable diagnosis of treatable precancerous lesions. In particular, WHO guidelines emphasize visual triage of women testing positive for human papillomavirus (HPV) as the primary screen, and AI could assist in this triage task. Published AI reports have exhibited overfitting, lack of portability, and unrealistic, near-perfect performance estimates. To surmount recognized issues, we implemented a comprehensive deep-learning model selection and optimization study on a large, collated, multi-institutional dataset of 9,462 women (17,013 images). We evaluated relative portability, repeatability, and classification performance. The top performing model, when combined with HPV type, achieved an area under the Receiver Operating Characteristics (ROC) curve (AUC) of 0.89 within our study population of interest, and a limited total extreme misclassification rate of 3.4%, on held-aside test sets. Our work is among the first efforts at designing a robust, repeatable, accurate and clinically translatable deep-learning model for cervical screening.

Association between salt intake and gastric atrophy by Helicobacter pylori infection: first results from the Epidemiological Investigation of Gastric Malignancy (ENIGMA).

PURPOSE: Gastric atrophy (GA), usually linked to chronic infection with Helicobacter pylori (H. pylori), may over time evolve into gastric malignancy. Besides H. pylori, high salt intake may play a role in GA development. This study evaluates cross sectionally the association between salt intake and GA in Chilean adults. METHODS: Population-based samples were recruited from two sites, Antofagasta and Valdivia, partaking in the Epidemiological Investigation of Gastric Malignancies. At recruitment, participants answered questionnaires and provided biospecimens. Salt intake (g/day) was estimated from casual spot urine samples using the Tanaka equation. GA was determined by serum pepsinogen levels. Only participants ≥ 40 to 70 years of age were considered in this analysis, n = 565. For the association between salt intake (as sex-specific quartiles) and GA, odds ratios (ORs) and the corresponding 95% confidence intervals (CI) were estimated through multivariable logistic regression. RESULTS: In women, the multivariable-adjusted OR for GA comparing quartile 4 of the estimated salt intake (12.8 g/day) to quartile 1 (6.6 g/day) was 1.18 (95% CI 0.52-2.68, P-trend = 0.87). The corresponding OR in men was 0.49 (95% CI 0.19-1.27, P-trend = 0.17) with salt intakes of 12.8 g/day and 7.1 g/day for quartiles 4 and 1, respectively. CONCLUSION: There was little evidence for an association between salt intake estimated from spot urine and GA risk in our cross-sectional analysis of middle aged and older adults in Chile. Reverse causation bias cannot be ruled out and the sample size was limited to provide more precise estimates.

Performance of standardised colposcopy to detect cervical precancer and cancer for triage of women testing positive for human papillomavirus: results from the ESTAMPA multicentric screening study.

BACKGROUND: Colposcopy, currently included in WHO recommendations as an option to triage human papillomavirus (HPV)-positive women, remains as the reference standard to guide both biopsy for confirmation of cervical precancer and cancer and treatment approaches. We aim to evaluate the performance of colposcopy to detect cervical precancer and cancer for triage in HPV-positive women. METHODS: This cross-sectional, multicentric screening study was conducted at 12 centres (including primary and secondary care centres, hospitals, laboratories, and universities) in Latin America (Argentina, Bolivia, Colombia, Costa Rica, Honduras, Mexico, Paraguay, Peru, and Uruguay). Eligible women were aged 30-64 years, sexually active, did not have a history of cervical cancer or treatment for cervical precancer or a hysterectomy, and were not planning to move outside of the study area. Women were screened with HPV DNA testing and cytology. HPV-positive women were referred to colposcopy using a standardised protocol, including biopsy collection of observed lesions, endocervical sampling for transformation zone (TZ) type 3, and treatment as needed. Women with initial normal colposcopy or no high-grade cervical lesions on histology (less than cervical intraepithelial neoplasia [CIN] grade 2) were recalled after 18 months for another HPV test to complete disease ascertainment; HPV-positive women were referred for a second colposcopy with biopsy and treatment as needed. Diagnostic accuracy of colposcopy was assessed by considering a positive test result when the colposcopic impression at the initial colposcopy was positive minor, positive major, or suspected cancer, and was considered negative otherwise. The main study outcome was histologically confirmed CIN3+ (defined as grade 3 or worse) detected at the initial visit or 18-month visit. FINDINGS: Between Dec 12, 2012, and Dec 3, 2021, 42 502 women were recruited, and 5985 (14·1%) tested positive for HPV. 4499 participants with complete disease ascertainment and follow-up were included in the analysis, with a median age of 40·6 years (IQR 34·7-49·9). CIN3+ was detected in 669 (14·9%) of 4499 women at the initial visit or 18-month visit (3530 [78·5%] negative or CIN1, 300 [6·7%] CIN2, 616 [13·7%] CIN3, and 53 [1·2%] cancers). Sensitivity was 91·2% (95% CI 88·9-93·2) for CIN3+, whereas specificity was 50·1% (48·5-51·8) for less than CIN2 and 47·1% (45·5-48·7) for less than CIN3. Sensitivity for CIN3+ significantly decreased in older women (93·5% [95% CI 91·3-95·3] in those aged 30-49 years vs 77·6% [68·6-85·0] in those aged 50-65 years; p<0·0001), whereas specificity for less than CIN2 significantly increased (45·7% [43·8-47·6] vs 61·8% [58·7-64·8]; p<0·0001). Sensitivity for CIN3+ was also significantly lower in women with negative cytology than in those with abnormal cytology (p<0·0001). INTERPRETATION: Colposcopy is accurate for CIN3+ detection in HPV-positive women. These results reflect ESTAMPA efforts in an 18-month follow-up strategy to maximise disease detection with an internationally validated clinical management protocol and regular training, including quality improvement practices. We showed that colposcopy can be optimised with proper standardisation to be used as triage in HPV-positive women. FUNDING: WHO; Pan American Health Organization; Union for International Cancer Control; National Cancer Institute (NCI); NCI Center for Global Health; National Agency for the Promotion of Research, Technological Development, and Innovation; NCI of Argentina and Colombia; Caja Costarricense de Seguro Social; National Council for Science and Technology of Paraguay; International Agency for Research on Cancer; and all local collaborative institutions.

Excess mortality from COVID 19 in Costa Rica: a registry based study using Poisson regression.

Background: Official death toll related to COVID-19 has been considerably underestimated in reports from some Latin American countries. This study aimed to analyze the mortality associated with the COVID-19 pandemic in Costa Rica between March 2020 and December 2021. Methods: A registry based study based on 2017-2021 data from the National Institute of Statistics and Census was designed (N = 128,106). Excess deaths were defined by the WHO as "the difference in the total number of deaths in a crisis compared to those expected under normal conditions"; and were estimated using a Poisson regression, and mortality and years of potential life lost (YPLL) rates were calculated. Findings: The COVID-19 pandemic represented 15% of the deaths in Costa Rica between March 2020 and December 2021. The mortality rate related to COVID-19 was 83 per 100,000 person-years. Between March and July 2020 (low-incidence period), observed number of deaths was 9%-lower than expected, whereas it was 15% and 24% higher than expected between July 2020 and March 2021 (high incidence period - no vaccination), and between March 2021 and December 2021 (high incidence period - progressive vaccination) respectively. Between July 2020 and December 2021, excess deaths observed and COVID-19 deaths reported were comparable (7461 and 7620 respectively). Nevertheless, there were more deaths than expected for conditions that predispose to COVID-19 deaths. YPLL and mortality rates increased with age, but significant excess deaths were observed in all age-groups older than 30-39 years. No large differences were noted by districts' socioeconomic characteristics although excess death rate was lower in rural compared to urban areas. Interpretation: Reporting of deaths was only slightly underestimated. In the pre-vaccination period, mortality rate and YPLL rates increased with age, being highest in people aged 60 years or older and justifying the decision to initially prioritize vaccination of older individuals. Funding: The study was supported by the University of Costa Rica and the Agencia Costarricense de Investigaciones Biomédicas - Fundación Inciensa.

Trends in incidence rates of head and neck squamous cell carcinomas overall and by potential relatedness to human papillomavirus, Costa Rica 2006 to 2015.

In Costa Rica (CR), only one report on head and neck cancer (HNC) incidence trends (1985-2007) has been published and no investigations on the epidemiology of potentially human papillomavirus (HPV)-related and HPV-unrelated HNCs have been done. We examined the age-standardized incidence rates (IRs) and trends of head and neck squamous cell carcinomas (HNSCC) and compared incidence trends of potentially HPV-related and HPV-unrelated HNSCCs. We obtained all available HNC cases for the period 2006-2015 from the Costa Rican National Cancer Registry of Tumors and the population estimates from the Costa Rican National Institute of Statistics and Census. The analysis was restricted to invasive HNSCCs (n = 1577). IRs and incidence rate ratios were calculated using SEER*Stat software and were age-standardized for the 2010 Costa Rican population. Joinpoint regression analysis program was used to calculate trends and annual percent changes (APCs) in rates. For all HNSCCs, the age-standardized IR was 34.0/million person-years; 95% CI 32.4, 35.8. There was a significant decline in the incidence of nasopharyngeal cancer (APC: -5.9% per year; 95% CI -10.8, -0.7) and laryngeal cancer (APC: -5.4% per year; -9.2, 1.5). The incidence trends for hypopharyngeal, oropharyngeal and oral cavity cancers each remained stable over time. HNSCCs were categorized by their potential relatedness to HPV infection. Though the APCs were not statistically significant, IRs of potentially HPV-related HNSCCs trended upward, while HPV-unrelated HNSCCs trended downward. HNSCCs are uncommon in CR and decreased over time. We observed a divergent pattern of decreasing HPV-unrelated with increasing HPV-related HNSCCs that should be further informed by HPV genotyping tumor samples.

Risk factors for head and neck cancer in more and less developed countries: Analysis from the INHANCE consortium.

OBJECTIVE: We analyzed the pooled case-control data from the International Head and Neck Cancer Epidemiology (INHANCE) consortium to compare cigarette smoking and alcohol consumption risk factors for head and neck cancer between less developed and more developed countries. SUBJECTS AND METHODS: The location of each study was categorized as either a less developed or more developed country. We compared the risk of overall head and neck cancer and cancer of specific anatomic subsites associated with cigarette smoking and alcohol consumption. Additionally, age and sex distribution between categories was compared. RESULTS: The odds ratios for head and neck cancer sites associated with smoking duration differed between less developed and more developed countries. Smoking greater than 20 years conferred a higher risk for oral cavity and laryngeal cancer in more developed countries, whereas the risk was greater for oropharynx and hypopharynx cancer in less developed countries. Alcohol consumed for more than 20 years conferred a higher risk for oropharynx, hypopharynx, and larynx cancer in less developed countries. The proportion of cases that were young (<45 years) or female differed by country type for some HNC subsites. CONCLUSION: These findings suggest the degree of industrialization and economic development affects the relationship between smoking and alcohol with head and neck cancer.

Performance of visual inspection of the cervix with acetic acid (VIA) for triage of HPV screen-positive women: results from the ESTAMPA study.

VIA is recommended for triage of HPV-positive women attending cervical screening. In the multicentric ESTAMPA study, VIA performance for detection of cervical intraepithelial neoplasia grade 3 or worse (CIN3+) among HPV-positive women was evaluated. Women aged 30-64 years were screened with HPV testing and cytology and referred to colposcopy if either test was positive. At colposcopy visit, study-trained midwives/nurses/GPs performed VIA ahead of colposcopy. VIA was considered positive if acetowhite lesions were observed in or close to the transformation zone. Ablative treatment eligibility was assessed for VIA positives. Performance indicators were estimated. Three thousand one hundred and forty-two HPV-positive women were included. Sensitivity for CIN3+ was 85.9% (95% CI 81.2-89.5) among women <50 years and, although not significant, slightly lower in women 50+ (78.0%, 95% CI 65.9-86.6). Overall specificity was 58.6% (95% CI 56.7-60.5) and was significantly higher among women 50+ (70.3%, 95% CI 66.8-73.5) compared to women <50 (54.3%, 95% CI 52.1-56.5). VIA positivity was lower among women 50+ (35.2%, 95% CI 31.9-38.6) compared to women <50 (53.2, 95% CI 51.1-55.2). Overall eligibility for ablative treatment was 74.5% and did not differ by age. VIA sensitivity, specificity, and positivity, and ablative treatment eligibility varied highly by provider (ranges: 25%-95.4%, 44.9%-94.4%, 8.2%-65.3%, 0%-98.7%, respectively). VIA sensitivity for cervical precancer detection among HPV-positive women performed by trained providers was high with an important reduction in referral rates. However, scaling-up HPV screening triaged by VIA will be challenging due to the high variability of VIA performance and providers' need for training and supervision.