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1.  Global Genomic Diversity of Human Papillomavirus 6 Based on 724 Isolates and 190 Complete Genome Sequences 
Journal of Virology  2014;88(13):7307-7316.
ABSTRACT
Human papillomavirus type 6 (HPV6) is the major etiological agent of anogenital warts and laryngeal papillomas and has been included in both the quadrivalent and nonavalent prophylactic HPV vaccines. This study investigated the global genomic diversity of HPV6, using 724 isolates and 190 complete genomes from six continents, and the association of HPV6 genomic variants with geographical location, anatomical site of infection/disease, and gender. Initially, a 2,800-bp E5a-E5b-L1-LCR fragment was sequenced from 492/530 (92.8%) HPV6-positive samples collected for this study. Among them, 130 exhibited at least one single nucleotide polymorphism (SNP), indel, or amino acid change in the E5a-E5b-L1-LCR fragment and were sequenced in full. A global alignment and maximum likelihood tree of 190 complete HPV6 genomes (130 fully sequenced in this study and 60 obtained from sequence repositories) revealed two variant lineages, A and B, and five B sublineages: B1, B2, B3, B4, and B5. HPV6 (sub)lineage-specific SNPs and a 960-bp representative region for whole-genome-based phylogenetic clustering within the L2 open reading frame were identified. Multivariate logistic regression analysis revealed that lineage B predominated globally. Sublineage B3 was more common in Africa and North and South America, and lineage A was more common in Asia. Sublineages B1 and B3 were associated with anogenital infections, indicating a potential lesion-specific predilection of some HPV6 sublineages. Females had higher odds for infection with sublineage B3 than males. In conclusion, a global HPV6 phylogenetic analysis revealed the existence of two variant lineages and five sublineages, showing some degree of ethnogeographic, gender, and/or disease predilection in their distribution.
IMPORTANCE This study established the largest database of globally circulating HPV6 genomic variants and contributed a total of 130 new, complete HPV6 genome sequences to available sequence repositories. Two HPV6 variant lineages and five sublineages were identified and showed some degree of association with geographical location, anatomical site of infection/disease, and/or gender. We additionally identified several HPV6 lineage- and sublineage-specific SNPs to facilitate the identification of HPV6 variants and determined a representative region within the L2 gene that is suitable for HPV6 whole-genome-based phylogenetic analysis. This study complements and significantly expands the current knowledge of HPV6 genetic diversity and forms a comprehensive basis for future epidemiological, evolutionary, functional, pathogenicity, vaccination, and molecular assay development studies.
doi:10.1128/JVI.00621-14
PMCID: PMC4054425  PMID: 24741079
2.  Comprehensive Control of Human Papillomavirus Infections and Related Diseases 
Vaccine  2013;31(0 8):I1-31.
Infection with human papillomavirus (HPV) is recognized as one of the major causes of infection-related cancer worldwide, as well as the causal factor in other diseases. Strong evidence for a causal etiology with HPV has been stated by the International Agency for Research on Cancer for cancers of the cervix uteri, penis, vulva, vagina, anus and oropharynx (including base of the tongue and tonsils). Of the estimated 12.7 million new cancers occurring in 2008 worldwide, 4.8% were attributable to HPV infection, with substantially higher incidence and mortality rates seen in developing versus developed countries. In recent years, we have gained tremendous knowledge about HPVs and their interactions with host cells, tissues and the immune system; have validated and implemented strategies for safe and efficacious prophylactic vaccination against HPV infections; have developed increasingly sensitive and specific molecular diagnostic tools for HPV detection for use in cervical cancer screening; and have substantially increased global awareness of HPV and its many associated diseases in women, men, and children. While these achievements exemplify the success of biomedical research in generating important public health interventions, they also generate new and daunting challenges: costs of HPV prevention and medical care, the implementation of what is technically possible, socio-political resistance to prevention opportunities, and the very wide ranges of national economic capabilities and health care systems. Gains and challenges faced in the quest for comprehensive control of HPV infection and HPV-related cancers and other disease are summarized in this review. The information presented may be viewed in terms of a reframed paradigm of prevention of cervical cancer and other HPV-related diseases that will include strategic combinations of at least four major components: 1) routine introduction of HPV vaccines to women in all countries, 2) extension and simplification of existing screening programs using HPV-based technology, 3) extension of adapted screening programs to developing populations, and 4) consideration of the broader spectrum of cancers and other diseases preventable by HPV vaccination in women, as well as in men. Despite the huge advances already achieved, there must be ongoing efforts including international advocacy to achieve widespread—optimally universal—implementation of HPV prevention strategies in both developed and developing countries.
This article summarizes information from the chapters presented in a special ICO Monograph ‘Comprehensive Control of HPV Infections and Related Diseases’ Vaccine Volume 30, Supplement 5, 2012. Additional details on each subtopic and full information regarding the supporting literature references may be found in the original chapters.
doi:10.1016/j.vaccine.2013.07.026
PMCID: PMC4062073  PMID: 24229716
HPV; Cervical cancer; Anal cancer; Penile cancer; Vaginal cancer; Vulvar cancer; Oropharyngeal cancer; Screening; HPV vaccination; HPV testing; Prevention
3.  Determinants of baseline seroreactivity to human papillomavirus type 16 in the Ludwig-McGill cohort study 
BMC Infectious Diseases  2014;14(1):578.
Background
Immunity plays an important role in controlling human papillomavirus (HPV) infection and associated lesions. Unlike infections caused by other viruses, natural HPV infection does not always result in a protective antibody response. Therefore, HPV antibodies are also considered markers of cumulative exposure. The aim of this study was to identify determinants of HPV16 seroreactivity at enrollment among women from the Ludwig-McGill cohort, a natural history study of HPV infection and risk of cervical neoplasia.
Methods
HPV16 serology was assessed by ELISA for L1 and L2 capsid antigens, while HPV typing and viral load measurements were performed by PCR-based methods. The associations were analyzed by unconditional logistic regression.
Results
Of 2049 subjects, 425 (20.7%) were strongly seropositive for HPV16. In multivariate analysis, seroreactivity was positively correlated with age, lifetime number of sexual partners, frequency of sex, and HPV16 viral load, and negatively associated with duration of smoking.
Conclusions
HPV16 seroreactivity is determined by factors that reflect viral exposure.
doi:10.1186/s12879-014-0578-0
PMCID: PMC4247698
Serology; HPV; Natural antibodies; HPV16 seropositivity
4.  Women’s intentions to self-collect samples for human papillomavirus testing in an organized cervical cancer screening program 
BMC Public Health  2014;14(1):1060.
Background
Mounting evidence affirms HPV testing as an effective cervical cancer screening tool, and many organized screening programs are considering adopting it as primary testing. HPV self-collection has comparable sensitivity to clinician collected specimens and is considered a feasible option in hard-to-reach women. We explored women’s intentions to HPV self-collect for cervical cancer screening from a cohort participating in a Canadian randomized controlled cervical cancer screening trial.
Methods
Women aged 25–65 were invited to complete an online survey assessing intentions to be screened with HPV testing instead of the Pap smear. The survey was based in the Theory of Planned Behaviour and questions were included to assess women’s intentions to self-collect for HPV. Demographic characteristics of women who intended to self-collect were compared with those who did not. Demographic and scale variables achieving a p-value <0.1 in the univariate and bivariate analyses were included in the stepwise logistic regression model. The final model was created to predict factors associated with women’s intentions to self-collect an HPV specimen for cervical cancer. Odds ratios were calculated with 95% confidence intervals to identify variables associated with a woman’s intention to self-collect for cervical cancer screening.
Results
The overall survey response rate was 63.8% (981/1538) with 447 (45.6%) reporting they intended to self-collect, versus 534 (54.4%) reporting they did not. In the univariate analysis, women with more than high school education were more likely to self-collect. Women who intended to receive HPV testing versus the Pap smear were 1.94 times as likely to be in favour of self-collection and those who intended to self-collect had significantly higher attitudinal scores towards HPV self-collection. The adjusted odds ratio and 95% confidence interval from the multivariate analysis demonstrated attitude towards self-collection was the only significant variable predicting a woman’s intention to self-collect (OR 1.25; 95% CI: 1.22, 1.29).
Conclusions
The primary predictor of a woman’s intention to HPV self-collect for cervical cancer screening was her attitude towards the procedure. From a program planning perspective, these results indicate that education and awareness may be significant contributing factors to improving acceptance of self-collection and subsequently, improving screening attendance rates.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2458-14-1060) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2458-14-1060
PMCID: PMC4203923  PMID: 25303975
Human papillomavirus (HPV); Cervical cancer screening; Self-collection; Intention; Theory of planned behaviour
5.  PATTERNS OF PERSISTENT GENITAL HUMAN PAPILLOMAVIRUS INFECTION AMONG WOMEN WORLDWIDE: A LITERATURE REVIEW AND META-ANALYSIS 
Persistent high-risk human papillomavirus (HR-HPV) infection is the strongest risk factor for high-grade cervical precancer. We performed a systematic review and meta-analysis of HPV persistence patterns worldwide. Medline and ISI Web of Science were searched through January 1, 2010 for articles estimating HPV persistence or duration of detection. Descriptive and meta-regression techniques were used to summarize variability and the influence of study definitions and characteristics on duration and persistence of cervical HPV infections in women. Among 86 studies providing data on over 100,000 women, 73% defined persistence as HPV positivity at a minimum of two time points. Persistence varied notably across studies and was largely mediated by study region and HPV type, with HPV-16, 31, 33 and 52 being most persistent. Weighted median duration of any-HPV detection was 9.8 months. HR-HPV (9.3 months) persisted longer than low-risk HPV (8.4 months), and HPV-16 (12.4 months) persisted longer than HPV-18 (9.8 months). Among populations of HPV positive women with normal cytology, the median duration of any-HPV detection was 11.5 and HR-HPV detection was10.9 months. In conclusion, we estimated that approximately half of HPV infections persist past 6–12 months. Repeat HPV testing at 12 month intervals could identify women at increased risk of high-grade cervical precancer due to persistent HPV infections.
doi:10.1002/ijc.27828
PMCID: PMC3707974  PMID: 22961444
human papillomavirus; HPV; duration; persistence; clearance; natural history; repeat testing; literature review; screening; cervical cancer; meta-analysis
6.  Epidemiologic Approaches to Evaluating the Potential for Human Papillomavirus Type Replacement Postvaccination 
American Journal of Epidemiology  2013;178(4):625-634.
Currently, 2 vaccines exist that prevent infection by the genotypes of human papillomavirus (HPV) responsible for approximately 70% of cervical cancer cases worldwide. Although vaccination is expected to reduce the prevalence of these HPV types, there is concern about the effect this could have on the distribution of other oncogenic types. According to basic ecological principles, if competition exists between ≥2 different HPV types for niche occupation during natural infection, elimination of 1 type may lead to an increase in other type(s). Here, we discuss this issue of “type replacement” and present different epidemiologic approaches for evaluation of HPV type competition. Briefly, these approaches involve: 1) calculation of the expected frequency of coinfection under independence between HPV types for comparison with observed frequency; 2) construction of hierarchical logistic regression models for each vaccine-targeted type; and 3) construction of Kaplan-Meier curves and Cox models to evaluate sequential acquisition and clearance of HPV types according to baseline HPV status. We also discuss a related issue concerning diagnostic artifacts arising when multiple HPV types are present in specific samples (due to the inability of broad-spectrum assays to detect certain types present in lower concentrations). This may result in an apparent increase in previously undetected types postvaccination.
doi:10.1093/aje/kwt018
PMCID: PMC3736757  PMID: 23660798
cervical cancer; human papillomavirus; HPV type replacement; vaccination
7.  Polymorphism in the promoter region of the Toll-like receptor 9 gene and cervical human papillomavirus infection 
The Journal of General Virology  2013;94(Pt 8):1858-1864.
Polymorphism in the Toll-like receptor (TLR) 9 gene has been shown to have a significant role in some diseases; however, little is known about its possible role in the natural history of human papillomavirus (HPV) infections. We investigated the association between a single-nucleotide polymorphism (SNP) (rs5743836) in the promoter region of TLR9 (T1237C) and type-specific HPV infections. Specimens were derived from a cohort of 2462 women enrolled in the Ludwig–McGill Cohort Study. We randomly selected 500 women who had a cervical HPV infection detected at least once during the study as cases. We defined two control groups: (i) a random sample of 300 women who always tested HPV negative, and (ii) a sample of 234 women who were always HPV negative but had a minimum of ten visits during the study. TLR9 genotyping was performed using bidirectional PCR amplification of specific alleles. Irrespective of group, the WT homozygous TLR9 genotype (TT) was the most common form, followed by the heterozygous (TC) and the mutant homozygous (CC) forms. There were no consistent associations between polymorphism and infection risk, either overall or by type or species. Likewise, there were no consistently significant associations between polymorphism and HPV clearance or persistence. We concluded that this polymorphism in the promoter region of TLR9 gene does not seem to have a mediating role in the natural history of the HPV infection.
doi:10.1099/vir.0.052811-0
PMCID: PMC3749521  PMID: 23677790
8.  Human papillomavirus type 16 viral load measurement as a predictor of infection clearance 
The Journal of General Virology  2013;94(Pt 8):1850-1857.
Viral load measurements may predict whether human papillomavirus (HPV) type 16 infections may become persistent and eventually lead to cervical lesions. Today, multiple PCR methods exist to estimate viral load. We tested three protocols to investigate viral load as a predictor of HPV clearance. We measured viral load in 418 HPV16-positive cervical smears from 224 women participating in the Ludwig–McGill Cohort Study by low-stringency PCR (LS-PCR) using consensus L1 primers targeting over 40 known HPV types, and quantitative real-time PCR (qRT-PCR) targeting the HPV16 E6 and L1 genes. HPV16 clearance was determined by MY09/11 and PGMY PCR testing on repeated smears collected over 5 years. Correlation between viral load measurements by qRT-PCR (E6 versus L1) was excellent (Spearman’s rank correlation, ρ = 0.88), but decreased for L1 qRT-PCR versus LS-PCR (ρ = 0.61). Viral load by LS-PCR was higher for HPV16 and related types independently of other concurrent HPV infections. Median duration of infection was longer for smears with high copy number by all three PCR protocols (log rank P<0.05). Viral load is inversely related to HPV16 clearance independently of concurrent HPV infections and PCR protocol.
doi:10.1099/vir.0.051722-0
PMCID: PMC4093775  PMID: 23677791
9.  HPV infection and re-infection in adult women: the role of sexual activity and natural immunity 
Cancer research  2010;70(21):8569-8577.
There is paucity of data on whether or not women can be re-infected with human papillomavirus (HPV) types to which they were exposed earlier in life and on the role of natural immunity. The observation of HPV infection at older ages may be explained by reactivation of a latent infection or new exposure from sexual activity. Our objective was to analyze the association between re-infection and sexual activity. We analyzed data from 2462 women enrolled in the Ludwig-McGill cohort and followed every 4-6 months for up to 10 years. We performed HPV typing and viral load measurements via polymerase chain reaction and determined HPV-16 seroreactivity at enrolment. Incidence of infection and re-infection were estimated for individual types. Adjusted relative risks (RR) for the association between infection/re-infection and new sexual partners were calculated using Cox regression. Rates of initial infection and re-infection post-clearance were statistically comparable. RRs of initial infection or re-infection were consistently associated with new sexual partners (2.4 [95%CI: 2.0-3.1] for first infection, 3.7 [1.1-13.8] for re-infection with the same type, and 2.3 [1.5-3.7] for re-infection with a different type). Re-infection in older women was also associated with new sexual partners (RR=2.8, 95%CI: 1.4-5.3) as were new infections with HPV-16 among women with serological evidence of prior HPV-16 exposure (RR=3.0, 95%CI: 1.6-5.3). Viral loads at initial infection and at re-infection were comparable. HPV infection and re-infection were strongly associated with sexual activity. This study suggests that natural immunity does not play a role in controlling the extent of re-infections.
doi:10.1158/0008-5472.CAN-10-0621
PMCID: PMC4068337  PMID: 20978200
Human papillomavirus; re-infection; adult women; sexual behavior; natural immunity; epidemiology
10.  American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology Screening Guidelines for the Prevention and Early Detection of Cervical Cancer 
An update to the American Cancer Society (ACS) guideline regarding screening for the early detection of cervical precancerous lesions and cancer is presented. The guidelines are based on a systematic evidence review, contributions from six working groups, and a recent symposium co-sponsored by the ACS, American Society for Colposcopy and Cervical Pathology (ASCCP), and American Society for Clinical Pathology (ASCP), which was attended by 25 organizations. The new screening recommendations address age-appropriate screening strategies, including the use of cytology and high-risk human papillomavirus (HPV) testing, follow-up (e.g., management of screen positives and screening interval for screen negatives) of women after screening, age at which to exit screening, future considerations regarding HPV testing alone as a primary screening approach, and screening strategies for women vaccinated against HPV16 and HPV18 infections.
doi:10.1097/LGT.0b013e31824ca9d5
PMCID: PMC3915715  PMID: 22418039
11.  American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology Screening Guidelines for the Prevention and Early Detection of Cervical Cancer 
An update to the American Cancer Society (ACS) guideline regarding screening for the early detection of cervical precancerous lesions and cancer is presented. The guidelines are based on a systematic evidence review, contributions from six working groups, and a recent symposium cosponsored by the ACS, American Society for Colposcopy and Cervical Pathology (ASCCP), and American Society for Clinical Pathology (ASCP), which was attended by 25 organizations. The new screening recommendations address age-appropriate screening strategies, including the use of cytology and high-risk human papillomavirus (HPV) testing, follow-up (e.g., management of screen positives and screening interval for screen negatives) of women after screening, age at which to exit screening, future considerations regarding HPV testing alone as a primary screening approach, and screening strategies for women vaccinated against HPV16 and HPV18 infections.
doi:10.3322/caac.21139
PMCID: PMC3801360  PMID: 22422631
12.  Circulating Biomarkers of Iron Storage and Clearance of Incident Human Papillomavirus Infection 
Background
Iron is an essential mineral for both cellular and pathogen survival and is essential for viral replication. In turn, iron metabolism has been shown to be altered by several viral infections. However, little is known regarding the association between iron status and HPV natural history. We hypothesize iron to be an HPV-cofactor that is associated with longer duration of infection.
Methods
Ferritin and soluble transferrin receptor (sTfR) were measured in baseline serum samples from 327 women enrolled in the Ludwig-McGill Cohort. Incident HPV clearance rates (any-type, oncogenic HPV, non-oncogenic HPV, and HPV-16) over 36 months were estimated from Cox-proportional hazard models accounting for correlations between multiple infections.
Results
Women with ferritin levels above the median were less likely to clear an incident oncogenic HPV (AHR=0.73; 95%CI 0.55–0.96) and HPV-16 infections (AHR=0.29; 95%CI 0.11–0.73). Using physiological cut-points, women with enriched iron stores (≥120ug/L) were less likely to clear incident oncogenic HPV infections compared to those with low-levels of iron (<20ug/L)(AHR=0.34; 95%CI 0.15–0.81).
Conclusion
This study observed that women with the highest ferritin levels were less likely to clear incident oncogenic and HPV-16 infections compared to women with low ferritin. Rising iron stores may decrease probability of clearing new HPV infection, possibly by promoting viral activity and contributing to oxidative DNA damage.
Impact
This novel study suggests that elevated iron stores may put women at risk for persistent HPV infection, an early event in cervical carcinogenesis. Further examination of the association between iron status and HPV natural history is warranted.
doi:10.1158/1055-9965.EPI-12-0073
PMCID: PMC3709556  PMID: 22426142
Human Papillomavirus; clearance; Ferritin; Iron; Transferrin
13.  Biomarkers of oxidant load and type-specific clearance of prevalent oncogenic human papillomavirus infection: Markers of immune response? 
Human papillomavirus (HPV) infection is the cause of cervical cancer. Increased production of reactive oxygen species (ROS) maybe the common mechanism through which HPV-cofactors (i.e. smoking and inflammation) influence duration of infections. Biomarkers of total oxidant load may serve as cumulative measures of ROS exposure due to these cofactors. Therefore, we conducted a study evaluating the association between biomarkers of oxidant load and duration of HPV infections, early HPV natural history events. Serum samples were obtained from 444 HPV-positive women in the Ludwig-McGill Cohort Study. Anti-5-hydroxymethyl-2’-deoxyuridine autoantibody (anti-HMdU aAb) and malondialdehyde (MDA) were measured at baseline. Cox-proportional hazard models were used to estimate the probability of clearing any HPV, oncogenic HPV, non-oncogenic HPV, and HPV-16 infections. Women with elevated MDA were significantly more likely to clear prevalent oncogenic HPV infections compared to those with lower MDA levels (Adjusted Hazard Ratio (AHR)=2.7; 95%CI=1.4–5.1). There did not appear to be an association between elevated MDA and clearance of incident oncogenic HPV infections. Similarly, women with elevated anti-HMdU aAb levels had higher rates of prevalent oncogenic HPV infection clearance (Quartile 3:AHR=2.2; 95%CI=1.2–4.4; Quartile 4:AHR=2.4; 95%CI=1.2–4.9). Higher levels of oxidant load biomarkers were associated with increased clearance of prevalent HPV infections. However, oxidant load biomarkers measured prior to incident infections were not associated, suggesting that the elevation of MDA and anti-HMdU aAb may reflect an ongoing effective immune response, such as increased innate immunity. More research focused on the immune responses to HPV and elevated markers of oxidant load is needed.
doi:10.1002/ijc.26363
PMCID: PMC3319468  PMID: 21858808
Human Papillomavirus; clearance; cervical cancer; oxidative stress; reactive oxygen species
14.  Vaccinating Girls and Boys with Different Human Papillomavirus Vaccines: Can It Optimise Population-Level Effectiveness? 
PLoS ONE  2013;8(6):e67072.
Background
Decision-makers may consider vaccinating girls and boys with different HPV vaccines to benefit from their respective strengths; the quadrivalent (HPV4) prevents anogenital warts (AGW) whilst the bivalent (HPV2) may confer greater cross-protection. We compared, to a girls-only vaccination program with HPV4, the impact of vaccinating: 1) both genders with HPV4, and 2) boys with HPV4 and girls with HPV2.
Methods
We used an individual-based transmission-dynamic model of heterosexual HPV infection and diseases. Our base-case scenario assumed lifelong efficacy of 100% against vaccine types, and 46,29,8,18,6% and 77,43,79,8,0% efficacy against HPV-31,-33,-45,-52,-58 for HPV4 and HPV2, respectively.
Results
Assuming 70% vaccination coverage and lifelong cross-protection, vaccinating boys has little additional benefit on AGW prevention, irrespective of the vaccine used for girls. Furthermore, using HPV4 for boys and HPV2 for girls produces greater incremental reductions in SCC incidence than using HPV4 for both genders (12 vs 7 percentage points). At 50% vaccination coverage, vaccinating boys produces incremental reductions in AGW of 17 percentage points if both genders are vaccinated with HPV4, but increases female incidence by 16 percentage points if girls are switched to HPV2 (heterosexual male incidence is incrementally reduced by 24 percentage points in both scenarios). Higher incremental reductions in SCC incidence are predicted when vaccinating boys with HPV4 and girls with HPV2 versus vaccinating both genders with HPV4 (16 vs 12 percentage points). Results are sensitive to vaccination coverage and the relative duration of protection of the vaccines.
Conclusion
Vaccinating girls with HPV2 and boys with HPV4 can optimize SCC prevention if HPV2 has higher/longer cross-protection, but can increase AGW incidence if vaccination coverage is low among boys.
doi:10.1371/journal.pone.0067072
PMCID: PMC3694081  PMID: 23840589
15.  Dietary Consumption of Antioxidant Nutrients and Risk of Incident Cervical Intraepithelial Neoplasia 
Gynecologic oncology  2010;118(3):289-294.
Objective
Women with human papillomavirus (HPV) infections are at risk for developing squamous intraepithelial lesions (SIL) of the cervix; however, other factors are required for infections to progress to SIL. We hypothesize that consumption of fruits and vegetables high in antioxidant nutrients may prevent, in part, the development of HPV-associated SIL.
Methods
This study is a nested case-control study of 265 HPV-positive women (93 SIL cases and 172 cytologically normal controls) in the Ludwig-McGill Cohort Study, Sao Paulo, Brazil. Diet was assessed by a self-administered food frequency questionnaire. The association between food and nutrient intake of antioxidants and incident SIL was determined by logistic regression and multinomial regression when comparing LSIL and HSILs.
Results
Higher reported consumption of papaya was inversely associated with risk of SIL (p trend=0.01) and strongest for ≥1 time/week (adjusted odds ratios (AORs)=0.19; 95%CI, 0.08-0.49). Risk of SIL was reduced among women reporting consumption of oranges ≥1 time/week (AOR=0.32; 95%CI, 0.12-0.87; p-trend = 0.02). Nutrient intakes of ß-cryptoxanthin and α-carotene were marginally protective against SIL.
Conclusions
Frequent consumption of fruits high in antioxidant nutrients appears to be associated with reduced risk of incident SIL among Brazilian women.
doi:10.1016/j.ygyno.2010.05.022
PMCID: PMC3691953  PMID: 20691333
cervical cancer; cervical intraepithelial neoplasia; human papillomavirus; diet; antioxidant nutrient
16.  Factors associated with cervical cancer screening uptake among Inuit women in Nunavik, Quebec, Canada 
BMC Public Health  2013;13:438.
Background
The Canadian circumpolar Inuit population has a higher incidence rate of cervical cancer than the general population and the majority of cases occur among underscreened women. The objectives of this study were to determine Pap smear utilization rates and to determine factors associated with time-inappropriate use of cervical cancer screening among a cohort of Inuit women from Nunavik, Quebec, Canada.
Methods
This study utilizes baseline information collected from a cohort formed between January 2002 and December 2007 to study the natural history of HPV among Inuit women aged 21–69 years in Nunavik, Quebec. Cervical cancer screening history and other variables were obtained from a baseline questionnaire and medical chart review. Unconditional logistic regression was used to estimate the odds ratios and 95% confidence intervals for potential predictors of not having a Pap smear within the previous 3 years prior to cohort entry.
Results
A total of 403 Inuit women who had a baseline questionnaire and chart review were included. The mean age of the study population was 34.2 years. In the three years prior to study entry, 25% of women did not have a Pap smear. Older age and never giving birth were significant predictors of time-inappropriate Pap smear use.
Conclusions
Our results suggest that older women and women who are not accessing reproductive care have a lower compliance with time-appropriate cervical cancer screening and future research should address potential strategies to increase screening coverage among this group.
doi:10.1186/1471-2458-13-438
PMCID: PMC3653732  PMID: 23642072
17.  Minimal alterations on the enamel surface by micro-abrasion: in vitro roughness and wear assessments 
Journal of Applied Oral Science  2013;21(2):112-117.
Objective:
To evaluate the in vitro changes on the enamel surface after a micro-abrasion treatment promoted by different products.
Material and Methods:
Fifty (50) fragments of bovine enamel (15 mm x 5 mm) were randomly assigned to five groups (n=10) according to the product utilized: G1 (control)= silicone polisher (TDV), G2= 37% phosphoric acid (3M/ESPE) + pumice stone (SS White), G3= Micropol (DMC Equipment), G4= Opalustre (Ultradent) and G5= Whiteness RM (FGM Dental Products). Roughness and wear were the responsible variables used to analyze these surfaces in four stages: baseline, 60 s and 120 s after the micro-abrasion and after polishing, using a Hommel Tester T1000 device. After the tests, a normal distribution of data was verified, with repeated ANOVA analyses (p≤0.05) which were used to compare each product in different stages. One-way ANOVA and Tukey tests were applied for individual comparisons between the products in each stage (p≤0.05).
Results:
Means and standard deviations of roughness and wear (mm) after all the promoted stages were: G1=7.26(1.81)/13.16(2.67), G2=2.02(0.62)/37.44(3.33), G3=1.81(0.91)/34.93(6.92), G4=1.92(0.29)/38.42(0.65) and G5=1.98(0.53)/33.45(2.66). At 60 seconds, all products tended to produce less surface roughness with a variable gradual decrease over time. After polishing, there were no statistically significant differences between the groups, except for G1. Independent of the product utilized, the enamel wear occurred after the micro-abrasion.
Conclusions:
In this in vitro study, enamel micro-abrasion presented itself as a conservative approach, regardless of the type of the paste compound utilized. These products promoted minor roughness alterations and minimal wear. The use of phosphoric acid and pumice stone showed similar results to commercial products for the micro-abrasion with regard to the surface roughness and wear.
doi:10.1590/1678-7757201302117
PMCID: PMC3881870  PMID: 23739863
Micro-abrasion; Enamel; Roughness; Wear
18.  Accuracy of p53 Codon 72 Polymorphism Status Determined by Multiple Laboratory Methods: A Latent Class Model Analysis 
PLoS ONE  2013;8(2):e56430.
Introduction
Studies on the association of a polymorphism in codon 72 of the p53 tumour suppressor gene (rs1042522) with cervical neoplasia have inconsistent results. While several methods for genotyping p53 exist, they vary in accuracy and are often discrepant.
Methods
We used latent class models (LCM) to examine the accuracy of six methods for p53 determination, all conducted by the same laboratory. We also examined the association of p53 with cytological cervical abnormalities, recognising potential test inaccuracy.
Results
Pairwise disagreement between laboratory methods occurred approximately 10% of the time. Given the estimated true p53 status of each woman, we found that each laboratory method is most likely to classify a woman to her correct status. Arg/Arg women had the highest risk of squamous intraepithelial lesions (SIL). Test accuracy was independent of cytology. There was no strong evidence for correlations of test errors.
Discussion
Empirical analyses ignore possible laboratory errors, and so are inherently biased, but test accuracy estimated by the LCM approach is unbiased when model assumptions are met. LCM analysis avoids ambiguities arising from empirical test discrepancies, obviating the need to regard any of the methods as a “gold” standard measurement. The methods we presented here to analyse the p53 data can be applied in many other situations where multiple tests exist, but where none of them is a gold standard.
doi:10.1371/journal.pone.0056430
PMCID: PMC3575334  PMID: 23441193
19.  The frequency of HLA alleles in a population of Inuit women of northern Quebec 
International Journal of Circumpolar Health  2013;72:10.3402/ijch.v72i0.21350.
Background
Human leukocyte antigen (HLA) alleles code for proteins that are involved in the recognition of foreign antigens and activation of the immune system. The frequency of HLA alleles varies across different populations.
Objective
To describe the frequency of HLA alleles in a population of Inuit women of Nunavik, Quebec, Canada.
Design
A cohort of women was recruited from 4 different communities between January 2002 and December 2007. HLA-B*07, HLA-DQB1*03, DQB1*06:02, DRB1*13 and DRB1*15:01 alleles were typed by PCR sequence-specific primers (PCR-SSP) and HLA-E and G alleles were type by DNA-sequencing procedures.
Results
We obtained data on 524 participants. The most frequent HLA alleles in this population were HLA-E*01:03, HLA-G*01:04:01 and HLA-DQB1*03, and they were found in 89, 75 and 94% of the population, respectively.
Conclusions
The distribution of HLA alleles in Nunavik, Quebec is unique when compared to other populations in Canada or around the world.
doi:10.3402/ijch.v72i0.21350
PMCID: PMC3754547  PMID: 23986892
human leukocyte antigen; Inuit; Nunavik; Canada
20.  Genital Transmission of Human Papillomavirus in Recently Formed Heterosexual Couples 
The Journal of Infectious Diseases  2011;204(11):1723-1729.
We estimated human papillomavirus (HPV) transmission rates among persons with documented sexual exposure to an infected partner. Recently formed couples enrolled in the HITCH Study (HPV Infection and Transmission among Couples through Heterosexual activity) in Montreal, Canada, and provided genital specimens for DNA testing of 36 HPV genotypes. At enrollment, 179 couples were discordant for ≥1 HPV types; transmission was observed at follow-up in 73 partnerships. There was little difference between the male-to-female (3.5 per 100 person-months, 95% confidence interval [CI], 2.7–4.5) and female-to-male (4.0 per 100 person-months, 95% CI, 3.0–5.5) transmission rates. Rates did not vary with the lifetime number of partners reported by the initially uninfected partner, providing no evidence of reduced susceptibility for those with extensive sexual histories. Transmission was also relatively homogeneous across HPV genotypes and alpha species and oncogenic risk categories. The findings contribute to a small but growing evidence base regarding the natural history of HPV transmission.
doi:10.1093/infdis/jir644
PMCID: PMC3203235  PMID: 21984739
21.  The influence of "C-factor" and light activation technique on polymerization contraction forces of resin composite 
Journal of Applied Oral Science  2012;20(6):603-606.
Objectives
This study evaluated the influence of the cavity configuration factor ("C-Factor") and light activation technique on polymerization contraction forces of a Bis-GMA-based composite resin (Charisma, Heraeus Kulzer).
Material and Methods
Three different pairs of steel moving bases were connected to a universal testing machine (emic DL 500): groups A and B - 2x2 mm (CF=0.33), groups C and D - 3x2 mm (CF=0.66), groups e and F - 6x2 mm (CF=1.5). After adjustment of the height between the pair of bases so that the resin had a volume of 12 mm3 in all groups, the material was inserted and polymerized by two different methods: pulse delay (100 mW/cm2 for 5 s, 40 s interval, 600 mW/cm2 for 20 s) and continuous pulse (600 mW/cm2 for 20 s). Each configuration was light cured with both techniques. Tensions generated during polymerization were recorded by 120 s. The values were expressed in curves (Force(N) x Time(s)) and averages compared by statistical analysis (ANOVA and Tukey's test, p<0.05).
Results:
For the 2x2 and 3x2 bases, with a reduced C-Factor, significant differences were found between the light curing methods. For 6x2 base, with high C-Factor, the light curing method did not influence the contraction forces of the composite resin.
Conclusions
Pulse delay technique can determine less stress on tooth/restoration interface of adhesive restorations only when a reduced C-Factor is present.
doi:10.1590/S1678-77572012000600003
PMCID: PMC3881863  PMID: 23329240
Composite resins; Physical properties; Bis-GMA
22.  Ano-genital human papillomavirus type 97 infection is detected in Canadian men but not women at risk or infected with the human immunodeficiency virus 
Virology Journal  2012;9:243.
Background
Human papillomavirus type 97 (HPV97) DNA was detected in nearly 5% of anal samples collected from HIV-seropositive men living in Montreal, Canada. The rate of detection of HPV97 in the genital tract of Canadian women is unknown. Whether HPV97 is a local epidemic in HIV-seropositive men living in Montreal is also unknown. The prevalence of human papillomavirus type 97 (HPV97) was assessed in cervicovaginal cells from women living in Canada and in anal samples from HIV-seropositive men living in Toronto.
Findings
Cervicovaginal lavages collected from 904 women (678 HIV-seropositive, 226 HIV-seronegative) women living in Canada and anal cells collected from 123 HIV-seropositive men living in Toronto were tested for the presence of HPV97 with PCR. HPV97-positive samples were further tested by PCR-sequencing for molecular variant analysis to assess if all HPV97-positive men were infected with the same strain. All cervicovaginal samples were negative for HPV97. HPV97 was detected in anal samples from 6 HIV-seropositive men (4.9%, 95% confidence interval 2.0-10.5%), of whom five had high-grade and one had low-grade anal intraepithelial neoplasia, in addition to 2 to 8 HPV genital genotypes per sample. Four HPV97 variants were defined by four variation sites in the viral control region.
Conclusion
These findings indicate that HPV97 infects in the anal canal of HIV-seropositive men but is not detected in the genital tract of women.
doi:10.1186/1743-422X-9-243
PMCID: PMC3499219  PMID: 23092191
HPV; STD; HIV; AIN; Dysplasia
23.  Human Papillomavirus (HPV) DNA Triage of Women with Atypical Squamous Cells of Undetermined Significance with cobas 4800 HPV and Hybrid Capture 2 Tests for Detection of High-Grade Lesions of the Uterine Cervix 
Journal of Clinical Microbiology  2012;50(4):1240-1244.
The triage of women with high-risk (HR) human papillomavirus (HPV)-positive smears for atypical squamous cells of undetermined significance (ASC-US) to colposcopy is now an integrated option in clinical guidelines. The performance of cobas 4800 HPV and that of Hybrid Capture 2 (HC2) for HR HPV DNA detection in cervical samples in PreservCyt were compared in 396 women referred to colposcopy for ASC-US. Of these, 316 did not have cervical intraepithelial neoplasia (CIN), 47 had CIN1, 29 had CIN2 or CIN3 (CIN2+), and 4 had CIN of unknown grade. HR HPV was detected in 129 (32.6%) and 149 (37.6%) samples with HC2 and cobas 4800 HPV, respectively (P = 0.15). The clinical sensitivities and specificities for detecting CIN2+ were 89.7% (95% confidence interval [CI], 72.8 to 97.2%) and 66.7% (95% CI, 61.7 to 71.3%) with cobas 4800 HPV and 93.1% (95% CI, 77.0 to 99.2%) and 72.2% (95% CI 67.4 to 76.5%) with HC2. The performance of cobas 4800 HPV was similar to that of HC2 for identifying women with ASC-US who would benefit the most from colposcopy.
doi:10.1128/JCM.06656-11
PMCID: PMC3318562  PMID: 22301023
24.  Associations between serum carotenoids and tocopherols and type-specific HPV persistence: The Ludwig-McGill cohort study 
Although oncogenic HPV infections have been established as the necessary cause of cervical cancer, most HPV infections are transient and rarely progress to cervical lesions. Current research is focused on identifying factors associated with viral persistence and clearance, such as nutritional status. We evaluated the association between serum antioxidant nutrients (retinol, 10 carotenoids and 3 tocopherols) and type-specific HPV persistence over 4 visits among 405 women participating in the Ludwig-McGill cohort study. We measured circulating carotenoids and tocopherol at 4 different clinical visits for each woman. We report the results from different analytic approaches (a case–control approach at both the woman and viral level, and a prospective approach based on persistent events) that examined the association between these micronutrients and type-specific oncogenic and nononcogenic HPV persistence. In the case–control analysis at the viral level, midcirculating levels of α-tocopherol were inversely associated with nononcogenic HPV persistent infection (adjusted odds ratio (AOR) = 0.28, 95% CI 0.14–0.57), while high levels were marginally associated (AOR = 0.59, 95% CI 0.28–1.19). Similarly, utilizing generalized estimating equation models, circulating levels of α- and δ-tocopherol in the middle or upper tertiles were inversely associated with type-specific nononcogenic HPV persistence (AOR = 0.44, 95% CI 0.19–0.97 and AOR = 0.46, 95% CI 0.19–1.11, respectively). Our study among Brazilian women suggests that serum levels of tocopherols may be protective against nononcogenic HPV persistence. However, we did not find a strong protective effect (as hypothesized) of other serum antioxidant nutrients and type-specific oncogenic HPV persistence measured over 4 clinical visits.
doi:10.1002/ijc.22346
PMCID: PMC3458424  PMID: 17096322
human papillomavirus; persistence; carotentoid; tocopherol

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