Impact of major life events on breast-cancer-specific mortality : A case fatality study on 8000 breast cancer patients

Background: It has been suggested that long-term activation of the body's stress-response system and subsequent overexposure to stress hormones may be associated with increased morbidity. However, evidence on the impact of major life events on mortality from breast cancer (BC) remains inconclusive. The main aim of this study is to investigate whether major negatively or positively experienced life events before or after diagnosis have an effect on BC-specific mortality in women who have survived with BC for at least 2 years. Methods: We conducted a case fatality study with data on life events from a self-administered survey and data on BC from the Finnish Cancer Registry. Cox models were fitted to estimate BC mortality hazard ratios (MRs) between those who have undergone major life events and those who haven't. Results: None of the pre-diagnostic negative life events had any effect on BC-specific mortality. Regarding post-diagnostic events, the effect was greatest in women with moderate scores of events. As for event-specific scores, increased BC mortality was observed with spouse unemployment, relationship problems, and death of a close friend. By contrast, falling in love and positive developments in hobbies were shown to be associated with lower BC mortality (MRs 0.67, 95% CI: 0.49-0.92 and 0.74, 95% CI: 0.57-0.96, respectively). In an analysis restricted to recently diagnosed cases (2007), also death of a child and of a mother was associated with increased BC mortality. Conclusions: Some major life events regarding close personal relationships may play a role in BC-specific mortality, with certain negative life events increasing BC mortality and positive events decreasing it. The observed favorable associations between positive developments in romantic relationships and hobbies and BC mortality are likely to reflect the importance of social interaction and support. (C) 2017 Elsevier Ltd. All rights reserved.Peer reviewe

Decreasing trend and changing indications of hysterectomy in Finland

Introduction Hysterectomy has been one of the most common surgical procedures in women in Finland. We studied the population-based trends of hysterectomy and its indications from 1986 to 2017. Material and methods A retrospective population-based cohort was created from the Care Register for Health Care by identifying women who had a hysterectomy from 1986 to 2017 and calculating the number of women from the Digital and Population Data Services Agency. We estimated the number and incidence of hysterectomy by period and age as well as by indication. We considered the primary diagnosis at the time of surgery as the indication of hysterectomy. Results The number of hysterectomies increased from 7492 procedures in 1986 to 12 404 procedures in 1998, and reduced substantially after that to 5971 procedures in 2017, the turning point being in 1999. The incidence rate of hysterectomy has decreased on average by 2.5% annually from 432.6 per 100 000 women in 1998-2001 to 224.5 per 100 000 women in 2014-2017. The median age at the time of hysterectomy has increased from 51 years in 1998-2001 to 55 years in 2014-2017. The cumulative burden of hysterectomy by age of 60 years has nearly halved from the first 4-year period (23%) to the last (12%). After 2010, the most common indication has been genital prolapse and incontinence, whereas earlier it was uterine fibroids. Conclusions The number and incidence of hysterectomies have fluctuated during the observation period 1986-2017 and decreased considerably during the past 17 years in Finland. This is probably a result of the availability of hormonal and other conservative treatment options for bleeding disorders and uterine fibroids. As hysterectomy practically removes the risk for endometrial cancer, the change in hysterectomy incidence over time emphasizes the importance of correcting endometrial cancer incidence according to hysterectomy incidence.Peer reviewe

The association of statin use with reduced incidence of venous thromboembolism : a population-based cohort study

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Does Hair Dye Use Increase the Risk of Breast Cancer? A Population-Based Case-Control Study of Finnish Women

Introduction Role of hair dyes in the etiology of breast cancer has occasionally raised concern but previous research has concluded with mixed results. Remnants of prohibited aromatic amines have been found in many hair dye products, and elevated levels of DNA-adducts of these amines have been detected from breast epithelial cells of hair dye users. However, the IARC working group has concluded that there is inadequate evidence for carcinogenicity of personal hair dye use and limited evidence in experimental animals for carcinogenicity of hair colorants. Material and Methods We investigated whether the use of hair dyes is associated with breast cancer risk in women. The study design was a retrospective population-based case-control study in Finland, with a self-administered questionnaire from 6,567 breast cancer patients, aged 22-60 years and diagnosed in 2000-2007, and their 21,598 matched controls. We report odds ratios (OR) with 95% confidence interval (95% CI) from a conditional logistic regression model applied to the frequency matched sets of cases and controls. Bias-adjusted odds ratios from the sensitivity analysis are also presented. Results After adjusting for potential confounders, the odds of breast cancer increased by 23% (OR: 1.23, 95% CI: 1.11-1.36) among women who used hair dyes compared to those who did not. In women born before 1950 an increase of 28% was noted (OR: 1.28, 95% CI: 1.10-1.48). We also observed a significant trend between the OR and cumulative use of hair dyes (P: 0.005). Bias-adjusted odds ratios varied between 1.04 and 2.50. Conclusions Our results suggest that use of hair dyes is associated with breast cancer incidence. The impact on public health may be substantial due to vast popularity of hair coloring in modern societies. It should be noted that regardless of all efforts, a possibility of bias cannot definitively be ruled out and use of a prospective design is warranted. Based on the present results, it may be concluded however that safety of hair dyes in relation to breast cancer cannot yet be fully acknowledged and lack of external safety assessment within the cosmetics industry is of major concern.Peer reviewe

Transformation and outcome of nodular lymphocyte predominant Hodgkin lymphoma: a Finnish Nationwide population-based study

Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is a rare B-cell malignancy associated with excellent survival. However, some patients experience histological transformation into aggressive large B-cell lymphoma. Population-based data on transformation in patients with NLPHL is limited. We conducted a nationwide population-based study to estimate the risk of transformation and relative survival in patients diagnosed with NLPHL in Finland between 1995 and 2018. We identified a total of 453 patients (median age, 48 years; 76% males) with the incident NLPHL from the Finnish Cancer Registry. The cumulative incidence of transformation was 6.3% (95% CI, 4.2-9.6) at 10 years. After adjusting for sex, age and year of diagnosis, transformation was associated with a substantially increased risk of death (HR 8.55, 95% CI 4.49-16.3). Ten-year relative survival was 94% (95% CI, 89%-100%). The patients diagnosed at a later calendar year had lower excess risk of death (HR, 0.38 per 10-year increase; 95% CI, 0.15-0.98). We conclude that while the 10-year relative survival for the patients with NLPHL was excellent in this large population-based cohort for the entire study period, transformation resulted in a substantially increased mortality compared with the patients without transformation. Our results also suggest a reduction in excess mortality over time

Genome-wide landscape establishes novel association signals for metabolic traits in the Arab population

While the Arabian population has a high prevalence of metabolic disorders, it has not been included in global studies that identify genetic risk loci for metabolic traits. Determining the transferability of such largely Euro-centric established risk loci is essential to transfer the research tools/resources, and drug targets generated by global studies to a broad range of ethnic populations. Further, consideration of populations such as Arabs, that are characterized by consanguinity and a high level of inbreeding, can lead to identification of novel risk loci. We imputed published GWAS data from two Kuwaiti Arab cohorts (n = 1434 and 1298) to the 1000 Genomes Project haplotypes and performed meta-analysis for associations with 13 metabolic traits. We compared the observed association signals with those established for metabolic traits. Our study highlighted 70 variants from 9 different genes, some of which have established links to metabolic disorders. By relaxing the genome-wide significance threshold, we identified ‘novel’ risk variants from 11 genes for metabolic traits. Many novel risk variant association signals were observed at or borderline to genome-wide significance. Furthermore, 349 previously established variants from 187 genes were validated in our study. Pleiotropic effect of risk variants on multiple metabolic traits were observed. Fine-mapping illuminated rs7838666/CSMD1 rs1864163/CETP and rs112861901/[INTS10,LPL] as candidate causal variants influencing fasting plasma glucose and high-density lipoprotein levels. Computational functional analysis identified a variety of gene regulatory signals around several variants. This study enlarges the population ancestry diversity of available GWAS and elucidates new variants in an ethnic group burdened with metabolic disorders.Peer reviewe

The Genetic Liability to Disability Retirement: A 30-Year Follow-Up Study of 24,000 Finnish Twins

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Reference values of spirometry for Finnish adults

BackgroundDiagnostic assessment of lung function necessitates up-to-date reference values. The aim of this study was to estimate reference values for spirometry for the Finnish population between 18 and 80years and to compare them with the existing Finnish, European and the recently published global GLI2012 reference values. MethodsSpirometry was performed for 1380 adults in the population-based FinEsS studies and for 662 healthy non-smoking volunteer adults. Detailed predefined questionnaire screening of diseases and symptoms, and quality control of spirometry yielded a sample of 1000 native Finns (387 men) healthy non-smokers aged 18-83years. Sex-specific reference values, which are estimated using the GAMLSS method and adjusted for age and height, are provided. ResultsThe predicted values for lung volumes are larger than those obtained by GLI2012 prediction for the Caucasian subgroup for forced vital capacity (FVC) by an average 62% and 51% and forced expiratory volume in 1s (FEV1) by an average 42% and 30% in men and women, respectively. GLI2012 slightly overestimated the ratio FEV1/FVC with an age-dependent trend. Most reference equations from other European countries, with the exception of the Swiss SAPALDIA study, showed an underestimation of FVC and FEV1 to varying degrees, and a slight overestimation of FEV1/FVC. ConclusionThis study offers up-to-date reference values of spirometry for native Finns with a wide age range. The GLI2012 predictions seem not to be suitable for clinical use for native Finns due to underestimation of lung volumes.Peer reviewe

Decreased levels of keratin 8 sensitize mice to streptozotocin-induced diabetes

AimDiabetes is a result of an interplay between genetic, environmental and lifestyle factors. Keratin intermediate filaments are stress proteins in epithelial cells, and keratin mutations predispose to several human diseases. However, the involvement of keratins in diabetes is not well known. K8 and its partner K18 are the main ?-cell keratins, and knockout of K8 (K8?/?) in mice causes mislocalization of glucose transporter 2, mitochondrial defects, reduced insulin content and altered systemic glucose/insulin control. We hypothesize that K8/K18 offer protection during ?-cell stress and that decreased K8 levels contribute to diabetes susceptibility.MethodsK8-heterozygous knockout (K8+/?) and wild-type (K8+/+) mice were used to evaluate the influence of keratin levels on endocrine pancreatic function and diabetes development under basal conditions and after T1D streptozotocin (STZ)-induced ?-cell stress and T2D high-fat diet (HFD).ResultsMurine K8+/? endocrine islets express ~50% less K8/K18 compared with K8+/+. The decreased keratin levels have little impact on basal systemic glucose/insulin regulation, ?-cell health or insulin levels. Diabetes incidence and blood glucose levels are significantly higher in K8+/? mice after low-dose/chronic STZ treatment, and STZ causes more ?-cell damage and polyuria in K8+/? compared with K8+/+. K8 appears upregulated 5 weeks after STZ treatment in K8+/+ islets but not in K8+/?. K8+/? mice showed no major susceptibility risk to HFD compared to K8+/+.ConclusionPartial K8 deficiency reduces ?-cell stress tolerance and aggravates diabetes development in response to STZ, while there is no major susceptibility to HFD

ACEt : An R Package for Estimating Dynamic Heritability and Comparing Twin Models

Estimating dynamic effects of age on the genetic and environmental variance components in twin studies may contribute to the investigation of gene-environment interactions, and may provide more insights into more accurate and powerful estimation of heritability. Existing parametric models for estimating dynamic variance components suffer from various drawbacks such as limitation of predefined functions. We present ACEt, an R package for fast estimating dynamic variance components and heritability that may change with respect to age or other moderators. Building on the twin models using penalized splines, ACEt provides a unified framework to incorporate a class of ACE models, in which each component can be modeled independently and is not limited by a linear or quadratic function. We demonstrate that ACEt is robust against misspecification of the number of spline knots, and offers a refined resolution of dynamic behavior of the genetic and environmental components and thus a detailed estimation of age-specific heritability. Moreover, we develop resampling methods for testing twin models with different variance functions including splines, log-linearity and constancy, which can be easily employed to verify various model assumptions. We evaluated the type I error rate and statistical power of the proposed hypothesis testing procedures under various scenarios using simulated datasets. Potential numerical issues and computational cost were also assessed through simulations. We applied the ACEt package to a Finnish twin cohort to investigate age-specific heritability of body mass index and height. Our results show that the age-specific variance components of these two traits exhibited substantially different patterns despite of comparable estimates of heritability. In summary, the ACEt R package offers a useful tool for the exploration of age-dependent heritability and model comparison in twin studies.Peer reviewe