Chlamydia trachomatis and risk of cervical intraepithelial neoplasia grade 3 or worse in women with persistent human papillomavirus infection: a cohort study.

OBJECTIVES: Some studies suggest that Chlamydia trachomatis (CT) enhances cervical carcinogenesis; however, a possible confounding effect of persistent human papillomavirus (HPV) infection was not addressed. We examined the potential role of CT infection in the development of subsequent cervical intraepithelial neoplasia grade 3 or worse (CIN3+) in women with prevalent HPV infection and in a subgroup of women with persistent HPV infection. METHODS: Participants in this population-based cohort study underwent a structured interview, including history of CT infection, and subsequently cervical exfoliated cells were obtained for HPV DNA and CT DNA testing. Women with high-risk HPV DNA infection and no prevalent cervical disease constituted the overall study population (n=1390). A subgroup of women with persistent HPV infection (n=320) was also identified. All women were passively followed for development of cervical lesions in the national Pathology Data Bank. HRs and 95% CIs for CIN3+ during follow-up (up to 19 years) were estimated in an accelerated failure time model. RESULTS: Women who reported more than one CT infection had a statistically significantly increased risk of CIN3+ (high-risk HPV-positive, HR=2.51, 95% CI 1.44 to 4.37) (persistent HPV infection, HR=3.65, 95% CI 1.53 to 8.70). We found no association between CT DNA and subsequent risk of CIN3+ among women who were HPV-positive or had a persistent HPV infection at baseline. CONCLUSIONS: Repeated CT infections increased the risk of CIN3+ among women with prevalent as well as persistent high-risk HPV infection.

Risk for cervical intraepithelial neoplasia grade 3 or worse in relation to smoking among women with persistent human papillomavirus infection.

BACKGROUND: Smoking has been associated with cervical cancer. We examined whether smoking increases the risk for high-grade cervical lesions in women with high-risk human papillomavirus (HPV) infection. METHODS: In a population-based cohort study, 8,656 women underwent a structured interview, and subsequently cervical cells were obtained for HPV DNA testing. Women with high-risk HPV infection and no prevalent cervical disease at baseline (n = 1,353) were followed through the Pathology Data Bank for cervical lesions for up to 13 years. Separate analyses of women with persistent high-risk HPV infection (n = 312) were also conducted. HRs for a diagnosis of cervical intraepithelial neoplasia grade 3 or worse/high-grade squamous intraepithelial lesions or worse (CIN3+) and the corresponding 95% confidence intervals (CI) were calculated in the two groups. RESULTS: Among high-risk HPV-positive women, an increased risk for CIN3+ was associated with long-term smoking (≥10 years) and heavy smoking (≥20 cigarettes/d). In the subgroup of women with persistent HPV infection, heavy smoking was also associated with a statistically significantly higher risk for CIN3+ than never smoking (HR, 1.85; 95% CI, 1.05-3.22, adjusted for length of schooling, parity, and HPV type at baseline). The average number of cervical cytology screening tests per year during follow-up did not explain the differences in risk in relation to smoking (P = 0.4). CONCLUSIONS: Smoking is associated with an increased risk for subsequent high-grade cervical lesions in women with persistent high-risk HPV infection. IMPACT: Our study adds to the understanding of the role of smoking in the natural history of HPV and cervical carcinogenesis.

Statistical power of disease cluster and clustering tests for rare diseases: a simulation study of point sources.

Two recent epidemiological studies on clustering of childhood leukemia showed different results on the statistical power of disease cluster and clustering tests, possibly an effect of spatial data aggregation. Eight different leukemia cluster scenarios were simulated using individual addresses of all 1,009,332 children living in Denmark in 2006. For each scenario, a number of point sources were defined with an increased risk ratio at centroid, decreasing linearly to 1.0 at the edge; aggregation levels were administrative units of Danish municipalities and squares of 5, 12.5 and 25 km(2). Six statistical methods were compared. Generally, statistical power decreased with increasing size of aggregated units. In our scenarios, statistical tests based on individual data usually had lower statistical power than the best test based on aggregated data. In conclusion, spatial aggregation does not necessarily blur a clustering effect; this depends on the nature of clustering and the aggregated units.

Knowledge and attitude of final - year medical students in Germany towards palliative care - an interinstitutional questionnaire-based study.

BACKGROUND: To care for terminally ill and dying patients requires a thorough medical education, encompassing skills, knowledge, and attitudes in the field of palliative care. Undergraduate medical students in Germany will receive mandatory teaching in palliative care in the near future driven by recent changes in the Medical Licensure Act. Before new curricula can be implemented, the knowledge of medical students with respect to palliative care, their confidence to handle palliative care situations correctly, their therapeutic attitude, and their subjective assessment about previous teaching practices have to be better understood. METHOD: We designed a composite, three-step questionnaire (self estimation of confidence, knowledge questions, and opinion on the actual and future medical curriculum) conducted online of final - year medical students at two universities in Germany. RESULTS: From a total of 318 enrolled students, 101 responded and described limited confidence in dealing with specific palliative care issues, except for pain therapy. With regard to questions examining their knowledge base in palliative care, only one third of the students (33%) answered more than half of the questions correctly. Only a small percentage of students stated they had gained sufficient knowledge and experience in palliative care during their studies, and the vast majority supported the introduction of palliative care as a mandatory part of the undergraduate curriculum. CONCLUSION: This study identifies medical students' limited confidence and knowledge base in palliative care in 2 German universities, and underlines the importance of providing a mandatory palliative care curriculum.

Suicide in Danish women evaluated for fertility problems.

BACKGROUND: Women with fertility problems often experience higher levels of stress, anxiety and depressive symptoms associated with both the infertility diagnosis and eventual fertility treatment. The authors investigated whether women who do not succeed in having a child after an infertility evaluation are at a higher risk of suicide than women who succeed in having a child after an infertility evaluation. METHODS: A cohort of 51 221 Danish women with primary or secondary infertility and referred to hospitals or private fertility clinics in Denmark during 1973-1998 was established. The cohort was linked to four Danish administrative population-based registries. Each woman was followed from the date of her initial fertility evaluation at the clinic or hospital until 2006. Cox proportional hazards regression analyses was used to calculate hazard ratios (HRs) for suicide and their corresponding 95% confidence intervals (CIs) adjusted for potential confounders. RESULTS: Women who did not have a child after an initial fertility evaluation had a >2-fold (HR: 2.43; 95% CI: 1.38-3.71) greater risk of suicide than women who had at least one child after a fertility evaluation. Women with secondary infertility, i.e. women who had a child before a fertility evaluation but did not succeed in having one after, also had an increased risk for suicide (HR: 1.68; 95% CI, 0.82-3.41) compared with women who succeeded in having another child, although the risk estimate failed to reach significance. CONCLUSIONS: Health-care personnel treating women with fertility problems should be aware of the emotional response of their patients in order to recognize and treat possible psychiatric morbidity after fertility problems.

Spatial clustering of leukemia and type 1 diabetes in children in Denmark.

It has been proposed that type 1 diabetes (T1D) and leukemia in children may cluster in space and time due to common spatially mediated etiologies. We investigated this hypothesis and clustering of both diseases separately in Danish children aged 0-14 years, using 1,168 leukemia cases diagnosed in the period 1980-2006, 2,443 T1D cases diagnosed 1996-2006, and population-based controls matched on age, gender, and time of diagnosis. Residential histories from birth to diagnosis were collected. For leukemia in ages 0-14 years, we found no evidence of clustering; we did find spatial clustering at time of diagnosis for children aged 2-6 years with acute lymphoblastic leukemia (ALL) (observed/expected [95% confidence interval]: 1.35 [1.15-1.54]). T1D cases showed clustering at birth for ages 0-14 years; for ages 0-4 years at diagnosis, and when the residential history was accounted for. T1D cases clustered near leukemia cases particularly in the age group 2-6 years at diagnosis. Leukemia and T1D in this age group thus may share etiological factors mediated by geographic location. This suggests common environmental risk factors, with exposure to infections as first possible candidate, geographically localized exposure to agents that compromise development and/or response of the immune system being a second, and chance being a third.

Integrated genetic and epigenetic analysis of bladder cancer reveals an additive diagnostic value of FGFR3 mutations and hypermethylation events.

The bladder cancer genome harbors numerous oncogenic mutations and aberrantly methylated gene promoters. The aim of our study was to generate a profile of these alterations and investigate their use as biomarkers in urine sediments for noninvasive detection of bladder cancer. We systematically screened FGFR3, PIK3CA, TP53, HRAS, NRAS and KRAS for mutations and quantitatively assessed the methylation status of APC, ARF, DBC1, INK4A, RARB, RASSF1A, SFRP1, SFRP2, SFRP4, SFRP5 and WIF1 in a prospective series of tumor biopsies (N = 105) and urine samples (N = 113) from 118 bladder tumor patients. We also analyzed urine samples from 33 patients with noncancerous urinary lesions. A total of 95 oncogenic mutations and 189 hypermethylation events were detected in the 105 tumor biopsies. The total panel of markers provided a sensitivity of 93%, whereas mutation and methylation markers alone provided sensitivities of 72% and 70%, respectively. In urine samples, the sensitivity was 70% for all markers, 50% for mutation markers and 52% for methylation markers. FGFR3 mutations occurred more frequently in tumors with no methylation events than in tumors with one or more methylation events (78% vs. 33%; p < 0.0001). FGFR3 mutation in combination with three methylation markers (APC, RASSF1A and SFRP2) provided a sensitivity of 90% in tumors and 62% in urine with 100% specificity. These results suggest an inverse correlation between FGFR3 mutations and hypermethylation events, which may be used to improve noninvasive, DNA-based detection of bladder cancer.

Spatial clustering and space-time clusters of leukemia among children in Germany, 1987-2007.

Leukemia is the most frequent malignancy in children under the age of 15 years. The question of whether childhood leukemia has a tendency for clustering or forms clusters has been studied for several decades. The environmental risk factor discussed most often is infection, which might result in spatial clustering and space-time clusters. The German Childhood Cancer Registry provided data on 11,946 children with leukemia diagnosed during 1987-2007, as classified in the International Classification for Childhood Cancer (third edition), aggregated by municipality. We used the Potthoff-Whittinghill model to test for a general trend for clustering and the spatial scan statistic to search for localized clusters. No evidence of global clustering was found, neither for the whole study population nor in sub-groups by age, period or population density, or for different types of leukemia. A similar result was found for localized clusters. The analysis shows no evidence of a tendency to clustering, however, aggregation of data at the municipality level might have diluted small localized clusters. The results of this study do not provide support for the hypothesis of an infectious or a spatial environmental etiology of childhood leukemia.

Testicular germ cell cancer incidence in an immigration perspective, Denmark, 1978 to 2003.

PURPOSE: The incidence rate of testicular germ cell cancer in Denmark increased up to the 1990s to become among the highest in the world. Since recently rate stabilization was suggested, we determined whether it is due to an increasing number of immigrants at lower risk for this cancer. MATERIALS AND METHODS: The immigration status of more than 3.6 million men registered in the Danish Central Population Register between 1978 and 2003 was defined by birthplace (first generation immigrant) or parental birthplace (second generation immigrant). Linkage with the Danish Cancer Registry yielded 6,478 testicular cancer cases. Differences between populations are shown as SIR with the 95% CI. RESULTS: The testicular germ cell cancer incidence rate in first generation immigrants was lower than in native born Danish men (SIR 0.4, 95% CI 0.4-0.5). The rate in second generation immigrants was similar (SIR 0.9, 95% CI 0.7-1.1). The impact of immigrant status on the incidence rate increased with time from 0.6% in 1978 to 8.2% in 2003. Recent incidence rates in all men and only in men born in Denmark suggest stabilization. CONCLUSIONS: Our finding of a higher incidence rate in second generation immigrants than in their immigrant fathers confirms the early life programming of environmental factors in the etiology of testicular cancer. Our study also shows that trend analysis of the incidence rate of this cancer should consider immigration due to considerable country specific differences in morbidity.

An evaluation of exposure metrics in an epidemiologic study on radio and television broadcast transmitters and the risk of childhood leukemia.

Electric field strength values calculated by wave propagation modeling were applied as an exposure metric in a case-control study conducted in Germany to investigate a possible association between radio frequency electromagnetic fields (RF-EMF) emitted from television and radio broadcast transmitters and the risk of childhood leukemia. To validate this approach it was examined at 850 measurement sites whether calculated RF-EMF are an improvement to an exposure proxy based on distance from the place of residence to a transmitter. Further, the agreement between measured and calculated RF-EMF was explored. For dichotomization at the 90% quantiles of the exposure distributions it was found that distance agreed less with measured RF-EMF (Kappa coefficient: 0.55) than did calculated RF-EMF (Kappa coefficient: 0.74). Distance was a good exposure proxy for a single transmitter only which uses the frequency bands of amplitude modulated radio, whereas it appeared to be of limited informative value in studies involving several transmitters, particularly if these are operating in different frequency bands. The analysis of the agreement between calculated RF-EMF and measured RF-EMF showed a sensitivity of 76.6% and a specificity of 97.4%, leading to an exposure misclassification that still allows one to detect a true odds ratio as low as 1.4 with a statistical power of >80% at a two-sided significance level of 5% in a study with 2,000 cases and 6,000 controls. Thus, calculated RF-EMF is confirmed to be an appropriate exposure metric in large-scale epidemiological studies on broadcast transmitters.

Childhood leukemia in relation to radio frequency electromagnetic fields in the vicinity of TV and radio broadcast transmitters.

A case-control study of radio frequency electromagnetic fields (RF-EMFs) and childhood leukemia was conducted in West Germany. The study region included municipalities near high-power radio and TV broadcast towers, including 16 amplitude-modulated and 8 frequency-modulated transmitters. Cases were aged 0-14 years, were diagnosed with leukemia between 1984 and 2003, and were registered at the German Childhood Cancer Registry. Three age-, gender-, and transmitter-area-matched controls per case were drawn randomly from population registries. The analysis included 1,959 cases and 5,848 controls. Individual exposure to RF-EMFs 1 year before diagnosis was estimated with a field strength prediction program. Considering total RF-EMFs, the odds ratio derived from conditional logistic regression analysis for all types of leukemia was 0.86 (95% confidence interval: 0.67, 1.11) when upper (>or=95%/0.701 V/m) and lower (<90%/0.504 V/m) quantiles of the RF-EMF distribution were compared. An analysis of amplitude-modulated and frequency-modulated transmitters separately did not show increased risks of leukemia. The odds ratio for all types of leukemia was 1.04 (95% confidence interval: 0.65, 1.67) among children living within 2 km of the nearest broadcast transmitter compared with those living at a distance of 10-<15 km. The data did not show any elevated risks of childhood leukemia associated with RF-EMFs.

Social inequality and incidence of and survival from tumours of the central nervous system in a population-based study in Denmark, 1994-2003.

We investigated the effects of socioeconomic, demographic and health-related indicators on the incidence of and survival from tumours of the central nervous system (CNS) diagnosed in 1994-2003 with follow-up through 2006 in Denmark using information from nationwide Danish administrative registers. The analyses were based on data on 5622 patients with CNS tumours in a cohort of 2.7 million people born between 1925 and 1973 and aged >or=30 years. Socioeconomic and demographic factors were not associated with the incidence of CNS tumours, except for a significantly increased incidence rate ratio (IRR) amongst men in the agricultural class (IRR, 1.23; 95% CI, 1.04-1.45). The 1- and 5-year survival was significantly longer in higher socioeconomic groups, as assessed by education, income, affiliation to the work market and size of dwelling. Socioeconomic position does not affect the incidence of CNS tumours but appears to be a prognostic factor for survival from CNS tumours in Denmark.

Case-control study on childhood cancer in the vicinity of nuclear power plants in Germany 1980-2003.

The 1984 Windscale study raised concern about a possible association between living in the vicinity of nuclear power plants and childhood cancer. No such effect for all cancers was seen in ecological studies in Germany (1980-1995). Results from exploratory analyses led to a new study. Pre-selected areas around all 16 major nuclear power plants in Germany formed the study area. The design is a matched case-control study; cases are all cancers under five years diagnosed in 1980-2003: 1592 cases, and 4735 controls. Inverse distance of place of residence to the nearest nuclear power plant at the time of diagnosis was used as the independent variable in a conditional logistic regression model. Results show an increased risk for childhood cancer under five years when living near nuclear power plants in Germany. The inner 5-km zone shows an increased risk (odds ratio 1.47; lower one-sided 95% confidence limit 1.16). The effect was largely restricted to leukaemia. The results are compatible with the corresponding subgroups in the previous German ecological studies, with which this study shares most of the cases. They contrast with the lack of an effect observed or expected from other studies due to low doses from routine nuclear power plant operation.

Leukaemia in young children living in the vicinity of German nuclear power plants.

A case control study was conducted where cases were children younger than 5 years (diseased between 1980 and 2003) registered at the german childhood cancer registry (GCCR). Population-based matched controls (1:3) were selected from the corresponding registrar's office. Residential proximity to the nearest nuclear power plant was determined for each subject individually (with a precision of about 25 m). The report is focused on leukaemia and mainly on cases in the inner 5-km zone around the plants. The study includes 593 leukaemia cases and 1,766 matched controls. All leukaemia combined show a statistically significant trend for 1/distance with a positive regression coefficient of 1.75 [lower 95%-confidence limit (CL): 0.65]; for acute lymphoid leukaemia 1.63 (lower 95%-CL: 0.39), for acute nonlymphocytic leukaemia 1.99 (lower 95%-CL: -0.41). This indicates a negative trend for distance. Cases live closer to nuclear power plants than the randomly selected controls. A categorical analysis shows a statistically significant odds ratio of 2.19 (lower 95%-CL: 1.51) for residential proximity within 5 km compared to residence outside this area. This result is largely attributed to cases in previous studies of the GCCR (especially in the inner zone) as there is clearly some overlap between those studies. The result was not to be expected under current radiation-epidemiological knowledge. Considering that there is no evidence of relevant accidents and that possible confounders could not be identified, the observed positive distance trend remains unexplained.