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Background: Little is known about community knowledge and stigma towards leprosy in endemic settings. The aim of this study was to evaluate community knowledge, attitudes and stigma towards leprosy in Nigeria., Methods: This was a mixed-methods study consisting of a quantitative cross-sectional survey of community members and qualitative focus group discussions with community members and people affected by leprosy as well as key informant interviews with healthcare workers and community leaders., Results: Of the 811 survey participants, 401 (49.4%) had a poor knowledge of leprosy that was driven by cultural beliefs, fear of its contagiousness and poor knowledge of its means of transmission. The participants reported high stigma levels with a mean score of 18.96±7.73 on the Explanatory Model Interview Catalogue Community Stigma Scale and 9.39±7.03 on the Social Distance Scale. Stigma levels were influenced by age, residence, education and knowledge of leprosy. Qualitative data suggested that community members were scared of leprosy infectiousness, and local illness concepts and misconceptions informed attitudes and behaviour towards leprosy in the community., Conclusion: Community members have a poor knowledge of, and high stigma levels towards leprosy. Culture-specific health education and behavioural change interventions are needed to address the identified gaps., (© The Author(s) 2024. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene.)

Context: Hyperinsulinemic hypoglycemia (HI) can be the presenting feature of Kabuki syndrome (KS), which is caused by loss-of-function variants in KMT2D or KDM6A. As these genes play a critical role in maintaining methylation status in chromatin, individuals with pathogenic variants have a disease-specific epigenomic profile -an episignature., Objective: We evaluated the pathogenicity of three novel partial KDM6A duplications identified in three individuals presenting with neonatal-onset HI without typical features of KS at the time of genetic testing., Methods: Three different partial KDM6A duplications were identified by routine targeted next generation sequencing for HI and initially classified as variants of uncertain significance (VUS) as their location, and hence their impact on the gene, was not known. Whole genome sequencing (WGS) was undertaken to map the breakpoints of the duplications with DNA methylation profiling performed in two individuals to investigate the presence of a KS-specific episignature., Results: WGS confirmed the duplication in proband 1 as pathogenic as it caused a frameshift in the normal copy of the gene leading to a premature termination codon. The duplications identified in probands 2 and 3 did not alter the reading frame and therefore their significance remained uncertain after WGS. Subsequent DNA methylation profiling identified a KS-specific episignature in proband 2 but not in proband 3., Conclusions: Our findings confirm a role for KDM6A partial gene duplications in the etiology of KS and highlight the importance of performing in-depth molecular genetic analysis to properly assess the clinical significance of VUS's in the KDM6A gene., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: Colorectal cancer (CRC) is the third-most-common cancer worldwide and its rates are increasing. Elevated body mass index (BMI) is an established risk factor for CRC, although the molecular mechanisms behind this association remain unclear. Using the Mendelian randomization (MR) framework, we aimed to investigate the mediating effects of putative biomarkers and other CRC risk factors in the association between BMI and CRC., Methods: We selected as mediators biomarkers of established cancer-related mechanisms and other CRC risk factors for which a plausible association with obesity exists, such as inflammatory biomarkers, glucose homeostasis traits, lipids, adipokines, insulin-like growth factor 1 (IGF1), sex hormones, 25-hydroxy-vitamin D, smoking, physical activity (PA) and alcohol consumption. We used inverse-variance weighted MR in the main univariable analyses and performed sensitivity analyses (weighted-median, MR-Egger, Contamination Mixture). We used multivariable MR for the mediation analyses., Results: Genetically predicted BMI was positively associated with CRC risk [odds ratio per SD (5 kg/m2) = 1.17, 95% CI: 1.08-1.24, P-value = 1.4 × 10-5] and robustly associated with nearly all potential mediators. Genetically predicted IGF1, fasting insulin, low-density lipoprotein cholesterol, smoking, PA and alcohol were associated with CRC risk. Evidence for attenuation was found for IGF1 [explained 7% (95% CI: 2-13%) of the association], smoking (31%, 4-57%) and PA (7%, 2-11%). There was little evidence for pleiotropy, although smoking was bidirectionally associated with BMI and instruments were weak for PA., Conclusions: The effect of BMI on CRC risk is possibly partly mediated through plasma IGF1, whereas the attenuation of the BMI-CRC association by smoking and PA may reflect confounding and shared underlying mechanisms rather than mediation., (© The Author(s) 2024. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Scaling up established physical activity (PA) opportunities for broader population reach requires practitioners to carefully consider strategies implemented to recruit and attract new participants to their PA programs. This scoping review examines the effectiveness of recruitment strategies for engaging adults in organized (established and sustained) PA programs. Electronic databases were searched for articles published between March 1995 and September 2022. Qualitative, quantitative and mixed methods papers were included. Recruitment strategies were assessed against Foster et al. (Recruiting participants to walking intervention studies: a systematic review. Int J Behav Nutr Phys Act 2011;8:137-137.) assessment of quality for reporting recruitment and the determinants of recruitment rates were examined. 8394 titles and abstracts were screened; 22 articles were assessed for eligibility; 9 papers were included. Three of the 6 quantitative papers adopted a combination of passive and active recruitment strategies and 3 relied solely on active strategies. All 6 quantitative papers reported on recruitment rates; 2 evaluated the efficacy of recruitment strategies based on the achieved levels of participation. The evaluation evidence on how individuals are successfully recruited into organized PA programs, and how recruitment strategies influence or address inequities in PA participation, is limited. Culturally sensitive, gender sensitive and socially inclusive recruitment strategies based on building personal relationships show promise for engaging hard-to-reach populations. Improving the reporting and measurement of recruitment strategies into PA programs is essential to better understand which strategies are attracting various population groups thus allowing program implementers to employ recruitment strategies best suited to the needs of their community while making efficient use of program funding., (© The Author(s) 2023. Published by Oxford University Press.)

Mass participation sports event (MPSE)s have been identified as a potential referral pathway for engaging inactive patients in regular physical activity. This study aimed to review evidence of physical activity behaviour and associated health-related outcomes of engaging in MPSEs among the general population. A systematic review was performed of quantitative studies that examined the relationship between MPSEs and physical activity behaviour or secondary outcomes (e.g. physical activity motivation or confidence, physical or mental health) or any intervention to maintain physical activity following MPSEs. Search methods included searching five electronic databases and checking reference lists. Methodological quality was assessed using the Mixed Methods Appraisal Tool. A total of 2079 papers were identified, 142 were independently assessed for eligibility and 39 were included. Data from prospective cohort studies suggested that levels of physical activity achieved in training for MPSEs tended to drop in the months after, but increases were reported in some studies of novice participants. Interventions involving health promotion materials provided post-event led to small increases in physical activity. Perceived benefits of participating in MPSEs included physical and mental health, fitness, self-efficacy and social connections. Existing evidence suggests that MPSEs can act as a motivator to initiate exercise in preparation for the event, but there is limited evidence on how best to sustain physical activity post-event. Given the short duration of most studies, longer prospective analyses are needed to delineate patterns of habitual and event-related activity and account for seasonal effects., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Obesity is an established risk factor for colorectal cancer (CRC), but the evidence for the association is inconsistent across molecular subtypes of the disease., Methods: We pooled data on body mass index (BMI), tumor microsatellite instability status, CpG island methylator phenotype status, BRAF and KRAS mutations, and Jass classification types for 11 872 CRC cases and 11 013 controls from 11 observational studies. We used multinomial logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) adjusted for covariables., Results: Higher BMI was associated with increased CRC risk (OR per 5 kg/m2 = 1.18, 95% CI = 1.15 to 1.22). The positive association was stronger for men than women but similar across tumor subtypes defined by individual molecular markers. In analyses by Jass type, higher BMI was associated with elevated CRC risk for types 1-4 cases but not for type 5 CRC cases (considered familial-like/Lynch syndrome microsatellite instability-H, CpG island methylator phenotype-low or negative, BRAF-wild type, KRAS-wild type, OR = 1.04, 95% CI = 0.90 to 1.20). This pattern of associations for BMI and Jass types was consistent by sex and design of contributing studies (cohort or case-control)., Conclusions: In contrast to previous reports with fewer study participants, we found limited evidence of heterogeneity for the association between BMI and CRC risk according to molecular subtype, suggesting that obesity influences nearly all major pathways involved in colorectal carcinogenesis. The null association observed for the Jass type 5 suggests that BMI is not a risk factor for the development of CRC for individuals with Lynch syndrome., (© The Author(s) 2022. Published by Oxford University Press.)

Research has highlighted the importance of gendered approaches to engage men with health. Sheds for Life (SFL) is a health and wellbeing initiative that utilizes evidence-based and gender-specific approaches to engage hard to reach men with health promotion directly in the Men's Sheds (Sheds) setting. To understand the impact of SFL and how participants (Shedders) experienced SFL in practice, this qualitative study applied a framework of constructivism and aimed to explore how gendered approaches impacted engagement with SFL through Shedder's own accounts of their attitudes, opinions and experiences. Qualitative methods incorporating ethnographical observations, focus groups (n = 8) and short semi-structured interviews (n = 19) were conducted with SFL participants in the Shed setting. Reflexive thematic analysis was used to analyse the data to faithfully capture Shedders' experiences while acknowledging the reflexive influence of the researcher. Findings led to three key themes: Creating the 'right environment'; Normalizing meaningful conversations; a legacy for 'talking health' with subthemes of creating safety and trust and strengthening of bonds; and transforming perceptions of how men 'do health' with subthemes of reaping the benefits of engaging with health and reframing attitudes towards health. This is first study to capture Shedders' experiences of a structured health promotion initiative in the Shed setting. Findings highlight the value in utilizing the Shed setting to engage men with health and the importance of gender-specific strategies which encourage a gender-transformative approach to men's health promotion., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Despite a clear distinction between aerobic and muscle strengthening (MS) components in the physical activity guidelines, public health surveillance has largely focused only on aerobic components, limiting the reach of epidemiological research on the physical activity guidelines. Hence, this study investigated the association between adherence to both components (i.e. aerobic and muscle-strengthening) of the World Health Organization's physical activity guidelines and mental health among the college student population. A cross-sectional study was conducted among a nationally representative sample of Irish college students (7088 participants, M age: 23.17 years; 50.9% female). Participants were categorized as meeting both components of the guidelines (n = 41%), only the aerobic component (n = 25.3%) or the MS component (n = 7.3%), and neither (n = 26.4%). Group membership effects on mental health was determined through mixed univariate ANOVAs, with a Bonferroni correction for post hoc analyses to assess multiple comparisons. Results revealed that meeting both components of the guidelines was significantly (all p < 0.01) associated with greater self-reported happiness, body image and general health, and less mental ill-being, relative to all other respective groupings. Meeting aerobic or MS components in isolation was significantly (p < 0.05) associated with better happiness, general health and body image compared to not meeting either component. To conclude, 59% of the college-aged population are insufficiently active, and adherence to both guideline components is positively associated with mental health. Co-produced, evidence-based, physical activity interventions are needed in students and could contribute to mental health promotion., (© Crown copyright 2022.)

It is unclear if body weight in early life affects cancer risk independently of adult body weight. To investigate this question for 6 obesity-related cancers, we performed univariable and multivariable analyses using 1) Mendelian randomization (MR) analysis and 2) longitudinal analyses in prospective cohorts. Both the MR and longitudinal analyses indicated that larger early life body size was associated with higher risk of endometrial (odds ratioMR = 1.61, 95% confidence interval = 1.23 to 2.11) and kidney (odds ratioMR = 1.40, 95% confidence interval = 1.09 to 1.80) cancer. These associations were attenuated after accounting for adult body size in both the MR and cohort analyses. Early life body mass index (BMI) was not consistently associated with the other investigated cancers. The lack of clear independent risk associations suggests that early life BMI influences endometrial and kidney cancer risk mainly through pathways that are common with adult BMI., (© World Health Organization, 2022. All rights reserved. The World Health Organization has granted the Publisher permission for the reproduction of this article.)

Background: The use of menopausal hormone therapy (MHT) may interact with genetic variants to influence colorectal cancer (CRC) risk., Methods: We conducted a genome-wide, gene-environment interaction between single nucleotide polymorphisms and the use of any MHT, estrogen only, and combined estrogen-progestogen therapy with CRC risk, among 28 486 postmenopausal women (11 519 CRC patients and 16 967 participants without CRC) from 38 studies, using logistic regression, 2-step method, and 2- or 3-degree-of-freedom joint test. A set-based score test was applied for rare genetic variants., Results: The use of any MHT, estrogen only and estrogen-progestogen were associated with a reduced CRC risk (odds ratio [OR] = 0.71, 95% confidence interval [CI] = 0.64 to 0.78; OR = 0.65, 95% CI = 0.53 to 0.79; and OR = 0.73, 95% CI = 0.59 to 0.90, respectively). The 2-step method identified a statistically significant interaction between a GRIN2B variant rs117868593 and MHT use, whereby MHT-associated CRC risk was statistically significantly reduced in women with the GG genotype (OR = 0.68, 95% CI = 0.64 to 0.72) but not within strata of GC or CC genotypes. A statistically significant interaction between a DCBLD1 intronic variant at 6q22.1 (rs10782186) and MHT use was identified by the 2-degree-of-freedom joint test. The MHT-associated CRC risk was reduced with increasing number of rs10782186-C alleles, showing odds ratios of 0.78 (95% CI = 0.70 to 0.87) for TT, 0.68 (95% CI = 0.63 to 0.73) for TC, and 0.66 (95% CI = 0.60 to 0.74) for CC genotypes. In addition, 5 genes in rare variant analysis showed suggestive interactions with MHT (2-sided P < 1.2 × 10-4)., Conclusion: Genetic variants that modify the association between MHT and CRC risk were identified, offering new insights into pathways of CRC carcinogenesis and potential mechanisms involved., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Findings and limitations of previous studies on persistent organic pollutants (POPs) and pancreatic cancer risk support conducting further research in prospective cohorts., Methods: We conducted a prospective case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Participants were 513 pancreatic cancer cases and 1020 matched controls. Concentrations of 22 POPs were measured in plasma collected at baseline., Results: Some associations were observed at higher concentrations of p, p'-DDT, trans-nonachlor, β-hexachlorocyclohexane and the sum of six organochlorine pesticides and of 16 POPs. The odds ratio (OR) for the upper quartile of trans-nonachlor was 1.55 (95% confidence interval 1.06-2.26; P for trend = 0.025). Associations were stronger in the groups predefined as most valid (participants having fasted >6 h, with microscopic diagnostic confirmation, normal weight, and never smokers), and as most relevant (follow-up ≥10 years). Among participants having fasted >6 h, the ORs were relevant for 10 of 11 exposures. Higher ORs were also observed among cases with microscopic confirmation than in cases with a clinical diagnosis, and among normal-weight participants than in the rest of participants. Among participants with a follow-up ≥10 years, estimates were higher than in participants with a shorter follow-up (for trans-nonachlor: OR = 2.14, 1.01 to 4.53, P for trend = 0.035). Overall, trans-nonachlor, three PCBs and the two sums of POPs were the exposures most clearly associated with pancreatic cancer risk., Conclusions: Individually or in combination, most of the 22 POPs analysed did not or only moderately increased the risk of pancreatic cancer., (© The Author(s) 2021. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background: Glycemic traits-such as hyperinsulinemia, hyperglycemia, and type 2 diabetes-have been associated with higher colorectal cancer risk in observational studies; however, causality of these associations is uncertain. We used Mendelian randomization (MR) to estimate the causal effects of fasting insulin, 2-hour glucose, fasting glucose, glycated hemoglobin (HbA1c), and type 2 diabetes with colorectal cancer., Methods: Genome-wide association study summary data were used to identify genetic variants associated with circulating levels of fasting insulin (n = 34), 2-hour glucose (n = 13), fasting glucose (n = 70), HbA1c (n = 221), and type 2 diabetes (n = 268). Using 2-sample MR, we examined these variants in relation to colorectal cancer risk (48 214 case patient and 64 159 control patients)., Results: In inverse-variance models, higher fasting insulin levels increased colorectal cancer risk (odds ratio [OR] per 1-SD = 1.65, 95% confidence interval [CI] = 1.15 to 2.36). We found no evidence of any effect of 2-hour glucose (OR per 1-SD = 1.02, 95% CI = 0.86 to 1.21) or fasting glucose (OR per 1-SD = 1.04, 95% CI = 0.88 to 1.23) concentrations on colorectal cancer risk. Genetic liability to type 2 diabetes (OR per 1-unit increase in log odds = 1.04, 95% CI = 1.01 to 1.07) and higher HbA1c levels (OR per 1-SD = 1.09, 95% CI = 1.00 to 1.19) increased colorectal cancer risk, although these findings may have been biased by pleiotropy. Higher HbA1c concentrations increased rectal cancer risk in men (OR per 1-SD = 1.21, 95% CI = 1.05 to 1.40), but not in women., Conclusions: Our results support a causal effect of higher fasting insulin, but not glucose traits or type 2 diabetes, on increased colorectal cancer risk. This suggests that pharmacological or lifestyle interventions that lower circulating insulin levels may be beneficial in preventing colorectal tumorigenesis., (© The Author(s) 2022. Published by Oxford University Press.)

Background: The incidence of colorectal cancer (CRC) among individuals aged younger than 50 years has been increasing. As screening guidelines lower the recommended age of screening initiation, concerns including the burden on screening capacity and costs have been recognized, suggesting that an individualized approach may be warranted. We developed risk prediction models for early-onset CRC that incorporate an environmental risk score (ERS), including 16 lifestyle and environmental factors, and a polygenic risk score (PRS) of 141 variants., Methods: Relying on risk score weights for ERS and PRS derived from studies of CRC at all ages, we evaluated risks for early-onset CRC in 3486 cases and 3890 controls aged younger than 50 years. Relative and absolute risks for early-onset CRC were assessed according to values of the ERS and PRS. The discriminatory performance of these scores was estimated using the covariate-adjusted area under the receiver operating characteristic curve., Results: Increasing values of ERS and PRS were associated with increasing relative risks for early-onset CRC (odds ratio per SD of ERS = 1.14, 95% confidence interval [CI] = 1.08 to 1.20; odds ratio per SD of PRS = 1.59, 95% CI = 1.51 to 1.68), both contributing to case-control discrimination (area under the curve = 0.631, 95% CI = 0.615 to 0.647). Based on absolute risks, we can expect 26 excess cases per 10 000 men and 21 per 10 000 women among those scoring at the 90th percentile for both risk scores., Conclusions: Personal risk scores have the potential to identify individuals at differential relative and absolute risk for early-onset CRC. Improved discrimination may aid in targeted CRC screening of younger, high-risk individuals, potentially improving outcomes., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Retransplantation candidates are disadvantaged owing to lack of good-quality liver grafts. Strategies that can facilitate transplantation of suboptimal grafts into retransplant candidates require investigation. The aim was to determine whether late liver retransplantation can be performed safely with suboptimal grafts, following normothermic machine perfusion., Methods: A prospectively enrolled group of patients who required liver retransplantation received a suboptimal graft preserved via normothermic machine perfusion. This group was compared with both historical and contemporaneous cohorts of patient who received grafts preserved by cold storage. The primary outcome was 6-month graft and patient survival., Results: The normothermic machine perfusion group comprised 26 patients. The historical (cold storage 1) and contemporaneous (cold storage 2) groups comprised 31 and 25 patients respectively. The 6-month graft survival rate did not differ between groups (cold storage 1, 27 of 31, cold storage 2, 22 of 25; normothermic machine perfusion, 22 of 26; P = 0.934). This was despite the normothermic machine perfusion group having significantly more steatotic grafts (8 of 31, 7 of 25, and 14 of 26 respectively; P = 0.006) and grafts previously declined by at least one other transplant centre (5 of 31, 9 of 25, and 21 of 26; P < 0.001)., Conclusion: In liver retransplantation, normothermic machine perfusion can safely expand graft options without compromising short-term outcomes., (© The Author(s) 2022. Published by Oxford University Press on behalf of BJS Society Ltd. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Observational studies have consistently reported that postmenopausal hormone therapy use is associated with lower colon cancer risk, but epidemiologic studies examining the associations between circulating concentrations of endogenous estrogens and colorectal cancer have reported inconsistent results., Methods: We investigated the associations between circulating concentrations of estrone, estradiol, free estradiol, testosterone, free testosterone, androstenedione, dehydroepiandrosterone (DHEA), progesterone, and sex hormone-binding globulin (SHBG) with colon cancer risk in a nested case-control study of 1028 postmenopausal European women (512 colon cancer cases, 516 matched controls) who were noncurrent users of exogenous hormones at blood collection. Multivariable conditional logistic regression models were used to compute odds ratios and 95% confidence intervals to evaluate the association between circulating sex hormones and colon cancer risk. We also conducted a dose-response meta-analysis of prospective studies of circulating estrone and estradiol with colorectal, colon, and rectal cancer risk in postmenopausal women. All statistical tests were 2-sided., Results: In the multivariable model, a nonstatistically significantly positive relationship was found between circulating estrone and colon cancer risk (odds ratio per log 2 1-unit increment   =   1.17 [95% confidence interval   =   1.00 to 1.38]; odds ratio quartile4-quartile1   =   1.33 [95% confidence interval   =   0.89 to 1.97], P trend   =   .20). Circulating concentrations of estradiol, free estradiol, testosterone, free testosterone, androstenedione, DHEA, progesterone, and SHBG were not associated with colon cancer risk. In the dose-response meta-analysis, no clear evidence of associations were found between circulating estradiol and estrone concentrations with colorectal, colon, and rectal cancer risk., Conclusion: Our observational and meta-analysis results do not support an association between circulating concentrations of endogenous sex hormones and colon or rectal cancer in postmenopausal women., (© The Author(s) 2021. Published by Oxford University Press.)

COVID-19 disproportionately affects males especially those who are older and more socio-economically disadvantaged. This study assessed wellbeing outcomes among men's shed members (Shedders) in Ireland at baseline (T1), 3 (T2), 6 (T3) and 12 months (T4) in response to a 10-week health promotion program 'Sheds for Life' (SFL). Two cohorts participated in SFL commencing in March and September 2019. This study compares the T3 findings from one cohort carried out during the COVID-19 pandemic [COVID cohort (n = 185)] with T3 findings from a comparator cohort [pre-COVID cohort (n = 195)], completed pre-COVID-19. Questionnaires assessing wellbeing [life satisfaction, mental health, loneliness, physical activity (PA), self-rated health and other lifestyle measures] were analyzed in both cohorts T1, T2 and T3. Self-rated Health and life satisfaction decreased in the COVID cohort at T3 (p < 0.001), while loneliness scores increased (p < 0.0005). Higher loneliness scores were correlated with lower health ratings, life satisfaction and PA during COVID-19 (p < 0.001). Days PA decreased in the COVID cluster at T3 from T2 (p < 0.01) with those in urban areas reporting lower activity levels than rural areas (p < 0.05). Those sufficiently active at baseline managed to maintain PA during COVID-19 while those not meeting guidelines were more likely to report decreases (p < 0.001). Shedders experiencing COVID-19 restrictions are at an increased risk of poorer wellbeing and increased levels of loneliness. Support and guidance are needed to safely encourage this cohort back into men's sheds, settings that protect against loneliness and positively promote health and wellbeing. Lay summary The COVID-19 pandemic will have wide-reaching implications on wellbeing, particularly on those who are older and more vulnerable. Evidence also suggests that COVID-19 disproportionately affects males. This study aimed to understand the impact that COVID-19 has had on men in the setting of Men's Sheds in Ireland. Two cohorts of men who were participating in a 10-week health and wellbeing program (Sheds for Life) at different stages were followed over time. At 6 months follow-up the first Cohort had not experienced COVID-19 whereas the second cohort was actively experiencing the COVID-19 pandemic. We measured wellbeing using questionnaires, comparing both groups of men for differences. We found that the men who were experiencing COVID-19 had lower self-rated health, physical activity and life satisfaction as well as higher rates of loneliness, with those who were more lonely reporting lower wellbeing scores. We also found that men in rural areas were more physically active during COVID-19 and that those were not active were more likely to become more inactive during COVID-19. This study suggests that support and guidance is needed to safely encourage this cohort back into Men's Sheds, settings that protect against loneliness and positively promote health and wellbeing., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Incidence of early-onset (younger than 50 years of age) colorectal cancer (CRC) is increasing in many countries. Thus, elucidating the role of traditional CRC risk factors in early-onset CRC is a high priority. We sought to determine whether risk factors associated with late-onset CRC were also linked to early-onset CRC and whether association patterns differed by anatomic subsite., Methods: Using data pooled from 13 population-based studies, we studied 3767 CRC cases and 4049 controls aged younger than 50 years and 23 437 CRC cases and 35 311 controls aged 50 years and older. Using multivariable and multinomial logistic regression, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) to assess the association between risk factors and early-onset CRC and by anatomic subsite., Results: Early-onset CRC was associated with not regularly using nonsteroidal anti-inflammatory drugs (OR = 1.43, 95% CI = 1.21 to 1.68), greater red meat intake (OR = 1.10, 95% CI = 1.04 to 1.16), lower educational attainment (OR = 1.10, 95% CI = 1.04 to 1.16), alcohol abstinence (OR = 1.23, 95% CI = 1.08 to 1.39), and heavier alcohol use (OR = 1.25, 95% CI = 1.04 to 1.50). No factors exhibited a greater excess in early-onset compared with late-onset CRC. Evaluating risks by anatomic subsite, we found that lower total fiber intake was linked more strongly to rectal (OR = 1.30, 95% CI = 1.14 to 1.48) than colon cancer (OR = 1.14, 95% CI = 1.02 to 1.27; P  = .04)., Conclusion: In this large study, we identified several nongenetic risk factors associated with early-onset CRC, providing a basis for targeted identification of those most at risk, which is imperative in mitigating the rising burden of this disease., (© The Author(s) 2021. Published by Oxford University Press.)

Background: Body mass index (BMI) is a complex phenotype that may interact with genetic variants to influence colorectal cancer risk., Methods: We tested multiplicative statistical interactions between BMI (per 5 kg/m2) and approximately 2.7 million single nucleotide polymorphisms with colorectal cancer risk among 14 059 colorectal cancer case (53.2% women) and 14 416 control (53.8% women) participants. All analyses were stratified by sex a priori. Statistical methods included 2-step (ie, Cocktail method) and single-step (ie, case-control logistic regression and a joint 2-degree of freedom test) procedures. All statistical tests were two-sided., Results: Each 5 kg/m2 increase in BMI was associated with higher risks of colorectal cancer, less so for women (odds ratio [OR] = 1.14, 95% confidence intervals [CI] = 1.11 to 1.18; P = 9.75 × 10-17) than for men (OR = 1.26, 95% CI = 1.20 to 1.32; P = 2.13 × 10-24). The 2-step Cocktail method identified an interaction for women, but not men, between BMI and a SMAD7 intronic variant at 18q21.1 (rs4939827; Pobserved = .0009; Pthreshold = .005). A joint 2-degree of freedom test was consistent with this finding for women (joint P = 2.43 × 10-10). Each 5 kg/m2 increase in BMI was more strongly associated with colorectal cancer risk for women with the rs4939827-CC genotype (OR = 1.24, 95% CI = 1.16 to 1.32; P = 2.60 × 10-10) than for women with the CT (OR = 1.14, 95% CI = 1.09 to 1.19; P = 1.04 × 10-8) or TT (OR = 1.07, 95% CI = 1.01 to 1.14; P = .02) genotypes., Conclusion: These results provide novel insights on a potential mechanism through which a SMAD7 variant, previously identified as a susceptibility locus for colorectal cancer, and BMI may influence colorectal cancer risk for women., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Postmenopausal hormone therapy (HT) is associated with a decreased colorectal cancer (CRC) risk. As CRC is a heterogeneous disease, we evaluated whether the association of HT and CRC differs across etiologically relevant, molecularly defined tumor subtypes and tumor location., Methods: We pooled data on tumor subtypes (microsatellite instability status, CpG island methylator phenotype status, BRAF and KRAS mutations, pathway: adenoma-carcinoma, alternate, serrated), tumor location (proximal colon, distal colon, rectum), and HT use among 8220 postmenopausal women (3898 CRC cases and 4322 controls) from 8 observational studies. We used multinomial logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CIs) for the association of ever vs never HT use with each tumor subtype compared with controls. Models were adjusted for study, age, body mass index, smoking status, and CRC family history. All statistical tests were 2-sided., Results: Among postmenopausal women, ever HT use was associated with a 38% reduction in overall CRC risk (OR =0.62, 95% CI = 0.56 to 0.69). This association was similar according to microsatellite instability, CpG island methylator phenotype and BRAF or KRAS status. However, the association was attenuated for tumors arising through the serrated pathway (OR = 0.81, 95% CI = 0.66 to 1.01) compared with the adenoma-carcinoma pathway (OR = 0.63, 95% CI = 0.55 to 0.73; P het  =.04) and alternate pathway (OR = 0.61, 95% CI = 0.51 to 0.72). Additionally, proximal colon tumors had a weaker association (OR = 0.71, 95% CI = 0.62 to 0.80) compared with rectal (OR = 0.54, 95% CI = 0.46 to 0.63) and distal colon (OR = 0.57, 95% CI = 0.49 to 0.66; P het  =.01) tumors., Conclusions: We observed a strong inverse association between HT use and overall CRC risk, which may predominantly reflect a benefit of HT use for tumors arising through the adenoma-carcinoma and alternate pathways as well as distal colon and rectal tumors., (© The Author(s) 2020. Published by Oxford University Press.)

Background: Bile acids have been proposed to promote colon carcinogenesis. However, there are limited prospective data on circulating bile acid levels and colon cancer risk in humans., Methods: Associations between prediagnostic plasma levels of 17 primary, secondary, and tertiary bile acid metabolites (conjugated and unconjugated) and colon cancer risk were evaluated in a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Bile acid levels were quantified by tandem mass spectrometry in samples from 569 incident colon cancer cases and 569 matched controls. Multivariable logistic regression analyses were used to estimate odds ratios (ORs) for colon cancer risk across quartiles of bile acid concentrations., Results: Positive associations were observed between colon cancer risk and plasma levels of seven conjugated bile acid metabolites: the primary bile acids glycocholic acid (ORquartile 4 vs quartile 1= 2.22, 95% confidence interval [CI] = 1.52 to 3.26), taurocholic acid (OR = 1.78, 95% CI = 1.23 to 2.58), glycochenodeoxycholic acid (OR = 1.68, 95% CI = 1.13 to 2.48), taurochenodeoxycholic acid (OR = 1.62, 95% CI = 1.11 to 2.36), and glycohyocholic acid (OR = 1.65, 95% CI = 1.13 to 2.40), and the secondary bile acids glycodeoxycholic acid (OR = 1.68, 95% CI = 1.12 to 2.54) and taurodeoxycholic acid (OR = 1.54, 95% CI = 1.02 to 2.31). By contrast, unconjugated bile acids and tertiary bile acids were not associated with risk., Conclusions: This prospective study showed that prediagnostic levels of certain conjugated primary and secondary bile acids were positively associated with risk of colon cancer. Our findings support experimental data to suggest that a high bile acid load is colon cancer promotive., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Most of the previous studies on diet and colorectal cancer were based on diets consumed during the 1990s., Methods: We used Cox-regression models to estimate adjusted hazard ratios for colorectal cancer by dietary factors in the UK Biobank study. Men and women aged 40-69 years at recruitment (2006-10) reported their diet on a short food-frequency questionnaire (n = 475 581). Dietary intakes were re-measured in a large sub-sample (n = 175 402) who completed an online 24-hour dietary assessment during follow-up. Trends in risk across the baseline categories were calculated by assigning re-measured intakes to allow for measurement error and changes in intake over time., Results: During an average of 5.7 years of follow-up, 2609 cases of colorectal cancer occurred. Participants who reported consuming an average of 76 g/day of red and processed meat compared with 21 g/day had a 20% [95% confidence interval (CI): 4-37] higher risk of colorectal cancer. Participants in the highest fifth of intake of fibre from bread and breakfast cereals had a 14% (95% CI: 2-24) lower risk of colorectal cancer. Alcohol was associated with an 8% (95% CI: 4-12) higher risk per 10 g/day higher intake. Fish, poultry, cheese, fruit, vegetables, tea and coffee were not associated with colorectal-cancer risk., Conclusions: Consumption of red and processed meat at an average level of 76 g/d that meets the current UK government recommendation (≤90 g/day) was associated with an increased risk of colorectal cancer. Alcohol was also associated with an increased risk of colorectal cancer, whereas fibre from bread and breakfast cereals was associated with a reduced risk., (© The Author(s) 2019. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background: There are observational data suggesting an inverse association between circulating concentrations of sex hormone binding globulin (SHBG) and risk of postmenopausal breast cancer. However, causality is uncertain and few studies have investigated this association by tumour receptor status. We aimed to investigate these associations under the causal framework of Mendelian randomization (MR)., Methods: We used summary association estimates extracted from published genome-wide association study (GWAS) meta-analyses for SHBG and breast cancer, to perform two-sample MR analyses. Summary statistics were available for 122 977 overall breast cancer cases, of which 69 501 were estrogen receptor positive (ER+ve) and 21 468 were ER-ve, and 105 974 controls. To control for potential horizontal pleiotropy acting via body mass index (BMI), we performed multivariable inverse-variance weighted (IVW) MR as the main analysis, with the robustness of this approach further tested in sensitivity analyses., Results: The multivariable IVW MR analysis indicated a lower risk of overall (odds ratio [OR]: 0.94; 95% confidence interval [CI]: 0.90, 0.98; P: 0.006) and ER+ve (OR: 0.92; 95% CI: 0.87, 0.97; P: 0.003) breast cancer, and a higher risk of ER-ve disease (OR: 1.09; 95% CI: 1.00, 1.18; P: 0.047) per 25 nmol/L higher SHBG levels. Sensitivity analyses were consistent with the findings of the main analysis., Conclusions: We corroborated the previous literature evidence coming from observational studies for a potentially causal inverse association between SHBG concentrations and risk of ER+ve breast cancer, but our findings also suggested a potential novel positive association with ER-ve disease that warrants further investigation, given the low prior probability of being true., (© The Author(s) 2019; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

The role of hormonal factors in the etiology of lymphoid neoplasms remains unclear. Previous studies have yielded conflicting results, have lacked sufficient statistical power to assess many lymphoma subtypes, or have lacked detailed information on relevant exposures. Within the European Prospective Investigation Into Cancer and Nutrition cohort, we analyzed comprehensive data on reproductive factors and exogenous hormone use collected at baseline (1992-2000) among 343,458 women, including data on 1,427 incident cases of B-cell non-Hodgkin lymphoma (NHL) and its major subtypes identified after a mean follow-up period of 14 years (through 2015). We estimated hazard ratios and 95% confidence intervals using multivariable proportional hazards modeling. Overall, we observed no statistically significant associations between parity, age at first birth, breastfeeding, oral contraceptive use, or ever use of postmenopausal hormone therapy and risk of B-cell NHL or its subtypes. Women who had undergone surgical menopause had a 51% higher risk of B-cell NHL (based on 67 cases) than women with natural menopause (hazard ratio = 1.51, 95% confidence interval: 1.17, 1.94). Given that this result may have been due to chance, our results provide little support for the hypothesis that sex hormones play a role in lymphomagenesis.

Background: Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk., Methods: We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided., Results: The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0., Conclusions: This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Trypanosoma cruzi causes Chagas disease in the Americas. The outcome of infection ranges from lifelong asymptomatic status to severe disease. Relationship between T. cruzi lineage (TcI-TcVI) infection history and prognosis is not understood. We previously described peptide-based lineage-specific enzyme-linked immunosorbent assay (ELISA) with trypomastigote small surface antigen (TSSA)., Methods: A novel rapid diagnostic test (RDT; Chagas Sero K-SeT) that incorporates a peptide that corresponds to the TSSA II/V/VI common epitope was developed and validated by comparison with ELISA. Patients from Bolivia and Peru, including individuals with varying cardiac pathology, and matched mothers and neonates, were then tested using Chagas Sero K-SeT., Results: Chagas Sero K-SeT and ELISA results, with a Bolivian subset of cardiac patients, mothers, and neonates, were in accord. In adult chronic infections (n = 121), comparison of severity class A (no evidence of Chagas cardiomyopathy) with class B (electrocardiogram suggestive of Chagas cardiomyopathy) and class C/D (decreased left ventricular ejection fraction; moderate/severe Chagas cardiomyopathy) revealed a statistically significant increase in Chagas Sero K-SeT reactivity with increasing severity (χ2 for trend, 7.39; P = .007). In Peru, Chagas Sero K-SeT detected the sporadic TcII/V/VI infections., Conclusions: We developed a low cost RDT that can replace ELISA for identification of TSSA II/V/VI immunoglobulin G. Most importantly, we show that response to this RDT is associated with severity of Chagas cardiomyopathy and thus may have prognostic value. Repeated challenge with T. cruzi infection may both exacerbate disease progression and boost the immune response to the TSSApep-II/V/VI epitope.

Despite the considerable interest in community-based physical activity (PA) interventions, there is a lack of clarity on which strategies are most effective and most likely to work in different contexts. The purpose of this study was to use existing community resources to promote PA in a population sample of insufficiently active women using a cluster RCT design. Participants (n = 402) were grouped into 32 geographical-based clusters, which were randomly allocated into 16 intervention (n = 193) and 16 control (n = 209) regions. The intervention was delivered in conjunction with regional units of the Irish Sports Council; participants received a pack containing tailored information about local PA options in their community, training plans, stage-matched behaviour change booklets and a pedometer. Control participants received health promotion leaflets. Evaluation was conducted using the RE-AIM framework to assess both effectiveness and generalizability. Repeated measures ANOVAs with adjustment for clustering revealed that both groups displayed an approximate 39 min increase in PA, but decreases in sitting were greater in the intervention group than the control group (32.9 versus 1.2 min). Recall of materials was high ranging between 85 and 97% for the various intervention components. Finally, those who received higher doses of the intervention (three or more components) reported an approximate 50 min increase in PA compared with 18 min among those who did not use any aspect of the intervention. While no clear intervention effect was evident, this research was successful in linking and implementing good research design with PA promoting networks., (© The Author (2013). Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Postmenopausal hormone therapy use has been associated with lower colorectal cancer risk in observational studies. However, the role of endogenous sex hormones in colorectal cancer development in postmenopausal women is uncertain., Methods: The relation of colorectal cancer risk with circulating levels of estradiol, estrone, free (bioactive) estradiol, progesterone and sex hormone-binding globulin (SHBG) was determined in a nested case-control study of 1203 postmenopausal women (401 case patients and 802 age and race/ethnicity-matched control patients) enrolled in the Women's Health Initiative Clinical Trial (WHI-CT) who were not assigned to the estrogen-alone or combined estrogen plus progestin intervention groups. We used multivariable-adjusted conditional logistic regression models that included established colorectal cancer risk factors. All statistical tests were two-sided., Results: Comparing extreme quartiles, estrone (odds ratio [OR]q4-q1 = 0.44, 95% confidence interval [CI] = 0.28 to 0.68, P trend = .001), free estradiol (ORq4-q1 = 0.43, 95% CI = 0.27 to 0.69, P trend ≤ .0001), and total estradiol (ORq4-q1 = 0.58, 95% CI = 0.38 to 0.90, P trend = .08) were inversely associated with colorectal cancer risk. SHBG levels were positively associated with colorectal cancer development (OR[q4-q1] = 2.30, 95% CI = 1.51 to 3.51, P trend ≤ .0001); this association strengthened after further adjustment for estradiol and estrone (ORq4-q1 = 2.50, 95% CI = 1.59 to 3.92, P trend < .0001). Progesterone was not associated with colorectal cancer risk., Conclusion: Endogenous estrogen levels were inversely, and SHBG levels positively, associated with colorectal cancer risk, even after control for several colorectal cancer risk factors. These results suggest that endogenous estrogens may confer protection against colorectal tumorigenesis among postmenopausal women., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Normal renal function is essential for vitamin D metabolism, but it is unclear whether circulating vitamin D is associated with risk of renal cell carcinoma (RCC). We assessed whether 25-hydroxyvitamin D3 (25(OH)D3) was associated with risk of RCC and death after RCC diagnosis in the European Prospective Investigation into Cancer and Nutrition (EPIC). EPIC recruited 385,747 participants with blood samples between 1992 and 2000. The current study included 560 RCC cases, 557 individually matched controls, and 553 additional controls. Circulating 25(OH)D3 was assessed by mass spectrometry. Conditional and unconditional logistic regression models were used to calculate odds ratios and 95% confidence intervals. Death after RCC diagnosis was assessed using Cox proportional hazards models and flexible parametric survival models. A doubling of 25(OH)D3 was associated with 28% lower odds of RCC after adjustment for season of and age at blood collection, sex, and country of recruitment (odds ratio = 0.72, 95% confidence interval: 0.60, 0.86; P = 0.0004). This estimate was attenuated somewhat after additional adjustment for smoking status at baseline, circulating cotinine, body mass index (weight (kg)/height (m)(2)), and alcohol intake (odds ratio = 0.82, 95% confidence interval: 0.68, 0.99; P = 0.038). There was also some indication that both low and high 25(OH)D3 levels were associated with higher risk of death from any cause among RCC cases., (© The Author 2014. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Donation after circulatory death (DCD) liver grafts have supplemented the donor organ pool, but certain adverse outcomes have prevented exploration of the full potential of such organs. The aim of this study was to determine key differences in basic energy metabolism between DCD and donation after brainstem death (DBD) grafts., Methods: Microdialysis samples from DCD and DBD allograft parenchyma from cold storage to 48 h after reperfusion were analysed by colorimetric methods. Interstitial lactate, pyruvate and glycerol levels were measured and the lactate/pyruvate ratio was calculated to estimate energy depletion of the grafts. Histological features of ischaemia and reperfusion injury were assessed., Results: Donor age, extent of steatosis and cold ischaemia time were comparable between ten DCD and 20 DBD organs. DCD grafts had higher levels of interstitial lactate (median 11.6 versus 1.2 mmol/l; P = 0.015) and increased lactate/pyruvate ratio (792 versus 38; P = 0.001) during cold storage. There was no significant difference in glycerol levels between DCD and DBD grafts (225.1 versus 127.5 µmol/l respectively; P = 0.700). Rapid restoration of energy levels with lactate clearance, increased pyruvate levels and reduced lactate/pyruvate ratio was seen following reperfusion of functioning DCD grafts, parallel with levels in DBD grafts. Histology revealed more pronounced glycogen depletion in DCD grafts. Three allografts that failed owing to primary non-function showed energy exhaustion with severe glycogen depletion., Conclusion: Liver grafts from DCD donors exhibited depletion of intracellular energy reserves during cold storage. Failed allografts showed severe energy depletion. Modified organ preservation techniques to minimize organ injury related to altered energy metabolism may enable better utilization of donor organs after circulatory death., (© 2014 BJS Society Ltd. Published by John Wiley & Sons Ltd.)

Background: Few studies have investigated the association between whole-grain intake and colorectal cancer. Because whole-grain intake estimation might be prone to measurement errors, more objective measures (eg, biomarkers) could assist in investigating such associations., Methods: The association between alkylresorcinols, biomarkers of whole-grain rye and wheat intake, and colorectal cancer incidence were investigated using prediagnostic plasma samples from colorectal cancer case patients and matched control subjects nested within the European Prospective Investigation into Cancer and Nutrition. We included 1372 incident colorectal cancer case patients and 1372 individual matched control subjects and calculated the incidence rate ratios (IRRs) for overall and anatomical subsites of colorectal cancer using conditional logistic regression adjusted for potential confounders. Regional differences (Scandinavia, the Mediterranean, Central Europe) were also explored., Results: High plasma total alkylresorcinol concentration was associated with lower incidence of distal colon cancer; the adjusted incidence rate ratio of distal colon cancer for the highest vs lowest quartile of plasma total alkylresorcinols was 0.48 (95% confidence interval [CI] = 0.28 to 0.83). An inverse association between plasma total alkylresorcinol concentrations and colon cancer was found for Scandinavian participants (IRR per doubling = 0.83; 95% CI = 0.70 to 0.98). However, plasma total alkylresorcinol concentrations were not associated with overall colorectal cancer, proximal colon cancer, or rectal cancer. Plasma alkylresorcinols concentrations were associated with colon and distal colon cancer only in Central Europe and Scandinavia (ie, areas where alkylresorcinol levels were higher)., Conclusions: High concentrations of plasma alkylresorcinols were associated with a lower incidence of distal colon cancer but not with overall colorectal cancer, proximal colon cancer, and rectal cancer.

Objective: Based on adult data, a peak cortisol response ≥500 nmol/l to insulin-induced hypoglycaemia constitutes a normal. Age-specific reference ranges for basal morning cortisol have been developed for clinical use in the paediatric population. Such reference ranges are not clearly established for peak cortisol responses to insulin-induced hypoglycaemia despite limited data suggesting an effect of age on peak cortisol. The aims of this study were to assess factors affecting the cortisol response to insulin-induced hypoglycaemia in children and to determine whether the peak cortisol response was related to age., Design: The present study was a retrospective cohort study., Methods: Retrospective analysis of children and adolescents aged ≤18 years undergoing the insulin tolerance test with adequate hypoglycaemia was undertaken. Patients with hypopituitarism or severe hypothalamic-pituitary-adrenal axis impairment (peak cortisol value <400 nmol/l) or using systemic glucocorticoids were excluded., Results: Two hundred and twenty-three tests were analysed. Peak cortisol responses ≥500 nmol/l occurred in 183 (82%) tests. Age was negatively associated with peak cortisol responses (r=-0.15, P=0.03). A peak cortisol response <500 nmol/l was significantly less common in patients aged <12 years (9/97 (9%) vs 31/126 (25%); P=0.004). In children aged <12 years, the median (5th-95th centiles) peak cortisol values were 610 (480-806) nmol/l compared with 574 (442-789) nmol/l in children aged ≥12 years (P<0.004). Similarly, median cortisol increment was significantly higher in younger patients (301 nmol/l compared with 226 nmol/l (P=0.0004))., Conclusions: Use of a single peak cortisol threshold in children of all ages is not appropriate and will result in overdiagnosis of adrenal insufficiency in adolescents.

Background: To date, no attempt has been made to systematically determine the apportionment of the hepatocellular carcinoma burden in Europe or North America among established risk factors., Methods: Using data collected from 1992 to 2006, which included 4,409,809 person-years in the European Prospective Investigation into Cancer and nutrition (EPIC), we identified 125 case patients with hepatocellular carcinoma, of whom 115 were matched to 229 control subjects. We calculated odds ratios (ORs) for the association of documented risk factors for hepatocellular carcinoma with incidence of this disease and estimated their importance in this European cohort., Results: Chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (OR = 9.10, 95% confidence interval [CI] = 2.10 to 39.50 and OR = 13.36, 95% CI = 4.11 to 43.45, respectively), obesity (OR = 2.13, 95% CI = 1.06 to 4.29), former or current smoking (OR = 1.98, 95% CI = 0.90 to 4.39 and OR = 4.55, 95% CI = 1.90 to 10.91, respectively), and heavy alcohol intake (OR = 1.77, 95% CI = 0.73 to 4.27) were associated with hepatocellular carcinoma. Smoking contributed to almost half of all hepatocellular carcinomas (47.6%), whereas 13.2% and 20.9% were attributable to chronic HBV and HCV infection, respectively. Obesity and heavy alcohol intake contributed 16.1% and 10.2%, respectively. Almost two-thirds (65.7%, 95% CI = 50.6% to 79.3%) of hepatocellular carcinomas can be accounted for by exposure to at least one of these documented risk factors., Conclusions: Smoking contributed to more hepatocellular carcinomas in this Europe-wide cohort than chronic HBV and HCV infections. Heavy alcohol consumption and obesity also contributed to sizeable fractions of this disease burden. These contributions may be underestimates because EPIC volunteers are likely to be more health conscious than the general population.

Objective: The phenotype associated with heterozygous HNF4A gene mutations has recently been extended to include diazoxide responsive neonatal hypoglycemia in addition to maturity-onset diabetes of the young (MODY). To date, mutation screening has been limited to patients with a family history consistent with MODY. In this study, we investigated the prevalence of HNF4A mutations in a large cohort of patients with diazoxide responsive hyperinsulinemic hypoglycemia (HH)., Subjects and Methods: We sequenced the ABCC8, KCNJ11, GCK, GLUD1, and/or HNF4A genes in 220 patients with HH responsive to diazoxide. The order of genetic testing was dependent upon the clinical phenotype., Results: A genetic diagnosis was possible for 59/220 (27%) patients. K(ATP) channel mutations were most common (15%) followed by GLUD1 mutations causing hyperinsulinism with hyperammonemia (5.9%), and HNF4A mutations (5%). Seven of the 11 probands with a heterozygous HNF4A mutation did not have a parent affected with diabetes, and four de novo mutations were confirmed. These patients were diagnosed with HI within the first week of life (median age 1 day), and they had increased birth weight (median +2.4 SDS). The duration of diazoxide treatment ranged from 3 months to ongoing at 8 years., Conclusions: In this large series, HNF4A mutations are the third most common cause of diazoxide responsive HH. We recommend that HNF4A sequencing is considered in all patients with diazoxide responsive HH diagnosed in the first week of life irrespective of a family history of diabetes, once K(ATP) channel mutations have been excluded.

Context: P450 oxidoreductase (POR) deficiency causes disordered steroidogenesis; severe mutations cause genital ambiguity in both sexes plus the Antley-Bixler skeletal malformation syndrome, whereas mild mutations can cause adult infertility., Objective: We describe four patients with POR deficiency and identify and characterize the activities of their mutations. A 46,XY male with micropenis and two 46,XX female infants with genital ambiguity presented with skeletal malformations, and a 46,XX adolescent presented with primary amenorrhea, elevated 17alpha-hydroxyprogesterone, and low sex steroids., Methods: The coding regions of the POR gene were sequenced, and the identified mutations were recreated in human POR cDNA expression vectors lacking 27 N-terminal residues. POR and human P450c17 were expressed in bacteria. POR activity was measured by four assays: reduction of cytochrome c, oxidation of reduced nicotinamide adenine dinucleotide phosphate, and support of the 17alpha-hydroxylase and 17,20 lyase activities of P450c17., Results: All four patients were compound heterozygotes for POR mutations, including five novel mutations: L577R, N185K, delE217, and frameshift mutations 1363delC and 697-698insGAAC. N185K and delE217 lacked measurable activity in the assays based on P450c17 but retained partial activity in the assays based on cytochrome c. As assessed by V(max)/Km, L577R supported 46% of 17alpha-hydroxylase activity but only 27% of 17,20 lyase activity. Computational modeling of these novel mutants revealed the structural basis for their reduced or absent activities., Conclusion: These patients illustrate the broad clinical spectrum of POR deficiency, including amenorrhea and infertility as the sole manifestation. POR assays based on P450c17 correlate well with hormonal and clinical phenotypes.

Objective: Associations between size at birth, postnatal weight gain, and potential risk for adult disease have been variably explained by in utero exposures or genetic risk that could affect both outcomes. We utilized a twin model to explore these hypotheses., Methods: One hundred pairs of healthy twins aged 8.9 yr (range, 7.2-10.9 yr) had fasting blood samples collected, blood pressure (BP) measured, and anthropometry assessed. All measurements were converted to sd scores (SDS) to adjust for age and sex., Results: Mean birth weights in both monozygotic and dizygotic twins were -0.90 SDS lower than the UK reference. In postnatal life, 58% of monozygotic twins and 59% of dizygotic twins showed rapid weight gain (a change of more than +0.67 in weight SDS) from birth. Postnatal weight gain was positively associated with sum of skinfolds (r = 0.51; P < 0.0005), fasting insulin levels (r = 0.35; P < 0.0005), systolic BP (r = 0.30; P < 0.0005), and diastolic BP (r = 0.15; P < 0.05) at follow-up. Heritability estimates (additive genetic components) were calculated using variance components models for: birth weight, 44%; postnatal weight gain, 80%; childhood height, 89%; body mass index, 72%; sum of skinfolds, 89%; waist circumference, 74%; fasting insulin, 65%; systolic BP, 33%; and diastolic BP, 29%., Conclusions: Postnatal weight gain from birth, rather than birth weight, was associated with childhood risk markers for adult metabolic disease. Childhood weight gain was highly heritable, and genetic factors associated with postnatal weight gain are likely to also contribute to risks for adult disease.

Using the compiled human genome sequence, we systematically cataloged all tandem repeats with periods between 20 and 2000 bp and defined two subsets whose consensus sequences were found at either single-locus tandem repeats (slTRs) or multilocus tandem repeats (mlTRs). Parameters compiled for these subsets provide insights into mechanisms underlying the creation and evolution of tandem repeats. Both subsets of tandem repeats are nonrandomly distributed in the genome, being found at higher frequency at many but not all chromosome ends and internal clusters of mlTRs were also observed. Despite the integral role of recombination in the biology of tandem repeats, recombination hotspots colocalized only with shorter microsatellites and not the longer repeats examined here. An increased frequency of slTRs was observed near imprinted genes, consistent with a functional role, while both slTRs and mlTRs were found more frequently near genes implicated in triplet expansion diseases, suggesting a general instability of these regions. Using our collated parameters, we identified 2230 slTRs as candidates for highly informative molecular markers.

Apoptosis signaling pathways are implicated in the pathogenesis of temporal lobe epilepsy (TLE), but the role of endoplasmic reticulum (ER) stress and ER-localized apoptosis signaling components remains largely unexplored. Presently, we investigated ER stress and ER localization of proapoptotic Bcl-2 family members and initiator and effector caspases in resected hippocampus from patients with intractable TLE and compared findings with autopsy controls. Hippocampal immunoreactivity for KDEL (Lys-Asp-Glu-Leu), a motif in ER stress chaperones glucose-regulated proteins 78 and 94, and calnexin, was significantly higher in TLE hippocampus compared with controls. The ER-containing microsomal fraction in control brain contained Bid, Bim, and caspase 3, whereas Bad and caspases 6, 7, and 9 were very low or absent. In contrast, caspases 6, 7, and 9 were present within the microsomal fraction of TLE brain. Furthermore, cleaved caspases 7 and 9 were detected in TLE samples but not controls, and KDEL-expressing neurons coexpressed cleaved caspase 9. Potentially adaptive changes were also detected, including lowered Bim levels in this fraction, and binding of caspase 7 to the X-linked inhibitor of apoptosis protein. These data suggest seizures may induce ER stress and trigger proapoptotic signaling pathways in the ER that are counteracted by antiapoptotic signals in chronic human TLE.

The purpose of this study was first to clarify postnatal trends in sera T(4), free T(4) (FT(4)), T(4)-binding globulin, TSH, T(3), rT(3), and T(4) sulfate levels in cord and at 7, 14, and 28 d in groups of preterm infants at 23-27 wk (n = 101), 28-30 wk (n = 196), and 31-34 (n = 253) wk gestation, and second to compare these trends to those of term infants and also with cord sera levels of equivalent gestational ages (n = 812; 23-42 wk gestation). In all preterm groups, TSH and rT(3) decrease to below, T(4)-binding globulin increases to within, and T(3) and T(4) sulfate increase to above cord levels of equivalent gestational age. Term infants are hyperthyroxinemic relative to cord and nonpregnant adult levels of T(4). Postnatal T(4) increases are attenuated in 31- to 34-wk infants, absent in 28- to 30-wk infants (although levels are equivalent to gestational age), and crucially reversed in 23- to 27-wk infants. This immature group is hypothyroxinemic relative to other groups and to cord levels of equivalent gestational age. Compared with term infants, postnatal FT(4) increases are lower in 31- to 34-wk infants, attenuated in 28- to 30-wk infants, and absent in 23- to 27-wk infants. The 23- to 27-wk group is distinctive; they are hypothyroxinemic on T(4) levels, yet FT(4) levels are within the cord levels of equivalent gestational age.