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Background: Reductions in breast cancer mortality observed over the last three decades are partly due to improved patient management, which may erode the benefit-harm balance of mammography screening., Methods: We estimated the numbers of women needed to invite (NNI) to prevent one breast cancer death within 10 years. Four scenarios of screening effectiveness (5-20% mortality reduction) were applied on 10,580 breast cancer deaths among Norwegian women aged 50-75 years from 1986 to 2016. We used three scenarios of overdiagnosis (10-40% excess breast cancers during screening period) for estimating ratios of numbers of overdiagnosed breast cancers for each breast cancer death prevented., Results: Under the base case scenario of 20% breast cancer mortality reduction and 20% overdiagnosis, the NNI rose from 731 (95% CI: 644-830) women in 1996 to 1364 (95% CI: 1181-1577) women in 2016, while the number of women with overdiagnosed cancer for each breast cancer death prevented rose from 3.2 in 1996 to 5.4 in 2016. For a mortality reduction of 8.7%, the ratio of overdiagnosed breast cancers per breast cancer death prevented rose from 7.4 in 1996 to 14.0 in 2016. For a mortality reduction of 5%, the ratio rose from 12.8 in 1996 to 25.2 in 2016., Conclusions: Due to increasingly potent therapeutic modalities, the benefit in terms of reduced breast cancer mortality declines while the harms, including overdiagnosis, are unaffected. Future improvements in breast cancer patient management will further deteriorate the benefit-harm ratio of screening., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Public Health Association.)

Background: Relative reduction in breast cancer mortality is the preferred outcome measure for evaluation of mammography screening. However, mean survival time has been advocated as a better and more intuitive outcome for risk communication. We have previously introduced a method to predict difference in mean survival time from empirical hazard ratios for all-cause mortality. In this article, we aim to investigate the association between hazard ratios for breast cancer mortality and the difference in mean survival time for women diagnosed with breast cancer., Methods: We retrieved data on all women diagnosed with first-time invasive breast cancer in Norway from 1960 through 2004. Women were followed until emigration or end of follow-up on 31 December 2015, whichever came first. Observed differences in mean survival times and hazard ratios for both breast cancer death and death from causes other than breast cancer were obtained for neighbouring time periods defined by women's age and year of diagnosis. Based on previously developed methods, we fitted a linear relationship between observed differences in mean survival and logarithmic hazard ratios., Results: A linear association was found between breast cancer-specific hazard ratios and difference in mean survival time for women diagnosed with breast cancer. This association was also estimated with adjustment for other causes of death than breast cancer., Conclusions: The change in mean survival time could be predicted from an estimated reduction in breast cancer mortality. This outcome measure can contribute to better and more understandable risk information about the effect of mammography screening programmes., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Public Health Association. All rights reserved.)

Background: Population-level knowledge on individuals at high risk of severe and fatal coronavirus disease 2019 (COVID-19) is urgently needed to inform targeted protection strategies in the general population., Methods: We examined characteristics and predictors of hospitalization and death in a nationwide cohort of all Danish individuals tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from 27 February 2020 until 19 May 2020., Results: We identified 11 122 SARS-CoV-2 polymerase chain reaction-positive cases of whom 80% were community-managed and 20% were hospitalized. Thirty-day all-cause mortality was 5.2%. Age was strongly associated with fatal disease {odds ratio [OR] 15 [95% confidence interval (CI): 9-26] for 70-79 years, increasing to OR 90 (95% CI: 50-162) for ≥90 years, when compared with cases aged 50-59 years and adjusted for sex and number of co-morbidities}. Similarly, the number of co-morbidities was associated with fatal disease [OR 5.2 (95% CI: 3.4-8.0), for cases with at least four co-morbidities vs no co-morbidities] and 79% of fatal cases had at least two co-morbidities. Most major chronic diseases were associated with hospitalization, with ORs ranging from 1.3-1.4 (e.g. stroke, ischaemic heart disease) to 2.6-3.4 (e.g. heart failure, hospital-diagnosed kidney disease, organ transplantation) and with mortality with ORs ranging from 1.1-1.3 (e.g. ischaemic heart disease, hypertension) to 2.5-3.2 (e.g. major psychiatric disorder, organ transplantation). In the absence of co-morbidities, mortality was <5% in persons aged ≤80 years., Conclusions: In this nationwide population-based COVID-19 study, increasing age and multimorbidity were strongly associated with hospitalization and death. In the absence of co-morbidities, the mortality was, however, <5% until the age of 80 years., (© The Author(s) 2020. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Study Question: Do maternal hypertensive disorders affect pubertal development in daughters and sons?, Summary Answer: Pubertal development tended to occur earlier in daughters of mothers with 'preeclampsia, eclampsia or HELLP syndrome' (hemolysis, elevated liver enzymes and low blood platelets) or hypertension in pregnancy compared to daughters born of normotensive mothers., What Is Known Already: The existing literature suggests some or no association between preeclampsia and pubertal development in daughters, but not in sons. None of the previous studies has investigated the possible association between other types of hypertensive disorders (hypertension, eclampsia or HELLP syndrome) and pubertal timing in children., Study Design, Size, Duration: Longitudinal cohort study consisting of 15 819 mother-child pairs with information on maternal hypertensive disorders collected during pregnancy and information on pubertal development collected half-yearly from the age of 11 years and until fully developed or 18 years of age., Participants/materials, Setting, Methods: Participants are children from the Puberty Cohort nested within the Danish National Birth Cohort. The exposure was register-based and self-reported information on maternal hypertensive disorders during pregnancy. The outcomes were children's self-reported information on pubertal development, including Tanner stage 1-5 (pubic hair (both daughters and sons) and breast development (daughters) or genital development (sons)), first menstrual bleeding (daughters) or first ejaculation (sons), voice break episode (sons), axillary hair development and acne occurrence (both daughters and sons). The main outcome was mean difference in age at attaining each pubertal milestone and a combined pubertal marker in children of mothers with hypertensive disorders in pregnancy (either hypertension (n = 490), 'preeclampsia, eclampsia or HELLP syndrome' (n = 419) or 'unspecific hypertensive disorders' (n = 334) with unexposed children as reference (n = 14 576))., Main Results and the Role of Chance: In daughters of mothers with 'preeclampsia, eclampsia or HELLP syndrome', we observed tendencies of earlier pubertal timing (combined marker: -2.0 (95% CI: -3.9; 0.0) months). In daughters of mothers with hypertension, several pubertal milestones tended to occur earlier than in daughters of normotensive mothers; however, all 95% CIs overlapped the null resulting in a combined pubertal marker of -1.0 (95% CI: -3.2; 1.1) months. In sons of mothers with any of the hypertensive disorders, we observed no difference in pubertal timing (combined markers: 'preeclampsia, eclampsia or HELLP syndrome': 0.1 (95% CI: -2.0; 2.1) months; hypertension: -0.6 (95% CI: -2.3; 1.1) months; 'unspecific hypertensive disorders': 0.2 (95% CI: -1.9; 2.2) months)., Limitations, Reasons for Caution: The study is subject to non-differential misclassification of self-reported information on maternal hypertensive disorders in pregnancy and current pubertal status; possibly causing bias toward the null., Wider Implications of the Findings: Hypertensive disorders in pregnancy might accelerate pubertal timing in daughters; however, more studies are needed for causal conclusions., Study Funding/competing Interest(s): The study was funded by the Faculty of Health at Aarhus University. The authors have no financial relationships or competing interests to disclose., Trial Registration Number: N/A., (© The Author(s) 2020. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: When comparing mammography-screening participants and non-participants, estimates of reduction in breast-cancer mortality may be biased by poor baseline comparability. We used negative controls to detect uncontrolled confounding., Methods: We designed a closed cohort of Danish women invited to a mammography-screening programme at age 50-52 years in Copenhagen or Funen from 1991 through 2001. We included women with a normal screening result in their first-invitation round. Based on their second-invitation round, women were divided into participants and non-participants and followed until death, emigration or 31 December 2014, whichever came first. We estimated hazard ratios (HRs) of death from breast cancer, causes other than breast cancer and external causes. We added dental-care participation as an exposure to test for an independent association with breast-cancer mortality. We adjusted for civil status, parity, age at first birth, educational attainment, income and hormone use., Results: Screening participants had a lower hazard of breast-cancer death [HR 0.47, 95% confidence interval (CI) 0.32, 0.69] compared with non-participants. Participants also had a lower hazard of death from other causes (HR 0.43, 95% CI 0.39, 0.46) and external causes (HR 0.35, 95% CI 0.23, 0.54). Reductions persisted after covariate adjustment. Dental-care participants had a lower hazard of breast-cancer death (HR 0.75, 95% CI 0.56, 1.01), irrespective of screening participation., Conclusions: Negative-control associations indicated residual uncontrolled confounding when comparing breast-cancer mortality among screening participants and non-participants., (© The Author(s) 2020. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background: Mammography screening increases incidence because cancers are detected earlier in time and because of overdiagnosis. We developed an Excel-based model to visualize the expected increase from lead-time amplified by increasing background incidence. Subsequently, we added overdiagnosis to the model., Methods: We constructed two hypothetical populations of women aged 50-79 in 5-year age and calendar groups: one with screening for women aged 50-69 and one without. The user enters information on population at risk, number of breast cancers, trends in background incidence, average length of lead-time and, optionally, overdiagnosis. The model computes incidence rate ratios (IRRs) comparing incidence changes with screening to changes without in open and closed cohorts., Results: We entered information from Norway from 1990 to 1994, the period preceding the gradual introduction of a national mammography screening programme. As expected, the Screening Illustrator showed prevalence peaks and compensatory drops. Only the closed cohort approach remained unaffected by increasing background incidence. The model showed a 20% sustained increase in incidence (IRR: 1.20) from lead-time and increasing background incidence in the open cohort approach for women aged 50-69. However, real life Norwegian data show a corresponding 38% increase. For the model to achieve the observed incidence, 10-14% overdiagnosis had to be added., Conclusion: The observed breast cancer incidence increase in Norway after screening implementation could not be obtained from an average lead-time of 2.5 years and empirical background incidence trends, but had to incorporate overdiagnosis.

Background: Screening is intended to advance diagnosis thereby shifting the stage distribution towards more locally confined stages. Consequently we aimed to estimate trends in stage-specific breast cancer in relation to the introduction of population-based screening., Methods: From the Cancer Registry of Norway we retrieved cancer stage, age and year of diagnosis on all women aged 20 or older diagnosed with breast cancer during the period 1987-2010 in Norway (approximate source population: 1.8 million). Three calendar-time periods were defined: before (1987-95), during (1996-2004), and after (2005-10) screening was introduced; and two age groups: women eligible for screening (50-69 years) or younger (20-49 years). Poisson regression was used to estimate the incidence of localized (stage I) and more advanced cancer (stages II+), respectively, and logistic regression to estimate the proportion of localized cancer., Results: The annual incidence of localized breast cancer among women aged 50-69 years rose from 63.9 per 100 000 before the introduction of screening to 141.2 afterwards, corresponding to a ratio of 2.21 (95% confidence interval: 2.10; 2.32). The incidence of more advanced cancers increased from 86.9 to 117.3 per 100 000 afterwards, corresponding to a 1.35 (1.29; 1.42)-fold increase. Advanced cancers also increased among younger women not eligible for screening, whereas their incidence of localized cancers remained nearly constant., Conclusion: Incidence of localized breast cancer increased significantly among women aged 50-69 years old after introduction of screening, while the incidence of more advanced cancers was not reduced in the same period when compared to the younger unscreened age group., (© The Author 2014. Published by Oxford University Press on behalf of the European Public Health Association. All rights reserved.)

Study Question: Does perfluorooctane sulfonate (PFOS) and perfluorooctanate (PFOA) exposure disrupt the menstrual cyclicity?, Summary Answer: The female reproductive system may be sensitive to PFOA exposure, with longer menstrual cycle length at higher exposure., What Is Known Already: PFOS and PFOA are persistent man-made chemicals. Experimental animal studies suggest they are reproductive toxicants but epidemiological findings are inconsistent., Study Design, Size, Duration: A cross-sectional study including 1623 pregnant women from the INUENDO cohort enrolled during antenatal care visits between June 2002 and May 2004 in Greenland, Poland and Ukraine., Participants/materials, Setting, Methods: Information on menstrual cycle characteristics was obtained by questionnaires together with a blood sample from each pregnant woman. Serum concentrations of PFOS and PFOA were measured by liquid chromatography tandem mass spectrometry. Multiple imputations were performed to account for missing data. The association between PFOS/PFOA and menstrual cycle length (short cycle: ≤24 days, long cycle: ≥32 days) and irregularities (≥7 days in difference between cycles) was analyzed using logistic regression with tertiles of exposure. Estimates are given as adjusted odds ratios (ORs) with 95% confidence intervals (CIs)., Main Results and the Role of Chance: Higher exposure levels of PFOA were associated with longer menstrual cycles in pooled estimates of all three countries. Compared with women in the lowest exposure tertile, the adjusted OR of long cycles was 1.8 (95% CI: 1.0; 3.3) among women in the highest tertile of PFOA exposure. No significant associations were observed between PFOS exposure and menstrual cycle characteristics. However, we observed a tendency toward more irregular cycles with higher exposure to PFOS [OR 1.7 (95% CI: 0.8; 3.5)]. The overall response rate was 45.3% with considerable variation between countries (91.3% in Greenland, 69.1% in Poland and 26.3% in Ukraine)., Limitations, Reasons for Caution: Possible limitations in our study include varying participation rates across countries; a selected study group overrepresenting the most fertile part of the population; retrospective information on menstrual cycle characteristics; the determination of cut-points for all three outcome variables; and lacking information on some determinants of menstrual cycle characteristics, such as stress, physical activity, chronic diseases and gynecological disorders, thus confounding cannot be excluded., Wider Implications of the Findings: The generalizability of the study results is restricted to fertile women who manage to conceive and women who do not use oral contraceptives when getting pregnant or within 2 months before getting pregnant. To our knowledge only one previous epidemiological study has addressed the possible association between perfluorinated chemical exposure and menstrual disturbances. Though pointing toward different disturbances in cyclicity, both studies suggest that exposure to PFOA may affect the female reproductive function. This study contributes to the limited knowledge on effects of exposure to PFOA and PFOS on female reproductive function and suggests that the female reproductive system may be affected by environmental exposure to PFOA., Study Funding/competing Interest(s): Supported by a scholarship from Aarhus University Research Foundation. The collection of questionnaire data and blood samples was part of the INUENDO project supported by The European Commission (Contract no. QLK4-CT-2001-00 202), www.inuendo.dk. The Ukrainian part of the study was possible by a grant from INTAS (project 012 2205). Determination of PFOA and PFOS in serum was part of the CLEAR study (www.inuendo.dk/clear) supported by the European Commission's 7th Framework Program (FP7-ENV-2008-1-226217). No conflict of interest declared.

Background: Late diagnosis of cancer may partly be explained by the fact that some patients do not seek health care promptly when experiencing an alarm symptom. Socioeconomic and demographic differences exist concerning knowledge and awareness of cancer alarm symptoms in the general population and socioeconomic differences are found in cancer incidence and survival. We therefore hypothesise that socioeconomic and demographic differences in health care-seeking behaviour are present among people with alarm symptoms., Objectives: To analyse associations between health care seeking and socioeconomic and demographic factors among people reporting cancer alarm symptoms., Methods: A questionnaire survey comprising 20000 people aged >20 from the Danish population. The questionnaire concerned alarm symptoms of common cancers and subsequent health care seeking. Data on socioeconomic factors were obtained from Statistics Denmark., Main Outcomes: health care seeking and patient interval., Results: A total of 26.1% of all subjects reported that they did not seek health care when having experienced an alarm symptom. Women-subjects aged >40, subjects living with a partner and subjects having a cancer diagnosis-were more likely to seek health care, whereas medium educational level was negatively associated with health care seeking. Further, women were more likely to seek health care within 1 month, whereas subjects out of the workforce were less likely to do so., Conclusions: Approximately three out of four subjects sought health care when having experienced an alarm symptom but 50% waited for at least 1 month. Some demographic factors were found to be associated with health care-seeking behaviour and the patient interval, whereas no consistent associations were found with regard to socioeconomics.

Background: The European Heart SCORE model constitutes the basis for national guidelines for primary prevention and treatment of cardiovascular disease (CVD) in several European countries. The model estimates individuals' 10-year CVD mortality risks from age, sex, smoking status, systolic blood pressure, and total cholesterol level. The SCORE model, however, is not mathematically consistent and does not estimate all-cause mortality. Our aim is to modify the SCORE model to allow consistent estimation of both CVD-specific and all-cause mortality., Methods: Using a competing risk approach, we first re-estimated the cause-specific risk of dying from cardiovascular disease, and secondly we incorporated non-CVD mortality. Finally, non-CVD mortality was allowed to also depend on smoking status, and not only age and sex. From the models, we estimated CVD-specific and all-cause 10-year mortality risk, and the expected residual lifetime together with corresponding expected effects of statin treatment., Results: The modified model provided CVD-specific 10-year mortality risks similar to those of the European Heart SCORE model. Incorporation of non-CVD mortality increased 10-year mortality risks, in particular for older individuals. When non-CVD mortality was assumed unaffected by smoking status, the absolute risk reduction due to statin treatment ranged from 0.0% to 3.5%, whereas the gain in expected residual lifetime ranged from 3 to 11 months. Statin effectiveness increased for non-smokers and declined for smokers, when smoking was allowed to influence non-CVD mortality., Conclusion: The modified model provides mathematically consistent estimates of mortality risk and expected residual lifetime together with expected benefits from statin treatment.

Ephedrine and herbal ephedra preparations have been shown to induce a small-to-moderate weight loss. Owing to reports on serious cardiovascular events, they were banned from the US market in 2004. There have been no large controlled studies on the possible association between prescribed ephedrine/caffeine and cardiovascular events in general. The authors linked data from four different sources within Statistics Denmark, using data on 257,364 users of prescribed ephedrine/caffeine for the period 1995-2002. The data were analyzed using a case-crossover technique with a composite endpoint: death outside of a hospital, myocardial infarction, or stroke. To account for effects of chronic exposure and effects in naïve users, the authors performed a secondary case-control study nested within the cohort of ephedrine/caffeine ever users. Among 2,316 case subjects, 282 (12.2%) were current users of ephedrine/caffeine. The case-crossover analysis yielded an odds ratio of 0.84 (95% confidence interval: 0.71, 1.00); after adjustment for trends in ephedrine/caffeine use, it was 0.95 (95% confidence interval: 0.79, 1.16). Subgroup analyses revealed no strata with significantly elevated risk. In the case-control substudy, there was no increased risk among naïve users or users with large cumulative doses. Prescribed ephedrine/caffeine was not associated with a substantially increased risk of adverse cardiovascular outcomes in this study.

Studies in the United States have indicated that maternal first trimester smoking and infant transforming growth factor alpha (TGFA) locus mutations are associated with non-syndromic cleft lip and/or palate (CLP) and that a synergistic effect of these two risk factors occurs. Based on a Danish case-control study of CLP, the authors studied the effects of smoking and TGFA alleles in an ethnically homogeneous setting. Interview information was obtained for mothers of 302 CLP cases (96% of eligible) and for 567 mothers of nonmalformed children (94% of eligible). Multivariate logistic regression analyses revealed that smoking was associated with a moderately increased risk of cleft lip +/- cleft palate (CL(P)) (odds ratio = 1.40, 95% confidence interval 0.99-2.00). No association between smoking and isolated cleft palate (CP) was observed. TGFA genotype was not associated with either CL(P) or CP, and no synergistic effect with smoking was observed. The "rare" TGFA allele occurred in 25% of both cases and controls compared with an average of 14% in other white control groups. Furthermore, the frequency of CLP in Scandinavia is among the highest in the world. Hence, it is possible that the previously reported association between TGFA and CLP to some degree can be attributable to confounding by ethnicity.