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Background: The American Cancer Society recommends physicians inform average-risk women about endometrial cancer risk on reaching menopause, but new diagnoses are rising fastest in women aged younger than 50 years. Educating these younger women about endometrial cancer risks requires knowledge of risk factors. However, endometrial cancer in young women is rare and challenging to study in single study populations., Methods: We included 13 846 incident endometrial cancer patients (1639 aged younger than 50 years) and 30 569 matched control individuals from the Epidemiology of Endometrial Cancer Consortium. We used generalized linear models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for 6 risk factors and endometrial cancer risk. We created a risk score to evaluate the combined associations and population attributable fractions for these factors., Results: In younger and older women, we observed positive associations with body mass index and diabetes and inverse associations with age at menarche, oral contraceptive use, and parity. Current smoking was associated with reduced risk only in women aged 50 years and older (Phet < .01). Body mass index was the strongest risk factor (OR≥35 vs<25 kg/m2 = 5.57, 95% CI = 4.33 to 7.16, for ages younger than 50 years; OR≥35 vs<25 kg/m2 = 4.68, 95% CI = 4.30 to 5.09, for ages 50 years and older; Phet = .14). Possessing at least 4 risk factors was associated with approximately ninefold increased risk in women aged younger than 50 years and approximately fourfold increased risk in women aged 50 years and older (Phet < .01). Together, 59.1% of endometrial cancer in women aged younger than 50 years and 55.6% in women aged 50 years and older were attributable to these factors., Conclusions: Our data confirm younger and older women share common endometrial cancer risk factors. Early educational efforts centered on these factors may help mitigate the rising endometrial cancer burden in young women., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: It is not clear whether the association between younger age at menopause and increased risk of dementia is modified by type of menopause. We examined the association of age at menopause or hysterectomy with dementia risk in three groups of women: those with natural menopause, premenopausal bilateral oophorectomy (surgical menopause) or premenopausal hysterectomy (without bilateral oophorectomy)., Study Design: Individual-level data from 233 802 women in five prospective cohort studies (from four countries) were harmonized and pooled. Cox proportional hazards models were used to assess the associations of age at natural menopause, surgical menopause or premenopausal hysterectomy, with age at dementia, death (where available) or end of follow-up, whichever came first., Results: The study followed women to the median age of 72 years (quartiles 67, 76 years). The median follow-up time was 13 years, with 3262 dementia cases during this period. Compared with women with menopause at 50-52 years, women with menopause <40 years had a higher risk of dementia (adjusted hazard ratio (aHR): 1.47, 95% confidence interval (CI): 1.39, 1.56). This level of risk was comparable to that of current smoking and stroke, which are well-established risk factors for dementia. Increased risk of dementia associated with surgical menopause or premenopausal hysterectomy (compared to natural menopause) was not apparent after adjustment for age at menopause (aHR 0.99, 95% CI: 0.93, 1.04 and aHR 0.97, 95% CI: 0.95, 1.00, respectively)., Conclusion: Women who experience menopause before the age of 40 years have a higher risk of dementia irrespective of type of menopause., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Geriatrics Society.)

Background: Adult obesity is a strong risk factor for endometrial cancer (EC); however, associations of early life obesity with EC are inconclusive. We evaluated associations of young adulthood (18-21 years) and adulthood (at enrolment) body mass index (BMI) and weight change with EC risk in the Epidemiology of Endometrial Cancer Consortium (E2C2)., Methods: We pooled data from nine case-control and 11 cohort studies in E2C2. We performed multivariable logistic regression analyses to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for BMI (kg/m2) in young adulthood and adulthood, with adjustment for BMI in adulthood and young adulthood, respectively. We evaluated categorical changes in weight (5-kg increments) and BMI from young adulthood to adulthood, and stratified analyses by histology, menopausal status, race and ethnicity, hormone replacement therapy (HRT) use and diabetes., Results: We included 14 859 cases and 40 859 controls. Obesity in adulthood (OR = 2.85, 95% CI = 2.47-3.29) and young adulthood (OR = 1.26, 95% CI = 1.06-1.50) were positively associated with EC risk. Weight gain and BMI gain were positively associated with EC; weight loss was inversely associated with EC. Young adulthood obesity was more strongly associated with EC among cases diagnosed with endometrioid histology, those who were pre/perimenopausal, non-Hispanic White and non-Hispanic Black, among never HRT users and non-diabetics., Conclusions: Young adulthood obesity is associated with EC risk, even after accounting for BMI in adulthood. Weight gain is also associated with EC risk, whereas weight loss is inversely associated. Achieving and maintaining a healthy weight over the life course is important for EC prevention efforts., (Published by Oxford University Press on behalf of the International Epidemiological Association 2023.)

Background: It has been suggested that maternal type 1 diabetes (T1D) increases the risk of autism spectrum disorder (ASD) in the offspring. However, it is unclear whether this risk is mediated by pre-term birth, affecting around one-third of pregnancies with T1D, and whether maternal levels of glycated haemoglobin (HbA1c) impact the risk., Methods: A cohort of 1.4 million Swedish children born between 1998 and 2015, and their parents. Maternal T1D and HbA1c before or in early pregnancy, gestational and ASD diagnoses were obtained from Swedish national registers. Relative risk (RR) and 95% CIs of ASD were estimated by hazard ratios (HRs) from Cox regression or RR from log-binomial regression., Results: Of 1 406 650 children, 8003 (0.6%) were born to mothers with T1D, 24 941 (1.8%) were diagnosed with ASD and 81 915 (5.8%) were born pre-term. The risk of ASD was increased in offspring of mothers with T1D was HR = 1.40 (1.21-1.61). The RR for each +5-mmol/mol excess HbA1c was estimated at HR = 1.03 (0.97-1.10). The T1D effect on ASD mediated through pre-term birth was estimated at RR = 1.06 (1.05 to 1.08), corresponding to 22% (16% to 41%) of the total effect. T1D in pregnancy was associated with increased ASD risk in the offspring. Twenty percent of the total effect was accounted for by pre-term birth. HbA1c was not associated with ASD risk, beyond the risk associated by the T1D diagnosis itself., Conclusion: Awareness of ASD in the offspring of mothers with T1D may be warranted, especially considering the additional effect of pre-term birth., (© The Author(s) 2022. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Telomeres, the ends of linear chromosomes, are composed of repetitive DNA sequences, histones and a protein complex called shelterin. How DNA is packaged at telomeres is an outstanding question in the field with significant implications for human health and disease. Here, we studied the architecture of telomeres and their spatial association with other chromatin domains in different cell types using correlative light and electron microscopy. To this end, the shelterin protein TRF1 or TRF2 was fused in tandem to eGFP and the peroxidase APEX2, which provided a selective and electron-dense label to interrogate telomere organization by transmission electron microscopy, electron tomography and scanning electron microscopy. Together, our work reveals, for the first time, ultrastructural insight into telomere architecture. We show that telomeres are composed of a dense and highly compacted mesh of chromatin fibres. In addition, we identify marked differences in telomere size, shape and chromatin compaction between cancer and non-cancer cells and show that telomeres are in direct contact with other heterochromatin regions. Our work resolves the internal architecture of telomeres with unprecedented resolution and advances our understanding of how telomeres are organized in situ., (© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Few studies have comprehensively examined the profile of cognitive functioning in first episode psychosis patients throughout the lifespan, and from first episode to chronic stage. We assessed functioning in general and specific cognitive functions, comparing both schizophrenia (N = 64) and bipolar I (N = 19) patients to controls (N = 103). Participants were from a population-based, case-control study of first episode psychosis patients, who were followed prospectively up to 10 years post first admission. A cognitive battery was administered at baseline and follow-up. By combining longitudinal and cross-sectional data, we were able to examine the cognitive profile of patients and controls throughout the entire age range of our sample (16-65). Schizophrenia patients exhibited widespread declines in IQ, executive function, visual memory, language ability, and verbal knowledge. However, the ages at which these declines occurred differed between functions. Deficits in verbal memory, working memory, processing speed, and visuospatial ability, on the other hand, were present at the first episode, and remained relatively static thereafter. Bipolar I patients also showed declines in IQ, verbal knowledge, and language ability, albeit at different ages to schizophrenia patients and only in verbal functions. Deficits on measures of verbal memory, processing speed, and executive function remained relatively static. Thus, both schizophrenia and bipolar I patients experienced cognitive decline in general and specific functions after the first episode, but the age at which these declines occurred differed between disorder and function. Cognitive remediation efforts may be most fruitful when targeting individual functions during specific time periods throughout adulthood., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Background: The history of gestational diabetes mellitus (GDM) has been associated with breast cancer risk in some studies, particularly in young women, but results of cohort studies are conflicting., Methods: We pooled data from 257 290 young (age <55 years) women from five cohorts. We used multivariable Cox proportional-hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between GDM history and risk of breast cancer, overall and by oestrogen receptor (ER) status, before age 55 years, adjusted for established breast cancer risk factors., Results: Five percent of women reported a history of GDM and 6842 women reported an incident breast-cancer diagnosis (median follow-up = 16 years; maximum = 24 years). Compared with parous women without GDM, women with a history of GDM were not at increased risk of young-onset breast cancer overall (HR = 0.90; 95% CI: 0.78, 1.03) or by ER status (HR = 0.96; 95% CI: 0.79, 1.16 for ER-positive; HR = 1.07; 95% CI: 0.78, 1.47 for ER-negative). Compared with nulliparous women, parous women with a history of GDM had a lower risk of breast cancer overall (HR = 0.79; 95% CI: 0.68, 0.91) and of ER-positive (HR = 0.82; 95% CI: 0.66, 1.02) but not ER-negative (HR = 1.09; 95% CI: 0.76, 1.54) invasive breast cancer. These results were consistent with the HRs comparing parous women without GDM to nulliparous women., Conclusions: Results of this analysis do not support the hypothesis that GDM is a risk factor for breast cancer in young women. Our findings suggest that the well-established protective effect of parity on risk of ER-positive breast cancer persists even for pregnancies complicated by GDM., (© The Author(s) 2021; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Study Question: How does the risk of cardiovascular disease (CVD) vary with type and age of menopause?, Summary Answer: Earlier surgical menopause (e.g. <45 years) poses additional increased risk of incident CVD events, compared to women with natural menopause at the same age, and HRT use reduced the risk of CVD in women with early surgical menopause., What Is Known Already: Earlier age at menopause has been linked to an increased risk of CVD mortality and all-cause mortality, but the extent that this risk of CVD varies by type of menopause and the role of postmenopausal HRT use in reducing this risk is unclear., Study Design, Size, Duration: Pooled individual-level data of 203 767 postmenopausal women from 10 observational studies that contribute to the International collaboration for a Life course Approach to reproductive health and Chronic disease Events (InterLACE) consortium were included in the analysis., Participants/materials, Setting, Methods: Postmenopausal women who had reported menopause (type and age of menopause) and information on non-fatal CVD events were included. Type of menopause (natural menopause and surgical menopause) and age at menopause (categorised as <35, 35-39, 40-44, 45-49, 50-54 and ≥55 years) were exposures of interest. Natural menopause was defined as absence of menstruation over a period of 12 months (no hysterectomy and/or oophorectomy) and surgical menopause as removal of both ovaries. The study outcome was the first non-fatal CVD (defined as either incident coronary heart disease (CHD) or stroke) event ascertained from hospital medical records or self-reported. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% CI for non-fatal CVD events associated with natural menopause and surgical menopause., Main Results and the Role of Chance: Compared with natural menopause, surgical menopause was associated with over 20% higher risk of CVD (HR 1.22, 95% CI 1.16-1.28). After the stratified analysis by age at menopause, a graded relationship for incident CVD was observed with lower age at menopause in both types of natural and surgical menopause. There was also a significant interaction between type of menopause and age at menopause (P < 0.001). Compared with natural menopause at 50-54 years, women with surgical menopause before 35 (2.55, 2.22-2.94) and 35-39 years (1.91, 1.71-2.14) had higher risk of CVD than those with natural menopause (1.59, 1.23-2.05 and 1.51, 1.33-1.72, respectively). Women who experienced surgical menopause at earlier age (<50 years) and took HRT had lower risk of incident CHD than those who were not users of HRT., Limitations, Reasons for Caution: Self-reported data on type and age of menopause, no information on indication for the surgery (e.g. endometriosis and fibroids) and the exclusion of fatal CVD events may bias our results., Wider Implications of the Findings: In clinical practice, women who experienced natural menopause or had surgical menopause at an earlier age need close monitoring and engagement for preventive health measures and early diagnosis of CVD. Our findings also suggested that timing of menopause should be considered as an important factor in risk assessment of CVD for women. The findings on CVD lend some support to the position that elective bilateral oophorectomy (surgical menopause) at hysterectomy for benign diseases should be discouraged based on an increased risk of CVD., Study Funding/competing Interest(s): InterLACE project is funded by the Australian National Health and Medical Research Council project grant (APP1027196). GDM is supported by Australian National Health and Medical Research Council Principal Research Fellowship (APP1121844). There are no competing interests., (© 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: The positive association between caesarean section (CS) and autism spectrum disorder (ASD) may be attributed to preterm delivery. However, due to lack of statistical power, no previous study thoroughly examined this association across gestational age. Moreover, most studies did not differentiate between emergency and planned CS., Methods: Using population-based registries of four Nordic countries and Western Australia, our study population included 4 987 390 singletons surviving their first year of life, which included 671 646 CS deliveries and 31 073 ASD children. We used logistic regression to estimate odds ratios (OR) and their 95% confidence intervals (CI) for CS, adjusted for gestational age, site, maternal age and birth year. Stratified analyses were conducted by both gestational age subgroups and by week of gestation. We compared emergency versus planned CS to investigate their potential difference in the risk of ASD., Results: Compared with vaginal delivery, the overall adjusted OR for ASD in CS delivery was 1.26 (95% CI 1.22-1.30). Stratified ORs were 1.25 (1.15-1.37), 1.16 (1.09-1.23), 1.34 (1.28-1.40) and 1.17 (1.04-1.30) for subgroups of gestational weeks 26-36, 37-38, 39-41 and 42-44, respectively. CS was significantly associated with risk of ASD for each week of gestation, from week 36 to 42, consistently across study sites (OR ranged 1.16-1.38). There was no statistically significant difference between emergency and planned CS in the risk of ASD., Conclusion: Across the five countries, emergency or planned CS is consistently associated with a modest increased risk of ASD from gestational weeks 36 to 42 when compared with vaginal delivery., (© The Author 2016; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association)

Study Question: Are parity and the timing of menarche associated with premature and early natural menopause?, Summary Answer: Early menarche (≤11 years) is a risk factor for both premature menopause (final menstrual period, FMP <40 years) and early menopause (FMP 40-44 years), a risk that is amplified for nulliparous women., What Is Known Already: Women with either premature or early menopause face an increased risk of chronic conditions in later life and of early death. Findings from some studies suggest that early menarche and nulliparity are associated with early menopause, however overall the evidence is mixed. Much of the evidence for a direct relationship is hampered by a lack of comparability across studies, failure to adjust for confounding factors and inadequate statistical power., Study Design, Size, Duration: This pooled study comprises 51 450 postmenopausal women from nine observational studies in the UK, Scandinavia, Australia and Japan that contribute to the International collaboration for a Life course Approach to reproductive health and Chronic disease Events (InterLACE)., Participants/materials, Setting, Methods: Age at menarche (categorized as ≤11, 12, 13, 14 and 15 or more years) and parity (categorized as no children, one child and two or more children) were exposures of interest. Age at FMP was confirmed by at least 12 months of cessation of menses where this was not the result of an intervention (such as surgical menopause due to bilateral oophorectomy or hysterectomy) and categorized as premature menopause (FMP before age 40), early menopause (FMP 40-44 years), 45-49 years, 50-51 years, 52-53 years and 54 or more years. We used multivariate multinomial logistic regression models to estimate relative risk ratio (RRR) and 95% CI for associations between menarche, parity and age at FMP adjusting for within-study correlation., Main Results and the Role of Chance: The median age at FMP was 50 years (interquartile range 48-53 years), with 2% of the women experiencing premature menopause and 7.6% early menopause. Women with early menarche (≤11 years, compared with 12-13 years) were at higher risk of premature menopause (RRR 1.80, 95% CI 1.53-2.12) and early menopause (1.31, 1.19-1.44). Nulliparity was associated with increased risk of premature menopause (2.26, 1.84-2.77) and early menopause (1.32, 1.09-1.59). Women having early menarche and nulliparity were at over 5-fold increased risk of premature menopause (5.64, 4.04-7.87) and 2-fold increased risk of early menopause (2.16, 1.48-3.15) compared with women who had menarche at ≥12 years and two or more children., Limitations, Reasons for Caution: Most of the studies (except the birth cohorts) relied on retrospectively reported age at menarche, which may have led to some degree of recall bias., Wider Implications of the Findings: Our findings support early monitoring of women with early menarche, especially those who have no children, for preventive health interventions aimed at mitigating the risk of adverse health outcomes associated with early menopause., Study Funding/competing Interest(s): InterLACE project is funded by the Australian National Health and Medical Research Council project grant (APP1027196). G.D.M. is supported by Australian Research Council Future Fellowship (FT120100812). There are no competing interests., (© The Author 2017. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.)

The Volta phase plate is a recently developed electron cryo-microscopy (cryo-EM) device that enables contrast enhancement of biological samples. Here we have evaluated the potential of combining phase-plate imaging and single particle analysis to determine the structure of a small protein-DNA complex. To test the method, we made use of a 200 kDa Nucleosome Core Particle (NCP) reconstituted with 601 DNA for which a high-resolution X-ray crystal structure is known. We find that the phase plate provides a significant contrast enhancement that permits individual NCPs and DNA to be clearly identified in amorphous ice. The refined structure from 26,060 particles has an overall resolution of 3.9 Å and the density map exhibits structural features consistent with the estimated resolution, including clear density for amino acid side chains and DNA features such as the phosphate backbone. Our results demonstrate that phase-plate cryo-EM promises to become an important method to determine novel near-atomic resolution structures of small and challenging samples, such as nucleosomes in complex with nucleosome-binding factors., (© The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background: Research studies exploring the determinants of disease require sufficient statistical power to detect meaningful effects. Sample size is often increased through centralized pooling of disparately located datasets, though ethical, privacy and data ownership issues can often hamper this process. Methods that facilitate the sharing of research data that are sympathetic with these issues and which allow flexible and detailed statistical analyses are therefore in critical need. We have created a software platform for the Virtual Pooling and Analysis of Research data (ViPAR), which employs free and open source methods to provide researchers with a web-based platform to analyse datasets housed in disparate locations., Methods: Database federation permits controlled access to remotely located datasets from a central location. The Secure Shell protocol allows data to be securely exchanged between devices over an insecure network. ViPAR combines these free technologies into a solution that facilitates 'virtual pooling' where data can be temporarily pooled into computer memory and made available for analysis without the need for permanent central storage., Results: Within the ViPAR infrastructure, remote sites manage their own harmonized research dataset in a database hosted at their site, while a central server hosts the data federation component and a secure analysis portal. When an analysis is initiated, requested data are retrieved from each remote site and virtually pooled at the central site. The data are then analysed by statistical software and, on completion, results of the analysis are returned to the user and the virtually pooled data are removed from memory., Conclusions: ViPAR is a secure, flexible and powerful analysis platform built on open source technology that is currently in use by large international consortia, and is made publicly available at [http://bioinformatics.childhealthresearch.org.au/software/vipar/]., (© The Author 2015. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background: Studies in twins may be questioned with respect to their representativeness of the general population, not least considering the potential importance of the fetal environment for future health and disease. To better understand the influence twinning may have on health, we investigated long-term health outcomes of twins, their singleton siblings and singletons from the population., Methods: Morbidity and mortality in twins was contrasted to that of their singleton siblings. These singletons from families with twins were then compared with singletons of the population to further reveal potential twin family influences on health. Familial relations were identified through the Swedish Multi-Generation Register. Among individuals born between 1932 and 1958, the number of twins and their singleton siblings identified were 49,156 and 35,277, respectively. Outcomes were incident overall cancer, cardiovascular disease (CVD) and death, identified in national registers. Standardized survival functions were estimated using Cox proportional hazards regression and the corresponding cumulative risks plotted against age., Results: Cumulative risks of cancer, CVD and death in twins did not differ from singletons of families with twins, who in turn were found to be similar to singletons of families without twins. As could be expected from these findings, no differences in risks were found when twins were compared with singletons of the population., Conclusions: Despite their adverse intrauterine experience, twins do not seem to fare worse than singletons with respect to adult morbidity and mortality. The findings indicate that the unique experience of twinning does not lead to adverse long-term health outcomes.

This study was undertaken to disentangle the maternal genetic from the fetal genetic effects for preterm birth and to study the possibility of these effects being explained by known risk factors. By cross-linking of the population-based Swedish Multigeneration and Medical Birth registers, 989,027 births between 1992 and 2004 were identified. Alternating logistic regression was applied to model the familial clustering with pairwise odds ratios (PORs), and covariates were included to evaluate if the familial aggregation was explained by exposure to shared risk factors. Generalized linear mixed models were used to estimate the contribution of genetic and environmental effects. Sisters of women who had a preterm delivery had themselves an increased odds of having a preterm delivery (POR = 1.8, 95% confidence interval: 1.5, 2.1), while there was no corresponding increase in odds in families joined by brothers (POR = 1.1, 95% confidence interval: 0.9, 1.4). Twenty-five percent of the variation in preterm birth was explained by maternal genetic factors, whereas fetal genetic factors only marginally influenced the variation in liability. The increased odds ratio between offspring of sisters was independent of maternal risk factors for preterm birth, suggesting that the relative importance of maternal effects is not explained by these well-known risk factors.