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The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry (P= 0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups.

We evaluated the effect of sodium-glucose cotransporter 2 (SGLT2) inhibition on prostate cancer by evidence triangulation. Using Mendelian randomization, we found that genetically proxied SGLT2 inhibition reduced the risk of overall (odds ratio = 0.56, 95% confidence interval [CI] = 0.38 to 0.82; 79,148 prostate cancer cases and 61,106 controls), advanced, and early-onset prostate cancer. Using electronic healthcare data (nSGLT2i = 24,155; nDPP4i = 24,155), we found that the use of SGLT2 inhibitors was associated with a 23% reduced risk of prostate cancer (hazard ratio = 0.77, 95% CI = 0.61 to 0.99) in men with diabetes. Using data from two prospective cohorts (n4C = 57,779; nUK_Biobank = 165,430), we found little evidence to support the association of HbA1cwith prostate cancer, implying a non-glycemic effect of SGLT2 inhibition on prostate cancer. In summary, this study provides multiple layers of evidence to support the beneficial effect of SGLT2 inhibition on reducing prostate cancer risk. Future trials are warranted to investigate whether SGLT2 inhibitors can be recommended for prostate cancer prevention.

Polygenic risk influences susceptibility to cancer. We assessed whether polygenic risk scores could be used in conjunction with other predictors of future disease status in cost-effective risk-stratified screening for cancer.

Background: Measures of regional adiposity have been proposed as alternatives to the measurement of body mass index (BMI) for identifying persons at risk of future disease. Objective: The objective was to compare the magnitudes of association of BMI and alternative measurements of adiposity with coronary heart disease, diabetes, and cardiovascular disease risk factors and all-cause mortality. Design: Data from 4 cohorts of adults [3937 women from the British Women's Heart and Health Study (BWHHS); 2367 and 1950 men from phases 1 and 3, respectively, of the Caerphilly Prospective Study (CAPS); 403 men and women from the Boyd Orr Study; and 789 men and women from the Maidstone-Dewsbury Study] were analyzed. Results: The magnitudes of associations of BMI with incident coronary heart disease and cardiovascular disease risk factors were similar to those with measurements of central adiposity [waist circumference (WC), waist-hip ratio (WHR), or waist-height ratio (WHtR)] and more direct measurements of fat mass (bioimpedance/skinfold thickness). In CaPS (men only), there was no strong evidence of differences in the strengths of association with incident diabetes between BMI, WC, WHR, and WHtR (P for heterogeneity > 0.49 for all). In the BWHHS (women only), there was statistical evidence that WC [hazard ratio (HR): 2.35; 95% CI: 2.03, 2.73] and WHtR (HR: 2.29; 95% CI: 1.98, 2.66) were more strongly associated with diabetes than with BMI (HR: 1.80; 95% CI: 1.59, 2.04) (P for heterogeneity < 0.02 for both). Central adiposity measurements were positively associated with all-cause mortality, as was BMI, but only when those with a BMI (in kg/[m.sup.2]) Conclusion: No strong evidence supports replacing BMI in clinical or public health practice with other adiposity measures. Am J Clin Nutr 2010;91:547-56. doi: 10.3945/ajcn.2009.28757.

Background: Earlier studies have suggested that infant feeding may program long-term changes in cholesterol metabolism. Objective: We aimed to examine whether breastfeeding is associated with lower blood cholesterol concentrations in adulthood. Design: The study consisted of a systematic review of published observational studies relating initial infant feeding status to blood cholesterol concentrations in adulthood (ie, aged > 16 y). Data were available from 17 studies (17 498 subjects; 12 890 breastfed, 4608 formula-fed). Mean differences in total cholesterol concentrations (breastfed minus formula-fed) were pooled by using fixed-effect models. Effects of adjustment (for age at outcome, socioeconomic position, body mass index, and smoking status) and exclusion (of nonexclusive breast feeders) were examined. Results: Mean total blood cholesterol was lower (P = 0.037) among those ever breastfed than among those fed formula milk (mean difference: -0.04 mmol/L; 95% CI: -0.08, 0.00 mmol/L). The difference in cholesterol between infant feeding groups was larger (P = 0.005) and more consistent in 7 studies that analyzed 'exclusive' feeding patterns (-0.15 mmol/L; -0.23, -0.06 mmol/L) than in 10 studies that analyzed nonexclusive feeding patterns (-0.01 mmol/L; -0.06, 0.03 mmol/L). Adjustment for potential confounders including socioeconomic position, body mass index, and smoking status in adult life had minimal effect on these estimates. Conclusions: Initial breastfeeding (particularly when exclusive) may be associated with lower blood cholesterol concentrations in later life. Moves to reduce the cholesterol content of formula feeds below those of breast milk should be treated with caution.

Background: Dairy consumption affects biological pathways associated with carcinogenesis. Evidence for a link between cancer risk and dairy consumption in adulthood is increasing, but associations with childhood dairy consumption have not been studied adequately. Objective: We investigated whether dairy consumption in childhood is associated with cancer incidence and mortality in adulthood. Design: From 1937 through 1939, some 4999 children living in England and Scotland participated in a study of family food consumption, assessed from 7-d household food inventories. The National Health Service central register was used to ascertain cancer registrations and deaths between 1948 and 2005 in the 4383 traced cohort members. Per capita household intake estimates for dairy products and calcium were used as proxy for individual intake. Results: During the follow-up period, 770 cancer registrations or cancer deaths occurred. High childhood total dairy intake was associated with a near-tripling in the odds of colorectal cancer [multivariate odds ratio: 2.90 (95% CI: 1.26, 6.65); 2-sided P for trend = 0.005] compared with low intake, independent of meat, fruit, and vegetable intakes and socioeconomic indicators. Milk intake showed a similar association with colorectal cancer risk. High milk intake was weakly inversely associated with prostate cancer risk (P for trend = 0.11). Childhood dairy intake was not associated with breast and stomach cancer risk; a positive association with lung cancer risk was confounded by smoking behavior during adulthood. Conclusions: A family diet rich in dairy products during childhood is associated with a greater risk of colorectal cancer in adulthood. Confirmation of possible underlying biological mechanisms is needed. KEY WORDS Dairy products, neoplasms, life-course analysis, incidence, mortality, United Kingdom

Background: The evidence that breastfeeding protects against obesity and a variety of chronic diseases comes almost entirely from observational studies, which have a potential for bias due to confounding, selection bias, and selective publication. Objective: We assessed whether an intervention designed to promote exclusive and prolonged breastfeeding affects children's height, weight, adiposity, and blood pressure at age 6.5 y. Design: The Promotion of Breastfeeding Intervention Trial (PROBIT) is a cluster-randomized trial of a breastfeeding promotion intervention based on the WHO/UNICEF Baby-Friendly Hospital Initiative. A total of 17 046 healthy hreastfed infants were enrolled from 31 Belarussian maternity hospitals and their affiliated clinics; of those infants, 13 889 (81.5%) were followed up at 6.5 y with duplicate measurements of anthropometric variables and blood pressure. Analysis was based on intention to treat, with statistical adjustment for clustering within hospitals or clinics to permit inferences at the individual level. Results: The experimental intervention led to a much greater prevalence of exclusive breastfeeding at 3 mo in the experimental than in the control group (43.3% and 6.4%, respectively; P < 0.001) and a higher prevalence of any breastfeeding throughout infancy. No significant intervention effects were observed on height, body mass index, waist or hip circumference, triceps or subscapular skinfold thickness, or systolic or diastolic blood pressure. Conclusions: The breastfeeding promotion intervention resulted in substantial increases in the duration and exclusivity ofbreastfeeding, yet it did not reduce the measures of adiposity, increase stature, or reduce blood pressure at age 6.5 y in the experimental group. Previously reported beneficial effects on these outcomes may be the result of uncontrolled confounding and selection bias. KEY WORDS Breastfeeding, adiposity, obesity, blood pressure, programming

Background: Previous studies reported inconsistent associations between breastfeeding and body mass index (BML in kg/[m.sup.2]). Associations with body fatness are unknown. Objective: We investigated the association of breastfeeding with fatness measured by dual-energy X-ray absorptiometry. Design: The prospective cohort study involved 4325 singletons with measurements at 9-10 y of age to assess the main outcomes of BMI and total and trunk fat masses. Results: Prevalence of any breastfeeding was 82%. In crude analyses. breastfeeding was inversely associated with total fat mass [% change per category increase (4 categories)] in breastfeeding duration (-4.4%; 95% CI: -3.1%, -5.6%) and trunk fat mass (-0.5%: 95% CI: - 1.1%, 0.1%); the odds of adiposity were measured by total [odds ratio (OR): 0.81 ; 95% CI: 0.75, 0.88] and trunk (OR: 0.78; 95% CI: 0.71,0.84) fat masses in the top decile. In adjusted models, the inverse association of breastfeeding with mean total fat mass was attenuated by 59% (% change per category increase in breastfeeding duration: -1.8%: 95% CI: -0.5%, -3.1%), but associations with trunk fat mass (% change per category increase in breastfeeding duration: -0.6%; 95% CI: 0.0%, -1.3%) and the ORs for total (0.76; 95% CI: 0.69, 0.84) and trunk (0.74; 95% CI: 0.67, 0.81) fat masses in the top decile were little altered. Children breastfed [greater than or equal to] 6 mo had the lowest odds of total fat mass in the top decile (OR: 0.45; 95% CI: 0.33, 0.62). In multivariate models, there was little evidence that breastfeeding was associated with mean or threshold values of BMI. Conclusions: The protective association of breastfeeding with mean total fat mass was attenuated somewhat after adjustment for con-founders, which indicated that confounding may explain this association. Breastfeeding may protect against obesity if maintained for [greater than or equal to] 6 too. KEY WORDS Avon Longitudinal Study of Parents and Children, ALSPAC, epidemiology, diet, prevention and control, energy metabolism, feeding behavior

Background: Observational evidence suggests that having been breastfed in infancy may reduce the prevalence of type 2 diabetes in later life. Objective: The objective was to examine the influence of initial breastfeeding on type 2 diabetes and blood glucose and insulin concentrations. Design: A systematic review of published studies identified 1010 reports; 23 examined the relation between infant feeding and type 2 diabetes in later life or risk factors for diabetes. Risk factors in infants were examined separately from those in children and adults. All estimates were pooled by using fixed-effect models; differences Results: Subjects who were breastfed had a lower risk of type 2 diabetes in later life than did those who were formula fed (7 studies; 76 744 subjects; odds ratio: 0.61; 95% CI: 0.44, 0.85; P = 0.003). Children and adults without diabetes who had been breastfed had marginally lower fasting insulin concentrations than did those who were formula fed (6 studies; 4800 subjects; percentage difference: -3%; 95% CI: -8%, 1%; P = 0.13); no significant difference in fasting glucose concentrations was observed. Breastfed infants had lower mean preprandial blood glucose (12 studies; 560 subjects; mean difference: -0.17 mmol/L; 95% CI: -0.28, -0.05 mmol/L; P = 0.005) and insulin (7 studies; 291 subjects; mean difference: -2.86 pmol/L; 95% CI: -5.76, 0.04 pmol/L; P = 0.054) concentrations than did those who were formula fed. Conclusion: Breastfeeding in infancy is associated with a reduced risk of type 2 diabetes, with marginally lower insulin concentrations in later life, and with lower blood glucose and serum insulin concentrations in infancy. KEY WORDS Infant feeding, blood glucose, serum insulin, type 2 diabetes, systematic review

Background: It is unclear whether early life body mass index (BMI; in kg/[m.sup.2]) is associated with adult cardiovascular disease. Objective: The objective was to assess the association of early life BMI with the risk of ischemic heart disease (IHD) and stroke. Design: The association between early life BMI and risk of adult mortality from IHD and stroke was assessed in 3 historical cohort studies in which height and weight had been assessed by using standard procedures. Participants were traced and linked to national mortality data. Participants in the 3 cohorts were born between 1922 and 1937, 1927 and 1956, and 1928 and 1950 and were aged 2-15, 9-18, and 16-22 y, respectively, at the time of assessment of their height and weight. Results: Participants in all 3 cohorts had mean BMIs similar to those reported for contemporary children and young adults, but fewer of the cohort participants were overweight or obese. BMI was not associated with future risk of IHD or stroke in any cohort. The pooled (all 3 cohorts) adjusted hazard ratio per SD of early life BMI was 1.09 (95% CI: 1.01, 1.19) for IHD and 0.94 (95% CI: 0.82, 1.08) for stroke. The pooled hazard ratio of IHD when participants who were overweight or obese for their age were compared with all other participants was 1.34 (95% CI: 0.95, 1.91), and no association was found between overweight or obesity and stroke risk. The effects of BMI did not vary by cohort or by age. Conclusion: These results do not provide strong evidence that being overweight or obese in childhood is associated with future cardiovascular disease risk. KEY WORDS Body mass index, childhood, cardiovascular disease, life-course epidemiology

Background: Evidence from observational studies has suggested that breastfeeding may reduce the prevalence of obesity in later life. Objective: The objective was to examine whether initial breastfeeding is related to lower mean body mass index (BMI: in kg/[m.sup.2]) throughout life. Design: The study was a systematic review of published studies investigating the association between infant feeding and a measure of obesity or adiposity in later life, which was supplemented with data from unpublished sources. Analyses were based on the mean differences in BMI between those subjects who were initially breastfed and those who were formula-fed (expressed as breastfed minus bottle-fed), which were pooled by using fixed-effects models throughout. Results: From 70 eligible studies, 36 mean differences in BMI (from 355 301 subjects) between those breastfed and those formula-fed (reported as exclusive feeding in 20 studies) were obtained. Breast-feeding was associated with a slightly lower mean BMI than was formula feeding (-0.04; 95% CI: -0.05, -0.02). The mean difference in BMIs appeared larger in 15 small studies of < 1000 subjects (-0.19; 95% CI: -0.31, -0.08) and smaller in larger studies of [micro] 1000 subjects (-0.03; 95% CI: -0.05, -0.02). An Egger test was statistically significant (P = 0.002). Adjustment for socioeconomic status, maternal smoking in pregnancy, and maternal BMI in 11 studies abolished the effect (-0.10: 95% CI: -0.14, -0.06 before adjustment; -0.01: 95% CI: -0.05, 0.03 after adjustment). Conclusions: Mean BMI is lower among breastfed subjects. However, the difference is small and is likely to be strongly influenced by publication bias and confounding factors. Promotion of breastfeeding, although important for other reasons, is not likely to reduce mean BMI. KEY WORDS: Infant feeding, body mass index, systematic review

Background: Having been breast-fed has been suggested to influence cancer risk in adulthood. We investigated associations between breast-feeding during infancy and adult cancer incidence and mortality in a cohort study and meta-analyses of published studies. Methods: The Boyd Orr cohort consisted of 4999 subjects who were originally surveyed in 1937-39, when they were 0-19 years of age. Cancer outcomes from 1948 through 2003 were available for 4379 (88%) subjects, and 3844 had complete data on all covariates. Associations of breast-feeding with cancer were investigated using proportional hazards models. We also identified 14 studies on infant feeding and cancer published from 1966 through July 2005, of which 10 could be combined with the Boyd Orr cohort results in a meta-analysis of breast cancer using random-effect models. Results: In the Boyd Orr cohort, ever having been breast-fed, compared with never having been breast-fed, was not associated with the incidence of all cancers (hazard ratio [HR] = 1.07, 95% confidence interval [CI] = 0.89 to 1.28) or of any individual cancer type examined (prostate HR = 1.43, 95% CI = 0.58 to 3.52; breast HR = 1.62, 95% CI = 0.89 to 2.94; colorectal HR = 0.86, 95% CI = 0.45 to 1.63; gastric HR = 1.22, 95% CI = 0.47 to 3.15). In the meta-analysis, there was also no association between breast-feeding and breast cancer (regardless of menopausal status) (relative risk [RR] = 0.94, 95% CI = 0.85 to 1.04). However, breast-fed women had a reduced risk of premenopausal breast cancer (RR = 0.88, 95% CI = 0.79 to 0.98) but not of postmenopausal breast cancer (RR = 1.00, 95% CI = 0.86 to 1.16). Conclusion: Ever having been breast-fed was not associated with overall breast cancer risk, although the meta-analysis revealed a reduced risk of premenopausal breast cancer in women who had been breast-fed.

Background: Evidence suggests that environmental factors acting early in life may affect blood pressure in adulthood. Objective: The objective was to test the hypothesis that dried formula milk (derived from cow milk) intake in infancy is positively associated with blood pressure in early adulthood. Design: We conducted a long-term follow-up (1997-1999) of the Barry Caerphilly Growth study cohort (1972-1974) into which mothers and their offspring had originally been randomly assigned to receive a milk supplement or usual care. Participants were the offspring, who were aged 23-27 y at follow-up. The main outcome measures were systolic and diastolic blood pressure. Results: The social and demographic characteristics of the subjects who were (n = 679) and were not (n = 272) followed up were similar. For each increase in quartile of dried milk consumption (in oz) at 3 mo of age, there was a 1.28-mm Hg (95% CI: 0.46, 2.10 mm Hg) increase in systolic and a 0.63-mm Hg (95% CI: 0.04, 1.22 mm Hg) increase in diastolic blood pressure after adjustment for sex, intervention group, birth weight z scores, social class in childhood, age at follow-up, alcohol consumption, and pack-years of smoking. These coefficients were attenuated when adult body mass index and height were included in the models, but the association of dried milk consumption at 3 mo of age with systolic pressure remained significant (1.07 mm Hg; 95% CI: 0.27, 1.87 mm Hg). Conclusions: Our findings are consistent with the hypothesis that high blood pressure in later life is influenced by early postnatal nutrition. Thus, interventions to optimize infant nutrition may have important long-term health benefits. KEY WORDS Infant nutrition, formula feeding, blood pressure, hypertension, cardiovascular disease, cohort studies

Abstract Objectives To investigate the national distribution of prolonged waiting for elective day case and inpatient surgery, and to examine associations of prolonged waiting with markers of NHS capacity, activity [...]

ObjectivesPhysical inactivity and sedentary behaviour are associated with higher breast cancer risk in observational studies, but ascribing causality is difficult. Mendelian randomisation (MR) assesses causality by simulating randomised trial groups using genotype. We assessed whether lifelong physical activity or sedentary time, assessed using genotype, may be causally associated with breast cancer risk overall, pre/post-menopause, and by case-groups defined by tumour characteristics.MethodsWe performed two-sample inverse-variance-weighted MR using individual-level Breast Cancer Association Consortium case-control data from 130 957 European-ancestry women (69 838 invasive cases), and published UK Biobank data (n=91 105–377 234). Genetic instruments were single nucleotide polymorphisms (SNPs) associated in UK Biobank with wrist-worn accelerometer-measured overall physical activity (nsnps=5) or sedentary time (nsnps=6), or accelerometer-measured (nsnps=1) or self-reported (nsnps=5) vigorous physical activity.ResultsGreater genetically-predicted overall activity was associated with lower breast cancer overall risk (OR=0.59; 95% confidence interval (CI) 0.42 to 0.83 per-standard deviation (SD;~8 milligravities acceleration)) and for most case-groups. Genetically-predicted vigorous activity was associated with lower risk of pre/perimenopausal breast cancer (OR=0.62; 95% CI 0.45 to 0.87,≥3 vs. 0 self-reported days/week), with consistent estimates for most case-groups. Greater genetically-predicted sedentary time was associated with higher hormone-receptor-negative tumour risk (OR=1.77; 95% CI 1.07 to 2.92 per-SD (~7% time spent sedentary)), with elevated estimates for most case-groups. Results were robust to sensitivity analyses examining pleiotropy (including weighted-median-MR, MR-Egger).ConclusionOur study provides strong evidence that greater overall physical activity, greater vigorous activity, and lower sedentary time are likely to reduce breast cancer risk. More widespread adoption of active lifestyles may reduce the burden from the most common cancer in women.

The published evidence on whether workplace health and well-being interventions are as effective in male-dominated industries compared with mixed-gender environments has not been synthesised. We performed a systematic review of workplace interventions aimed at improving employee health and well-being in male-dominated industries. We searched Web of Knowledge, PubMed, Medline, Cochrane Database and Web of Science for articles describing workplace interventions in male-dominated industries that address employee health and well-being. The primary outcome was to determine the effectiveness of the intervention and the process evaluation (intervention delivery and adherence). To assess the quality of evidence, Cochrane Collaboration’s Risk of Bias Tool was used. Due to the heterogeneity of reported outcomes, meta-analysis was performed for only some outcomes and a narrative synthesis with albatross plots was presented. After full-text screening, 35 studies met the eligibility criteria. Thirty-two studies delivered the intervention face-to-face, while two were delivered via internet and one using postal mail. Intervention adherence ranged from 50% to 97%, dependent on mode of delivery and industry. 17 studies were considered low risk of bias. Albatross plots indicated some evidence of positive associations, particularly for interventions focusing on musculoskeletal disorders. There was little evidence of intervention effect on body mass index and systolic or diastolic blood pressure. Limited to moderate evidence of beneficial effects was found for workplace health and well-being interventions conducted within male-dominated industries. Such interventions in the workplace can be effective, despite a different culture in male-dominated compared with mixed industries, but are dependent on delivery, industry and outcome. CRD42019161283.

Abstract Objective: To examine inceptions and discontinuations of antidepressants in general practice. Design: An observational study analysing data from an ongoing cross sectional postal survey. Every three months a representative [...]

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84–5.29) for men of European ancestry to 3.74 (95% CI, 3.36–4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14–2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71–0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.

Background: Polygenic hazard scores (PHS) can identify individuals with increased risk of prostate cancer. We estimated the benefit of additional SNPs on performance of a previously validated PHS (PHS46). Materials and method: 180 SNPs, shown to be previously associated with prostate cancer, were used to develop a PHS model in men with European ancestry. A machine-learning approach, LASSO-regularized Cox regression, was used to select SNPs and to estimate their coefficients in the training set (75,596 men). Performance of the resulting model was evaluated in the testing/validation set (6,411 men) with two metrics: (1) hazard ratios (HRs) and (2) positive predictive value (PPV) of prostate-specific antigen (PSA) testing. HRs were estimated between individuals with PHS in the top 5% to those in the middle 40% (HR95/50), top 20% to bottom 20% (HR80/20), and bottom 20% to middle 40% (HR20/50). PPV was calculated for the top 20% (PPV80) and top 5% (PPV95) of PHS as the fraction of individuals with elevated PSA that were diagnosed with clinically significant prostate cancer on biopsy. Results: 166 SNPs had non-zero coefficients in the Cox model (PHS166). All HR metrics showed significant improvements for PHS166 compared to PHS46: HR95/50 increased from 3.72 to 5.09, HR80/20 increased from 6.12 to 9.45, and HR20/50 decreased from 0.41 to 0.34. By contrast, no significant differences were observed in PPV of PSA testing for clinically significant prostate cancer. Conclusions: Incorporating 120 additional SNPs (PHS166 vs PHS46) significantly improved HRs for prostate cancer, while PPV of PSA testing remained the same.

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Nutritional psychiatry is a growing area of research, with several nutritional factors implicated in the cause of psychiatric ill-health. However, nutritional research is highly complex, with multiple potential factors involved, highly confounded exposures and small effect sizes for individual nutrients. This Personal View considers whether Mendelian randomisation provides a solution to these difficulties, by investigating causality in a low-risk and low-cost way. We reviewed studies using Mendelian randomisation in nutritional psychiatry, along with the potential opportunities and challenges of using this approach for investigating the causal effects of nutritional exposures. Several studies have identified nutritional exposures that are potentially causal by using Mendelian randomisation in psychiatry, offering opportunities for further mechanistic research, intervention development, and replication. The use of Mendelian randomisation as a foundation for intervention development facilitates the best use of resources in an emerging discipline in which opportunities are rich, but resources are often poor.

IMPORTANCE: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation. OBJECTIVE: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases. DATA SOURCES: Genomewide association studies (GWAS) published up to January 15, 2015. STUDY SELECTION: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available. DATA EXTRACTION AND SYNTHESIS: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population. MAIN OUTCOMES AND MEASURES: Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation. RESULTS: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95% CI, 0.05-0.15]). CONCLUSIONS AND RELEVANCE: It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.

Data on side effects of newly launched drugs are limited,[1] highlighting the need for effective postmarketing surveillance. An inverted black triangle (??) on product literature identifies new products. Suspected adverse [...]

Purpose:This study aimed to quantify the probability of overdiagnosis of prostate cancer by polygenic risk.Methods:We calculated the polygenic risk score based on 66 known prostate cancer susceptibility variants for 17,012 men aged 50–69 years (9,404 men identified with prostate cancer and 7,608 with no cancer) derived from three UK-based ongoing studies. We derived the probabilities of overdiagnosis by quartiles of polygenic risk considering that the observed prevalence of screen-detected prostate cancer is a combination of underlying incidence, mean sojourn time (MST), test sensitivity, and overdiagnosis.Results:Polygenic risk quartiles 1 to 4 comprised 9, 18, 25, and 48% of the cases, respectively. For a prostate-specific antigen test sensitivity of 80% and MST of 9 years, 43, 30, 25, and 19% of the prevalent screen-detected cancers in quartiles 1 to 4, respectively, were likely to be overdiagnosed cancers. Overdiagnosis decreased with increasing polygenic risk, with 56% decrease between the lowest and the highest polygenic risk quartiles.Conclusion:Targeting screening to men at higher polygenic risk could reduce the problem of overdiagnosis and lead to a better benefit-to-harm balance in screening for prostate cancer.Genet Med 17 10, 789–795.

Instrumental variables can be used to estimate the causal effects of exposures on outcomes in the presence of residual or uncontrolled confounding. To assess the validity of analyses using instrumental variables, specific information about whether underlying assumptions are met must be presented, in particular to demonstrate that the instrument is associated with the exposure but not with measured confounding factors. We systematically reviewed the epidemiological literature in Embase and Medline for articles containing the term “instrumental variable” to investigate whether reporting of test statistics in studies using instrumental variables was sufficient to assess the validity of the results. We extracted the information each study reported about their instrumental variables, including specification tests used to check assumptions. The search found 756 studies of which 90 were relevant and were included. Only 25 (28) studies reported appropriate tests of the strength of the associations between instruments and exposure. Forty-four (49) studies reported associations between the instrumental variables and observed covariates. Studies using instrumental variables had wide confidence intervals and so effect estimates were imprecise. We propose a checklist of information and specification tests that studies using instrumental variables should report.

Instrumental variable analysis can estimate treatment effects in the presence of residual or unmeasured confounding. We compared ordinary least squares regression versus instrumental variable estimates of the effects of selective cyclooxygenase-2 inhibitors (COX-2s) relative to nonselective nonsteroidal anti-inflammatory drug (NSAID) prescriptions on incidence of upper gastrointestinal complications and myocardial infarction (MI).

Objective: To determine the relationship of serum total homocysteine (tHcy), serum folate and 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C→T genotype with ultrasonic arterial wall measurements associated with subclinical atherosclerosis. Study design: Cross-sectional analysis of 767 participants in an ongoing prospective study. Intima-media thickness (IMT) of the common carotid (IMTcc), IMT of the internal carotid including plaque when present (IMTmax) and the sum of the thickest plaques present in both carotid and both common femoral bifurcations (total plaque thickness (TPT)) were measured using ultrasound. Results: People in the upper homocysteine quartile were more likely to have clinical cardiovascular disease (CVD) than those in the lowest three quartiles. They were also more likely to have plaques. The MTHFR 677C→T genotype was not associated with any of the measures of subclinical atherosclerosis in either men or women but was the most important determinant of total homocysteine levels in men under 60 years of age. Conclusions: Increased homocysteine levels but not MTHFR 677C→T genotype, are associated with subclinical atherosclerosis and the presence of plaques. Our results indicate that measurements of blood levels of homocysteine and folate in people at intermediate risk for atherosclerotic CVD before symptoms occur, might improve risk stratification and facilitate the decision to provide folate/B vitamin intervention in primary prevention.

OBJECTIVE: To investigate the population impact on the incidence of suicide and non-fatal self harm of regulatory action in 2003 to restrict the use of selective serotonin reuptake inhibitors (SSRIs) in under 18s. Design Ecological time series study. Setting United Kingdom. Populations Young people in the UK aged 12-19 years (prescribing trends), in England and Wales aged 12-17 years (mortality), and in England aged 12-17 years (hospital admissions). MAIN OUTCOME MEASURES: Deaths from suicide and hospital admissions for self harm. RESULTS: Antidepressant prescribing doubled between 1999 and 2003 but fell to the 1999 level between 2004 and 2005. These large changes in prescribing did not seem to be associated with temporal trends in suicide or self harm. In the years 1993 to 2005 the annual percentage reduction for suicide among 12-17 year olds was –3.9% (95% confidence interval –6.2% to –1.5%) in males and –3.0% (–6.6% to 0.6%) in females, with no indication of a substantial change in this rate of decrease during that period. Similarly, hospital admission rates for self harm in the years 1999 to 2005 indicated an annual percentage increase for males of 1.1% (–0.5% to 2.7%) and for females of 5.7% (3.6% to 7.8%), again with no statistical evidence of a change in rate after the regulatory action. CONCLUSIONS: The noticeable reduction in prescribing of antidepressants since regulatory action in 2003 to restrict the use of SSRIs in under 18s does not seem to have been associated with changes in suicidal behaviour in young people. Specifically, these data for England do not indicate that reductions in antidepressant use have led to an increase in suicidal behaviour.

A person's birth weight is inversely related to both their own and their parents’ cardiovascular disease mortality risk, but mechanisms underlying such transgenerational associations are unclear. We investigated the influence of the childhood growth of the mother or father on the birth weight of their first-born offspring.

The prevalence of psychiatric morbidity appears to be lower in rural than urban areas. Using the Fourth National GP Morbidity Survey (1991-1992) we have compared patterns of GP consultation for mental illness by young people living in rural and urban areas to investigate whether patterns of morbidity are reflected in GP help-seeking. We investigated whether urban-rural differences were due to differences in the socio-economic characteristics of residents. The crude rate ratio for consultation for mental disorder in rural compared to urban males was 0.55 (95% CI 0.47 to 0.65) and for females was 0.78 (0.71 to 0.86). After controlling for socio-economic differences between rural and urban areas, consultation rates for mental illness were 30% (95% CI 19% to 41%) lower in males and 16 per cent (8% to 24%) lower in females in rural compared to urban areas. These findings are in line with population surveys indicating that levels of mental illness are lower in rural compared to urban areas. Part of the difference reflects differences in the socioeconomic characteristics of people living in these areas. Further studies are needed to investigate possible area effects on the prevalence of mental illness. [ABSTRACT FROM AUTHOR]

The adsorption of C60on Si(111) has been studied by means of first-principles density functional calculations. A 2×2 adatom surface reconstruction was used to simulate the terraces of the 7×7 reconstruction. The structure of several possible adsorption configurations was optimized using the ab initio atomic forces, finding good candidates for two different adsorption states observed experimentally. While the C60molecule remains closely spherical, the silicon substrate appears quite soft, especially the adatoms, which move substantially to form extra C–Si bonds, at the expense of breaking Si–Si bonds. The structural relaxation has a much larger effect on the adsorption energies, which strongly depend on the adsorption configuration, than on the charge transfer.

We examined socio-economic differences in consultation rates in 16-39 year old men using data collected in 1991/2 by the Fourth National Survey of Morbidity in General Practice. Mean annual consultation rates per person were 2.21 in men aged 16-24 years and 2.52 in those aged 25-39 years. In 25-39 year old men overall consultation rates were 42 per cent higher in social class IV/V than class I/II. Amongst 16-24 year olds, increasing deprivation as measured by type of housing and employment status were associated with increased consultation rates, but there was no clear association between social class and consultation rates. Amongst 25-39 year olds, increasing deprivation, as measured by social class, housing tenure or employment status, was associated with higher consultation rates for all illnesses, mental illness and injury and poisoning. In contrast, consultations for preventive health care were lower in young men in social class IV/V than class I/II and in council tenants rather than owner-occupiers. We conclude that socio-economically disadvantaged young men were more likely to consult general practice services in general and for mental illness and injury and poisoning. They received less preventive health care than more advantaged men who are at lower risk of premature mortality. [ABSTRACT FROM AUTHOR]

Donepezil was licensed in the UK in February 1997 for the treatment of Alzheimer's disease. To determine the advice from health authorities about prescribing Alzheimer's disease drugs. To determine whether the first general practitioners who prescribed donepezil in England differed from non-prescribers in terms of knowledge, opinions, background, and the prescribing-advice issued by their health authority. National postal survey of pharmaceutical advisors. Structured postal survey of all general practitioners in England who prescribed donepezil to two or more patients within the first 6 months of launch, compared with a random sample of non-prescribers. Pharmaceutical advisors' survey: 75/100 pharmaceutical advisors responded, of whom 83% indicated that general practitioners should not initiate prescribing of Alzheimer's disease drugs and 63% said that they should not prescribe, even under shared care arrangements. General practitioner survey: 311/473 (66%) prescribers and 484/947 (51%) non-prescribers responded after two mailings. Prescribers were similar to non-prescribers in terms of demographic and practice characteristics, knowledge about Alzheimer's disease, diagnostic and initial management strategies, and the prescribing advice from health authorities. Prescribers were significantly more likely than non-prescribers to strongly agree/agree that new drugs should be prescribed for mild (p=0.0008) and moderate (p=0.003) Alzheimer's disease, that they should normally be initiated (p=0.003) and monitored by a general practitioner (p&lt;0.0001), and that financial constraints should not be a consideration (p=0.0001). Early prescribers differed from non-prescribers in their opinions about using Alzheimer's disease drugs. Future research should examine methods to promote nationally equitable and rational prescribing of new drugs. Copyright © 1999 John Wiley & Sons, Ltd.

Churg–Strauss syndrome is characterised by hypereosinophilia, systemic vasculitis and asthma. The cause is usually unknown, but there have been reports of an association with particular drugs, including anti-asthma drugs. Our aim was to estimate the prevalence of Churg–Strauss syndrome and related conditions in post-marketing safety studies of new anti-asthma drugs. We accessed the prescription-event monitoring (PEM) database of the Drug Safety Research Unit (DSRU). This database currently has information on 622 294 patients observed during 58 completed PEM studies of individual drugs, including 35 799 patients in studies of new anti-asthma drugs. Overall, four cases of Churg–Strauss syndrome were identified during these studies, giving a period prevalence rate of 6.8 (95% confidence limits [CL]: 1.8–17.3) per million patient-years of observation. The period prevalence of Churg–Strauss syndrome was significantly greater in the PEM cohorts of anti-asthma drugs (64.4 million patient-years of observation; 95% CL: 13.3–188.1), than the other PEM drug cohorts (1.8 per million patient-years of observation; 95% CL: 0.05–10.2) (rate ratio: 35.1; 95% CL: 2.8–1839.9; p=0.002). Our data provide estimates of the prevalence of Churg–Strauss syndrome and related conditions in cohorts of asthmatic patients, which may be useful during the pharmacovigilance of new asthma drugs, including the new leukotriene receptor antagonists. Copyright © 1999 John Wiley & Sons, Ltd.

Using Q-technique, we examined conceptions of representation among a sample of delegates to the 1984 Democratic and Republican National Conventions. Analysis of the data revealed four perspectives on representation in the sample: the “trustee,” the belief that group interests should be represented, the belief that representation is a matter of the representative's conscience, and the “delegate-servant.” Surprisingly, no delegates saw themselves as representatives of party officials or presidential candidates. We conclude that representation is a subjective process and should be examined from that perspective.

Information on general practitioners' choices of initial and second-line antihypertensive treatment, and reasons for stopping therapy, are limited. We analysed data on the use of the four main classes of antihypertensive drugs (diuretics, beta-blockers, calcium antagonists and angiotensin-converting enzyme inhibitors) between 1990 and 1995 from an ongoing cross-sectional postal survey of general practitioners' prescribing activity (the New and Change Therapy Enquiry). There were 18,092 new courses and 9424 discontinuations between 1990 and 1995. Diuretics were the commonest first-line choice. Use of beta-blockers first-line decreased significantly in comparison with diuretics during the study period. Switches to calcium antagonists and angiotensin-converting enzyme inhibitors increased. The increased use of newer agents was not explained by increased use for concomitant conditions (diabetes or cardiovascular disease). Diuretics were most often discontinued because of poor efficacy (44% of diuretic stops). In contrast, most beta-blockers (55%), calcium antagonists (64%) and angiotensin-converting enzyme inhibitors (60%) were stopped because of side-effects. In conclusion, use of beta-blockers first-line decreased. Switches to calcium antagonists and angiotensin-converting enzyme inhibitors increased. The reasons may be due to greater perceived efficacy of newer agents rather than increased use for concomitant conditions. © 1997 John Wiley & Sons, Ltd.