Accurate histological grading of cervical intraepithelial neoplasia (CIN) lesions is important for clinical management of patients, because CIN1 and CIN2 and 3 lesions are treated differently. In ...general, there tends to be poor inter and intra-observer reproducibility of CIN grade evaluation among pathologists. In particular, the differential diagnosis between immature squamous metaplasia and CIN1 and 2, or between low-grade (CIN1) and high-grade (CIN2 and 3) lesions, tend to be difficult. These difficulties mean that patients tend to be over-treated for CIN lesions, which will naturally regress. Collectively, this highlights the need for alternative approaches and specific biomarkers to aid objective CIN lesion grading, and to identify true high-grade cervical disease. In this review we focus on the aetiology, pathobiology, the natural history of CIN, current issues with diagnosis and classification of CIN and the diagnostic and prognostic utility of specific biomarkers in identifying true cancerous precursor lesions.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Raman spectroscopy can provide a rapid, label-free, nondestructive measurement of the chemical fingerprint of a sample and has shown potential for cancer screening and diagnosis. Here we report a ...protocol for Raman microspectroscopic analysis of different exfoliative cytology samples (cervical, oral and lung), covering sample preparation, spectral acquisition, preprocessing and data analysis. The protocol takes 2 h 20 min for sample preparation, measurement and data preprocessing and up to 8 h for a complete analysis. A key feature of the protocol is that it uses the same sample preparation procedure as commonly used in diagnostic cytology laboratories (i.e., liquid-based cytology on glass slides), ensuring compatibility with clinical workflows. Our protocol also covers methods to correct for the spectral contribution of glass and sample pretreatment methods to remove contaminants (such as blood and mucus) that can obscure spectral features in the exfoliated cells and lead to variability. The protocol establishes a standardized clinical routine allowing the collection of highly reproducible data for Raman spectral cytopathology for cancer diagnostic applications for cervical and lung cancer and for monitoring suspicious lesions for oral cancer.
Primary care practitioners (PCP) play key roles in cervical cancer prevention. Human papillomavirus (HPV) knowledge is an important influence on PCPs' cervical cancer prevention-related behaviours. ...We investigated HPV knowledge, and associated factors, among general practitioners (GPs) and practice nurses.
A survey, including factual questions about HPV infection and vaccination, was mailed to GPs and practice nurses in Ireland. Multivariable logistic regression was used to determine which PCPs had low knowledge (questions correctly answered: infection ≤5/11; vaccination: ≤4/10). Questions least often answered correctly were identified.
697 PCPs participated. For HPV infection, GPs and practice nurses answered a median of nine and seven questions correctly, respectively (p<0.001). Significantly associated with low HPV infection knowledge were: being a practice nurse/male GP; working fewer hours/week; not having public patients; and having never taken a cervical smear. For HPV vaccination, both GPs and practice nurses answered a median of six questions correctly (p = 0.248). Significantly associated with low HPV vaccination knowledge were: being a practice nurse/male GP; working more years in general practice, fewer hours/week, in a smaller practice or in a practice not specialising in women's health; and having never taken a smear. Six HPV infection questions, and seven HPV vaccination questions, were not answered correctly by >⅓ of PCPs.
There are important limitations in HPV infection and vaccination knowledge among PCPs. By identifying factors associated with poor knowledge, and areas of particular uncertainty, these results can inform development of professional education initiatives thereby ensuring women have access to uniformly high-quality HPV-related information and advice.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The epidemic increase in the incidence of Human Papilloma Virus (HPV) related Oropharyngeal Squamous Cell Carcinomas (OPSCCs) in several countries worldwide represents a significant public health ...concern. Although gender neutral HPV vaccination programmes are expected to cause a reduction in the incidence rates of OPSCCs, these effects will not be evident in the foreseeable future. Secondary prevention strategies are currently not feasible due to an incomplete understanding of the natural history of oral HPV infections in OPSCCs. The key parameters that govern natural history models remain largely ill-defined for HPV related OPSCCs and cannot be easily inferred from experimental data. Mathematical models have been used to estimate some of these ill-defined parameters in cervical cancer, another HPV related cancer leading to successful implementation of cancer prevention strategies. We outline a “double-Bayesian” mathematical modelling approach, whereby, a Bayesian machine learning model first estimates the probability of an individual having an oral HPV infection, given OPSCC and other covariate information. The model is then inverted using Bayes’ theorem to reverse the probability relationship. We use data from the Surveillance, Epidemiology, and End Results (SEER) cancer registry, SEER Head and Neck with HPV Database and the National Health and Nutrition Examination Surveys (NHANES), representing the adult population in the United States to derive our model. The model contains 8,106 OPSCC patients of which 73.0% had an oral HPV infection. When stratified by age, sex, marital status and race/ethnicity, the model estimated a higher conditional probability for developing OPSCCs given an oral HPV infection in non-Hispanic White males and females compared to other races/ethnicities. The proposed Bayesian model represents a proof-of-concept of a natural history model of HPV driven OPSCCs and outlines a strategy for estimating the conditional probability of an individual’s risk of developing OPSCC following an oral HPV infection.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The relationship between infection with high-risk human papillomavirus (HPV) and cervical cancer is transforming cervical cancer prevention. HPV tests and vaccinations have recently become available. ...In Ireland, as elsewhere, primary care practitioners play a key role in prevention. ATHENS (A Trial of HPV Education and Support) aims to develop a theory-based intervention to support primary care practitioners in their HPV-related practice. This study, the first step in the intervention development process, aimed to: identify HPV-related clinical behaviours that the intervention will target; clarify general practitioners' (GPs') and practice nurses' roles and responsibilities; and determine factors that potentially influence clinical behaviour. A secondary objective was to informally assess the utility of the Theoretical Domains Framework (TDF) in understanding clinical behaviours in an area with an evolving evidence-base.
In-depth semi-structured telephone interviews were conducted with GPs and practice nurses. The topic guide, which contained open questions and HPV-related clinical scenarios, was developed through literature review and clinical experience. Interview transcripts were content-analysed using the TDF as the coding framework.
19 GPs and 14 practice nurses were interviewed. The major HPV-related clinical behaviours were: initiating a discussion about HPV infection with female patients; offering/recommending HPV vaccination to appropriate patients; and answering patients' questions about HPV testing. While the responsibility for taking smears was considered a female role, both male and female practitioners dealt with HPV-related issues. All 12 theoretical domains arose in relation to HPV infection; the domains judged to be most important were: knowledge, emotion, social influences, beliefs about capabilities and beliefs about consequences. Eleven domains emerged in relation to HPV vaccination, with beliefs about consequences, social influences, knowledge and environmental context and resources judged to be the most important. Nine domains were relevant to HPV testing, with knowledge and beliefs about capabilities judged to be the most important.
The findings confirm the need for an intervention to support primary care practitioners around HPV and suggest it should target a range of theoretical domains. The TDF proved valuable in analysing qualitative data collected using a topic guide not specifically designed to capture TDF domains and understanding clinical behaviours in an area with an evolving evidence-base.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Persistence hunting has been suggested to be a key strategy for meat acquisition in Homo erectus. However, prolonged locomotion in hot conditions is associated with considerable water losses due to ...sweating. Consequently, dehydration has been proposed to be a critical limiting factor, effectively curtailing the usefulness of persistence hunting prior to the invention of water containers. In this study, we aimed to determine the extent to which dehydration limited persistence hunting in H. erectus.
We simulated ambient conditions and spatiotemporal characteristics of nine previously reported persistence hunts in the Kalahari. We used a newly developed and validated heat exchange model to estimate the water loss in H. erectus and a recent Kalahari hunter. Water loss equivalent to 10% of the hunter's body mass was considered the physiological limit of a hunt with no drinking. Our criterion for ruling dehydration out of being a limit for persistence hunting was the ability to hunt without drinking for at least 5 h, as this was the longest duration reported for a successful persistence hunt of large prey.
Our results showed that H. erectus would reach the dehydration limit in 5.5–5.7 h of persistence hunting at the reported Kalahari conditions, which we argue represent a conservative model also for Early Pleistocene East Africa. Maximum hunt duration without drinking was negatively related to the relative body surface area of the hunter. Moreover, H. erectus would be able to persistence hunt over 5 h without drinking despite possible deviations from modern-like heat dissipation capacity, aerobic capacity, and locomotor economy. We conclude that H. erectus could persistence hunt large prey without the need to carry water.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
A cigarette purchase task (CPT) is a behavioral economic measure of the reinforcing value of smoking in monetary terms (ie, cigarette demand). This study investigated whether cigarette demand ...predicted response to contingent monetary rewards for abstinence among individuals with substance use disorders. It also sought to replicate evidence for greater price sensitivity at whole-dollar pack price transitions (ie, left-digit effects).
Participants (N = 338) were individuals in residential substance use disorder treatment who participated in a randomized controlled trial that compared contingent vouchers to noncontingent vouchers for smoking abstinence. Baseline demand indices were used to predict number of abstinent days during the 14-day voucher period (after the reduction lead-in) and at 1 and 3 months afterward.
Demand indices correlated with measures of smoking and nicotine dependence. As measured by elasticity, intensity and O max, higher demand significantly predicted fewer abstinent exhaled carbon monoxide readings during voucher period for individuals in the noncontingent vouchers condition. Breakpoint exhibited a trend-level association with abstinent exhaled carbon monoxide readings. Demand indices did not predict abstinence in the contingent vouchers group, and did not predict abstinence at 1- and 3-month follow-ups. Left-digit price transitions were associated with significantly greater reductions in consumption.
The association of cigarette demand with smoking behavior only in the group for whom abstinence was not incentivized indicates that CPT assesses the value of smoking more than the value of money per se and that vouchers counteract the effects of the intrinsic reinforcing value of cigarettes. Results provide initial short-term evidence of predictive validity for the CPT indices.
This study provides the first evidence of the validity of the CPT for predicting early response to brief advice for smoking cessation plus nicotine replacement in smokers with substance dependence. However, demand for cigarettes did not predict voucher-based treatment response, indicating that incentives serve as a powerful motivator not to smoke that acts in opposition to the intrinsic reinforcing value of cigarettes and that the indices reflect the value of smoking more than the value of money per se.
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BFBNIB, NMLJ, NUK, PNG, UL, UM, UPUK
Abstract
There are currently several validated HPV tests. However, longitudinal data which spans appropriate age ranges, as well as evaluation of potential screening algorithms are necessary for ...screening programmes choice of test. The objective of our study was to evaluate the performance of HPV mRNA and HPV DNA testing, including partial genotyping, in routine cervical screening. As part of the CERVIVA HPV Primary Screening Study, ThinPrep samples from 10 150 women were tested for HPV mRNA using the Aptima HPV assay and HPV DNA using the Cobas 4800 HPV test. HPV mRNA‐positive women were further assessed with the Aptima genotyping assay for HPV 16/18/45. Baseline cytology and prospective follow‐up data were collected. The performance of the two tests was examined over 42 months (to date). HPV mRNA demonstrated equivalent sensitivity to HPV DNA testing for detection of CIN2+ (93.2% 92.4‐93.9 vs 92.8% 92.0‐93.6, respectively) and CIN3+ (94.6% 93.8‐95.3 vs 94.6% 93.8‐95.3). HPV mRNA testing had significantly higher specificity compared to HPV DNA for detection of CIN2+ (84.0% 83.5‐84.5 vs 80.8% 80.2‐81.4, respectively) and CIN3+ (88.44% 88.2‐88.6 vs 85.62 85.4‐85.9). The proportion of CIN2+ and CIN3+, over 3 years (42 months), in HPV‐negative women was comparable for both RNA (0.20% and 0.10%) and DNA (0.22% and 0.11%). Genotyping data was comparable across both assay platforms. In the context of HPV primary screening HPV mRNA testing has potential to reduce triage tests and follow‐up tests at 12 months compared to DNA testing, with no significant difference in detection of CIN2+ and CIN3+.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
9.
Inkjet-like printing of single-cells Yusof, Azmi; Keegan, Helen; Spillane, Cathy D ...
Lab on a chip,
07/2011, Volume:
11, Issue:
14
Journal Article
Peer reviewed
Cell sorting and separation techniques are essential tools for cell biology research and for many diagnostic and therapeutic applications. For many of these applications, it is imperative that ...heterogeneous populations of cells are segregated according to their cell type and that individual cells can be isolated and analysed. We present a novel technique to isolate single cells encapsulated in a picolitre sized droplet that are then deposited by inkjet-like printing at defined locations for downstream genomic analysis. The single-cell-manipulator (SCM) developed for this purpose consists of a dispenser chip to print cells contained in a free flying droplet, a computer vision system to detect single-cells inside the dispenser chip prior to printing, and appropriate automation equipment to print single-cells onto defined locations on a substrate. This technique is spatially dynamic, enabling cell printing on a wide range of commonly used substrates such as microscope slides, membranes and microtiter plates. Demonstration experiments performed using the SCM resulted in a printing efficiency of 87% for polystyrene microbeads of 10 μm size. When the SCM was applied to a cervical cancer cell line (HeLa), a printing efficiency of 87% was observed and a post-SCM cell viability rate of 75% was achieved.
The mortality associated with cervical cancer can be reduced if detected at the precancer stage, but current methods are limited in terms of subjectivity, cost and time. Optical spectroscopic methods ...such as Raman spectroscopy can provide a rapid, label-free and nondestructive measurement of the biochemical fingerprint of a cell, tissue or biofluid. Previous studies have shown the potential of Raman spectroscopy for cervical cancer diagnosis, but most were pilot studies with small sample sizes. The aim of this study is to show the clinical utility of Raman spectroscopy for identifying cervical precancer in a large sample set with validation in an independent test set. Liquid-based cervical cytology samples (
= 662) (326 negative, 200 cervical intraepithelial neoplasia (CIN)1 and 136 CIN2+) were obtained as a training set. Raman spectra were recorded from single-cell nuclei and subjected to a partial least squares discriminant analysis (PLSDA). In addition, the PLSDA classification model was validated using a blinded independent test set (
= 69). A classification accuracy of 91.3% was achieved with only six of the blinded samples misclassified. This study showed the potential clinical utility of Raman spectroscopy with a good classification of negative, CIN1 and CIN2+ achieved in an independent test set.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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