Are Canadian Women Prepared for the Transition to Primary HPV Testing in Cervical Screening? A National Survey of Knowledge, Attitudes, and Beliefs

As Canadian provinces and territories prepare to transition to HPV-based primary screening for cervical cancer, failure to identify and address potential barriers to screening could hinder program implementation. We examined screening-eligible Canadians' attitudes towards and knowledge of cervical screening. A nationally representative sample of screening-eligible Canadians (N = 3724) completed a web-based survey in the summer of 2022. Oversampling ensured that half of the sample were underscreened for cervical cancer (>3 years since previous screening or never screened). The participants completed validated scales of cervical cancer, HPV, and HPV test knowledge and HPV test and self-sampling attitudes and beliefs. Between-group differences (underscreened vs. adequately screened) were calculated for scales and items using independent sample t-tests or chi-square tests. The underscreened participants (n = 1871) demonstrated significantly lower knowledge of cervical cancer, HPV, and the HPV test. The adequately screened participants (n = 1853) scored higher on the Confidence and Worries subscales of the HPV Test Attitudes and Beliefs Scale. The underscreened participants scored higher on the Personal Barriers and Social Norms subscales. The underscreened participants also endorsed greater Autonomy conferred by self-sampling. Our findings suggest important differential patterns of knowledge, attitudes, and beliefs between the underscreened and adequately screened Canadians. These findings highlight the need to develop targeted communication strategies and promote patient-centered, tailored approaches in cervical screening programs

The clinical features of the piriformis syndrome: a systematic review

Piriformis syndrome, sciatica caused by compression of the sciatic nerve by the piriformis muscle, has been described for over 70 years; yet, it remains controversial. The literature consists mainly of case series and narrative reviews. The objectives of the study were: first, to make the best use of existing evidence to estimate the frequencies of clinical features in patients reported to have PS; second, to identify future research questions. A systematic review was conducted of any study type that reported extractable data relevant to diagnosis. The search included all studies up to 1 March 2008 in four databases: AMED, CINAHL, Embase and Medline. Screening, data extraction and analysis were all performed independently by two reviewers. A total of 55 studies were included: 51 individual and 3 aggregated data studies, and 1 combined study. The most common features found were: buttock pain, external tenderness over the greater sciatic notch, aggravation of the pain through sitting and augmentation of the pain with manoeuvres that increase piriformis muscle tension. Future research could start with comparing the frequencies of these features in sciatica patients with and without disc herniation or spinal stenosis

Viral adaptation to immune selection pressure by HLA class I–restricted CTL responses targeting epitopes in HIV frameshift sequences

CD8+ cytotoxic T lymphocyte (CTL)–mediated immune responses to HIV contribute to viral control in vivo. Epitopes encoded by alternative reading frame (ARF) peptides may be targeted by CTLs as well, but their frequency and in vivo relevance are unknown. Using host genetic (human leukocyte antigen [HLA]) and plasma viral sequence information from 765 HIV-infected subjects, we identified 64 statistically significant (q < 0.2) associations between specific HLA alleles and sequence polymorphisms in alternate reading frames of gag, pol, and nef that did not affect the regular frame protein sequence. Peptides spanning the top 20 HLA-associated imprints were used to test for ex vivo immune responses in 85 HIV-infected subjects and showed responses to 10 of these ARF peptides. The most frequent response recognized an HLA-A*03–restricted +2 frame–encoded epitope containing a unique A*03-associated polymorphism at position 6. Epitope-specific CTLs efficiently inhibited viral replication in vitro when viruses containing the wild-type sequence but not the observed polymorphism were tested. Mutating alternative internal start codons abrogated the CTL-mediated inhibition of viral replication. These data indicate that responses to ARF-encoded HIV epitopes are induced during natural infection, can contribute to viral control in vivo, and drive viral evolution on a population level

A Proposed Classification of ICD-11 Severity Degrees of Personality Pathology Using the Self and Interpersonal Functioning Scale

Background: The 11th version of the World Health Organization's International Classification of Diseases (ICD-11) has adopted a dimensional approach to personality disorder (PD) nosology. Notably, it includes an assessment of PD degree of severity, which can be classified according to five categories. To date, there is no gold standard measure for assessing degree of PD severity based on the ICD-11 model, and there are no empirically-based anchor points to delineate the proposed categories. With the operationalization of PD degrees of severity in the ICD-11 PD model now being closely aligned with Criterion A of the DSM-5 Alternative Model for Personality Disorders (AMPD), sharing a focus on self and interpersonal dysfunction, self-report instruments developed for the latter model might prove useful as screening tools to determine degrees of severity in the former.Methods: The Self and Interpersonal Functioning Scale, a brief validated self-report questionnaire originally designed to assess level of personality pathology according to the AMPD framework, was used to derive anchor points to delineate the five severity degrees from the ICD-11 PD model. Data from five clinical and non-clinical samples (total N = 2,240) allowed identifying anchor points for classification, based on Receiver Operating Characteristic curve analysis, Latent Class Analysis, and data distribution statistics. Categories were validated using multiple indices pertaining to externalizing and internalizing symptoms relevant to PD.Results: Analyses yielded the following anchor points for PD degrees of severity: No PD = 0–1.04; Personality Difficulty = 1.05–1.29; Mild PD = 1.30–1.89; Moderate PD = 1.90–2.49; and Severe PD = 2.50 and above. A clear gradient of severity across the five categories was observed in all samples. A high number of significant contrasts among PD categories were also observed on external variables, consistent with the ICD-11 PD degree of severity operationalization.Conclusions: The present study provides potentially useful guidelines to determine severity of personality pathology based on the ICD-11 model. The use of a brief self-report questionnaire as a screening tool for assessing PD degrees of severity should be seen as a time-efficient support for clinical decision and treatment planning

Invited Commentary: Is Monitoring of Human Papillomavirus Infection for Viral Persistence Ready for Use in Cervical Cancer Screening?

Persistent cervical infections by approximately 15 carcinogenic genotypes of human papillomavirus (HPV) cause virtually all cases of cervical cancer and its immediate precancerous precursor, cervical intraepithelial neoplasia grade 3 or carcinoma in situ. As is shown in a meta-analysis by Koshiol et al. (Am J Epidemiol 2008;168:123–137), detection of carcinogenic HPV viral persistence could be used to identify women at the greatest risk of cervical precancer. Specifically, women who have carcinogenic HPV infection that persists for at least 1 year versus those whose infections clear are at significantly elevated risk of having or developing cervical precancer. However, before detection of HPV persistence can be used in cervical cancer screening, several considerations need to be addressed: 1) validation and Food and Drug Administration approval of a reliable HPV genotyping test, 2) rational clinical algorithms based on risk of precancer and cancer for the clinical management of HPV persistence, 3) clinician and patient acceptability of monitoring of HPV infections (including not responding excessively to the first positive HPV test and waiting 1–2 years for infections to either persist or resolve), and 4) patient compliance with recommended follow-up. Investigators will need to address these and other key issues in order to realize the potential utility of HPV viral monitoring for improving the accuracy of cervical cancer screening

Single-tube multiplex PCR using type-specific E6/E7 primers and capillary electrophoresis genotypes 21 human papillomaviruses in neoplasia

<p>Abstract</p> <p>Background</p> <p>Human papillomavirus (HPV) <it>E6/E7 </it>type-specific oncogenes are required for cervical carcinogenesis. Current PCR protocols for genotyping high-risk HPV in cervical screening are not standardized and usually use consensus primers targeting HPV capsid genes, which are often deleted in neoplasia. PCR fragments are detected using specialized equipment and extra steps, including probe hybridization or primer extension. In published papers, analytical sensitivity is typically compared with a different protocol on the same sample set.</p> <p>A single-tube multiplex PCR containing type-specific primers was developed to target the <it>E6/E7 </it>genes of two low-risk and 19 high-risk genotypes (HPV6, 11 and 16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68, 70, 73 and 82) and the resulting short fragments were directly genotyped by high-resolution fluorescence capillary electrophoresis.</p> <p>Results</p> <p>The method was validated using long oligonucleotide templates, plasmid clones and 207 clinical samples of DNA from liquid-based cytology, fresh and formalin-fixed specimens and FTA Microcards^®imprinted with cut tumor surfaces, swabbed cervical cancers or ejected aspirates from nodal metastases of head and neck carcinomas. Between one and five long oligonucleotide targets per sample were detected without false calls. Each of the 21 genotypes was detected in the clinical sample set with up to five types simultaneously detected in individual specimens. All 101 significant cervical neoplasias (CIN 2 and above), except one adenocarcinoma, contained <it>E6/E7 </it>genes. The resulting genotype distribution accorded with the national pattern with HPV16 and 18 accounting for 69% of tumors. Rare HPV types 70 and 73 were present as the sole genotype in one carcinoma each. One cervical SCC contained DNA from HPV6 and 11 only. Six of twelve oropharyngeal cancer metastases and three neck metastases of unknown origin bore <it>E6/E7 </it>DNA; all but one were HPV16. One neck aspirate contained atypical squames with HPV26.</p> <p>Analytical sensitivity in dilute plasmid mixes was variable.</p> <p>Conclusions</p> <p>A primer-rich PCR readily detects the <it>E6/E7 </it>oncogenes of 21 HPV types in cellular and fixed tissue specimens. The method is straightforward, robust and reproducible and avoids post-PCR enzymatic and hybridization steps while detecting HPV with high clinical sensitivity in significant HPV-related neoplasia regardless of specimen type.</p

Human papillomavirus (HPV) screening and cervical cancer burden. A Brazilian perspective

This review tackles the issues related to disease burden caused by cervical cancer (CC) and its precursor (CIN) lesions in Brazil. A special focus is given to new technologies with potential to interfere with the development of CC by reducing the high-risk human papillomavirus (hr-HPV)-induced lesions that remain a major public health burden in all developing countries where organized screening programs do not exist. Globally, 85 % of all incident CC and 50 % of CC deaths occur in the developing countries. Unfortunately, most regions of Brazil still demonstrate high mortality rates, ranking CC as the second most common cancer among Brazilian women. Recently, CC screening programs have been tailored in the country to enable early detection of CC precursor lesions and thereby reduce cancer mortality. A combination of HPV testing with liquid-based cytology (LBC) seems to be a promising new approach in CC screening, with high expectation to offer an adequate control of CC burden in this country

CTL Escape Mediated by Proteasomal Destruction of an HIV-1 Cryptic Epitope

Cytotoxic CD8+ T cells (CTLs) play a critical role in controlling viral infections. HIV-infected individuals develop CTL responses against epitopes derived from viral proteins, but also against cryptic epitopes encoded by viral alternative reading frames (ARF). We studied here the mechanisms of HIV-1 escape from CTLs targeting one such cryptic epitope, Q9VF, encoded by an HIVgag ARF and presented by HLA-B*07. Using PBMCs of HIV-infected patients, we first cloned and sequenced proviral DNA encoding for Q9VF. We identified several polymorphisms with a minority of proviruses encoding at position 5 an aspartic acid (Q9VF/5D) and a majority encoding an asparagine (Q9VF/5N). We compared the prevalence of each variant in PBMCs of HLA-B*07+ and HLA-B*07- patients. Proviruses encoding Q9VF/5D were significantly less represented in HLA-B*07+ than in HLA-B*07- patients, suggesting that Q9FV/5D encoding viruses might be under selective pressure in HLA-B*07+ individuals. We thus analyzed ex vivo CTL responses directed against Q9VF/5D and Q9VF/5N. Around 16% of HLA-B*07+ patients exhibited CTL responses targeting Q9VF epitopes. The frequency and the magnitude of CTL responses induced with Q9VF/5D or Q9VF/5N peptides were almost equal indicating a possible cross-reactivity of the same CTLs on the two peptides. We then dissected the cellular mechanisms involved in the presentation of Q9VF variants. As expected, cells infected with HIV strains encoding for Q9VF/5D were recognized by Q9VF/5D-specific CTLs. In contrast, Q9VF/5N-encoding strains were neither recognized by Q9VF/5N- nor by Q9VF/5D-specific CTLs. Using in vitro proteasomal digestions and MS/MS analysis, we demonstrate that the 5N variation introduces a strong proteasomal cleavage site within the epitope, leading to a dramatic reduction of Q9VF epitope production. Our results strongly suggest that HIV-1 escapes CTL surveillance by introducing mutations leading to HIV ARF-epitope destruction by proteasomes

A cost-utility analysis of cervical cancer vaccination in preadolescent Canadian females

<p>Abstract</p> <p>Background</p> <p>Despite the fact that approximately 70% of Canadian women undergo cervical cancer screening at least once every 3 years, approximately 1,300 women were diagnosed with cervical cancer and approximately 380 died from it in 2008. This study estimates the effectiveness and cost-effectiveness of vaccinating 12-year old Canadian females with an AS04-adjuvanted cervical cancer vaccine. The indirect effect of vaccination, via herd immunity, is also estimated.</p> <p>Methods</p> <p>A 12-health-state 1-year-cycle Markov model was developed to estimate lifetime HPV related events for a cohort of 12-year old females. Annual transition probabilities between health-states were derived from published literature and Canadian population statistics. The model was calibrated using Canadian cancer statistics. From a healthcare perspective, the cost-effectiveness of introducing a vaccine with efficacy against HPV-16/18 and evidence of cross-protection against other oncogenic HPV types was evaluated in a population undergoing current screening practices. The base-case analysis included 70% screening coverage, 75% vaccination coverage, $135/dose for vaccine, and 3$18,672-$31,687 per QALY-gained, the lower range representing inclusion of cross-protective efficacy and herd immunity. The cost per QALY-gained was most sensitive to duration of vaccine protection, discount rate, and the correlation between probability of screening and probability of vaccination.</p> <p>Conclusion</p> <p>In the context of current screening patterns, vaccination of 12-year old Canadian females with an ASO4-ajuvanted cervical cancer vaccine is estimated to significantly reduce cervical cancer and mortality, and is a cost-effective option. However, the economic attractiveness of vaccination is impacted by the vaccine's duration of protection and the discount rate used in the analysis.</p