Data from Egyptian studies provide widely varying estimates on the prevalence of pre-malignant and malignant cervical abnormalities and human papilloma virus (HPVs) infection. To define the prevalence and risk factors of pre-invasive and invasive cervical cancer (cacx), a community based full-scale cross sectional, household survey including 5453 women aged between 35 and 60 years was conducted.The study period was between February 2000 and December 2002. Initially, conventional Papanicolaou (Pap) smears were evaluated using the Bethesda system (TBS), followed by colposcopic guided biopsy (CGB) for all epithelial abnormalities (EA). In a third step, HPV was tested on all EA by in-situ hybridization (ISH) using first the broad spectrum HPV probe recognizing HPVs 6, 11, 16, 18, 30, 31, 35, 45, 51 and 52 followed by subtyping with probes 6/11, 16/18 and 31/33. Lastly, unequivocal cases were immunostained for herpes simplex type-2 (HSV-2), cytomegalovirus (CMV), and human immunodeficiency virus (HIV).EA representing 7.8% (424/5453), were categorized into atypical squamous cell of undetermined significance (ASCUS) (34.4%), atypical glandular cell of undetermined significance (AGCUS) (15.3%), combined ASCUS and AGCUS (3.1%), low grade squamous intraepithelial lesions (SIL) (41.0%), high grade SIL (5.2%) and invasive lesions (1%). CGB of EA (n = 281) showed non neoplastic lesions (12.8%), atypical squamous metaplasia (ASM) (19.2%), cervical intraepithelial neoplasia I (CIN) (44.4%), CIN II (4.4%), CINIII (2.8%), endocervical lesions (5.2%), combined squamous and endocervical lesions (10.0%), invasive squamous cell carcinoma (SCC) (0.02%) and extranodal marginal zone B cell lymphoma (MZBCL) (0.02%). The overall predictive value of cytology was 87% while the predictive value for high grade lesions was 80%. On histological basis, HPVs were present in 94.3% of squamous lesions while it was difficult to be identified in endocervical ones. ISH revealed positivity for pan HPV in 65.9% of the studied biopsies (n = 217), with incorporation of the viral genome HPV 6/11, 16/18 and 31/33 in 11.1%, 33.3% and 17.1% respectively. Multiple HPVs infections were identified in 0.02%.Pre-invasive high grade lesions and invasive cervical carcinoma represent 0.5% and 0.04% respectively in Egyptian women. HPV mostly 16/18 as a risk factor (p < 0.001), was frequently associated with mixed infections (p < 0.001) and bilharzial infestation (p < 0.001). In developed countries, with effective and extensive screening with Pap smears, it is usually possible to identify and treat asymptomatic precursor lesions of cacx, making it nearly 100% preventable . Data frIn the present work we looked for HPV and other risk factors -17 in thThis study was the first one to be conducted in Egypt at a National level as community based full-scale cross sectional survey. The main objective was to assess the prevalence of pre-invasive and invasive cacx among Egyptian women aged between 35 and 60 years. Specifically it aimed at assessing the prevalence of biopsy-confirmed squamous, endocervical lesions and invasive cancer, identifying the preventable risk factors and exploring the knowledge and practices of the target population toward cacx screening. Therefore representative data on this problem should permit better evaluation of possible alternative approaches for the design of a national cacx prevention program.The protocol was set up and approved by the funding agency "United States Agency for International Development (USAID) in January 2000. The field work started July 2000 and terminated in December 2002.The prevalence rates used for sample size calculations were chosen based on available data from Egyptian studies and results of recent computer modelling. A computer simulation model of incidence of cacx, based on a low risk population in the United States, suggested that the prevalence of SIL, in a previously unscreened population would be 2–3% among women 35 years old and above. The sample size estimates assume simple random sampling equal to 3012 eligible women. Assuming a design effect of 2 due to cluster sampling, the sample size needs to be doubled to be 6000. The target population was ever-married women aged 35 to 60 years. Women who were pregnant or menstruating at time of tests were excluded.A multi-stage sampling process was used, based on a sampling frame from the Egypt Demographic Health Survey (DHS) 2000 . A samplThe study protocol was approved by the Ministry of Health and Population Ethical Review Board. All women were informed about the procedures of the study, the possibility of abnormalities being found, including cacx and that further invasive procedures may be necessary. Consents were obtained from the women before participation.A total of 153 questions collected data about women's background and relevant risk factors including 1- socioeconomic and general characteristics of women and their husbands, living conditions, lifestyle, marital status, menstrual and obstetric history and use of family planning, 2- current general health problems with special emphasis on schistosomiaisis, 3- gynecological health problems including personal and family history of cacx or other cancers and women and husbands' history of genital tract infections.General clinical examinations and urine laboratory test for schistosomiasis by spotting positive ova were carried out. Problems such as cystocoele, rectocoele, adnexal tenderness, or masses, uterine prolapse, cervical polyps, warts and cervical discharge, were noted and evaluated. Pap smears were taken.Samples from the ectocervix and endocervix were collected using Ayer's spatula and endocervical brush and fixed onto labelled glass slides with cytospray. The cells were classified according to TBS 1991 . Strict All EA were biopsied in an attempt to evaluate the prevalence of low/high grade dysplastic changes and invasive lesions. The received biopsies were left for 24 hours in neutral buffered formalin. Tissue embedding and processing were followed by hematoxylin and eosin (H&E) staining. The presence of bilharzial infestation was evaluated in tissue sections. Serial sections from each biopsy were classified according to the World Health Organization (WHO) for cervical neoplasia . Here alISH for HPVs was effectuated for epithelial lesions starting from ASM. The materials used are summarized in table Immunohistochemistry (IHC) was effectuated for equivocal cases negative for HPV and cases with histological suspicion for infections with HSV-2 or CMV. In these instances, HSV-2, early and late CMV antigens were assessed. For other viral lesions not proven cytologically, histologically or by IHC to be HSV-2 or CMV infection, p24 capsid proteins for HIV was used. In addition, cytokeratin, leucocyte common antigen and CD79a were used to diagnose an extranodal MZBCL. The materials used are summarized in table Lesions were grouped according to histological results into: 1- normal without epithelial changes, 2- ASM, 3- low grade lesions including CINI with or without HPV and EGD alone or combined with either ASM or CINI, 4- High grade lesions including CINII, CINIII/CIS alone or combined with EGD and adenocarcinoma in situ (AIS), and 5- Invasive lesions. A cut-off point of 45 years was used to categorize two aged groups 35–45 and >45–60 years. SPSS version 9 was used for statistical analysis. Descriptive analysis was made of demographic, cytology and follow up CGB data. Cross tabulations with significance tests and Odd Ratio (OR) with 95% confidence interval (CI) were made. Multivariate analysis was carried out to estimate the main determinant risk factors for cacx in the study population.A pilot study was carried out to test methods of obtaining community cooperation and reactions of respondents to the research procedures and their desire to participate. All staff members were trained to ensure standardization of methods. A written operational manual explaining in details how to perform Pap smear and CGB and all staining steps was prepared. Random re-screening of 20% of the Pap smear and all EA was done for every cluster, in addition to the strict criteria used for evaluating abnormal lesions and was assessed by kappa test.Twelve women (0.2%) had a female relative diagnosed as cacx. Less than 2%, mostly from urban areas, had ever had Pap smear with normal results in 77% of them. Only three women mentioned having dysplastic/atypical changes before, however these finding were not documented by cytopathological reports and their Pap smears were normal in the present study. Only 2% could identify smoking, hormones, and infection as risk factors but not HPV.The total number of Pap smears studied was 5658. However, 5453 women with complete data were included in the study (97%). Unsatisfactory results were present in 195 smears (3%), mostly due to absence of endocervical/transformation zone and poor fixation in 66.15% and 16.92% respectively, and were more pronounced in the first three governorates. Two third of the women had inflammatory changes (63%), while epithelial abnormalities were identified among 8%.All the inflammatory smears were associated with reparative changes including reserve cells hyperplasia, early immature squamous metaplastic cells, cells merging to maturation and fully mature cells. This process was more pronounced in association with IUD devices. Three smears showed mature reparative changes only, probably representing post inflammatory squamous metaplasia. The most common infection was bacterial (49%) figure .Epithelial changes were found in 424 women (8%), more commonly among LE women (9%) and less commonly in rural UE (6%); one-third of these cases were among urban governorates residents (p < 0.005). The most common type was LGSIL including HPV infection (41%) . A total of 281 ones (66%) were available. Unsatisfactory biopsies were encountered in 30 cases (10.67%); the most common cause was absence of endocervical tissue in a lesion previously diagnosed as AGCUS (62%), and was more obvious in earlier governorates. The histological results are summarized in table 24 ones. Only one case cytologically diagnosed as ASCUS, was positive for HSV-2. All suspicious cases tested for CMV and HIV infections were negative by IHC. Accidentally, one case positive for leukocyte common antigen and CD79a was classified as extranodal MZBCL.ISH using pan HPV probe tested on 217 cases, was positive among 66%, negative in 29% and non significant in 5% of cases figures . The preRisk factors of ASM were infection with HPV especially subtypes 16/18 and 31/33 and ever usage of vaginal contraceptives (p <0.0001 for each). The risk factors for low grade CIN are still menstruating (p <0.001), working (p <0.0001), HPV infection with the three probes studied 6/11, 16/18 and 31/33 (p <0.000 for each), while for high grade CIN infection, with HPV mainly subtypes 16/18 and 31/33 (p <0.001) was the common threat. Multiple regression analysis revealed that being a working woman  and still menstruating  were the main risk factors.HPVs infection were more pronounced in younger age, actually married, still menstruating and ever used hormonal or vaginal contraceptives (p <0.05 for each), and unskilled workers (p <0.0001). In addition, there was an increasing positivity rate for HPV with increasing lesion severity. Applying multiple regression analysis revealed that being a working woman , still menstruating  and women who ever had hormonal contraception  were the main determinants for HPV infection. HPV infection seemed to be more among women whose husbands ever had another wife or travelled before, however this finding was not statistically significant.HPV has been recognized as the necessary cause of cervical cancer . HoweverASM cases were positive for HPV 16/18 and 31/33. ASM, a poorly characterized cervical lesion with uncertain biological and clinical significance, shares some but not all morphological features of SIL ,44. It hThis community based study confirms previous hospital based one reporting low prevalence rate for CIN; analysis of 4458 patients showed a prevalence of 0.36%, 0.23% and 0.12% for CINI, CINII and CINII respectively . In addiStudies showed significant geographic variation in the prevalence of oncogenic viral types in cervical lesions with roughly half of all cacx worldwide containing HPV 16. Other important high risk types are HPV 18, 45, and 31. Less prevalent high risk types include HPV 26, 33, 35, 39, 51, 52, 56, 58, 59, 68, 73, and W13b . In AfriOur data on schistosomiaisis as risk factor for the development of cacx confirm previous studies in Egypt ,10 and eThe study is limited by the fact that it covers a single period and had no opportunity to examine trends over time. Three obstacles reduced the number of satisfactory smears, noted mostly at the beginning of the study, implying the importance of training. These were, smears not interesting the squamo-columnar junction, inadequate fixation and hemorrhagic smears resulting from traumatisation of the mucosa by the cytobrush. Inadequate biopsies were encountered whenever they were performed in health units using portable colposcope. In addition, women of higher socioeconomic group refusal to participate may have led to missing the chance to describe the pattern of cervical lesions among this group. The drop out of women for CGB was due to their refusal to participate in spite of counselling. Concerning HPVs ISH, two points should be discussed. The first was fixation more than 24 hours in UE specimens, a point that may explain the negativity for all HPVs probes even with the presence of frank HPVs in biopsies. The second was the limited number of tested probes compared to the known HPVs subtypes. Cultural sensitivity for sexual relationships in the Egyptian community in general and among women specifically, made it difficult to get detailed information even with using probing questions for assessing sexually transmitted infections.In conclusion, this study is the first one at a national level describing the characteristics of women with cervical epithelial abnormalities. They were mostly of middle income, married, with three and more children, mostly uneducated and not working. The awareness of the Egyptian women by risk factors or symptoms of different reproductive health problems are extremely low. Prevalence of CIN and invasive lesions was 3.1% and 0.04%, while the prevalence of HPVs was 2.6% and was positive in 94.3% of cervical lesions confirming that it is the main causing agent. The study recommends introducing cacx screening for all women at least once every 10 years for women with normal cytological findings, and yearly for three successive years for inflammatory changes. CGB should be performed to all EA to avoid losing patients and subsequently tumor progression. In addition, raising awareness of Egyptian women on reproductive health and risk factors of cacx through specially designed health communication programs is mandatory.AGCUS: atypical glandular cells of undetermined significance, AIS: adenocarcinoma in situ, ASCUS: atypical squamous cells of undetermined significance, ASM: atypical squamous metaplasia, Cacx: cancer cervix, Chlamydia T: Chlamydia trachomatis, CIN: cervical intraepithelial neoplasia, EA: epithelial abnormalities, EGD: endocervical glandular dysplasia, HGSIL: high grade squamous intraepithelial lesion, HPVs: human papilloma viruses, IHC: Immunohistochemistry. ISH: in situ hybridization, LGSIL: low grade squamous intraepithelial lesion, Pap smears: Papanicolaou smears, TBS: the Bethesda System, SCC: squamous cell carcinoma.HA was the Principal Investigator for Pathology, AR was the Principal Investigator for Data Management and KD was the Principal Investigator for Field Work.


Life-history theory predicts that resource scarcity constrains individual optimal reproductive strategies and shapes the evolution of life-history traits. In species where the inherited structure of social class may lead to consistent resource differences among family lines, between-class variation in resource availability should select for divergence in optimal reproductive strategies. Evaluating this prediction requires information on the phenotypic selection and quantitative genetics of life-history trait variation in relation to individual lifetime access to resources. Here, we show using path analysis how resource availability, measured as the wealth class of the family, affected the opportunity and intensity of phenotypic selection on the key life-history traits of women living in pre-industrial Finland during the 1800s and 1900s. We found the highest opportunity for total selection and the strongest selection on earlier age at first reproduction in women of the poorest wealth class, whereas selection favoured older age at reproductive cessation in mothers of the wealthier classes. We also found clear differences in female life-history traits across wealth classes: the poorest women had the lowest age-specific survival throughout their lives, they started reproduction later, delivered fewer offspring during their lifetime, ceased reproduction younger, had poorer offspring survival to adulthood and, hence, had lower fitness compared to the wealthier women. Our results show that the amount of wealth affected the selection pressure on female life-history in a pre-industrial human population. Life-history theory predicts that resource availability plays a central role in the optimization of individual life-history strategies post-hoc, and partly because of our limited understanding of how natural selection varies in relation to variation in resource availability. Yet, human life-history evolution is not the only research area where information on the relationship between resource availability and the strength of natural selection and trait evolution is needed. Such information is relevant for any species where populations are socially structured or which show temporal and spatial heterogeneity in resource availability, as these factors can lead to differential selection regimes. Currently, we have no data to evaluate how important or general such phenomena are.Among-individual variation in resource availability has been suggested to affect trade-offs between human life-history traits, highlighting the importance of resource availability on human life-history evolution. In general, younger age at first and advanced age at last reproduction as well as the larger number of offspring born has been shown to be the most important components determining female fitness in both historical Sami Poecilia reticulata) In addition to resource-dependent trade-offs, life-history theory predicts that in iteroparous organisms an increase in extrinsic mortality selects for optimal life history that shifts towards earlier reproduction, and higher reproductive effort Previous studies considering how resource availability affects selection in humans have mainly focused on understanding the demographic transition: the association between reduced family sizes with increasing wealth in industrialized countries In summary, earlier studies have documented that resource availability may affect the expression of human life-history traits, and alter the trade-offs between them. Studies have also shown how natural selection may have shaped human life-history traits. Furthermore, recent studies have revealed relatively high heritability of key life-history traits in human populations, including those studied here, suggesting that also rather rapid evolutionary responses may have been possible n = 2038, 22χ = 25.92, P<0.0001, controlling for study parish and birth cohort with a linear model; n = 1289, 21χ = 21.53, P<0.0001) and the Middle-class  families throughout their lifespan, and women from the Rich families had higher survival than women from the Middle-class families  differed significantly between the wealth classes (fec) and longevity (Ilong), suggested similar trends as above between the wealth classes, but these differences were not statistically significant . These analyses showed that age at first and last reproduction and offspring survival to adulthood affected female fecundity differently among the wealth classes, whereas fecundity had similar effects on fitness across the wealth classes . PairwisVariation in maternal life-history traits by wealth class is summarized in 117t = −3.36, P = 0.003, adjusted by Tukey's test) and to the Poor (117t = −4.12 P = 0.0002), but that age at first reproduction did not differ between the Middle-class and the Poor (117t = −1.75 P = 0.2). Age at last reproduction did not differ significantly between the Rich and the Middle-class mothers , but the Poor had their last child, on average, two years earlier than the Rich  and Middle-class women   . Mean ma 60, 9%) , indicatTo our knowledge, this is the first study to show that resource availability influenced natural selection on female life-history traits in pre-industrial humans. In agreement with the life-history theory, the opportunity for total selection, the strength of natural selection on life-history traits, and trait means differed between women belonging to different wealth classes in the studied pre-industrial Finnish populations. We found higher opportunity for selection and stronger selection on earlier age at first reproduction among the mothers of the poorest wealth class compared to wealthier mothers. In contrast, selection favoured older age at reproductive cessation in the mothers of higher resource availability compared to poorer mothers. These results are in line with the prediction that selection should favour early reproductive effort in conditions where mortality is high, as women in the poorest wealth class suffered from the highest age-specific mortality. In the Middle-class mothers selection also favoured longer lifespan more than in the other wealth classes. Compared to the poorer mothers, Rich women started their reproduction earliest, had the highest fecundity and reproductive success and, finally, the highest number of grandchildren born.These results support the previous findings suggesting that parity, together with age at first and last reproduction are among the most important components of fitness in historical women per se. In the Rich wealth class, some noble women  might have also adopted the custom of hiring wet nurses to breast-feed their babies Rich mothers exhibited the highest fecundity and their offspring had the best survival. In many traditional societies unaffected by demographic transition, such as in the Gabbra pastoralists of Kenya, fecundity increases with wealth In contrast to the age at first reproduction, age at last reproduction was under stronger selection in wealthier mothers than in the Poor mothers. That is, the Rich and the Middle-class women gained more fitness benefits through continuing reproduction until older ages than the women in the Poor wealth class. The Poor mothers also delivered their last offspring earlier than the wealthier mothers. Hence, the wealthier mothers had longer reproductive lifespan to bear offspring than the poor mothers. Younger age at reproductive cessation in the Poor women might have however been adaptive, if reproduction in advanced age was especially risky for their health and survival, or if the Poor women achieved their desired family size sooner than other women. Alternatively, earlier age at last reproduction may have resulted from the scarcity of resources among the Poor women, restricting their reproduction into older ages. This conclusion is supported by our data, since the Poor women were not able to reproduce early even though it would have been particularly advantageous for their fitness. On the other hand, the highest correlation found between the age at first and last reproduction was in the Poor mothers, which may also indicate a more pronounced trade-off between early and late reproduction among these women. Finally, younger age at last reproduction may simply reflect the reduced survival of the poorest mothers later in life.Longevity and particularly long post-menopausal lifespan have been found to increase the fitness of pre-industrial mothers Life-history theory predicts that if variation in resource availability is predictable, or depends on age, plasticity of reproductive allocation should be selected for In conclusion, this study provides the first estimates of opportunity for natural selection and the strength of directional selection on several female life-history traits according to the socio-economic status. In line with the predictions of the life-history theory, mothers of the poorest wealth class, who suffered from the highest age-specific mortality, had stronger selection on earlier age at first reproduction than on the age at last reproduction. Instead, selection for later age at last reproduction outweighed selection for earlier age at first reproduction in wealthier mothers. Our results also suggest that low resource availability among the Poor women constrained their ability to maximise fitness, for example, by starting reproduction earlier and increasing offspring survival. Compared to the poorer mothers, Rich women started their reproduction earliest, had the highest fecundity and reproductive success and, finally, the highest number of grandchildren born. Because the ample gene flow between the wealth-classes likely decreased the rate of divergent evolution between the wealth classes, it is also plausible that the phenotypic trait means between the wealth classes differed due to phenotypic plasticity. Nevertheless, our results demonstrate that resource availability was likely to affect the strength of natural selection on life-history traits and had an important role in shaping the life-history evolution of pre-industrial women.th century n  =  704). During the study period these populations depended on farming and fishing for their livelihood The influence of wealth class in modifying selection for female life-history traits was studied using demographic data collected from Finnish population registers of the pre-industrial era. The Lutheran Church has kept census, birth/baptism, marriage and death/burial registers of each parish in the country since the 17th century, covering the whole population of Finland from 1749 onwards. We used demographic data collected from five Finnish parishes  of the 18–19We classified individuals according to their socio-economic status. Because we had no direct knowledge of the actual wealth of the families, such as taxes paid or farm size, and since women at our study period rarely had an occupation of their own, we used a husband's occupation as a reference to wealth and social status of women. We divided women to three wealth classes; rich, middle-class, and poor. The Rich class included noblemen, priests and free farmers, the Middle-class included mainly tenant farmers and craftsmen, while the Poor included servants and dependent lodgers. This categorization was based on the historical studies of Finnish populations Age-specific probability of survival according to the wealth class of the parentsProbability of marriage by the wealth class of the parents for those women who survived to age of 20 yearsAge at first reproduction (AFR), including illegitimate birthsTime in months from marriage date to birth of the first child excluding women who had their first child before marriageFecundity (FEC), the number of children born to a woman during her lifespanOffspring survival (%SURV), the proportion of children born that survived to age of 15 yearsAge at last reproduction (ALR)Lifetime reproductive success (LRS), the number of children who survived to age of 15Longevity (LONG), age at deathNumber of grandchildren bornTraits 3–9 included all women who had at least one child and for whom all studied life-history traits were known (n = 704).We studied the following female life-history traits:We used Cox regression to examine how parental wealth class affected the age-specific survival probability of females 2) on maternal fitness across wealth classes First, we estimated the overall constraint on total selection between the wealth classes by estimating the opportunity for selection  a priori theoretical model  and Middle-class women . Among Poor women only the fit of a priori model was acceptable . This indicates fundamental differences among the wealth classes, and one should not continue by the assessment of parameter equalities to compare path coefficients between groups P>0.05) from the models. Therefore, we estimated the strength of natural selection on female life-history traits separately for each wealth class, using final path models that remained after model reduction. As path coefficients, we present standardized selection gradients to make comparisons between wealth classes meaningful We started the path analysis by estimating the odel see a for eaThe differences of path coefficients between wealth classes were examined by analysing interactions between wealth class and selected path coefficients using general linear mixed models (GLMMs) General and generalized linear mixed models


Sex differences exist for many spatial tasks. This is true for circular vection, field dependence, and perception of veridical vertical with body tilt. However, explanations for these sex differences is lacking in the literature. In this study, we investigated the nature of individual differences in the perception of self-orientation in humans. Male and female participants were asked to identify their Morphological Horizon  in different body orientations relative to gravity  with and without prior whole body rotation.Sex explained the observed differences in the perception of self-orientation only when blood distribution was least altered  and without prior whole body rotation. Specifically, females presented a more footward bias than males in these conditions.These results add to the literature on sex differences for spatial orientation tasks. As the differences were only observed with static conditions and when blood distribution was least affected, we concluded that sex differences in the perception of self-orientation are associated with gravireceptors . The perception of spatial orientation is influenced by visual information and the inertial forces that affect our body. For example, the perception of true vertical is biased by a tilted visual environment ,2 and byWitkin and colleagues reported sex differences in the perception of verticality using the Rod-and-Frame Test (RFT). The RFT requires the participant to orient a rod to the perceived vertical with and without a tilted surrounding frame. Asch and Witkin  observedet al. [Reinking et al.  demonstret al. . Althouget al. ).In males, the utricle, saccule and superior semi-circular canals are significantly larger than in females . As suchThe present study was designed to determine what type of body orientation manipulations mediate sex difference in the PSO with the goal of identifying the type of receptor involved. Perceived morphological horizon (PMH) was measured immediately after a whole body rotation  or while remaining stable in the same orientation , and in different body pitch orientations  . In accordance to previous literature, we anticipated that sex differences in PMH would be observed only when the body orientation is altered, stable, and with the least amount of blood redistribution .F  = 6.63, p < .001 and an interaction between Sex and Condition, F  = 3.82, p < .05  = 5.39, p < .01, which revealed that individuals were more variable immediately after a whole body rotation condition  than in the Upright condition  = 6.91, p < .001. Specifically, participants showed less footward bias in the first trial than in trials five to ten. Likewise, there was a smaller footward bias in the second and the third trial than in trials eight to ten  = 14.13, p < .001 but no effect or interaction involved Sex. As depicted in Figure The constant error analysis for the 135° body pitch conditions yielded a main effect for Condition, F  = 12.28, p < .001. Post hoc analysis of this effect revealed that participants more variable immediately after a whole body rotation condition  than in both the Post-Rotate-135 and Upright conditions. As well, participants were less variable in the Upright condition than in all 135° orientation conditions.The variable error analysis for the 135° conditions revealed a main effect for Condition as in the 45° orientation conditions, F  = 3.54, p < .001, as well as a Condition by Trial interaction, F  = 4.21, p < .001, were observed. Specifically, there were greater footward biases in trials one and two than in trials eight and ten  trials in each condition .Correlation analyses were conducted to determine the relative contribution of sex and three indices of blood volume on PMH. These indices were weight, height, and body mass index. Body mass index is calculated by dividing the mass by the squared height of the participant. On average, females were 1.7 m tall, weighed 61 kg, which yielded an average body mass index of 21.3 kg/mp < .05) in PMH in both blocks of trials of the Stable-45 and the Post-Rotate-45 conditions . More specifically, females presented a greater footward bias than males. Sex did not have a significant impact on perceptual judgements in any of the other conditions. Moreover, sex differences at Stable-45 and Post-Rotate-45 were independent of all blood volume indices.As would be expected from the inferential statistics, sex accounted for a significant amount of variance (r = .48). Note that it is in the Rotate-to-135 condition that both males and females exhibited the largest footward bias. The relationship between body mass index and PMH indicates that people with lower body mass index present larger footward bias than people with higher body mass index. Thus, while the shifts in blood volume were sufficient to create an important perceptual bias in the 135° conditions, they did not contribute significantly to the observed sex effects found in the 45° conditions. Indeed, when body mass index, weight and height were included as covariates in the 45° conditions analyses of variance, they accounted for 6.2%, 0.71%, and 4.15% of the between-participant variability, respectively, and they accounted for 13.4%, 0.27%, and 5.9% of the between-participant variability, respectively, in the ANOVA for the 135° conditions.Interestingly, while our indices of blood volume failed to explain the obtained sex differences in the 45° conditions, body mass index and perceptual bias were significantly correlated in the second block of the Rotate-to-135  . Our reFemales demonstrated a footward bias in PMH when submitted to the 45° conditions  as compared to the Upright condition. Conversely, males were not affected by the sole modification of the direction of inertial forces. Although we did not expect sex differences in PMH in the Rotate-to-45 condition, the correlational analyses for the 45° conditions fully supported our predictions. Indeed, sex explained a significant amount of variance of the PMH biases in the stable 45° body pitch conditions only . These findings indicate that variations in the direction of inertial forces are associated with sex differences in the PMH. Certainly, further investigations in the perception of self-orientation are required to better explain the observed individual differences and further test our anatomical difference explanation . At the Fmax  > 6, p < .05). Thus, stating that the perception of self-orientation – under visually deprived environment and altered vestibular stimulation  – is less biased for males than for females is misleading. Indeed, if the observed sex differences in this type of work stem from of anatomical differences , then tSex differences have been found for many spatial tasks ,22. Our In this study, 20 members of the McMaster community  participated in exchange for a financial compensation ($5). All participants had normal or corrected-to-normal vision and were unaware of the goal of the experiment. The mean age of the group was 21.6 years old (SD = 2.3 years) and all participants but three males and one female participant were right-handed.The equipment consisted of a MH perception device and a body pitch device located in a dark room. The MH perception device first consisted of an arc with a radius of 53.5 cm. In the center, we placed a round smooth manipulandum equipped with a potentiometer and a laser pointer  and a set of carabiners. Spine board straps  were used to stabilize the shoulders and a pair of Velcro straps was used for the feet. An adjustable cervical immobilization collar (Wizloc: Ferno Canada) restricted head movements. The bed was equipment with an 8 cm thick foam mattress for comfort. Two pairs of straps were used to maintain the bed in the appropriate positions.This research has been performed in accordance to the ethical standars set in the 1964 Declaration of Helsinki. Before the experimental session, the participant provided informed consent according to the rules and guidelines of the ethics board of McMaster University. Afterward, the participant was secured to the bed with the above-mentioned pieces of equipment. Two experimenters were required for the experimental sessions. One experimenter manipulated the participant's body orientation by adjusting the bed while the other experimenter collected perceived morphological horizon data.A typical trial was as follows. One experimenter oriented the laser of the manipulandum in a random position. From trial to trial, this position was alternated between upward and downward from objective morphological horizon. Then, the same experimenter gave a "GO" signal to the participant. At that point, the participant was allowed to open her/his eyes and place the laser beam at the PMH. Participants were also asked to keep their eyes still during each trial. The laser beam on the arc was the only source of visual information in an otherwise dark environment. Indeed, we insured that participants could only perceive a single point of light in space during the trials, without any other visual reference available to them during the experiment . The parAll participants were first placed in vertical upright orientation for 10 trials. Then, participants were asked to perform 10 trials at the 45° and 135° orientations preceded by a 90 s period . It is important to note that only supine  pitch orientations were used in this experiment. The starting position was counterbalanced across participants but only the start with Stable-45 condition is described here . This condition was followed by a 90 s waiting period followed by another 10 trials in the same orientation (Post-Rotate-45). Then, the same sequence was performed going to the 135° position (Rotate-to-135 and Post-Rotate-135).Altogether, the set of conditions combined PMH measurements with and without whole body rotation prior to the trials. This occurred both without (45° conditions) and with (135° conditions) unusual blood distribution . As wellAs the literature on sex differences in spatial orientation tasks does not typically involve whole body rotations and unusual blood distribution, we hypothesized that sex differences in PMH would be observed only in the Stable-45 and Post-Rotate-45 conditions. Such a result would provide some support for our "hardware" hypothesis, which stipulates that sex differences in the perception of spatial orientation stem from differences in utilizing afferent information from the otoliths .We calculated the constant error (CE) and variable error (VE) in degrees from the spatial error measures and performed separate analyses of variance for each experimental orientation . Thus, separate 2 Sex  by 4 Condition  mixed analyses of variance were conducted. As well, in order to test for trial to trial adaptation, we also performed two separate 2 Sex by 4 Condition by 10 Trials (1–10) mixed analyses of variance on the error observed on each trial. For an unknown reason, the cervical collar was not properly fitted to one of the males and moved during testing. Not surprisingly, the data of that participant presented variability greater than two standard deviations from the average variability of the group and were removed from the analyses.LT and DE participated in the design of the study, performed statistical analyses, and worked on the drafting of the manuscript. Only LT performed data collection and reduction. All authors read and approved the final manuscript.


Chlamydiatrachomatis or herpes simplex virus. Most HPV infections arecleared by the immune system and do not result in clinicalcomplications. Clinical sequelae in cases of low-risk HPVinfection consist of genital warts, and clinical manifestations ofhigh-risk HPV infection include abnormal Pap test results,low-grade squamous intraepithelial lesions (LSIL), high-gradesquamous intraepithelial lesions (HSIL), and cervical cancer.LSIL, HSIL, and cervical cancer carry significant morbidity and/ormortality; genital warts and abnormal Pap test results are oftensignificant sources of psychosocial distress. Currently, there areneither effective means of preventing HPV transmission nor curesfor clinical manifestations: infection can only be prevented viacomplete sexual abstinence, while treatment for clinical sequelaesuch as genital warts and cytologic abnormalities consists ofremoving the problematic cells and watching for recurrence; thismethod consumes significant health care resources and is costly.New prophylactic HPV vaccines promise to dramatically reduce theincidence of HPV infection, genital warts, and cytologicabnormalities. Human papillomavirus (HPV) is the most common newly diagnosedsexually transmitted infection in the United States. Although themajority of sexually active adults will be infected with HPV atleast once in their lives, it is sexually active women less than25 years of age who consistently have the highest rates ofinfection. Besides youth and gender, common risk factors for HPVinfection and clinical sequelae of infection include high numberof sexual partners and coinfection with  Human papillomavirus (HPV) is a significant source of morbidityand mortality in the United States and worldwide. High-risk,oncogenic HPV types (including HPV 16 and HPV 18) are associatedwith 99.7% of all cervical cancers, as well as low-gradesquamous intraepithelial lesions (LSIL), high-grade squamousintraepithelial lesions (HSIL), and abnormal Papanicolaou (Pap)test results, which carry significant health care costs andpsychosocial morbidity. Low-risk HPV types (HPV 6 and HPV 11) areresponsible for additional abnormal Pap test results, as well asalmost all cases of genital warts. HPV is so common that more thanhalf of all sexually active adults will be infected in theirlifetime, although young, sexually active women bear the brunt ofboth infection and clinical complications. Currently there areneither effective HPV prevention strategies nor good treatmentsfor individuals with genital warts or cervical lesions; availabletreatments focus on removing the affected area, and recurrence iscommon. Prophylactic vaccines will soon become available, andpromise to significantly reduce the morbidity and mortalityassociated with these infections.Approximately 6.2 million new HPV infections occur every year inthe United States, and approximately 20 million individuals arecurrently infected . HPV is HPV 16 alone is linked to more than 50% of all cervical cancers[Sexual activity is the primary risk factor for HPV infection, butcondoms, although effective at preventing the spread of many othersexually transmitted infections, may not prevent all HPVinfections. A meta-analysis of more than 20 trials investigatingthe role of condoms in HPV transmission and the development ofclinical complications concluded that, although condoms do notprotect against cervical infection, they may offer some protectionagainst HPV-associated disease. Specifically, although there isconflicting evidence as to whether condom use protects against CIN2/3, condoms may protect against cervical cancer . ArecenHPV is a small DNA virus with a genome of approximately 8000 basepairs . HPV tarThe degree of expression of HPV E6 and E7 is highly correlatedwith the type of cervical lesion: in low-grade lesions, E6 and E7are expressed at low levels in the basal cells and higher levelsin the upper layers of the epithelium, whereas in high-gradelesions E6 and E7 are expressed at high levels throughout theepithelium . In low-HPV infection, unlike many genitourinary infections, is notusually associated with immediate symptoms such as itching,burning, and vaginal discharge . Rather,C. trachomatis infection are also associated withcervical cancer. Smith et al performed a pooled analysis thatfound prior exposure to HSV-2 was associated with 2-fold increasedrisk of squamous cell carcinoma of the cervix in patients with HPV[C. trachomatis infection is associated with a similarlyincreased risk of squamous cell carcinoma[C. trachomatis infection is also associated with morepersistent HPV infection, which may contribute to the increasedrisk of clinical complications of HPV infection in individualscoinfected with C. trachomatis [A number of factors are associated with an increased risk ofinitial infection and/or clinical sequelae such as genital warts,CIN or invasive cancer. Individuals who smoke are more likely todevelop cancer, and it is thought that smoking increases thelikelihood of developing SIL . Herpes with HPV; C. tracarcinoma.C. tracchomatis .3 counts are associatedwith both incident and persistent HPV infection, although theassociation with incident infection is stronger [Immunosuppressed and HIV positive individuals are at a high riskof both HPV infection and HPV-associated disease. High HIV RNAlevels and CD4 < 200 cells per mmstronger . Amongwstronger .Data coSteps that occur from initial infection leading to the developmentof cancer include overcoming host immune resistance, possibleintegration of HPV DNA into the host genome, and accumulation ofadditional mutations within the infected host cell . HPVmusThe strong correlation between infection with high-risk types ofHPV and LSIL, HSIL, and cervical cancer suggests that HPV DNAtesting would be a useful tool for the management of women withabnormal Pap test results, especially in the case of those withequivocal test results. In the case of an equivocal Pap testresult, HPV DNA testing can help determine whether the individualshould be referred for colposcopic assessment .HPV is one of the most common infections of the female genitaltract, and it is also one of the most costly. HPV-associatedhealth care costs include routine Pap tests, treatment of genitalwarts, follow-up of cytological abnormalities, and management ofcervical malignancies. An observational study of the KaiserPermanente health plan found that the annual cost of screening andtreatment of HPV-related cervical neoplasia was $26,415 per1000 women, with nearly 2/3 of that  attributable toroutine screening . AnotherCurrently there are no good methods for preventing HPV infection.Nor are there comprehensive and effective treatments for theclinical consequences of infection: for both genital warts andlesions, management entails removal of discrete lesions andmonitoring for recurrence. Prophylactic HPV vaccines that conferprotection against both high- and low-risk HPV types are expectedto substantially reduce the burden of HPV-associated disease. Abivalent vaccine formulated to protect against the two mostcommon high-risk HPV types, 16 and 18, and a quadrivalent vaccinethat will protect against HPV 16 and 18, and the two most commonlow-risk types, HPV 6 and 11, are in ongoing clinical testing.Phase 2 data suggest that both vaccines are safe, are capable ofproducing immune responses in orders of magnitude larger thanthose produced in the wake of a natural infection, and are morethan 90% effective at preventing persistent HPV infection andthe clinical manifestations of HPV infection; recent phase 3 datasuggest that the quadrivalent vaccine may be 100% effective atpreventing HPV 16/18-associated disease –27.The vast majority of sexually active men and women will becomeinfected with HPV. Although the host immune system successfullyclears most of these infections, some women will develop fulminantdisease such as genital warts, cervical dysplasia, and invasivecervical cancer. Current treatment options are not curative;therefore, preventative vaccines that lower the incidence of HPVinfection and its associated diseases may offer a promisingalternative to current therapies.


The aim of this study was to assess whether qualitative or semi-quantitative detection of human papillomavirus type 16 (HPV 16) can help to identify women with major grade cervical intraepithelial neoplasia (CIN 2 and CIN 3) among those referred with a smear suggesting mild dyskaryosis. The study population consisted of 200 women sequentially attending the Royal Free Hospital colposcopy clinic. All women were investigated by cytology, colposcopy and, where appropriate, histopathology, and HPV 16 DNA was detected in cervical scrape samples using the polymerase chain reaction (PCR). A final clinical diagnosis of normal, wart virus infected (WVI), CIN 1, CIN 2 or CIN 3 was made in 179 women. On the basis of the qualitative PCR data, the presence of HPV 16 DNA was of borderline use in identifying women with high grade cervical disease . However, semi-quantitative PCR analysis showed that a high/medium HPV 16 result was significantly associated with high-grade disease . Furthermore, semi-quantitative PCR and cytology were performed on the repeat smear taken immediately prior to colposcopy. The combined laboratory results show that 53/60 women with biopsy proven high-grade disease were identified, as were 26/95 women who were either normal or who had low grade cervical disease. The possibility of using such an approach for selecting women for more rapid or for routine colposcopy appointments in the two groups respectively is discussed.


A total of 8,427 women with breast cancer with height and weight measured prior to the diagnosis were followed up for on average 4.3 years. 2,383 women died from breast cancer and 430 from other causes. Among women diagnosed without any metastasis (stage I) the death rate was 1.70 times higher for those belonging to the highest quintile of body mass with respect to age compared to those in the lowest quintile. For patients with involved lymph nodes at diagnosis (stage II) the death rate was 1.42 times higher. Overweight was not a prognostic factor for stages III and IV patients. The prognostic effect of body mass in stages I and II was mainly connected to those in the highest quintile and was found for women in pre- as well as post-menopausal age. The effect did not depend on the length of time between measurement and diagnosis. Height was not found to be of prognostic relevance. The idea of the feasibility of a dietary trial in terms of the minimum trial size is given.


The relationship between c-erbB-2 gene expression , S-phase fraction (SPF) and prognosis has been analysed in 172 women with primary breast cancer. c-erbB-2 staining was independent of age, tumour size, number of nodes involved, tumour grade and DNA ploidy, but was more common in oestrogen receptor (ER) negative tumours (P = 0.02) and progesterone receptor (PgR) negative tumours (P = 0.03). A weak correlation between c-erbB-2 staining and SPF was observed (r = 0.18). Amongst women with node negative disease, SPF was significantly related to relapse free survival  while c-erbB-2 staining was not (P = 0.2). In contrast, both SPF (P = 0.002) and c-erbB-2 staining (P = 0.016) provided significant prognostic information on RFS for women with node positive disease. Multivariate analysis showed that c-erbB-2 staining and SPF gave independent information on RFS for women with node positive disease.


Chlamydia trachomatis (CT) is the most common cause of bacterial sexually transmitted infection (STI) worldwide, but current data concerning the prevalence of CT among women in Iran is scarce. Data regarding the frequency of CT infection among Iranian women can help to justify the implementation of a national CT screening program that can reduce the high morbidity associated with sequelae of CT infections by treating infected women. Endocervical secretions from 123 married women (20–55 years) with cervicitis were tested by a PCR-EIA method using primers to amplify a CT-specific plasmid. The digoxigenin-labeled amplicon was measured by hybridization to a biotin-labeled probe and a strepavidin-coated plate, followed by an enzyme-linked colorimetric analysis. Overall frequency of CT infection among women was 17% (21/123). The range of CT frequency among various age groups was 12–25%. The 31–40-year-age group comprised the majority (49%) of CT positive samples, followed by 20–30 year group (33%). Although the 20-to-30-year-old women reported the highest frequency of STI history, they had the lowest relative frequency of CT infection (12%). There is a high frequency of CT infection among women with cervicitis in Tehran, Iran, thus indicating a necessity to implement a routine CT screening program in the major cities of Iran and possibly nationwide. Identification of CT-infected women may prevent its spread, and thereby reduce the high morbidity associated with CT infections among women in Iran. Chlamydia trachomatis (CT) is the most common cause of bacterial sexually transmitted infections (STI), with millionsof cases reported annually throughout the world [e world . Mostgee world , 3. Earle world , 5. RegrμL ofphosphate buffered saline and the fluid was stored at−20°C. DNA was extracted from 100 μL of theendocervical sample fluid using the DIAtom Prep100 kit  and was stored at −20°C until used.A total of 123 married women (aged 20–55 years) with symptomaticcervicitis participated in this case series study. Participantsvisited the obstetrics and gynecology section of Mirza KouchekKhan Hospital in Tehran, Iran, between December 2004 to June 2005,primarily complaining of pelvic pain and/or vaginal discharge. Allwomen who received antibiotic treatment within three weeks priorto their visit were excluded from our study. Consentingparticipants completed a questionnaire before cervical examinationin which they were asked for demographic data and any STI history. Cervical examination included theevaluation for the presence of mucopurulent endocervicaldischarge, friability, and ectropin. After removing cervicalmucus, samples of the endocervical canal secretions were collectedon two cotton swabs, which were washed in 500 C. trachomatis) was amplified through 30 cycles in25 μL PCR reaction buffer ; 0.2 mmol/L each of dATP, dGTP, dCTP,and dTTP; 2.5U Taq DNA polymerase; and0.5 μmol/L primers for conserved plasmid nucleotidesequences of C. trachomatis (This method has been described in detail elsewhere . Brieflychomatis .C. trachomatis PCR products in amicrotiter-based enzyme immunoassay (PCR-EIA). Briefly,10 μL of amplicon was denatured with 20 μLNaOH and incubated at room temperature (RT), and after10 min, 220 μL of hybridization buffer containing10 pmol of the 5′ end biotin-labeled CT-specific internaloligonucleotide probe (complementary to the primers) was added.The amplicon was hybridized in solution for 30 min at54°C, and the mixture was added to a strepavidin-coated96-well microtiter plate. Using a hybridization-based EIA , 200 μL of 1 : 100 dilutedperoxidase-conjugated antidigoxigenin IgG was added to each well,incubated for 30 min at 37°C. After the wash (5X),200 μL of the ABTS substrate solution was added, and theplate was incubated for 30 min at 37°C. The opticaldensity (OD) of the samples was measured by spectrophotometry at405 nm absorbance (reference filter: 492 nm). The PCR-EIArun was considered valid if (−) control OD values were <0.1,and the PCR positive control value was >1.0. The background ODvalue was 0.055, calculated as the mean of all (−) controlsamples plus 3 standard deviations (SD). A sample was considered(+) if its OD value was greater than the background cutoff valueby threefold . The mean OD value of CT positivecontrol samples was 1.81 ± 0.789.The amplicon was measured by the detection ofdigoxigenin-labeled C. trachomatis infection among all four age groups of married women studied.Overall, 17% (21/123) of the specimens were positive forchlamydial DNA by the PCR-EIA assay. The CT infection frequencyrate ranged from 12% to 25% among the patient age groups of patients reported to have STI history.Interestingly, even though the youngest group (20–30 years) inour study reported the highest adjusted rate of STI history 35%(20/57), these women showed the lowest (12.3%) adjustedfrequency of CT infection with . With thThe 17% frequency rate of CT genital infections among marriedwomen in Iran is in contrast with the 7% rate previouslyreported from Iran in the early 1980s , 8–11. TC. trachomatis to susceptible individuals and avoid severecomplications that eventually develop in older women. Initially,screening programs may focus on patients visiting the infertilityor STI clinics in large cities of Iran and can later expand tocover the symptomatic as well as asymptomatic CT-infected womenthroughout the country.Our findings highlight the need for routine CT screening,particularly among Iranian women aged <40 years, for earlydetection of genital chlamydial infection to reduce the morbidityassociated with sequelae. It has been shown that the level ofchlamydial cervicitis decreases quickly in countries where routinescreening for CT has become mandatory [We acknowledge that our results would have been enhanced by alarger sample size as well as additional demographic andbehavioral data  which would haveallowed for advanced data analysis. Overcoming obstacles, whichhinder studies like ours, such as the social stigma associatedwith patients visiting the STD clinics plus increasing the numberof women's health centers offering diagnostic services formanagement of CT cervicitis can make a significant impact onwomen's reproductive health by preventing the long-term sequelaeassociated with PID , 13. NevTo the best of our knowledge, this is the first report from Iranthat provides current data regarding frequency of genital CTinfection among married Iranian women with cervicitis, and may beparticularly helpful to physicians treating such patients in Iran,where the quality of women's health care requires drasticimprovement.In conclusion, the high frequency of CT genital infections amongmarried women in Iran warrants a comprehensive study to screen alarge number of women suffering from chlamydial infection, thusallowing for better estimates of the real magnitude of thereservoir of asymptomatic CT infections among Iranian women. Inlight of studies that have shown chlamydial genital infectionswhich can serve as biological cofactors for thetransmission of the human immunodeficiency virus (HIV)–17, and


Retrovirology publishes the meeting abstracts from the 10th annual Institute of Human Virology conference held August 29th to September 2nd, 2005 in Baltimore, Maryland, USA. In this editorial, the rationale for publishing meeting abstracts is discussed.This month  This compilation of meeting abstracts, as with all other items published in Retrovirology, will be listed in PubMed, indexed in MedLine, and permanently archived in PubMed Central. The IHV abstracts will be available for all to read in an unrestricted "Open Access" manner. This latter privilege is important because fully two-thirds of the users of free and open data bases such as PubMed are in fact not academics. The users may be patients, students, teachers, or healthcare professionals; and they would be barred from information-access by a fee-based format.To celebrate the 10Retrovirology, our experience with publishing meeting reports [Retrovirology 3668 times over the past 14 months. A separate report of the 2005 Twelfth West Coast Retrovirus meeting [et al. [Retrovirology meeting abstracts.Is there value to publishing Meeting Abstracts? On several levels, the answer appears to be "yes". While the IHV abstracts are the first of its kind for  reports -5 tells  reports , a meeti [et al. . Because [et al. . MoreoveLet me close this writing by telling you a personal anecdote which illustrated for me why archiving of meeting abstracts is important. In the early 1980's, I was a graduate student working in one of three laboratories worldwide which were competing on the cloning and the characterization of the cytomegalovirus (CMV) immediate-early (IE) promoter. This is the same CMV promoter that is resident in the many mammalian expression vectors which most of you purchase commercially. My memory tells me  that between 1981 to 1984, I made several presentations on CMV promoter research at the then annual Herpesvirus meeting held at Cold Spring Harbor. Later, in 1990, a patent for the use of the CMV IE promoter was filed by a competitor's group. Many years passed, until approximately five years ago when I unexpectedly received a telephone call from a patent attorney at a high-priced law firm in New York City. The attorney represented a biotech firm which was keen on contesting the issued CMV IE patent. The attorney wanted to know "What did I say publicly about my CMV IE promoter research at meetings?" "And when did I say them?". I recall at that moment when confronted to recall accurately minute historical details critical to a legal contest, I wished fervently for the existence of an open access, easily searchable, repository of meeting abstracts.Retrovirology is committed to the goal of free public access to permanently archived digitally formatted scientific information. Meeting abstracts published in Retrovirology are initially viewable online in our journal, and are then permanently deposited into the PubMed Central archive. Retrovirology is currently accessed ~1,000 times daily. If you are a meeting organizer interested in the rapid and broad dissemination (with permanent archiving) of the presentations from your conference, it may be worth your while to consider publishing your meeting in Retrovirology.


PLoS Medicine in which the researchers used a mathematical model to assess the effect of sexual transmission of HPV 16 in a Finnish population.Kim discusses a study by Barnabas and colleagues in Over the next few years, we can expect to see the licensing of one or more prophylactic vaccines against human papillomavirus (HPV) infection, considered a necessary precursor to cervical cancer. Among over 40 known types of HPV, 15 have been identified as being “high risk” or oncogenic. The vaccines will likely target at least two of these oncogenic types, HPV types 16 and 18, which have been found to contribute to nearly 70% of cervical cancer cases worldwide—although there is large variation in contribution by geographic region . AlthougPLoS Medicine, Barnabas and colleagues present a particular type of mathematical model known as a dynamic model to directly assess the effect of sexual transmission of HPV type 16 in a Finnish population [Mathematical models can be useful tools in exploring disease trends and health consequences of interventions in a population over time. In the case of cervical cancer, in which the time from acquisition of HPV infection to development of invasive cancer can be two decades or more, models can be used to translate short-term findings from vaccine trials into predictions of long-term health outcomes . In a neulation . This moThe model itself, although technically complicated, is conceptually straightforward when broken down into its vital parts. Adult men and women were modeled separately, and in the model they formed partnerships over time based on sexual history data from Finnish adults within the period of 1971–1999. HPV type 16 is transmitted between men and women in sexual relationships at a rate that is dependent on the prevalence of HPV 16 in the population, as well as on age and sexual activity level; women infected with HPV 16 can further develop precancerous lesions and invasive cervical cancer (ICC).Models can be used to translate short-term findings from vaccine trials into predictions of long-term health outcomes.As a general rule, not all parameters in a model are known, which requires adjustment  of model inputs to observed outcomes. One of the biggest unknowns in Barnabas and colleagues' model was the transmission rate of HPV 16 between partners. Since we cannot observe transmission per partnership directly, the authors calibrated this parameter using a maximum likelihood–based approach, which, in simple terms, derives an estimate of this parameter that achieves the best model fit to the observed HPV seroprevalence data from Finnish women. Borrowing other model inputs from previously published models ,12, theIn estimating the transmission rate of HPV 16 between men and women, the authors found that the model underestimated the empirically observed seroprevalence of HPV 16 when they assumed the same rate of partner change as reported in the Finnish surveys. Consequently, they explored the effects on the model of increasing the number of new partners per year, and derived a transmission rate of 0.6 per partner after doubling the reported rate of sexual partner change, and 0.4 after assuming that the number of reported lifetime partners is actually the number of new partners per year.Neither changes in sexual behavior nor smoking patterns were found to contribute substantially to the rising trends in HPV 16–associated cervical cancer over time for 35- to 39- year-old women. But the authors assumed only a one-time shift in age of sexual debut and in number of partners in the model, and assumed that smoking patterns of women were relatively constant from the late 1970s through the mid-1990s, as suggested by the empirical data. The authors note that other risk factors such as oral contraceptive use and parity may contribute to the changing patterns of incidence over time, but these were not included in the model.For the most part, the analyses evaluating vaccination policies showed intuitive results: vaccination of both men and women has a small incremental benefit compared with vaccination of women alone; vaccine benefit decreases as age at vaccination—after sexual debut—increases; and a shorter duration of vaccine-induced immunity is shown to be associated with higher cancer incidence, particularly if waning immunity coincides with higher rates of persistent infections among older women. When vaccine protection is assumed to be lifelong, cytology-based screening is predicted to add little benefit to vaccination alone, but the outcome reported is for ICC associated with HPV 16 only. It is important to bear in mind that even under the most favorable conditions of vaccine coverage, efficacy, and duration, some form of screening will likely be necessary to reduce ICC associated with the 13 or more other oncogenic HPV types not targeted by the vaccine.This model represents an impressive step forward in the simulation of HPV transmission and in the exploration of the effects of risk factors and vaccination over time. However, the conclusions drawn from this analysis should be interpreted with an appreciation of the model's limitations. Most obviously, the model in its current form reflects HPV infection and cervical cancer associated with only a single HPV type. Therefore, the model cannot provide a comprehensive picture of cervical cancer over time after the introduction of vaccination; indeed, another 30% of cervical cancer cases (and more in some regions of the world) are caused by oncogenic HPV types other than type 16. And while the potential for cross-protection or cross-reactivity among HPV types seems plausible, this potential cannot be explored using a single-type HPV model such as this one.Furthermore, the authors conclude that the transmission probability per partnership lies above 0.4, which is based on the extreme assumption that the number of new annual partners is equivalent to the number of reported lifetime partners. While there are known biases in sexual behavior survey data, this value of per-partner transmission relies on many other uncertain parameters and assumptions in the model. Assumptions such as lifelong acquired immunity, where women are no longer susceptible to repeat infections after initial infection and clearance, are acknowledged by the authors to affect the estimated HPV 16 transmission probability, but are not explored in the analysis. Holding all else constant, we would expect to see the transmission probability decrease below 0.4 if the assumption of lifelong acquired immunity is relaxed. Lastly, trends in sexual behavior as well as other risk factors will differ in other settings, meaning that Barnabas and colleagues' findings are not generalizable to other settings. The model itself, however, may be used for analyses in other countries, but preferably after a recalibration of the model using available country- or region-specific data.We can anticipate better data on the longitudinal nature of HPV infections, including immunity and interactions among multiple types and even the transmission rate of HPV among partners. In the meantime, models such as the current one can be valuable tools for exploring the impacts of known risk factors in the cervical carcinogenesis pathway for a single HPV type and for gaining insights into hypothetical scenarios of efficacy, duration, and long-term impact of type-specific vaccination. 3


Although it is not difficult for state-of-the-art gene finders to identify coding regions in prokaryotic genomes, exact prediction of the corresponding translation initiation sites (TIS) is still a challenging problem. Recently a number of post-processing tools have been proposed for improving the annotation of prokaryotic TIS. However, inherent difficulties of these approaches arise from the considerable variation of TIS characteristics across different species. Therefore prior assumptions about the properties of prokaryotic gene starts may cause suboptimal predictions for newly sequenced genomes with TIS signals differing from those of well-investigated genomes.E. coli and B. subtilis. Regarding genomes with high G+C content, in contrast to some previously proposed methods, our algorithm also provides good performance on P. aeruginosa, B. pseudomallei and R. solanacearum.We introduce a clustering algorithm for completely unsupervised scoring of potential TIS, based on positionally smoothed probability matrices. The algorithm requires an initial gene prediction and the genomic sequence of the organism to perform the reannotation. As compared with other methods for improving predictions of gene starts in bacterial genomes, our approach is not based on any specific assumptions about prokaryotic TIS. Despite the generality of the underlying algorithm, the prediction rate of our method is competitive on experimentally verified test data from On reliable test data we showed that our method provides good results in post-processing the predictions of the widely-used program GLIMMER. The underlying clustering algorithm is robust with respect to variations in the initial TIS annotation and does not require specific assumptions about prokaryotic gene starts. These features are particularly useful on genomes with high G+C content. The algorithm has been implemented in the tool »TICO«(TIs COrrector) which is publicly available from our web site. Recent publications have shown that gene prediction in prokaryotes is still a challenging problem in bioinformatics. While existing gene finders -3 are liIn order to cope with this insufficiency of conventional gene finders, several methods have been proposed for improving the predictions of prokaryotic TIS. Common approaches require prior knowledge about the characteristics of the ribosome binding site (RBS) as achieved by analysis of the 16SrRNA or by some supervised method for inferring model parameters from sequences of known gene starts -9. In coEscherichia coli K-12. In the present paper we give a detailed description of the underlying algorithm and we provide a thorough evaluation of the method on a significantly enlarged set of genomes. In particular, we present a detailed comparison with three other tools for improving predictions of prokaryotic TIS. In addition, we present an extension of the algorithm for automatic adaptation of a smoothing parameter which had to be specified by the user in the first version of »TICO«. The results indicate that, despite its generality, our algorithm yields overall good performance, which also involves predictions on the high-G+C genomes we tested.We recently introduced the tool »TICO« (TIs COrrector) for improving the results of conventional gene finders. TICO is based on a very general model which does not involve any parameters for representing specific characteristics of translation starts. In a previous publication  we descrstrong and weak candidates, respectively. Each of the two classes is represented by an inhomogeneous second order probability model. The position-dependent probabilities are estimated from the trinucleotide occurrences in the proximity of potential start sites. In order to cope with vanishing probabilities, we apply positional smoothing    with N-tE. coli genome we also studied the performance of our method on the genome of Bacillus subtilis, Pseudomonas aeruginosa, Burkholderia pseudomallei and Ralstonia solanacearum. Among these species the last three ones are known to have high-G+C genomes with a G+C content exceeding 66%. For Bacillus subtilis [GenBank:NC_000964]  , we usedrt sites ,8. Additlodurans . The vergy (CTB)  at Pekinublished  the analublished  in orderBurkholderia pseudomallei strain K96243 chromosome 1 [GenBank:NC_006350] and chromosome 2 [GenBank:NC_006351] [Ralstonia solanacearum chromosome [GenBank:NC_003295] and megaplasmid [GenBank:NC_003296]   with a G_003296]  with a Gnstitute . The Genanalysis . The Genanalysis , expliciB. subtilis, P. aeruginosa, B. pseudomallei and R. solanacearum have not been verified experimentally, even though, in many cases the gene products are well characterized or gene starts have been annotated manually.Note that the TIS locations of We first study the performance of our method, using the automatic adaptation of the smoothing parameter, as described in the previous sections. The corresponding cross-validation procedure (see section »Automatic Adaptation of the Smoothing Parameter«) has been implemented as an extension of the tool TICO  where itE. coli, GLIMMER2.02 found 846 (99.1%) of the 854 verified genes in EcoGene. For these 846 detected genes only 63.2% of the predicted TIS locations were correct. Using TICO for post-processing of the GLIMMER predictions, this rate was increased by 31%. Also for B. subtilis we achieved a considerable improvement of the initial GLIMMER prediction with a resulting increase of 28.1%. The improvement for the high-G+C genomes was not as large for all species. While for P. aeruginosa we still achieved an increase of 27.4%, the improvement for R. solanacearum was 23.4% (chromosome) and 21.2% (plasmid), respectively and for B. pseudomallei it was 16.4% (chromosome 1) and 18.1% (chromosome 2), respectively. These rates show that our method provides a valuable tool for the annotation of prokaryotic genomes. Because the underlying algorithm performs in a completely unsupervised manner, it especially applies to the case where no knowledge exists about the signals, initiating the translation. Obviously, this situation is usually encountered for newly sequenced genomes. Another problem, well-suited for the application of our algorithm, is the reannotation of published genomes. As mentioned above, the annotation of many genes is based on results obtained from conventional gene finders. Therefore, the annotation of the TIS locations is likely to contain errors. Comparing the GenBank annotation of E. coli K-12 with the experimentally verified data from the EcoGene dataset, only 89.8% of these TIS are annotated correctly. We initialized our algorithm with the GenBank annotation and could increase the accuracy of the TIS annotation to a rate of 95.1% correct sites.With respect to the genome of σ), TICO also allows the user to specify the degree of smoothing manually, like in the first version of that tool [σ = 0.1, 0.15, 0.2, ..., 2.0. The prediction performance was measured on the corresponding test sets as described above. The resulting prediction rates are shown in figure Ralstonia, Pseudomonas and Burkholderia. For sigma-values above 1.5 an »over-smoothing« effect becomes apparent for all genomes.As an alternative to the automatic adaptation of the smoothing parameter sigma (hat tool . In ordeE. coli the difference was negligible with rates 94.3% (σ = 0.5) and 94.2% (σ = 0.45) for user and automatic mode, respectively. For B. subtilis the best rate (84.4%) and sigma (σ = 0.45) were the same in both cases. Also for P. aeruginosa the corresponding rates were identical, with the best user-selected sigma (σ = 0.6) slightly above the automatic selection (σ = 0.55). The only deviation which is noteworthy at all, we observed for R. solanacearum on the plasmid with rates 71.0% (σ = 0.6) and 70.1% (σ = 0.45) for the user and automatic mode, respectively. In that case, the automatic selection seemed to result in a slight under-smoothing. In all other cases the difference between rates was at most 0.3%. Comparing the small differences between the best-case user selection and the automatic selection with those differences which can be obtained for a worst-case user-selection . With the default setting, in the latest version of TICO this parameter is adapted automatically (see section »Automatic Adaptation of the Smoothing Parameter«).In contrast, our method does not require any specific model assumptions about prokaryotic TIS. Only rather general assumptions about the TIS relocation problem can be found to be implemented in the default values of TICO. These defaults concern the search range for alternative TIS around the initial predictions and the size of the sequence window for scoring the TIS candidates. We would like to point out that this kind of assumptions can be found in all post-processors considered here and that these assumptions should be distinguished from assumptions about TIS related sequence content features. These specific assumptions which can be found in other post-processors as indicated above, have been avoided in TICO because they may not hold across different species with different sequence characteristics. Therefore our algorithm performs without any specification of parameters concerning the composition and location of SD motifs or the usage of start codons. This is of particular importance for genomes with a lower information content in the SD motifs, as is usually the case in high-G+C genomes . FurtherE. coli and B. subtilis. With respect to the rate of correctly predicted TIS from the reference set, the maximum difference between these tools is 3.9%. The improvement of the GLIMMER-prediction is at least 26.6%. The rates achieved by RBSfinder are about 10% below the results of the former tools. For E. coli the best rates are 94.2% (TICO) on the EcoGene dataset and 95.4% (MED-Start) on the Link dataset. On the large dataset of B. subtilis the best rate was 89.4% (TICO), on the small subset the best result was 94.8% . Note that the rates on the small dataset of B. subtilis containing 58 sequences are not as representative as the rates on the larger dataset in terms of statistical significance.In order to compare our algorithm with the other three tools on the test data described above, we used the predictions of the tool GLIMMER2.02 for initial annotation of the coding regions in all cases. The results of GLIMMER, TICO, RBSfinder, MED-Start and GS-Finder are summarized in Table P. aeruginosa is 85.2% (TICO), on B. pseudomallei it is 69.6% (TICO) and 67.5% (GS-Finder) for chromosome 1 and 2, respectively and on R. solanacearum the maximum rate is 74.9% (TICO) and 70.1% (TICO) for the chromosome and the plasmid, respectively. The performance of RBSfinder is about 15 to 20 percent below these rates. MED-Start completely failed on these genomes. The best rate, MED-Start achieved on the high-G+C genomes was 6.0%. Only 3.6% of the predicted TIS were in correspondence with the PseudoCAP annotation. To explain these results, we evaluated the SD motifs suggested by MED-Start. The following five motifs were proposed to be related with the translation initiation in P. aeruginosa: CCTGG, GCGCC, GCCTG, CGCCG and CGGCG. Our first impression was that these motifs are very different from patterns of known SD motifs, which are usually described by the regular expression RGGRGGTGAT (R = A or G) [On the high-G+C genomes only TICO and GS-Finder provide good results with a maximum difference of 5.3% between both tools. The maximum prediction rate on  A or G) . CompariWe introduced a completely unsupervised approach to the problem of TIS prediction in prokaryotic genomes. We showed that our clustering algorithm provides a valuable tool for genome annotation and reannotation, respectively. We found that even on high-G+C genomes, a considerable improvement of TIS prediction accuracy can be achieved by means of our algorithm. In summary, we expect our method to offer advantages for the analysis of new genomes where nothing is known a priori about the associated Shine-Dalgarno motif or other specific sequence features of the underlying gene starts. The latest version of the corresponding tool is publicly available at .PM had the main idea of the algorithm, implemented the clustering scheme and drafted most parts of the manuscript. MT contributed biological expertise, implemented the tool TICO, performed the experimental evaluation and drafted substantial parts of the manuscript. Both authors read and approved the final manuscript.


This article describes the prevalence of risky behaviors known to be associated with increased cancer morbidity and mortality among Ohio Appalachian adults. These behaviors, or risk factors, include: 1) tobacco use; 2) energy imbalance ; and 3) sexual behaviors. We report current estimates of the prevalence of these behaviors among Ohio Appalachian adult residents and review social, psychological, and biological variables associated with these risky behaviors. We also present recent empirical studies that have been completed or are in progress in Ohio Appalachia. Finally, we discuss how these studies help bridge well-documented gaps in the literature. Disparities in cancer incidence have been recently reported in rural regions of Appalachia that include Kentucky, Pennsylvania, and West Virginia . SimilarThe Appalachian region of Ohio includes 29 of the state's total 88 counties, or 33% of the state in square miles, and accounts for 12% of Ohio's total population . CompareOhio Appalachian residents have logistical barriers to overcome in accessing health care. With only 32 registered hospitals and 1723 physicians for more than 1.4 million residents, Ohio Appalachian residents are more likely than other Ohioans to travel greater distances to obtain health care, and they do so without the infrastructure of a public transportation system . The risTobacco use is the single most preventable cause of premature morbidity and mortality , and theAn estimated 44.5 million people, or 20.9% of the U.S. adult population, smoke . SociodeThe factors responsible for an increased prevalence of tobacco use in Ohio Appalachia remain poorly understood. There is a growing body of evidence confirming that tobacco use occurs in greater proportions among certain groups within the United States, including Ohio Appalachia. Those who are poor and less educated have higher rates of smoking than their more privileged counterparts. As such, they also suffer tobacco-attributable morbidity and mortality at significantly higher rates. Women who smoke, like men, are at increased risk of cancer, heart disease, and lung disease . Smokingself-medication, primarily because of the reinforcing effects associated with nicotine  than were residents of urban, suburban, or rural non-Appalachian counties (13.4%–15.9%)  variants. The residents of Ohio Appalachia are relatively isolated geographically because of topographical boundaries created by hills and valleys. Although this isolation has led to self-reliant communities, it may also contribute to the high prevalence of risky behaviors, including risky sexual behaviors. Risky sexual behaviors for cervical cancer have been described as 1) engaging in sexual intercourse at an earlier age than 18 years, 2) having more than two sexual partners, 3) having a history of being treated for a sexually transmitted infection, or 4) having a current or past sexual partner who has been treated for a sexually transmitted infection .Risky sexual behaviors are influenced by determinants such as acceptance of risky sexual behavior, access to health care, SES, and cultural or physical environment. Little is known about the cultural or physical environmental influences in Appalachia on risky sexual behaviors. Cultural norms related to casual sexual relations may be important to determine, as extramarital sexual relationships have been found to be associated with HPV positivity . UnfortuRisky sexual behaviors place women at high risk for acquiring HPV, the primary etiologic agent in cervical cancer ,28. PersPrevalence data on risky sexual behaviors in Ohio Appalachia are not readily available. Data on rates of sexually-transmitted infections do not indicate differences between rural and nonrural populations, and there are no data on HPV rates in rural or Appalachian populations. Compared with the median of all female students in the 2003 Youth Risk Behavioral Surveillance System (YRBSS), more female high school students in West Virginia reported having had sexual intercourse , having had sexual intercourse before age 13 , having had sexual intercourse with four or more partners , or having had sexual intercourse with one or more partners within the last 3 months  . HPV is Factors associated with cervical cancer are not limited to risky sexual behaviors, but the sexual behaviors listed above may elevate the likelihood for cervical disease. The risky sexual behaviors of women living in Ohio Appalachia may be influenced by family-related demographics, neighborhood, or by the culture of Ohio Appalachia. Risky sexual behaviors, influenced by geographic isolation and local culture and norms, put women at increased risk for acquiring HPV.Rural adult Ohio Appalachian residents have participated in a smoking cessation study entitled Tobacco Risk and Counseling (TRAC). The study was approved by The Ohio State University's institutional review board. This project was jointly designed by researchers and community residents from two Ohio Appalachian counties. The project described tobacco consumption variables among rural adult Appalachian tobacco users . ParticiQualitative information was obtained through four focus groups (with former and current tobacco users) and indicated that nicotine addiction was a major theme for engaging in the behavior . DependeInformation about tobacco use characteristics and apparent themes for continued use, as well as reasons for quitting, should assist in the generation of additional hypotheses to be tested among Appalachian smokers. These factors may assist researchers and community leaders in the design and testing of prevention and cessation interventions that are specifically tailored to Appalachian tobacco users.why there are high rates of cervical cancer and deaths from cervical cancer in Ohio Appalachia.A multidisciplinary group of investigators from The Ohio State University and the University of Michigan received funding in 2003 to establish a Center for Population Health and Health Disparities. The Center will initially focus on the goal of understanding http://sph.osu.edu/divisions/abouttheschool/diversity/cervical.)The Center will conduct three related projects in 14 clinics that represent the general population of women aged 18 and older in the Appalachian region and enlist the help of an internal and an external advisory committee. Community partners organized into a community advisory board and a consortium of community organizations have been established to facilitate the accomplishment of project goals. The goal of the first project is to increase early detection of cervical cancer by increasing the proportion of Appalachian women who receive Papanicolaou (Pap) tests at appropriate intervals and return for follow-up when necessary. The second project will test the effectiveness of an intervention facilitated by a lay health educator for women who smoke. The intervention will promote smoking cessation and validate cessation with saliva cotinine measurements. The third project will examine the social, behavioral, and biological variables that contribute to an increased risk of an abnormal Pap test among Appalachian women.  and included 134 completed interviews (72 women and 62 men). Approximately 60% of those interviewed lived in the same Ohio county their entire lives. During the ongoing research process, the research team members have participated in several events to maintain a productive partnership with Amish community members. The researchers have presented study updates at several Amish leadership meetings, have participated in county-level Amish health fairs, and have continued to communicate with study participants. The researchers plan to provide the Amish community with the results of the project. As an outgrowth of this collaboration, the researchers will work with the Amish community to design and implement cancer prevention programs.The Amish Cancer-related Lifestyle Project demonstrates how an individual's health is embedded within a social and physical environment. Rather than focusing on risk factors, this study focuses on lifestyle factors that may protect individuals from cancer. Strengths of this project are built upon the collaborative partnership developed between the Amish community and university researchers.Although there is an abundance of data about smoking and tobacco use across the United States, knowledge of tobacco use behaviors in Appalachia is limited to prevalence estimates. Understanding the social, behavioral, and biological dimensions of tobacco use among Ohio Appalachian women will assist in the development and testing of scientifically valid cessation interventions and may subsequently contribute to reduced risk of cancer among this vulnerable population. The role of social and contextual variables, such as the environment, neighborhood, community, and culture must be integrated into future investigations that attempt to understand the mechanisms responsible for tobacco use.Inequality in the built environment and limited access to healthy food choices present challenges for behavioral interventions focusing on energy balance for residents of Ohio Appalachia. Future behavioral interventions to reduce cancer disparities must address these issues within the cultural context of Ohio Appalachia.Additional efforts should be directed toward understanding what places Ohio Appalachian women at increased risk for cervical abnormalities and HPV infection. As noted, HPV is an important cause of cervical cancer. Better understanding of HPV prevalence rates in Appalachia and the impact of known risk factors, immune function, tobacco use, and diet on HPV infection is needed in this population. In addition, questions about differences in HPV virulence, prevalence types, oncogenic potential, transmission, reservoirs, and resistance in this population are important. This information is needed to begin intervention efforts focused on this topic in the Appalachian region of the United States. The projects of the Center for Population Health and Health Disparities are examples of community-based participatory research that is poised to answer questions associated with the increase in cervical cancer incidence and mortality among women living in Ohio Appalachia.


PLoS Medicine [My remark, in my recent Essay in Medicine , that deSeveral colleagues have rightly pointed out that the evidence for the effect is less clear than I implied: it comes from women who have experienced it , but theTo convey the uncertainty of the facts, I wish to amend my statement as follows: “The irreversible deepening of the voice that has been reported to occur with long-term use of tamoxifen for breast cancer is an example of a side effect that prescribers, manufacturers, and drug regulators seem to have considered trivial and have not investigated.”