Population fraction of cervical neoplasia attributable to high-risk human papillomaviruses.

AIMS: The efficacy of human papillomavirus (HPV) type 16 and 18 vaccines against cervical intraepithelial neoplasia grade II (CIN2+) has been verified, but the active follow-up of studies with invasive cervical cancer or cervical intraepithelial neoplasia grade III (CIN3) as primary end points are ethically not possible. Furthermore, ongoing registry-based passive follow-up studies with invasive cervical cancer as the end point will take time. MATERIALS & METHODS: To evaluate the feasibility of CIN3 as a surrogate end point, we compared high-risk (hr) HPV-associated relative risk and population attributable fraction (PAF) of CIN3 and/or squamous cell carcinoma (SCC) estimated in a large serological case-cohort HPV study. Our case-cohort comprised 83 SCC and 389 CIN3 cases and a subcohort of 7862 out of 230,998 Finnish women, who at baseline were under 32 years of age and had undergone a minimum of two pregnancies within 5 years during 1983-1997. RESULTS: PAFs of the case-cohort, approach-based, serologically defined and misclassification-corrected HPV16 and hrHPV (HPV types 16, 18, 31 and 33) exposures in the SCC samples were 61% (95% CI: 18-85) and 73% (95% CI: 13-93), respectively. Considerably lower HPV16 and hrHPV PAF estimates in CIN3 of 6% (95% CI: -19-35) and 36% (95% CI: -5-65), respectively, were obtained. A meta-analysis-derived, PCR-based, hrHPV-associated relative risk estimate of 20.3 in CIN2/3+ yielded a PAF estimate for hrHPV in CIN2/3+ of 86% (90% CI: 63-95) in our study population. The former, hrHPV serology-based CIN3 PAF estimates were biased owing to low sensitivity of HPV16 and/or HPV16/18/31/33 serology, most notably in cervical cancer precursor lesions, but the latter estimate overlapped with our hrHPV serology-based cervical cancer PAF estimate. CONCLUSION: CIN3 may be a valid surrogate efficacy end point for HPV vaccination studies, but the associated causality of multiple hrHPV exposures needs to be unambigously defined.

Shift work, occupational noise and physical workload with ensuing development of blood pressure and their joint effect on the risk of coronary heart disease.

OBJECTIVES: The change in systolic blood pressure (SBP) over an 8-year period was explored in groups defined according to exposure to shift work, occupational noise, and physical workload. The impact of baseline SBP and its increase in relation to coronary heart disease (CHD) risk due to these exposures was also studied. METHODS: The study cohorts (N=1288 for CHD follow-up, N=884 for SBP follow-up) consisted of industrially employed middle-aged men from the Helsinki Heart Study. Shiftwork status was obtained from a questionnaire, and other exposures were determined with the Finnish job-exposure matrix. SBP was measured in the Helsinki Heart Study, and CHD end points were obtained from official Finnish registers. The joint effects of baseline SBP, its change, and the exposure in question were estimated via Cox s regression models. RESULTS: During the SBP follow-up, the steepest SBP gradient was found for physical workload only and physical workload combined with noise; shift work alone or combined with noise primarily entailed a lower mean SBP level than no such exposure. However, the shift workers had a relative risk of 1.71 [95% confidence interval (95% CI) 1.01-2.87] even without an increase in SBP, but, with a baseline SBP of > or = 140 mmHg and an additional increase, their relative risk rose to 4.62 (95% CI 2.31-9.24) when they were compared with day workers with an SBP of <140 mmHg and no increase. CONCLUSIONS: In general, shift workers do not develop higher SBP levels than day workers, but, if they do, it entails high CHD risk. Noise shows a similar pattern. In contrast, physical workload entails a significant increase in SBP, and SBP is a key pathway to CHD risk.

The sense of coherence and incidence of cancer--role of follow-up time and age at baseline.

OBJECTIVE: We studied the effect of the sense of coherence (SOC) on cancer incidence, the role of age at baseline, and the length of the follow-up in that association. METHODS: Five thousand eight hundred sixty-six middle-aged men initially in working life were followed up for 12 years after measurement of the SOC. The relative risks (RRs) of cancer were estimated using Cox regression models. RESULTS: For all cancers combined in 8-year follow-up, those with a weak SOC had a higher RR of cancer 1.52 [95% confidence interval (CI), 1.12-2.06] than those with a strong SOC. However, the effect weakened in 12-year follow-up (RR 1.14; 95% CI 0.93-1.42). The greatest risk was seen in a subcohort consisting of those aged >or=55 years at baseline with a weak SOC: the RR was 1.65 (1.12-2.43) in 8-year follow-up and 1.40 (1.05-1.85) in 12-year follow-up. CONCLUSION: A strong SOC seemed to delay the onset of cancer more clearly among men over 55 years of age.

Chlamydia pneumoniae antibody levels before coronary events in the Helsinki Heart Study as measured by different methods.

The lack of specific tests for the diagnosis of chronic Chlamydia pneumoniae infection has led to the use of enzyme immunoassay (EIA) instead of the gold standard, that is, microimmunofluorescence (MIF), in the measurement of C. pneumoniae antibodies. We assessed the predictive values of C. pneumoniae antibody levels and seroconversions measured by MIF and EIA for coronary events in the prospective Helsinki Heart Study. Sera from 239 cases with coronary events and 239 controls were available at the baseline and data from 210 cases and 211 controls before and after the event. The agreement between MIF and EIA antibody levels was best in high antibody titers. In conditional logistic regression analysis, only high IgA MIF titers (>/=40) at the baseline predicted future coronary events, and the participants with MIF seroconversion between consecutive sera had a higher (nonsignificant) risk for coronary events than the controls. The difference in the kinetics of EIA and MIF antibodies demonstrated that MIF should remain the gold standard.

Gemfibrozil in the treatment of dyslipidemia: an 18-year mortality follow-up of the Helsinki Heart Study.

BACKGROUND: The Helsinki Heart Study was a double-blind, placebo-controlled primary prevention trial among 4081 dyslipidemic middle-aged men to test the efficacy of gemfibrozil in the prevention of coronary heart disease (CHD). After the 5-year trial, the participants were notified of their treatment group and invited to continue or start gemfibrozil therapy free of charge through 1995. Approximately two thirds of participants in both groups chose gemfibrozil therapy. In this 18-year follow-up through 2000, we compared the CHD, cancer, and all-cause mortality among subjects in the original gemfibrozil (OG) group (n = 2046) with those in the original placebo (OP) group (n = 2035). METHODS: To provide an overview of the absolute risks in the 2 treatment groups as well as risk differences between them, we calculated crude mortality rates and presented Kaplan-Meier plots of survival with log-rank tests. We also estimated the relative risks (RRs) using Cox proportional hazards models with and without covariates. RESULTS: During the follow-up until 1995, subjects in the OG group had a 32% lower RR of CHD mortality (P = .03) compared with those in the OP group, and when followed up until 2000, the RR was 23% lower (P = .05). Overall, there were no differences in all-cause or cancer mortality. However, those in the OG group with both body mass index and triglyceride level in the highest tertiles had a 71% lower RR of CHD mortality (P<.001), a 33% lower RR of all-cause mortality (P = .03), and a 36% lower RR of cancer mortality (P = .22) compared with those in the OP group. CONCLUSION: Long-term mortality follow-up showed that patients with dyslipidemia benefited from beginning treatment with gemfibrozil early, especially if their dyslipidemia entailed factors related to the metabolic syndrome.

Effects of different phases of an invitational screening program on breast cancer incidence.

The aim of this study was to quantify the effects of separate phases of an invitational screening program on breast cancer incidence at different ages. Our database included detailed municipality-specific information about invitations for mass-screening for breast cancer in 267 Finnish municipalities from time period 1987-2001. The age range was 50-74. For this study, the program was divided into 7 separate phases, and those that had not been invited served as a baseline. The incidence rate was modeled using Poisson regression. To study the differences between age groups within each program phase, an interaction term between age group and phase of screening was included in the model. The modeling was done separately for localized breast cancers, nonlocalized breast cancers and all stages combined. For localized cancers, the risk compared to the noninvited increased during the first years of the 2-year screening rounds in all age groups, and declined below the baseline during the second years. This effect was larger during the first round compared to the subsequent ones. In nonlocalized cancers, a clear incidence peak was detected only during the first year of the first round. A decreasing post screening effect was detected in nonlocalized cancers in women aged 60-69, but not in localized cancers. Cumulating over ages 50-74, extra incidence caused by regular screening in localized cancers was 5.2% if the program was continued up to age 59, and 28.0% if it continued up to age 69. Corresponding figures for nonlocalized cancers were decreases of 19.8% and 20.9%, respectively.

Long-term effect of occupational noise on the risk of coronary heart disease.

OBJECTIVES: The aim of the study was to investigate the short- and long-term effects of occupational exposure to continuous and impulse noise on the risk of CHD. METHODS: The effect of noise on CHD was studied among 6005 Finnish middle-aged industrially employed men (part of the screeners in the Helsinki Heart Study) in a prospective 18-year follow-up study. The CHD end points (codes 410-414 in the ninth revision of the International Classification of Diseases and codes I20-I25 in the tenth revision) were obtained from official Finnish registers. The Finnish job-exposure matrix FINJEM provided estimates of the proportion of exposed persons and the mean level of exposure among those exposed by occupation. The relative risks (RR) of CHD and the 95% confidence intervals (95% CI) for noise exposure were calculated from Cox's proportional hazard models with adjustment for some other risk factors of CHD. RESULTS: The short-term (9-year follow-up) relative risk of CHD for the combined noise (continuous noise exceeding 80 decibels and impulse noise) was 1.38 (95% CI 1.04-1.82), and the long-term (18-year follow-up) RR was 1.54 (95% CI 1.28-1.86). For blue-collar workers the corresponding estimates were 1.11 (95% CI 0.82-1.51) and 1.29 (95% CI 1.05-1.57). Adjustment for other relevant risk factors did not materially change the results. CONCLUSIONS: In our long-term follow-up of industrially employed men, exposure to noise, especially to impulse noise, was associated with a moderate, but statistically significant increase in CHD risk that persisted even after the workers had passed the age of retirement.

Synergistic effect of persistent Chlamydia pneumoniae infection, autoimmunity, and inflammation on coronary risk.

BACKGROUND: Given the role of chronic infections, autoimmunity, and inflammation in atherosclerosis, we studied the joint effect of chronic Chlamydia pneumoniae infection, persistently elevated human heat-shock protein 60 (hHsp60) antibodies, and C-reactive protein (CRP) on coronary risk. METHODS AND RESULTS: The participants for this prospective nested case-control study were obtained from the Helsinki Heart Study, during which 241 nonfatal myocardial infarctions or coronary deaths occurred among 4081 dyslipidemic middle-aged men. Serum samples taken at baseline and 3 to 6 months before the coronary events that occurred during the 8.5-year period were analyzed for antibodies to C pneumoniae and hHsp60 and the CRP concentration. Compared with persistently low levels, the risk of coronary events was 2-fold for persistently elevated immunocomplex (IC)-bound and/or serum IgA antibodies to C pneumoniae (OR, 1.96; 95% CI, 1.14 to 3.36) and also for serum IgA antibodies to hHsp60 (OR, 2.11; 95% CI, 1.08 to 4.13). The risks associated with elevated antibodies were much higher when CRP was also elevated. Compared with low or transiently elevated levels, the risk of coronary events, with adjustment for age and smoking, was 4.5-fold for persistently elevated CRP and C pneumoniae IC/IgA antibodies together (OR, 4.47; 95% CI, 1.84 to 10.83) and was similar for CRP and hHsp60 IgA antibodies together (OR, 4.36; 95% CI, 1.53 to 12.39). CONCLUSIONS: Persistently but not transiently elevated C pneumoniae IC/IgA and hHsp60 IgA antibodies, especially when present together with an elevated CRP level, predicted coronary events.

Autoimmunity to human heat shock protein 60, Chlamydia pneumoniae infection, and inflammation in predicting coronary risk.

Heat shock protein 60 (Hsp60) and Chlamydia pneumoniae infection have both been associated with cardiovascular diseases. Our aim was to study the role of Hsp60 antibodies as coronary risk predictors and their association with C pneumoniae infection and inflammation. This was a prospective, nested, case-control study. The cases consisted of 239 middle-aged Finnish men who developed myocardial infarction or coronary death during the follow-up. Baseline levels of IgA and IgG antibodies to human-specific and C pneumoniae-specific Hsp60 were measured by enzyme immunoassay. Human Hsp60 IgA, but not IgG or C pneumoniae Hsp60, antibodies were a significant risk factor for coronary events (odds ratio 2.0, 95% CI 1.1 to 3.6, when the fourth and first quartiles are compared). When an elevated human Hsp60 IgA antibody level (above the second quartile) was present simultaneously with a high C pneumoniae IgA antibody level (the third quartile) and an elevated C-reactive protein level (the second quartile), compared with all factors at low levels, the risk was 7.0 (95% CI 2.6 to 19.1) without adjustment and 5.0 (95% CI 1.8 to 14.2) when adjustment was made for age and smoking. In conclusion, an elevated human Hsp60 IgA antibody level was a risk factor for coronary events, especially when it was present together with C pneumoniae infection and inflammation.