Hypothesis: Metformin is a potential reproductive toxicant.

Metformin is the first-line oral treatment for type 2 diabetes mellitus and is prescribed to more than 150 million people worldwide. Metformin's effect as a glucose-lowering drug is well documented but the precise mechanism of action is unknown. A recent finding of an association between paternal metformin treatment and increased numbers of genital birth defects in sons and a tendency towards a skewed secondary sex ratio with less male offspring prompted us to focus on other evidence of reproductive side effects of this drug. Metformin in humans is documented to reduce the circulating level of testosterone in both men and women. In experimental animal models, metformin exposure in utero induced sex-specific reproductive changes in adult rat male offspring with reduced fertility manifested as a 30% decrease in litter size and metformin exposure to fish, induced intersex documented in testicular tissue. Metformin is excreted unchanged into urine and feces and is present in wastewater and even in the effluent of wastewater treatment plants from where it spreads to rivers, lakes, and drinking water. It is documented to be present in numerous freshwater samples throughout the world - and even in drinking water. We here present the hypothesis that metformin needs to be considered a potential reproductive toxicant for humans, and probably also for wildlife. There is an urgent need for studies exploring the association between metformin exposure and reproductive outcomes in humans, experimental animals, and aquatic wildlife.

Development in life expectancy with good and poor cognitive function in the elderly European Population from 2004-05 to 2015.

BACKGROUND: Living not just longer, but also cognitively healthier, and more independent lives is essential if European countries are to cope with the financial challenges that the shifting age composition of Europe's population presents. Here we investigate the change in life expectancy (LE) spent with good and poor cognitive function among older adults across Europe. METHODS: LE with good/poor cognitive function was estimated by the Sullivan Method. Cross-sectional data on cognitive functioning was obtained from 23,213 (wave 1, 2004-05) and 40,874 (wave 6, 2015) 50+-year-olds of the Survey of Health, Ageing and Retirement in Europe (SHARE). Information on mortality was obtained from the Eurostat Database. Results for 70+-year-olds were emphasized. RESULTS: LE with good cognitive function increased with 1.6 years from 10.7 years (95% CI: 10.6-10.9) in 2004-05 to 12.4 years (95% CI: 12.3-12.5) in 2015 for 70+-year-olds. Disparity was observed across sex and region. In 2004-05, a 70+-year-old woman could expect to spend 30.9% (95% CI: 29.4-32.4) of her remaining LE with poor cognitive function compared to 27.7% (95% CI: 26.0 -29.4) for men. In 2015, women (24.4% (95% CI: 23.4-25.3)) had considerably caught up with men (24.8% (95% CI:23.7.25.8)), shifting the pattern in favor of women. In 2004-05 and 2015, Northern Europeans had the lowest LE with poor cognitive function while Southern Europeans had the highest, but made the most improvement during the period. CONCLUSIONS: Overall we find that LE with poor cognitive function has been compressed in the European population of 70+-year-olds.

Preconception Antidiabetic Drugs in Men and Birth Defects in Offspring : A Nationwide Cohort Study.

BACKGROUND: Diabetes reduces semen quality and increasingly occurs during reproductive years. Diabetes medications, such as metformin, have glucose-independent effects on the male reproductive system. Associations with birth defects in offspring are unknown. OBJECTIVE: To evaluate whether the risk for birth defects in offspring varies with preconceptional pharmacologic treatment of fathers with diabetes. DESIGN: Nationwide prospective registry-based cohort study. SETTING: Denmark from 1997 to 2016. PARTICIPANTS: All liveborn singletons from mothers without histories of diabetes or essential hypertension. MEASUREMENTS: Offspring were considered exposed if their father filled 1 or more prescriptions for a diabetes drug during the development of fertilizing sperm. Sex and frequencies of major birth defects were compared across drugs, times of exposure, and siblings. RESULTS: Of 1 116 779 offspring included, 3.3% had 1 or more major birth defects (reference). Insulin-exposed offspring (n = 5298) had the reference birth defect frequency (adjusted odds ratio [aOR], 0.98 [95% CI, 0.85 to 1.14]). Metformin-exposed offspring (n = 1451) had an elevated birth defect frequency (aOR, 1.40 [CI, 1.08 to 1.82]). For sulfonylurea-exposed offspring (n = 647), the aOR was 1.34 (CI, 0.94 to 1.92). Offspring whose fathers filled a metformin prescription in the year before (n = 1751) or after (n = 2484) sperm development had reference birth defect frequencies (aORs, 0.88 [CI, 0.59 to 1.31] and 0.92 [CI, 0.68 to 1.26], respectively), as did unexposed siblings of exposed offspring (3.2%; exposed vs. unexposed OR, 1.54 [CI, 0.94 to 2.53]). Among metformin-exposed offspring, genital birth defects, all in boys, were more common (aOR, 3.39 [CI, 1.82 to 6.30]), while the proportion of male offspring was lower (49.4% vs. 51.4%, P = 0.073). LIMITATION: Information on underlying disease status was limited. CONCLUSION: Preconception paternal metformin treatment is associated with major birth defects, particularly genital birth defects in boys. Further research should replicate these findings and clarify the causation. PRIMARY FUNDING SOURCE: National Institutes of Health.

Nervous system drugs taken by future fathers and birth defects in offspring: a prospective registry-based cohort study.

OBJECTIVES: To evaluate the association of paternal intake of antipsychotics, anxiolytics, hypnotics and sedatives, antidepressants, selective serotonin reuptake inhibitors (SSRIs) and (benzo)diazepines during the development of fertilising sperm with birth defects in offspring. DESIGN: Prospective registry-based cohort study. SETTING: Total Danish birth cohort 1997-2016 using Danish national registries. PARTICIPANTS: All 1 201 119 Danish liveborn singletons born 1997-2016 were eligible, 39 803 (3.3%) of whom had at least one major birth defect. EXPOSURE: Offspring were considered exposed if their father had filled at least one prescription in the relevant drug category during development of fertilising sperm (the 3 months prior to conception). PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome was the diagnosis, in the first year of life, of at least one major birth defect as categorised in the EUROCAT guidelines. Secondary outcome was the diagnosis, in the first year of life, of at least one major birth defect in any of the EUROCAT subcategories. Adjusted ORs (AORs) were calculated, along with their 95% CIs, adjusted for year, education, smoking status and age of the mother, and education, disposable income and age of the father. RESULTS: This study found weak or null associations between birth defects and selected drugs. Specifically, antidepressants (17 827 exposed births) gave 3.5% birth defects (AOR 0.97 (0.89 to 1.05)). Diazepines, oxazepines, thiazepines and oxepines (as antipsychotics, 1633 offspring) gave 4.7% birth defects (AOR 1.22 (0.97 to 1.54)), attenuated to 1.13 when excluding by mothers' prescriptions. The study was well powered assuming 100% therapy adherence, while assuming 50% therapy adherence, the study remained well powered for the largest groups (SSRIs and antidepressants overall). CONCLUSIONS: Antipsychotics, anxiolytics, hypnotics and sedatives, antidepressants, SSRIs and benzodiazepine-derived anxiolytics, when taken by the father during development of fertilising sperm, are generally safe with regard to birth defects.

Balsalazide Exposure During the Development of Fertilizing Sperm May Be Associated With Offspring Birth Defects.

We report an association between balsalazide exposure during the development of fertilizing sperm and birth defects in offspring. Exposed offspring were approximately 8 times more likely to have a birth defect. There were no pre-existing reasons to suspect such a relationship, which should be confirmed in other data.

Spousal order of migration, gender, and hospitalization among immigrants in Denmark.

Background: Certain migration contexts that may help clarify immigrants' health needs are understudied, including the order in which married individuals migrate. Research shows that men, who are healthier than women across most populations, often migrate to a host country before women. Using Danish register data, we investigate descriptive patterns in the order that married men and women arrive in Denmark, as well as whether migration order is related to overnight hospitalizations. Methods: The study base includes married immigrants who lived in Denmark between January 1, 1980 and December 31, 2014 (N = 13,680). We use event history models to examine the influence of spousal migration order on hospitalizations. Results: The order that married individuals arrive in Denmark is indeed highly gendered, with men tending to arrive first, and varies by country of origin. Risk of hospitalization after age 50 does not depend on whether an individual migrated before, after, or at the same time as their spouse among either men or women. However, among those aged 18+, men migrating before their wives are more likely to experience hospitalizations within the first 5 years of arrival. Conclusions: These findings provide the first key insights about gendered migration patterns in Denmark. Although spousal order of migration is not related to overnight hospitalization among women, our findings provide preliminary evidence that men age 18+ who are first to arrive experience more hospitalization events in the following 5 years. Future research should explore additional outcomes and whether other gendered migration contexts are related to immigrants' health.

Burden and prevalence of risk factors for severe COVID-19 in the ageing European population - a SHARE-based analysis.

Aim: International health authorities suggest that individuals aged 65 years and above and people with underlying comorbidities such as hypertension, chronic lung disease, cardiovascular disease, cancer, diabetes, and obesity are at increased risk of severe Coronavirus Disease 2019 (COVID-19); however, the prevalence of risk factors is unknown in many countries. Therefore, we aimed to describe the distribution of these risk factors across Europe. Subject and methods: Prevalence of risk factors for severe COVID-19 was identified based on interviews from 73,274 Europeans aged 50+ participating in the Survey of Health, Ageing and Retirement in Europe (SHARE) in 2017. Burden of disease was estimated using population data from Eurostat. Results: A total of 75.3% of the study population (corresponding to approx. 60 million European men and 71 million women) had at least one risk factor for severe COVID-19, 45.9% (approx. 36 million men and 43 million women) had at least two factors, and 21.2% (approx. 17 million men and 20 million women) had at least three risk factors. The prevalence of underlying medical conditions ranged from 4.5% for cancer to 41.4% for hypertension, and the region-specific prevalence of having at least three risk factors ranged from 18.9% in Northern Europe to 24.6% in Eastern Europe. Conclusions: Information about the prevalence of risk factors might help authorities to identify the most vulnerable subpopulations with multiple risk factors of severe COVID-19 and thus to decide appropriate strategies to mitigate the pandemic. Supplementary Information: The online version contains supplementary material available at 10.1007/s10389-021-01537-7.

Environmental factors in declining human fertility.

A severe decline in child births has occurred over the past half century, which will lead to considerable population declines, particularly in industrialized regions. A crucial question is whether this decline can be explained by economic and behavioural factors alone, as suggested by demographic reports, or to what degree biological factors are also involved. Here, we discuss data suggesting that human reproductive health is deteriorating in industrialized regions. Widespread infertility and the need for assisted reproduction due to poor semen quality and/or oocyte failure are now major health issues. Other indicators of declining reproductive health include a worldwide increasing incidence in testicular cancer among young men and alterations in twinning frequency. There is also evidence of a parallel decline in rates of legal abortions, revealing a deterioration in total conception rates. Subtle alterations in fertility rates were already visible around 1900, and most industrialized regions now have rates below levels required to sustain their populations. We hypothesize that these reproductive health problems are partially linked to increasing human exposures to chemicals originating directly or indirectly from fossil fuels. If the current infertility epidemic is indeed linked to such exposures, decisive regulatory action underpinned by unconventional, interdisciplinary research collaborations will be needed to reverse the trends.

Gender differences in time to first hospital admission at age 60 in Denmark, 1995-2014.

Women have consistently lower mortality rates than men at all ages and with respect to most causes. However, gender differences regarding hospital admission rates are more mixed, varying across ages and causes. A number of intuitive metrics have previously been used to explore changes in hospital admissions over time, but have not explicitly quantified the gender gap or estimated the cumulative contribution from cause-specific admission rates. Using register data for the total Danish population between 1995 and 2014, we estimated the time to first hospital admission for Danish men and women aged 60. This is an intuitive population-level metric with the same interpretive and mathematical properties as period life expectancy. Using a decomposition approach, we were able to quantify the cumulative contributions from eight causes of hospital admission to the gender gap in time to first hospital admission. Between 1995 and 2014, time to first admission increased for both, men (7.6 to 9.4 years) and women (8.3 to 10.3 years). However, the magnitude of gender differences in time to first admission remained relatively stable within this time period (0.7 years in 1995, 0.9 years in 2014). After age 60, Danish men had consistently higher rates of admission for cardiovascular conditions and neoplasms, but lower rates of admission for injuries, musculoskeletal disorders, and sex-specific causes. Although admission rates for both genders have generally declined over the last decades, the same major causes of admission accounted for the gender gap. Persistent gender differences in causes of admission are, therefore, important to consider when planning the delivery of health care in times of population ageing. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10433-021-00614-w.

Skewness of X-chromosome inactivation increases with age and varies across birth cohorts in elderly Danish women.

Mosaicism in blood varies with age, and cross-sectional studies indicate that for women, skewness of X-chromosomal mosaicism increases with age. This pattern could, however, also be due to less X-inactivation in more recent birth cohorts. Skewed X-chromosome inactivation was here measured longitudinally by the HUMARA assay in 67 septuagenarian and octogenarian women assessed at 2 time points, 10 years apart, and in 10 centenarian women assessed at 2 time points, 2-7 years apart. Skewed X-chromosome inactivation was also compared in 293 age-matched septuagenarian twins born in 1917-1923 and 1931-1937, and 212 centenarians born in 1895, 1905 and 1915. The longitudinal study of septuagenarians and octogenarians revealed that 16% (95% CI 7-29%) of the women developed skewed X-inactivation over a 10-year period. In the cross-sectional across-birth cohort study, the earlier-born septuagenarian (1917-1923) and centenarian women (1895) had a higher degree of skewness than the respective recent age-matched birth cohorts, which indicates that the women in the more recent cohorts, after the age of 70, had not only changed degree of skewness with age, they had also undergone less age-related hematopoietic sub-clone expansion. This may be a result of improved living conditions and better medical treatment in the more recent birth cohorts.

Healthy life expectancy by frailty state in Europe from 2004 to 2015: findings from SHARE.

BACKGROUND: As populations age, the possible consequences of increased frailty are a major concern for the health sector. Here, we investigate how life expectancy with and without frailty has changed during a 10-11-year-period across Europe. METHODS: The Sullivan method was used to investigate changes in life expectancy with and without frailty in 10 European countries. Frailty status (non-frail, pre-frail and frail) was determined by use of the Survey of Health, Ageing and Retirement in Europe Frailty Instrument (SHARE-FI). Data on frailty prevalence was obtained from 21 698 individuals in wave 1 (2004-05) and 38 859 individuals in wave 6 (2015) of the SHARE. Information on mortality was obtained from the Eurostat Database. RESULTS: In 2015, women aged 70 spent 25.0% (95% CI: 24.0-26.1) of their remaining life expectancy in a frail state, and the number for men was 11.5% (95% CI: 10.7-12.3). Southern Europeans spent 24.2% (95% CI: 22.9-25.4) of their remaining life expectancy in a frail state and the numbers for Central Europeans and Northern Europeans were 17.0% (95% CI: 16.0-17.9) and 12.2% (95% CI: 10.9-13.5), respectively. From 2004-05 to 2015, life expectancy increased by 1.1 years (from 15.3 to 16.4 years) for 70-year-old Europeans. Similarly, non-frail life expectancy increased by 1.1 years (95% CI: 0.8-1.4), whereas no significant changes in life expectancy in frail states were observed. CONCLUSIONS: This study suggests that Europeans today spend more years in a non-frail state than Europeans did 10-11 years ago. Our findings reflect a considerable inequality by gender and region.

Sex and age differences in COVID-19 mortality in Europe.

AIM: To examine the magnitude of sex differences in survival from the coronavirus disease 2019 (COVID-19) in Europe across age groups and regions. We hypothesized that men have a higher mortality than women at any given age but that sex differences will decrease with age as only the healthiest men survive to older ages. METHODS: We used population data from the Institut National D'Études Démographiques on cumulative deaths due to COVID-19 from February to June 2020 in 10 European regions: Denmark, Norway, Sweden, The Netherlands, England and Wales, France, Germany, Italy, Spain and Portugal. For each region, we calculated cumulative mortality rates stratified by age and sex and corresponding relative risks for men vs. women. RESULTS: The relative risk of dying from COVID-19 was higher for men than for women in almost all age groups in all regions. The overall relative risk ranged from 1.11 (95% confidence interval, CI 1.01-1.23) in Portugal to 1.54 (95% CI 1.49-1.58) in France. In most regions, sex differences increased until the ages of 60-69 years, but decreased thereafter with the smallest sex difference at age 80+ years. CONCLUSION: Despite variability in data collection and time coverage among regions, the study showed an overall similar pattern of sex differences in COVID-19 mortality in Europe.

Risk of pre-term births and major birth defects resulting from paternal intake of COVID-19 medications prior to conception.

OBJECTIVE: With the ongoing COVID-19 pandemic, large numbers of people will receive one of the several medications proposed to treat COVID-19, including patients of reproductive age. Given that some medications have shown adverse effects on sperm quality, there might be a transgenerational concern. We aim at examining the association between drugs proposed to treat COVID-19 when taken by the father around conception and any pre-term birth or major birth defects in offspring in a nation-wide cohort study using Danish registry data. Offspring whose father filled at least one prescription of the following medications in the 3 months preceding conception were considered exposed: chloroquine, hydroxychloroquine, losartan, azithromycin, naproxen, dexamethasone and prednisone. RESULTS: For azithromycin and naproxen, large numbers of offspring were exposed (> 1800 offspring), and we found no association with adverse birth outcomes. For chloroquine, losartan and dexamethasone, exposure was intermediate (~ 900 offspring), and there was no statistically significant association with birth defects. For hydroxychloroquine and prednisone, exposure was limited (< 300 offspring). Our evidence suggests that azithromycin and naproxen are safe with respect to pre-term birth and birth defects. For the other drugs investigated larger exposures are needed for conclusive statements.

Preparing for the future: The changing demographic composition of hospital patients in Denmark between 2013 and 2050.

BACKGROUND: Population aging will pose huge challenges for healthcare systems and will require a promotion of positive attitudes towards older people and the encouragement of careers in geriatrics to attract young professionals into the field and to meet the needs of a rapidly growing number of old-aged patients. We describe the current demographic profile of hospital care use in Denmark and make projections for changes in the patient profile up to 2050. METHODS: The Danish population in 2013 (N = 5.63 million) was followed up for inpatient and emergency admissions recorded in Danish hospitals in 2013 using population-based registers. We combined age- and sex-specific hospital care use in 2013 with official population estimates to forecast the profile of hospital days up to 2050 with respect to age and sex. RESULTS: The total number of hospital days per year is projected to increase by 42% between 2013 and 2050, from 4.66 to 6.72 million days. While small changes are projected for the population aged 0-69, the largest change is projected to occur for the population aged 70+. The 2013 levels were 0.82 and 0.93 million days for men and women aged 70+, respectively. By 2050, these levels are projected to have reached 1.94 and 1.84 million days. While the population aged 70+ accounted for 37.5% of all days in 2013, its contribution is projected to increase to 56.2% by 2050. CONCLUSION: Our study shows one possible scenario for changes in the hospital days due to population aging by 2050: Assuming no changes in hospital care use over the forecast period, the absolute contribution of individuals aged 70+ to the total hospital days will more than double, and the relative contribution of persons aged 70+ will account for nearly 60% of all hospital days by 2050, being largest among men.

Risk of pre-term births and major birth defects resulting from paternal intake of COVID-19 medications prior to conception.

Objective: With the ongoing COVID-19 pandemic, large numbers of people will receive one of the several medications proposed to treat COVID-19, including patients of reproductive age. Given that some medications have shown adverse effects on sperm quality, there might be a transgenerational concern. We aim at examining the association between drugs proposed to treat COVID-19 when taken by the father around conception and any pre-term birth or major birth defects in offspring in a nation-wide cohort study using Danish registry data. Offspring whose father filled at least one prescription of the following medications in the three months preceding conception were considered exposed: chloroquine, hydroxychloroquine, losartan, azithromycin, naproxen, dexamethasone and prednisone. Results: For azithromycin and naproxen, large numbers of offspring were exposed (> 1800 offspring), and we found no association with adverse birth outcomes. For chloroquine, losartan and dexamethasone, exposure was intermediate (~900 offspring), and there was no statistically significant association with birth defects. For hydroxychloroquine and prednisone, exposure was limited (<300 offspring). Our evidence suggests that azithromycin and naproxen are safe with respect to pre-term birth and birth defects. For the other drugs investigated larger exposures are needed for conclusive statements.

Burden and prevalence of risk factors for severe COVID-19 disease in the ageing European population - A SHARE-based analysis.

Aim: International health authorities suggest that individuals aged 65 years and above and people with underlying comorbidities such as hypertension, chronic lung disease, cardiovascular disease, cancer, diabetes, and obesity are at increased risk of severe Coronavirus Disease 2019 (COVID-19); however, the prevalence of risk factors is unknown in many countries. Therefore, we aim to describe the distribution of these risk factors across Europe. Subject and Methods: Prevalence of risk factors for severe COVID-19 was identified based on interview for 73,274 Europeans aged 50+ participating in the Survey of Health, Ageing and Retirement in Europe (SHARE) in 2017. Burden of disease was estimated using population data from Eurostat. Results: A total of 75.3% of the study population (corresponding to app. 60 million European men and 71 million women) had at least one risk factor for severe COVID-19, 45.9% (app. 36 million men and 43 million women) had at least two factors and 21.2% (app. 17 million men and 20 million women) had at least three risk factors. The prevalences of underlying medical conditions ranged from 4.5% for cancer to 41.4% for hypertension, and the region-specific prevalence of having at least three risk factors ranged from 18.9% in Northern Europe to 24.6% in Eastern Europe. Conclusions: Information about the prevalences of risk factors might help authorities to identify the most vulnerable subpopulations with multiple risk factors of severe COVID-19 disease and thus to decide appropriate strategies to mitigate the pandemic.

Sex and age differences in COVID-19 mortality in Europe .

Aim: To examine the magnitude of sex differences in survival from the Coronavirus Disease 2019 (COVID-19) in Europe across age and countries. We hypothesise that men have higher mortality than women at any given age, but that sex differences will decrease with age as only the strongest men survive to older ages. Methods: We used population data from Institut National D'Études Démographiques on cumulative deaths due to COVID-19 from February to June 2020 in 10 European countries: Denmark, Norway, Sweden, The Netherlands, England & Wales, France, Germany, Italy, Spain and Portugal. For each country, we calculated cumulative mortality rates stratified by age and sex and corresponding relative risks for men vs. women. Results: The relative risk of dying from COVID-19 was higher for men than for women in almost all age groups in all countries. The overall relative risk ranged from 1.11 (95% CI 1.01-1.23) in Portugal to 1.54 (95% CI 1.49-1.58) in France. In most countries, sex differences increased until ages 60-69 years, but decreased thereafter with the smallest sex difference at ages 80+. Conclusions: Despite variability in data collection and time coverage among countries, we illustrate an overall similar pattern of sex differences in COVID-19 mortality in Europe.

Heritability of subfertility among Danish twins.

OBJECTIVE: To investigate the relative contribution of genetic and environmental components to subfertility. DESIGN: Twin design using a quantitative genetic liability threshold model that splits the variation of subfertility into additive genetic effects, common environmental effects, and unique environmental effects. SETTING: Not applicable. PATIENTS: A total of 9053 Danish monozygotic and dizygotic same-sex twins aged 18+ years from nationwide twin surveys (twins born 1931-1976). INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: Time to pregnancy (TTP) restricted to first pregnancy as a binary outcome, with a cut-off point of 10 months. RESULTS: Based on the Akaike information criterion, a model including additive genetic and unique environmental factors resulted in the best model fit. For females, the relative contribution of additive genetic factors to TTP was 28% (95% confidence interval [CI] 15%, 41%), whereas unique environmental factors explained 72% (95% CI 59%, 85%). For males, additive genetic factors explained 4% (95% CI 0%, 22%) of the variation in TTP, while unique environmental factors accounted for 96% (95% CI 78%, 100%). Results were overall similar for the crude model and consistent across surveys. CONCLUSION: Unique environmental factors explain most of the observed variation in subfertility, when measured as waiting time to pregnancy.

Age-specific cancer rates: a bird's-eye view on progress.

PURPOSE: We aim to shed light on progress in cancer medicine through studying time trends in age-specific rates of cancer incidence and mortality over the last quarter century. METHODS: We analyzed age-specific incidence and mortality rates of all cancer sites combined using the high-quality population-based databases of Denmark, Finland, Norway, Sweden, and the Netherlands for the period 1990-2016. RESULTS: Over these 26 years, cancer incidence rates increased in all investigated countries irrespective of age by about 22%. By contrast, cancer mortality rates decreased across all ages, also by about 22%, except ages 80+ years in Denmark, Norway, and Sweden, where they remained unchanged. This pattern is consistent with earlier diagnoses and more effective treatments of cancer. CONCLUSIONS: This bird's-eye view on cancer reveals substantive progress in cancer medicine.