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Scripta medica  2010;83(1):16-32.
Three spectral components with periods of about (~) 0.41, ~0.5 and ~1.0 year had been found with serially independent sampling in human circulating melatonin. The time series consisted of around-the-clock samples collected for 24 hours at 4-hour intervals from different patients over several years. Some of these components had been found to be circadian stage-dependent, the daytime measurements following mostly a circannual variation, whereas a half-year characterized the nighttime samples. The latter were incorporated into a circasemiannual map. The relative brevity of the series prevented a check for the coexistence of all three spectral components, even if each component seemed to have a raison d’être. In time series of transdisciplinary data, a 1.00-year synchronized component is interpreted as representing the seasons. The half-year may qualify the circannual waveform, but it is also a signature of geomagnetics. An ~0.41-year (~5-month) component is the signature of solar flares. It has been called a cis-half-year (cis = on this side of a half-year) and may be detected only intermittently. Charles L. Wolff predicted the existence, among others, of ~0.42- and ~0.56-year components as beat periods of rotations at different solar latitudes.
The multiple components characterizing circulating melatonin could also be found in a (to our knowledge unique) data set of a clinically healthy scientist (RBS). Herein, we focus on vascular data self-measured by RBS as he aged from ~20 to ~60 years. A multi-component model consisting of cosine curves with periods of 0.41, 0.50 and 1.00 year was fitted to weekly means of systolic (S) and diastolic (D) blood pressure (BP) and heart rate (HR) collected ~5 times a day over 39 years by RBS. All three components can coexist for a while, although all of them are nonstationary in their characteristics and come and go by the criterion of statistical significance.
Intermittently, BP and HR are synchronized selectively with one or the other aspect of RBS′ physical environment, namely the seasons (at ~1.0 year), earth magnetism (at ~0.5 year) and/or solar flares (at ~0.42 year). Cosmic-biotic transfer of information, albeit hardly of energy (the biospheric amplitudes are very small) may be mediated in this set of frequency windows. As found earlier, RBS′ circulation is also frequency-trapped environmentally in multidecadal windows, HR being locked into the transtridecadal Brückner, or rather Brückner-Egeson-Lockyer, BEL sunspot and terrestrial weather cycle, while his BP follows Hale’s didecadal cycle in the changing polarity of sunspots.
The ~0.41-year HR cycle may be associated with changes in solar flares, the cis-half-year amplitude of HR showing a cross-correlation coefficient of 0.79 with the total solar flare index (from both solar hemispheres) at a lag of ~3.2 years. The superposed time courses of these two variables indicate the presence of a shared Horrebow-Arago-Schwabe sunspot cycle of ~11 years, the cis-half-year in HR being more prominent after the total solar flare index reaches its ~11-year peak. Differences in the time-varying behavior of BP vs. HR are also described.
PMCID: PMC3091818  PMID: 21566725
Blood pressure variability; Heart rate variability; Melatonin cycles; Earth magnetism
2.  Geographically selective assortment of cycles in pandemics: meta-analysis of data collected by Chizhevsky 
Epidemiology and infection  2012;141(10):10.1017/S0950268812002804.
In the incidence patterns of cholera, diphtheria and croup during the past when they were of epidemic proportions, we document a set of cycles (periods), one of which was reported and discussed by A. L. Chizhevsky in the same data with emphasis on the mirroring in human disease of the ~11-year sunspot cycle. The data in this study are based on Chizhevsky’s book The Terrestrial Echo of Solar Storms and on records from the World Health Organization. For meta-analysis, we used the extended linear and nonlinear cosinor. We found a geographically selective assortment of various cycles characterizing the epidemiology of infections, which is the documented novel topic of this paper, complementing the earlier finding in the 21st century or shortly before, of a geographically selective assortment of cycles characterizing human sudden cardiac death. Solar effects, if any, interact with geophysical processes in contributing to this assortment.
PMCID: PMC3815457  PMID: 23228468
Analysis of data; cholera; diphtheria; epidemics; outbreaks
3.  Cyclic patterns of incidence rate for skin malignant melanoma: association with heliogeophysical activity*  
Background: Our previous studies revealed cyclicity in the incidence rate of skin malignant melanoma (SMM; ICD9, Dx:172) in the Czech Republic (period T=7.50~7.63 years), UK (T=11.00 years) and Bulgaria (T=12.20 years). Incidences compared with the sunspot index Rz (lag-period dT=+2, +4, +6, +10 or +12 years) have indicated that maximal rates are most likely to appear on descending slopes of the 11-year solar cycle, i.e., out of phase. We summarized and explored more deeply these cyclic variations and discussed their possible associations with heliogeophysical activity (HGA) components exhibiting similar cyclicity. Methods: Annual incidences of SMM from 5 countries (Czech Republic, UK, Bulgaria, USA and Canada) over various time spans during the years 1964~1992 were analyzed and their correlations with cyclic Rz (sunspot number) and aa (planetary geomagnetic activity) indices were summarized. Periodogram regression analysis with trigonometric approximation and phase-correlation analysis were applied. Results: Previous findings on SMM for the Czech Republic, UK and Bulgaria have been validated, and cyclic patterns have been revealed for USA (T=8.63 years, P<0.05) and Canada (Ontario, T=9.91 years, P<0.10). Also, various ‘hypercycles’ were established (T=45.5, 42.0, 48.25, 34.5 and 26.5 years, respectively) describing long-term cyclic incidence patterns. The association of SMM for USA and Canada with Rz (dT=+6 and +7 years, respectively) and aa (dT=−10 and +9 years, respectively) was described. Possible interactions of cyclic non-photic influences (UV irradiation, Schumann resonance signal, low-frequency geomagnetic fluctuations) with brain waves absorbance, neuronal calcium dynamics, neuro-endocrine axis modulation, melatonin/serotonin disbalance and skin neuro-immunity impairment as likely causal pathways in melanoma appearance, were also discussed. Conclusion: The above findings on cyclicity and temporal association of SMM with cyclic environmental factors could not only allow for better forecasting models but also lead to a better understanding of melanoma aetiology.
PMCID: PMC2408703  PMID: 18543403
Melanoma incidence; Cyclicity; Heliogeophysical activity (HGA); Forecasting; Skin neurobiology
4.  Solar activity affects avian timing of reproduction 
Biology Letters  2009;5(6):739-742.
Avian timing of reproduction is strongly affected by ambient temperature. Here we show that there is an additional effect of sunspots on laying date, from five long-term population studies of great and blue tits (Parus major and Cyanistes caeruleus), demonstrating for the first time that solar activity not only has an effect on population numbers but that it also affects the timing of animal behaviour. This effect is statistically independent of ambient temperature. In years with few sunspots, birds initiate laying late while they are often early in years with many sunspots. The sunspot effect may be owing to a crucial difference between the method of temperature measurements by meteorological stations (in the shade) and the temperatures experienced by the birds. A better understanding of the impact of all the thermal components of weather on the phenology of ecosystems is essential when predicting their responses to climate change.
PMCID: PMC2827989  PMID: 19574283
timing of reproduction; sunspots; birds; Parus major; Cyanistes caeruleus
5.  A simplified and reliable HPV testing of archival Papanicolaou-stained cervical smears: application to cervical smears from cancer patients starting with cytologically normal smears 
British Journal of Cancer  2000;82(8):1421-1426.
The efficacy of four methods to recover DNA from Papanicolaou (Pap)-stained archival cervical smears for optimal detection of human papillomavirus (HPV) DNA by GP5+/bioGP6+ polymerase chain reaction (PCR) was investigated. Two of the methods were based on proteinase K treatment and two based on treatment with guanidinium thiocyanate (GTC). The quality of the DNA as measured by PCR assays amplifying different sizes of the β-globin gene appeared to be superior for the GTC-based assays. Using competitive β-globin PCR assays, one of the GTC-based, assays, provisionally named High Pure PCR Template Preparation (HPPTP) assay, yielded by far the highest quantity of amplifiable DNA. It allowed the recovery of 2.2 × 105to 3 × 105genome equivalents in smears containing 5 × 105to 20 × 105nucleated cells, indicating a mean efficiency of 26% (range of 15–44%). In contrast, the other methods revealed markedly lower efficiencies varying from 1% to 10%. The use of the HPPTP assay as a reliable processing procedure was validated by demonstrating a complete agreement in HPV detection and 93% agreement in HPV typing between 39 archival Pap-stained and paired fresh-frozen cervical smears. This method was applied to 40 archival smears from ten cervical cancer patients (selected from a group of 200 patients) which had a history of 3–6 smears with the first smear being Pap 1 or 2 taken at least 5 years before cancer was diagnosed. The average time period between the first Pap 1/2 smear that contained the same HPV type as in the corresponding carcinoma and diagnosis of cervical cancer was 12.0 ± 2.9 years. All subsequent smears were invariably positive for the same HPV type which was also found in the cervical cancer biopsy. In conclusion, the HPPTP assay provides a reliable and efficient means to extract DNA from Pap-stained archival cervical smears for the detection of HPV DNA by PCR and would be the method of choice for future HPV analysis of archival Pap-stained cervical smears. © 2000 Cancer Research Campaign
PMCID: PMC2363381  PMID: 10780521
HPV; PCR; archival Pap smears
6.  Cytomorphology of cervicovaginal melanoma: ThinPrep versus conventional Papanicolaou tests 
CytoJournal  2010;7:25.
Primary cervicovaginal melanoma is a rare malignancy associated with a high risk of recurrence. Prior studies discussing the cytomorphology of cervicovaginal melanoma have been based primarily on review of conventional Papanicolaou (Pap) smears. The aim of this study was to evaluate cervicovaginal melanomas identified in liquid-based Pap tests, in comparison with features seen on conventional Pap smear preparation.
Materials and Methods:
Cases of cervicovaginal melanoma identified on Pap tests with concurrent or subsequent histopathologic confirmation were collected from the Baystate Medical Center cytopathology files and personal archives of the authors over a total period of 34 years. All cytopathology (n = 6) and the available histology slides (n = 5) were reviewed. Cases were analyzed regarding clinical, histopathologic and cytomorphological findings.
A total of six cases with invasive cervicovaginal melanoma diagnosed on Pap tests were identified. Most patients were postmenopausal with contact bleeding, correlating with surface ulceration (identified in biopsy/excision material in 5/5 cases). Most cases had deeply invasive tumors (5/5: modified Breslow's thickness > 5 mm and Chung's level of invasion IV/V). Pap tests included four ThinPrep and two conventional smears. Overall, ThinPrep Pap tests exhibited a higher ratio of tumor cells to background squamous cells. While all Pap tests were bloodstained, tumor diathesis was prominent only within conventional smears. Melanoma cells were present both as clusters and scattered single cells in each Pap test type. Both the preparations contained epithelioid tumor cells, whereas spindled tumor cells were seen in only two ThinPrep cases. Prominent nucleoli and binucleation of tumor cells were seen in both the preparations. Melanin pigment was identified in only ThinPrep (3/4) cases and nuclear pseudo-inclusions in one conventional Pap smear. Cell blocks were made in three ThinPrep cases and immunocytochemistry (S-100, HMB45, Melan-A) performed on additional vial material (one ThinPrep slide and one cell block) was immunoreactive in melanoma cells.
Primary cervicovaginal melanoma, a rare malignancy seen predominantly in postmenopausal women, may be successfully diagnosed in either ThinPrep Pap tests or conventional Pap smears. While ThinPrep Pap tests did not demonstrate morphological advantage over conventional smears, liquid-based cytology specimens did provide additional material for cellblock preparation and immunocytochemical evaluation in a subset of cases.
PMCID: PMC3030001  PMID: 21298024
Cervix; conventional smear; cytology; melanoma; Pap test; ThinPrep; vagina
7.  Cervical Cancer Screening in the Urgent Care Setting 
To determine the feasibility of cervical cancer screening in an urgent care clinic.
Prospective randomized trial.
Public teaching hospital.
Women presenting to the urgent care clinic whose evaluation necessitated a pelvic examination were eligible for participation. Women who had a hysterectomy, had a documented Pap test at our institution in the past year, did not speak English or Spanish, or had significant vaginal bleeding were excluded. Women presenting to the gynecology clinic for a scheduled Pap test were used as a comparison group for rates of follow-up, Pap smear adequacy, and Pap smear abnormalities.
Women randomized to the intervention group had a Pap test performed as part of their pelvic examination, while women in the usual care group were encouraged to schedule an appointment in the gynecology clinic at a later date. The women in the two groups completed identical questionnaires regarding cervical cancer risk factors and demographic information.
Ninety-four (84.7%) of 111 women in the intervention group received a Pap test, as compared with 25 (29%) of 86 in the usual care group (P < .01). However, only 5 (24%) of 21 women with abnormal Pap smears in the intervention group received follow-up compared with 6 (60%) of 10 women seen during the same time period in the gynecology clinic for self-referred, routine annual examinations (P = .11). Pap smears obtained in the urgent care clinic were similar to those in the gynecology clinic with regard to abnormality rate (22.3% vs 20%; P = .75, respectively) and specimen adequacy (67% vs 72%; P = .54, respectively).
Urgent care clinic visits can be used as opportunities to perform Pap test screening in women who are unlikely to adhere to cervical cancer screening recommendations. However, to accrue the full potential benefit from this intervention, an improved process to ensure patient follow-up must be developed.
PMCID: PMC1495471  PMID: 10886473
cervical cancer screening; urgent care clinic; Pap smears
8.  The Frequency of Pap Smear Screening in the United States 
U.S. professional medical societies and the national health systems of all other industrialized nations recommend that most women need not undergo Papanicolaou (Pap) smear screening annually. There are no data, however, regarding the frequency at which women actually undergo screening.
To describe the frequency of cervical cancer screening in the United States.
National Health Interview Survey, a cross-sectional population-based telephone survey conducted by the National Center for Health Statistics.
Representative sample of U.S. women age 21 and older who denied a history of cancer (N = 16,467).
Pap smear screening frequency, categorized as no regular screening or screening at 1 of 3 discrete screening intervals (every year, every 2 years, or every 3 years) based on each woman's reported number of Pap smears in the previous 6 years.
The vast majority (93%) of American women report having had at least one Pap smear in their lifetime. Among women with no history of abnormal smears, 55% undergo Pap smear screening annually, 17% report a 2-year screening interval, 16% report being screened every 3 years, and 11% are not being screened regularly. Even the very elderly report frequent screening—38% of women age 75 to 84 and 20% of women age 85 and older reported annual Pap smears. Overall, 20% of women reported having had at least one abnormal Pap smear. Among these women, rates of frequent Pap smear screening are considerably higher—80% undergo annual screening, with only a modest decline in screening frequency with increasing age.
The majority of American women report being screened for cervical cancer more frequently than recommended. Lengthening the screening interval would not only reduce the volume of specimens that cytotechnologists are required to read, but would also reduce the follow-up testing after abnormal smears.
PMCID: PMC1492158  PMID: 15009779
cervical cancer screening; Pap smear; test frequency; overutilization
9.  Cost-effectiveness analysis of human papillomavirus DNA testing and Pap smear for cervical cancer screening in a publicly financed health-care system 
British Journal of Cancer  2010;103(12):1773-1782.
To evaluate the long-term cost-effectiveness of different strategies for human papillomavirus (HPV) DNA testing combined with Pap smear for cervical cancer screening in Taiwan.
This study adopts a perspective of Department of Health in cost-effectiveness analysis to compare a no-screening strategy with nine different screening strategies. These strategies comprise three screening tools (Pap smear alone, HPV DNA testing followed by Pap smear triage, and HPV DNA testing combined with Pap smear), and three screening intervals (annually, every 3 years, and every 5 years). Outcomes are life expectancy, quality-adjusted life years (QALYs), lifetime costs, and incremental cost-effectiveness ratios (ICERs). Probabilistic sensitivity analyses (PSAs) were conducted to assess parameter uncertainty.
When three times gross domestic product per capita is used as the decision threshold, all nine screening strategies were cost-effective compared with the no-screening strategy. Compared with the current screening strategy (an annual Pap smear), HPV DNA testing followed by Pap smear triage every 5 years and every 3 years were cost-effective. Results of PSA also indicated that a HPV DNA testing followed by Pap smear triage every 5 or every 3 years achieved the highest expected net benefits.
Possible economic advantages are associated with extending the cervical cancer screening interval from one Pap smear annually to HPV DNA testing followed by Pap smear triage every 5 years with an ICER $1 247 000 per QALY gained, especially in a country with a publicly financed health-care system.
PMCID: PMC3008604  PMID: 21102588
HPV DNA testing; Pap smear; cost-effectiveness analysis; cervical cancer; screening
10.  Geomagnetism during solar cycle 23: Characteristics 
Journal of Advanced Research  2012;4(3):265-274.
On the basis of more than 48 years of morphological analysis of yearly and monthly values of the sunspot number, the aa index, the solar wind speed and interplanetary magnetic field, we point out the particularities of geomagnetic activity during the period 1996–2009. We especially investigate the last cycle 23 and the long minimum which followed it. During this period, the lowest values of the yearly averaged IMF (3 nT) and yearly averaged solar wind speed (364 km/s) are recorded in 1996, and 2009 respectively. The year 2003 shows itself particular by recording the highest value of the averaged solar wind (568 km/s), associated to the highest value of the yearly averaged aa index (37 nT). We also find that observations during the year 2003 seem to be related to several coronal holes which are known to generate high-speed wind stream. From the long time (more than one century) study of solar variability, the present period is similar to the beginning of twentieth century. We especially present the morphological features of solar cycle 23 which is followed by a deep solar minimum.
PMCID: PMC4295039
Geomagnetic activity; Solar cycle; Solar wind
11.  Human Papillomavirus Typing in HIV-Positive Women 
Objective: Human papillomavirus (HPV) is the major cause of cervical carcinoma and cervical intraepithelial neoplasia worldwide. Certain HPV types have a strong association with and probably a causative role in the pathogenesis of premalignant cervical lesions. Epidemiologic studies in women infected by the human immunodeficiency virus (HIV) have shown an increased incidence of squamous intraepithelial lesions (SILs), whichwere predominantly high-grade. Six to 30 per cent of women diagnosed with atypical squamous cells of undetermined significance (ASCUS) on a Papanicolaou (Pap) smear harbor SIL in normal screening populations. This study was undertaken to determine the presence of low- and high-risk HPV types in women infected by HIV and to correlate the results to those of the Pap smear.
Study design: HPV DNA typing (low- and high-risk) by Digene™ (Digene Corporation, Gathesburg, MD) hybrid capture methodology was performed on cervical swabs from 209 HIV-positive women. The results of HPV typing were correlated with those of the Pap smear in a retrospective analysis.
Results: One hundred and one women (48%) tested positive for HPV subtypes by DNA typing by the hybrid capture method. Of these, 64 patients (63%) had Pap smears whichwere read as being normal, having benign cellular changes, or having ASCUS (favor reactive process). Of these, 19 patients tested positive for both high-risk and low-risk subtypes, 32 patients tested positive only for high-risk subtypes, and 13 patients tested positive only for low-risk subtypes.
Conclusion: HPV subtyping identifies a significant group of HIV-positive women who are at risk for developing cervical intraepithelial neoplasia, although they may not show significant abnormalities on their Pap smears.
PMCID: PMC1784640  PMID: 11495559
12.  Evidence for solar cycles in a late Holocene speleothem record from Dongge Cave, China 
Scientific Reports  2014;4:5159.
The association between solar activity and Asian monsoon (AM) remains unclear. Here we evaluate the possible connection between them based on a precisely-dated, high-resolution speleothem oxygen isotope record from Dongge Cave, southwest China during the past 4.2 thousand years (ka). Without being adjusted chronologically to the solar signal, our record shows a distinct peak-to-peak correlation with cosmogenic nuclide 14C, total solar irradiance (TSI), and sunspot number (SN) at multi-decadal to centennial timescales. Further cross-wavelet analyses between our calcite δ18O and atmospheric 14C show statistically strong coherence at three typical periodicities of ~80, 200 and 340 years, suggesting important roles of solar activities in modulating AM changes at those timescales. Our result has further indicated a better correlation between our calcite δ18O record and atmospheric 14C than between our record and TSI. This better correlation may imply that the Sun–monsoon connection is dominated most likely by cosmic rays and oceanic circulation (both associated to atmospheric 14C), instead of the direct solar heating (TSI).
PMCID: PMC4044623  PMID: 24894978
13.  Skin Cancer, Irradiation, and Sunspots: The Solar Cycle Effect 
BioMed Research International  2014;2014:538574.
Skin cancer is diagnosed in more than 2 million individuals annually in the United States. It is strongly associated with ultraviolet exposure, with melanoma risk doubling after five or more sunburns. Solar activity, characterized by features such as irradiance and sunspots, undergoes an 11-year solar cycle. This fingerprint frequency accounts for relatively small variation on Earth when compared to other uncorrelated time scales such as daily and seasonal cycles. Kolmogorov-Zurbenko filters, applied to the solar cycle and skin cancer data, separate the components of different time scales to detect weaker long term signals and investigate the relationships between long term trends. Analyses of crosscorrelations reveal epidemiologically consistent latencies between variables which can then be used for regression analysis to calculate a coefficient of influence. This method reveals that strong numerical associations, with correlations >0.5, exist between these small but distinct long term trends in the solar cycle and skin cancer. This improves modeling skin cancer trends on long time scales despite the stronger variation in other time scales and the destructive presence of noise.
PMCID: PMC4122154  PMID: 25126567
14.  Effect of an antepartum Pap smear on the coverage of a cervical cancer screening programme: a population-based prospective study 
Almost one-third of Norwegian women aged 25–69 years invited to have a Pap smear do not attend during the recommended period, and thus constitute a population with high-risk of cervical cancer (CC). Since the incidence of precancerous lesions of the cervix peak with occurrence of pregnancies within the same decade in women aged 25 to 35 years of age, antepartum care presents an opportunity to offer a Pap smear thereby increasing the coverage of the programme. The study objective was to describe the effect of the antepartum Pap smear on the coverage of a cytological CC screening programme.
Among 2 175 762 women resident in Norway in 31.12.1996, all women who gave birth in 1996–7 were identified from the Medical Birth Registry of Norway. Attendance to the cervical cancer screening was assessed by linkage to the Cytology Registry separately for the pregnant and non-pregnant women cohorts. The results were stratified by age, history of previous Pap smear and history of invitation to the CC screening programme. Logistic regression was used to estimate the relative probabilities of having a Pap smear adjusted for age, screening history, and time since invitation, for pregnant and non-pregnant women, respectively.
69% of the pregnant women had a Pap smear during one year of follow-up since beginning of the pregnancy with the majority taken during the antepartum period. Irrespectively of age or history of having a Pap smear, pregnant women were 4.3 times more likely to have a Pap smear during follow-up compared to non-pregnant women. 63.2% of the pregnant women had a smear as response to the invitation letter compared to 28.7% of the non-pregnant women, OR = 2.1 (95% CI 1.9 to 2.4). As an indication of "over-screening", 5397 pregnant women (57.8%) with a smear shortly before the start of follow-up also had a new Papsmear, compared to 83 023 (32.3%) in non-pregnant.
Pap smear screening during pregnancy increases the coverage of the CC screening programme. The contribution of the antepartum Pap smear to "over-screening" exists but its effect is modest in countries where women on average become pregnant after the start of recommended age of screening.
PMCID: PMC1790705  PMID: 17244348
15.  Detection of abnormal cervical cytology in Papanicolaou smears 
Cervical cytology by Papanicolaou (Pap) smears is an effective means of screening for cervical premalignant and malignant conditions. Cervical intra-epithelial neoplasia (CIN) and cervical cancer remain important health problems for women worldwide.
To study the role of Pap smear in detecting premalignant and malignant lesions of cervix; and to determine the prevalence of various lesions.
Materials and Methods:
This study is based on 300 patients who attended the out-patient Department of Obstetrics and Gynaecology. Pap smears were prepared from patients presenting with complaints like vaginal discharge, post-coital bleeding, inter-menstrual bleeding, dyspareunia, and pain lower abdomen. After fixation and staining, each smear was carefully examined.
Epithelial cell abnormalities were found in 5% smears, atypical squamous cells of undetermined significance (ASCUS) in 0.3%, squamous intraepithelial lesion (SIL) in 3.4% which includes low grade squamous intraepithelial lesion (LSIL) (2.7%) and high grade squamous intraepithelial lesion (HSIL) 0.7%. Invasive carcinoma was seen in 1.3% cases. Mean age of the patients with diagnosis of LSIL was 32.3 years and for HSIL, it was 40.5 years. The mean age of the patients with invasive carcinoma was 57 years.
Premalignant and malignant lesions of cervix are not uncommon in our set up and can be diagnosed early by Pap smears.
PMCID: PMC3307451  PMID: 22438616
Cervical cancer; cervical intraepithelial neoplasia; papanicolaou smear
16.  Papanicolaou test utilization and frequency of screening opportunities among women diagnosed with cervical cancer 
Open Medicine  2009;3(3):e140-e147.
Although the importance of Papanicolaou (Pap) smear test screening in reducing the incidence of cervical cancer is well established, in 1994–95 one in 4 women in Manitoba aged 18 to 69 years reported never having had a Pap test or not having had a Pap test in the last 3 years. The objectives of this study were to examine the screening history of women in Manitoba diagnosed with invasive cervical cancer and to explore whether opportunities for screening were missed.
In this case-control study women aged 18 years and older who resided in Manitoba and were diagnosed with invasive cervical cancer between 1989 and 2001 were each matched by age and area of residence to 5 controls, (N = 4009). Conditional logistic regression analyses were used to examine the association between Pap test utilization and the likelihood of diagnosis with invasive cervical cancer. Generalized linear models using the negative binomial distribution were used to assess the association between cancer status and rates of prior Pap testing and of opportunities to be screened. Logistic generalized estimating equation models were used for the analysis of physician characteristics.
Forty-six percent of women in Manitoba diagnosed with invasive cervical cancer and 67% of the control group had received a Pap test in the 5 years before the case’s diagnosis. After adjustment for age, income and residence, the rate of Pap testing was significantly higher in the control group (rate ratio [RR] = 1.57, 95% confidence interval [CI] 1.44–1.73). Conversely, when cervical cancer was the outcome, women who had not had Pap tests were more likely to be diagnosed with invasive cervical cancer (odds ratio [OR] = 2.77, 95% CI 2.30–3.30) than women who did have a Pap test. Although women diagnosed with invasive cervical cancer had fewer Pap tests, they had had as many opportunities to be screened as controls (RR = 1.04, 95% CI 0.96–1.12). Compared with urban family physicians, rural family physicians were less likely to provide Pap tests (OR = 0.68, 95% CI 0.58–0.80) and specialists were more likely to provide Pap tests (OR = 1.70, 95% CI 1.30–2.22).
Women who were diagnosed with invasive cervical cancer in the province of Manitoba, Canada, had fewer Pap tests but the same frequency of opportunities to be screened as matched controls. These results reinforce the need to educate women about cervical cancer screening and the importance of receiving Pap tests.
PMCID: PMC3090124  PMID: 21603052
17.  Annual Papanicolaou screening for 5 years among human papillomavirus-negative women 
BMC Cancer  2013;13:379.
Primary human papilloma virus (HPV) screening is more effective than cytology in reducing the risk of cervical cancer, but screening intervals should be extended in HPV-negative women. However, some Markov models predicted that long intervals are associated with an excess risk of cervical cancer. The aim of this analysis was to estimate the real-life risks and benefits of annual Papanicolaou (Pap) screening in HPV-negative women with normal cytology.
Women with negative Hybrid Capture 2 (HC2) results and normal cytology at the time of inclusion in the Hannover HPV screening trial underwent annual Pap smears for 5 years. A subgroup was randomly selected for retesting with cytology, HC2, and colposcopy 60–68 months after recruitment.
Of 4236 women included, 3406 had at least one Pap smear, but only 1185 attended all five annual screening visits. The proportion of women with at least one abnormal smear was 14.4% in 60 months. The probability of abnormal smears increased continuously over time. No case of ≥ CIN2+ was observed during 5 years. Of 605 women selected for subgroup analysis, 292 agreed to be retested (48.3%). The rate of high-risk HPV at 60–68 months was 3.0% (9/296).
The long-term risk of high-grade neoplasia after an initial negative HC2 test and normal cytology result was low, while the rate of false-positive abnormal Pap smears was significant and increased constantly over time. Pap smear screening of HPV-negative women more frequently than every 5 years could be potentially harmful and seems to be of little clinical value.
PMCID: PMC3751119  PMID: 23937771
Annual papanicolaou smear; Cervical cancer screening; Human papillomavirus (HPV); HR-HPV DNA test; Screening intervals
18.  Negative Predictive Value of Pap Testing: Implications for Screening Intervals for Women With Human Immunodeficiency Virus 
Obstetrics and gynecology  2012;120(4):791-797.
To estimate the accuracy of Pap testing for women who are human immunodeficiency virus (HIV)-seropositive, with a focus on negative predictive value.
Participants in the Women’s Interagency HIV Study were followed with conventional Pap smears every 6 months. After excluding those with abnormal Pap tests before study, cervical disease, or hysterectomy, women with negative enrollment Pap results were followed for development within 15 or within 39 months of precancer, defined as a Pap read as high grade squamous intraepithelial lesion, atypical glandular cells favor neoplasia, or adenocarcinoma in situ, or a cervical biopsy read as cervical intraepithelial neoplasia 2+. Correlations between one or more consecutive negative Pap results and subsequent precancer were assessed using Cox proportional hazards models.
Among 942 HIV infected women with negative baseline Pap tests, 8 (1%) developed precancer within 15 months and 40 (4%) within 39 months. After three consecutive negative Pap tests, precancer was rare, with no cases within 15 months and 10/539 (2%) within 39 months. No women developed precancer or cancer within 39 months after 10 consecutive negative Pap tests. Risks for precancer within 15 months after negative Pap included current smoking (aHR 1.5, 95% CI 1.2, 2.0 vs nonsmokers), younger age (aHR=1.5, 95% CI 1.1, 2.1 for women aged younger than 31 years vs older than 45 years) and lower CD4 count (aHR 11.8, 95% CI 1.3, 2.3 for CD4 200–500, aHR 2.2, 95% CI 1.6, 2.9 for CD4 <200/cmm, vs CD4 >500/cmm).
Annual Pap testing appears safe for women infected with HIV; for those with serial negative tests, longer intervals are appropriate.
PMCID: PMC3448928  PMID: 22996096
19.  PA03.11. Evaluation of socioeconomic status and other factors with special reference to cervical cancer A survey based study 
Ancient Science of Life  2013;32(Suppl 2):S80.
Cervical cancer is cancer that starts in the cervix, the lower part of the uterus (womb) that opens at the top of the vagina. It is the third most common type of cancer in women. Cervical cancers start in the cells on the surface of the cervix. Most cervical cancers are from squamous cells. It starts as a precancerous condition called dysplasia. This precancerous condition can be detected by a Pap smear and is 100% treatable. It can take years for precancerous changes to turn into cervical cancer. The Papanicolaou test (also called Pap smear, Pap test, cervical smear, or smear test) is a screening test used to detect potentially precancerous and cancerous processes in the endocervical canal (transformation zone) of the female reproductive system. The test aims to detect potentially precancerous changes (called cervical intraepithelial neoplasia (CIN) or cervical dysplasia), which are usually caused by sexually transmitted human papillomaviruses. The present study was planned in the direction to evaluate.
In the present work, overall 50 patients of age group between 2050 yrs were selected to study their abnormal pap smear reports in relation to socioeconomic status, smoking, parity, and oral contraceptive and their relationship with abnormal cellular changes. So the patients were randomly selected for Pap smear from IPD or OPD of prasuti tantra and stri roga department of sdmca Hassan.
Out of 50 patients,10 patients belongs to higher class, 20 patients belongs to middle class,10 patients belongs lower middle class and 10 patients belongs to lower class.
Cervical cancer is ranked as the most frequent cancer in women in India. India has a population of approximately 365.71 million women above 15 years of age, who are at risk of developing cervical cancer. Getting regular Pap smears can help detect precancerous changes, which can be treated before they turn into cervical cancer. Pap smears effectively spot such changes, but they must be done regularly. Middle class women are more prone to this disease. PREVENTION IS BETTER THAN CURE.
PMCID: PMC4147555
20.  Risk of Cervical Pre-Cancer and Cancer Among HIV-Infected Women With Normal Cervical Cytology and No Evidence of Oncogenic HPV Infection 
U.S. cervical cancer screening guidelines for HIV-uninfected women 30 years of age and older have recently been revised, increasing the suggested interval between Pap tests from three years to five years among those with normal cervical cytology (the Pap test) who test negative for oncogenic human papillomavirus (HPV). Whether a three-year or five-year screening interval might be used in HIV-infected women who are cytologically normal and oncogenic HPV-negative is unknown.
To determine the risk of cervical pre-cancer or cancer defined cytologically (high-grade squamous intraepithelial lesions or greater [HSIL+]) or histologically (cervical intraepithelial neoplasia 2 or greater [CIN-2+]), as two separate endpoints, in HIV-infected women and HIV-uninfected women who at baseline had a normal Pap test and were negative for oncogenic HPV.
Design, Setting and Participants
Participants included 420 HIV-infected women and 279 HIV-uninfected women with normal cervical cytology at their enrollment in a multi-institutional cohort, between October 1, 2001 and September 30, 2002, with follow-up through April 30, 2011. Clinical sites were in the Bronx, Brooklyn, Chicago, Los Angeles, San Francisco, and Washington, DC. Semi-annual visits included Pap testing and, if indicated, cervical biopsy. Cervicovaginal lavage specimens from enrollment were tested for HPV DNA using PCR. The primary analysis was truncated at five years of follow-up.
Main Outcome Measure
The five-year cumulative incidence of cervical pre-cancer and cancer.
No oncogenic HPV was detected in 369 (88%; 95% CI, 84%-91%) of the HIV-infected women and 255 (91%; 95% CI, 88%-94%) of the HIV-uninfected women with normal cervical cytology at enrollment. Among these oncogenic HPV-negative women two cases of HSIL+ were observed; an HIV-uninfected woman and an HIV-infected woman with a CD4 cell count of 500/μL or greater. Histologic data were obtained from four of the six sites. There were six cases of CIN-2+ in N=145 HIV-uninfected women (cumulative incidence = 5% [95% CI, 1%-8%]) and nine cases in N=219 HIV-infected women (cumulative incidence = 5% [95% CI, 2%-8%]). This included one case of CIN-2+ in N=44 oncogenic HPV-negative HIV-infected women with CD4 cell counts less than 350/μL (cumulative incidence = 2% [95% CI, 0%-7%]), one case in N=47 women with CD4 cell counts of 350 to 499/μL (cumulative incidence = 2% [95% CI, 0%-7%]), and seven cases in N=128 women with CD4 cell counts of 500/μL or greater (cumulative incidence = 6% [95% CI, 2%-10%]). One HIV-infected and one HIV-uninfected woman had CIN-3, but none had cancer.
The five-year cumulative incidence of HSIL+ and CIN-2+ was similar in HIV-infected women and HIV-uninfected women who were cytologically normal and oncogenic HPV-negative at enrollment.
PMCID: PMC3556987  PMID: 22820789
21.  Anal Dysplasia Screening 
Executive Summary
This review considered the role of the anal Pap test as a screening test for anal dysplasia in patients at high risk of anal SCC. The screening process is now thought to be improved with the addition of testing for the human papillomavirus (HPV) in high-risk populations. High-resolution anoscopy (a method to view the rectal area, using an anoscope, a lighted instrument inserted into the rectum) rather than routine anoscopy-guided biopsy, is also now considered to be the diagnostic standard.
Clinical Need: Target Population and Condition
Anal cancer, like cervical cancer, is a member of a broader group of anogenital cancers known to be associated with sexually transmitted viral HPV infection. Human papillomavirus is extremely prevalent, particularly in young, sexually active populations. Sexual practices involving receptive anal intercourse lead to significantly elevated risk for anal dysplasia and cancer, particularly in those with immune dysfunctions.
Anal cancer is rare. It occurs at a rate of about 1 to 2 per 100,000 in the general population. It is the least common of the lower gastrointestinal cancers, representing about 4% of them, in contrast to colorectal cancers, which remain the third most commonly diagnosed malignancy. Certain segments of the population, however, such as HIV-positive men and women, other chronic immune-suppressed patients (e.g., after a transplant), injection drug users, and women with genital dysplasia /cancer, have a high susceptibility to anal cancer.
Those with the highest identified risk for anal cancer are HIV-positive homosexual and bisexual men, at a rate of 70 per 100,000 men. The risk for anal cancer is reported to be increasing dramatically in HIV-positive males and females, particularly since the introduction of highly active antiretroviral therapy in the mid-1990s. The introduction of effective viral therapy has been said to have transformed the AIDS epidemic in developed countries into a chronic disease state of long-term immunosuppression. In Ontario, there are about 25,000 people living with HIV infection; more than 6,000 of these are women. About 28% of the newly diagnosed HIV infections are in women, a doubling since 1999. It has also been estimated that 1 of 3 people living with HIV do no know it.
Health Technology Description
Anal Pap test screening involves the blind insertion of a swab into the anal canal and fixing cells either on a slide or in fluid for cytological examination. Anal cytology classified by the standardized Bethesda System is the same classification used for cervical cytology. It has 4 categories: normal, atypical squamous cells of uncertain significance, or squamous intraepithelial lesions which are further classified into low- or high-grade lesions. Abnormal cytological findings are subjected to further evaluations by high-resolution anoscopy, a technique similar to cervical colposcopy, and biopsy. Several HPV deoxyribonucleic acid detection technologies such as the Hybrid 11 Capture and the polymerase chain reaction are available to detect and differentiate HPV viral strains.
Unlike cervical cancer, there are no universally accepted guidelines or standards of care for anal dysplasia. Moreover, there are no formal screening programs provincially, nationally, or internationally. The New York State Department of Health AIDS Institute has recently recommended (March 2007) annual anal pap testing in high-risk groups. In Ontario, reimbursement exists only for Pap tests for cervical cancer screening. That is, there is no reimbursement for anal Pap testing in men or women, and HPV screening tests for cervical or anal cancer are also not reimbursed.
The scientific evidence base was evaluated through a systematic literature review. Assessments of current practices were obtained through consultations with various agencies and individuals including the Ministry of Health and Long-Term Care AIDS Bureau; Public Health Infectious Diseases Branch, Ministry of Health and Long-Term Care; Cancer Care Ontario; HIV/AIDS researchers; pathology experts; and HIV/AIDS clinical program directors. An Ontario-based budget impact was also done.
No direct evidence was found for the existence of controlled studies evaluating the effectiveness of anal Pap test screening programs for impact on anal cancer morbidity or mortality. In addition, no studies were found on the use of HPV DNA testing in the screening or diagnostic setting for anal dysplasia. The reported prevalence of HPV infection in high-risk groups, particularly HIV-positive males, however, was sufficiently high to preclude any utility of HPV testing as an adjunct to anal Pap testing.
Nine reports involving studies in the United States, United Kingdom, and Canada were identified that evaluated the performance characteristics of anal Pap test screening for anal dysplasia. All involved hospital-based specialty HIV/AIDS care clinics with mainly HIV-positive males. All studies involved experienced pathologists, so the results generally represent best-case scenarios. Estimates of anal Pap test sensitivity and specificity were highly variable, and depended on the varying prevalence of cytology abnormality and differential thresholds for abnormality for both cytology and histopathology.
In the largest study of HIV-positive males, sensitivity varied from 46% (95% confidence interval [CI], 36%–56%) to 69% (95% CI, 60%–78%). Specificity ranged from 59% (95% CI, 53%–65%) to 81% (95% CI, 76%–85%). In the only study of HIV-negative males, sensitivity ranged from 26% (95% CI, 5%-47%) to 47% (95% CI, 26%–68%). Specificity ranged from 81% (95% CI, 76%–85%) to 92% (95% CI, 89%–95%).
In comparison, cervical Pap testing has also been evaluated mainly in settings where there is a high prevalence of the disease, and estimates of sensitivitykij and specificity were also low and highly variable. In a systematic review involving cervical Pap testing, sensitivity ranged from 30% to 87% (mean, 47%) and specificity from 86% to 100% (mean, 95%).
No direct evidence exists to support the effectiveness of an anal Pap test screening program to reduce anal cancer mortality or morbidity. There are, however, strong parallels with cervical pap testing for cervical cancer. Sexually transmitted HPV viral infection is currently the acknowledged common causative agent for both anal and cervical cancer. Anal cancer rates in high-risk populations are approaching those of cervical cancer before the implementation of Pap testing.
The anal Pap test, although it has been mainly evaluated only in HIV-positive males, has similar operating characteristics of sensitivity and specificity as the cervical Pap test. In general, the treatment options for precancer dysplasia in the cervix and the anus are similar, but treatment involving a definitive surgical resection in the anus is more limited because of the higher risk of complications. A range of ablative therapies has been applied for anal dysplasia, but evidence on treatment effectiveness, tolerability and durability, particularly in the HIV-positive patient, is limited.
PMCID: PMC3377578  PMID: 23074504
22.  Frequency of Cervical Cancer and Breast Cancer Screening in HIV–Infected Women in a County-Based HIV Clinic in the Western United States 
Journal of Women's Health  2010;19(4):709-712.
Women's primary-care services are frequently dispensed to HIV-infected women through HIV specialty clinics. Our objective was to evaluate cervical cancer and breast cancer screening practices in a county-based HIV clinic in San Mateo, California.
This was a retrospective cohort study of medical records of HIV-infected women obtaining HIV care at this site.
Between January 1, 2002 and December 31, 2006, 69 women were documented to have at least 12 months of medical care at the clinic. Median followup time was 51 months. Over 253 person-years of followup, there were 656 pap smears performed per 1,000 person-years; 77.9% of women had at least one Pap smear during the study time period. A total of 59.5% (47/79) of normal pap smears had a followup pap smear within 18 months; 62.0% of abnormal pap smears had a followup pap smear within 12 months. A CD4 count of less than 200 cells/mm3 was associated with not receiving a pap smear in multivariable analysis. Mammogram screening was performed on 64.7% of women aged 40 or older.
Based on the results of this study, the majority of HIV-infected women at this clinic received cervical and breast cancer screening at some point during their care. Only two-thirds of abnormal pap smear results had followup pap smear screening within a year. With the increased risk of cervical cancer in HIV-infected women, efforts should be made to promote cervical cancer screening, particularly in high-risk women.
PMCID: PMC2867552  PMID: 20201703
23.  Confusion regarding cervical cancer screening and chlamydia screening among sexually active young women 
The American Congress of Obstetricians and Gynecologists (ACOG) recently recommended that cervical cancer screening begin at 21 years of age and occur biennially for low-risk women younger than 30 years. Earlier studies suggested that women may have limited understanding of the differences between cervical cancer screening and chlamydia screening. This study assessed the knowledge of chlamydia and cervical cancer screening tests and schedules in younger women.
A survey regarding knowledge of chlamydia and cervical cancer screening was administered to 60 younger women aged 18–25 years in an obstetrics and gynaecology clinic at an urban community health centre.
The majority of respondents recalled having had a Pap smear (93.3%) or chlamydia test (75.0%). Although many respondents understood that a Pap smear checks for cervical cancer (88.3%) and human papillomavirus (68.3%), 71.7% mistakenly believed that a Pap smear screens for chlamydia. No respondent correctly identified the revised cervical cancer screening schedule, and 83.3% selected annual screening. Few respondents (23.3%) identified the annual chlamydia screening schedule and 26.7% were unsure.
Many younger women in an urban community health centre believed that cervical cancer screening also screens for chlamydia and were confused about chlamydia screening schedules. As there is limited knowledge of the revised ACOG cervical cancer screening guidelines, there is a risk that currently low chlamydia screening rates may decrease further after these new guidelines are better known. Obstetrician gynaecologists and primary care providers should educate younger women about the differences between chlamydia and cervical cancer screening and encourage sexually active younger women to have annual chlamydia screening.
PMCID: PMC3724364  PMID: 22123163
24.  Quality of screening with conventional Pap smear in Austria – a longitudinal evaluation 
BMC Public Health  2013;13:998.
In recent decades, the incidence of cervical cancer and cervical cancer mortality in Austria has declined by varying degrees. The Pap smear is to be considered a causal factor for this decline.
This longitudinal analysis is based on a data set of Pap smear assessments collected by the Committee for Quality Assurance of the Austrian Society of Cytology. Data from 15 laboratories participating in a voluntary self-monitoring program was analyzed for the time span 2004–2008. The data was analyzed in terms of smear quality and assessment quality.
A rank-correlation-test for a monotonic trend analysis in the proportion of the three parameters Pap 0, “satisfactory, but limited/SBL”, and Pap IIID/IV for the timespan 2004 to 2008 was carried out.
For this study, we analyzed an average number of 730,000 smears per year over a five-year period. Specimens from all but two laboratories, i.e. < 2% of all smears, met the quality criterion for Pap 0 (Bethesda 2001 equivalent: Specimen processed and examined, but unsatisfactory for evaluation of epithelial abnormality), whilst only four laboratories, i.e. < 10% of all smears, reached the national requirement for smears classified as “satisfactory, but limited/SBL”.
When using the Pap IIID/IV ratio (LSIL: HSIL/AIS ratio) of 3:1 to 8:1 as a surrogate quality marker for the interpretation of smears, only five laboratories met this criterion during the survey period.
The trend analysis indicated only that an increasing number of samples per year is correlated with an increased proportion of Pap 0 and “satisfactory, but limited/SBL” smears.
Although participants get regular feedback about their results, no general improvements in smear taking or assessment were observed over the years, so mandatory quality management, including the possibility of sanctions, is suggested in order to reduce adverse health effects for women.
PMCID: PMC4015555  PMID: 24152300
Quality assurance; Pap smear; Screening; Austria; Self-monitoring
25.  Community Health Worker Intervention to Decrease Cervical Cancer Disparities in Hispanic Women 
Journal of General Internal Medicine  2010;25(11):1186-1192.
U.S. Hispanic women suffer a disproportionate burden of cervical cancer, with incidence and mortality rates almost twice that of whites. Community health workers, or promotoras, are considered a potential strategy for eliminating such racial and ethnic health disparities. The current study is a randomized trial of a promotora-led educational intervention focused on cervical cancer in a local Hispanic community.
Four promotoras led a series of two workshops with community members covering content related to cervical cancer. Sociodemographic characteristics, cervical cancer risk, previous screening history, cervical cancer knowledge, and self-efficacy were measured by a pre-intervention questionnaire. The post-intervention questionnaire measured the following outcomes: cervical cancer knowledge (on a 0–6 scale), self-efficacy (on a 0–5 scale), and receipt of Pap smear screening during the previous 6 months (dichotomous). Univariate analyses were performed using chi square, t-test, and the Mann–Whitney test. Multivariate logistic regression was used to model the association between explanatory variables and receipt of Pap smear screening.
There were no statistically significant differences between the two experimental groups at baseline. Follow-up data revealed significant improvements in all outcome measures: Pap smear screening (65% vs. 36%, p-value 0.02), cervical cancer knowledge (5.4 vs. 3.5, p-value < 0.001), and self-efficacy (4.7 vs. 4.0, p-value 0.002). In multivariate analysis, cervical cancer knowledge (OR 1.68, 95% CI 1.10-2.81) and intervention group assignment (OR 6.74, 95% CI 1.77-25.66) were associated with receiving a Pap smear during the follow-up period.
Our randomized trial of a promotora-led educational intervention demonstrated improved Pap screening rates, in addition to increased knowledge about cervical cancer and self-efficacy. The observed association between cervical cancer knowledge and Pap smear receipt underscores the importance of educating vulnerable populations about the diseases that disproportionately affect them. Future research should evaluate such programs on a larger scale, and identify novel targets for intervention.
Electronic supplementary material
The online version of this article (doi:10.1007/s11606-010-1434-6) contains supplementary material, which is available to authorized users.
PMCID: PMC2947642  PMID: 20607434
cervical cancer; health disparities; community health worker; promotora

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