The rising prevalence of childhood obesity has been postulated as an explanation for the increasing rate of individuals diagnosed with type 1 diabetes (T1D). In this study, we use Mendelian randomization (MR) to provide evidence that childhood body size has an effect on T1D risk (OR = 2.05 per change in body size category, 95% CI = 1.20 to 3.50, P = 0.008), which remains after accounting for body size at birth and during adulthood using multivariable MR (OR = 2.32, 95% CI = 1.21 to 4.42, P = 0.013). We validate this direct effect of childhood body size using data from a large-scale T1D meta-analysis based on n = 15,573 cases and n = 158,408 controls (OR = 1.94, 95% CI = 1.21 to 3.12, P = 0.006). We also provide evidence that childhood body size influences risk of asthma, eczema and hypothyroidism, although multivariable MR suggested that these effects are mediated by body size in later life. Our findings support a causal role for higher childhood body size on risk of being diagnosed with T1D, whereas its influence on the other immune-associated diseases is likely explained by a long-term effect of remaining overweight for many years over the lifecourse.

Background Endometrial cancer is the most common gynaecological cancer in high-income countries. Elevated body mass index (BMI) is an established modifiable risk factor for this condition and is estimated to confer a larger effect on endometrial cancer risk than any other cancer site. However, the molecular mechanisms underpinning this association remain unclear. We used Mendelian randomization (MR) to evaluate the causal role of 14 molecular risk factors (hormonal, metabolic and inflammatory markers) in endometrial cancer risk. We then evaluated and quantified the potential mediating role of these molecular traits in the relationship between BMI and endometrial cancer using multivariable MR. Methods Genetic instruments to proxy 14 molecular risk factors and BMI were constructed by identifying single-nucleotide polymorphisms (SNPs) reliably associated (P < 5.0 × 10−8) with each respective risk factor in previous genome-wide association studies (GWAS). Summary statistics for the association of these SNPs with overall and subtype-specific endometrial cancer risk (12,906 cases and 108,979 controls) were obtained from a GWAS meta-analysis of the Endometrial Cancer Association Consortium (ECAC), Epidemiology of Endometrial Cancer Consortium (E2C2) and UK Biobank. SNPs were combined into multi-allelic models and odds ratios (ORs) and 95% confidence intervals (95% CIs) were generated using inverse-variance weighted random-effects models. The mediating roles of the molecular risk factors in the relationship between BMI and endometrial cancer were then estimated using multivariable MR. Results In MR analyses, there was strong evidence that BMI (OR per standard deviation (SD) increase 1.88, 95% CI 1.69 to 2.09, P = 3.87 × 10−31), total testosterone (OR per inverse-normal transformed nmol/L increase 1.64, 95% CI 1.43 to 1.88, P = 1.71 × 10−12), bioavailable testosterone (OR per natural log transformed nmol/L increase: 1.46, 95% CI 1.29 to 1.65, P = 3.48 × 10−9), fasting insulin (OR per natural log transformed pmol/L increase: 3.93, 95% CI 2.29 to 6.74, P = 7.18 × 10−7) and sex hormone-binding globulin (SHBG, OR per inverse-normal transformed nmol/L increase 0.71, 95% CI 0.59 to 0.85, P = 2.07 × 10−4) had a causal effect on endometrial cancer risk. Additionally, there was suggestive evidence that total serum cholesterol (OR per mg/dL increase 0.90, 95% CI 0.81 to 1.00, P = 4.01 × 10−2) had an effect on endometrial cancer risk. In mediation analysis, we found evidence for a mediating role of fasting insulin (19% total effect mediated, 95% CI 5 to 34%, P = 9.17 × 10−3), bioavailable testosterone (15% mediated, 95% CI 10 to 20%, P = 1.43 × 10−8) and SHBG (7% mediated, 95% CI 1 to 12%, P = 1.81 × 10−2) in the relationship between BMI and endometrial cancer risk. Conclusions Our comprehensive MR analysis provides insight into potential causal mechanisms linking BMI with endometrial cancer risk and suggests targeting of insulinemic and hormonal traits as a potential strategy for the prevention of endometrial cancer.

Purpose -The purpose of this paper is to examine the characteristics and usefulness of opinion leaders and market mavens in relation to theatre guides as a way for theatres to develop new audiences. Design/methodology/approach -Surveys and a small number of in-depth interviews are conducted within a sample of 1,200 theatre patrons. A univariate analysis of variance analysis determines degrees of correspondence between levels of opinion leadership or mavenism and reported influential behaviour. Findings -Opinion leaders are much more useful in the process of audience development than mavens given their propensity to engage in positive reinforcement behaviours particularly in their roles as theatre guides.Research limitations/implications -While the level of mavenism is related to provision of general market information, it is not related to diffusion of performance-specific information. Also, the portrayal of opinion leaders as living in a "closed world" unlikely to be an effective cultural influence on non-attendees, is not supported. A further limitation is that it could not gauge the effectiveness of the self-reported influential behaviour of non-attendees. Further research should measure the effectiveness of opinion leaders based on how many of the non-attendees they influenced came to the theatre. Practical implications -Theatres should identify opinion leaders and encourage their natural "guide" behaviour with targeted incentives and information as a method of building new audiences and developing new relationships. Originality/value -This paper will help theatres to use their resources more effectively to increase audience attendance. Further, the identification and establishment of theatre guides based on the characteristics of opinion leaders is within the capability of all arts organizations.

Background: Endometrial cancer is the most common gynaecological cancer in high-income countries. Elevated body mass index (BMI) is an established modifiable risk factor for this condition and is estimated to confer a larger effect on endometrial cancer risk than any other cancer site. However, the molecular mechanisms underpinning this association remain unclear. We used Mendelian randomization (MR) to evaluate the causal role of 14 molecular risk factors (hormonal, metabolic, and inflammatory markers) in endometrial cancer risk. We then evaluated and quantified the potential mediating role of these molecular traits in the relationship between BMI and endometrial cancer. Methods and Findings: Genetic instruments to proxy 14 molecular risk factors and BMI were constructed by identifying single-nucleotide polymorphisms (SNPs) reliably associated (P < 5.0 x 10-8) with each respective risk factor in previous genome-wide association studies (GWAS). Summary statistics for the association of these SNPs with overall and subtype-specific endometrial cancer risk (12,906 cases and 108,979 controls) were obtained from a GWAS meta-analysis of the Endometrial Cancer Association Consortium (ECAC), Epidemiology of Endometrial Cancer Consortium (E2C2), and UK Biobank. SNPs were combined into multi-allelic models and odds ratios (ORs) and 95% confidence intervals (95% CIs) were generated using inverse-variance weighted random-effects models. The mediating roles of the molecular risk factors in the relationship between BMI and endometrial cancer were then estimated using multivariable MR. In MR analyses, there was strong evidence that BMI (OR per SD increase: 1.88, 95% CI: 1.69 to 2.09, P = 3.87 x 10-31), total testosterone (OR per inverse normal transformed nmol/L increase: 1.64, 95% CI: 1.43 to 1.88, P = 1.71 x 10-12), bioavailable testosterone (OR per inverse normal transformed nmol/L increase: 1.46, 95% CI: 1.29 to 1.65, P = 3.48 x 10-9), fasting insulin (OR per natural log transformed pmol/L increase: 3.93, 95% CI: 2.29 to 6.74, P = 7.18 x 10-7) and sex hormone-binding globulin (SHBG, OR per inverse normal transformed nmol/L increase: 0.71, 95% CI: 0.59 to 0.85, P = 2.07 x 10-4) had a causal effect on endometrial cancer risk. Additionally, there was suggestive evidence that total serum cholesterol (OR per mg/dL increase: 0.90, 95% CI: 0.81 to 1.00, P = 4.01 x 10-2) had an effect on endometrial cancer risk. In mediation analysis using multivariable MR, we found evidence for a mediating role of fasting insulin (19% total effect mediated, 95% CI: 5 to 34%, P = 9.17 x 10-3), bioavailable testosterone (15% mediated, 95% CI: 10 to 20%, P = 1.43 x 10-8), and SHBG (7% mediated, 95% CI: 1 to 12%, P = 1.81 x 10-2) in the relationship between BMI and endometrial cancer risk. The primary limitations of this analysis include the assumption of linear relationships across univariable and multivariable analyses and the restriction of analyses to individuals of European ancestry. Conclusions: Our comprehensive Mendelian randomization analysis provides insight into potential causal mechanisms linking BMI with endometrial cancer risk and suggests pharmacological targeting of insulinemic and hormonal traits as a potential strategy for the prevention of endometrial cancer.