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BackgroundAlthough most epidemiological studies suggest that non-steroidal anti-inflammatory drug use is inversely associated with prostate cancer risk, the magnitude and specificity of this association remain unclear.MethodsWe examined self-reported aspirin and ibuprofen use in relation to prostate cancer risk among 29 450 men ages 55-74 who were initially screened for prostate cancer from 1993 to 2001 in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Men were followed from their first screening exam until 31 December 2009, during which 3575 cases of prostate cancer were identified.ResultsAfter adjusting for potential confounders, the hazard ratios (HRs) of prostate cancer associated with

Michael F Leitzmann1, Sabine Rohrmann21Department of Epidemiology and Preventive Medicine, Regensburg University Medical Center, Regensburg, Germany; 2Institute of Social and Preventive Medicine, University of Zurich, Zurich, SwitzerlandAbstract: At present, only three risk factors for prostate cancer have been firmly established; these are all nonmodifiable: age, race, and a positive family history of prostate cancer. However, numerous modifiable factors have also been implicated in the development of prostate cancer. In the current review, we summarize the epidemiologic data for age, location, and selected behavioral factors in relation to the onset of prostate cancer. Although the available data are not entirely consistent, possible preventative behavioral factors include increased physical activity, intakes of tomatoes, cruciferous vegetables, and soy. Factors that may enhance prostate cancer risk include frequent consumption of dairy products and, possibly, meat. By comparison, alcohol probably exerts no important influence on prostate cancer development. Similarly, dietary supplements are unlikely to protect against the onset of prostate cancer in healthy men. Several factors, such as smoking and obesity, show a weak association with prostate cancer incidence but a positive relation with prostate cancer mortality. Other factors, such as fish intake, also appear to be unassociated with incident prostate cancer but show an inverse relation with fatal prostate cancer. Such heterogeneity in the relationship between behavioral factors and nonadvanced, advanced, or fatal prostate cancers helps shed light on the carcinogenetic process because it discerns the impact of exposure on early and late stages of prostate cancer development. Inconsistent associations between behavioral factors and prostate cancer risk seen in previous studies may in part be due to uncontrolled detection bias because of current widespread use of prostate-specific antigen testing for prostate cancer, and the possibility that certain behavioral factors are systematically related to the likelihood of undergoing screening examinations. In addition, several genes may modify the study results, but data concerning specific gene–environment interactions are currently sparse. Despite large improvements in our understanding of prostate cancer risk factors in the past two decades, present knowledge does not allow definitive recommendations for specific preventative behavioral interventions.Keywords: prostate cancer, risk factors, etiology, epidemiology

Evidence for a protective role of physical activity in cancer prevention is rapidly accumulating. The most convincing epidemiologic data in support of a beneficial effect of physical activity on cancer risk exists for colon, breast, and endometrial cancers. Evidence is weaker for cancers of the lung, pancreas, stomach, prostate, and ovary. Inconsistent findings for a physical activity and cancer relation in the literature may reflect methodologic constraints of available studies, including the use of inaccurate physical activity measurement instruments, failure to assess physical activity performed at etiologically relevant time periods of carcinogenesis, inadequate assessment of the dose of physical activity (frequency, duration, and intensity), incomplete control for potential confounding, and lack of consideration of subgroup findings. These methodologic issues require heightened attention in future studies. Several biologic mechanisms mediate the relation between physical activity and cancer but most etiologic pathways remain poorly understood. Most research on physical activity and primary cancer prevention has been conducted in observational settings, which are not designed to provide evidence of causal associations. controlled physical activity intervention studies of cancer risk are needed to solidify existing mechanistic evidence and to further develop biologic models relating increased physical activity to decreased cancer risk. Key Words: Physical activity, cancer prevention, epidemiology, methodologic considerations

Little is known about the association between alcohol and breast cancer by different tumor characteristics. The study consisted of 184,418 postmenopausal women aged 50-71 years in the National Institutes of Health-AARP Diet and Health Study (1995-2003). Alcohol use, diet, and potential risk factors for cancer were assessed with a mailed questionnaire at baseline. The relative risks and 95% confidence intervals were estimated by using Cox proportional hazards regression. Breast cancer cases and estrogen receptor and progesterone receptor status were identified through linkage to state cancer registries. During an average of 7 years of follow-up, 5,461 breast cancer cases were identified. Alcohol was significantly positively associated with total breast cancer: Even a moderate amount of alcohol (>10 g/day) significantly increased breast cancer risk. In a comparison of >35 g versus 0 g/day, the multivariate relative risks were 1.35 (95% confidence interval (CI): 1.17, 1.56) for total breast cancer, 1.46 (95% CI: 1.22, 1.75) for ductal tumors, and 1.52 (95% CI: 0.95, 2.44) for lobular tumors. The multivariate relative risks for estrogen receptor-positive/progesterone receptor-positive, estrogen receptor-positive/progesterone receptor-negative, and estrogen receptor-negative/progesterone receptor-negative tumors were 1.46 (95% CI: 1.12, 1.91) for >35 g versus 0 g/day, 1.13 (95% CI: 0.73, 1.77) for >20 g versus 0 g/day, and 1.21 (95% CI: 0.79, 1.84) for >20 g versus 0 g/day, respectively. Moderate consumption of alcohol was associated with breast cancer, specifically hormone receptor-positive tumors. [ABSTRACT FROM AUTHOR]

Recommendations for intake of fruits and vegetables, whole grains, lean meats, and low-fat dairy form the underpinning of dietary guidance for health promotion. We examined the association of a summary index of food consumption behaviors compatible with the spirit of prevailing dietary guidance and mortality. We used data from the NIH-American Association of Retired Persons cohort (n = 350,886), aged 50-71 y and disease free at baseline in 1995-1996, to examine the association of a dietary behavior score (DBS) with mortality after 10.5 y of follow-up (deaths, n = 29,838). The DBS included 6 equally weighted components derived from responses to questions on usual dietary behaviors related to consumption of fruits, vegetables, low-fat dairy, whole grains, lean meat and poultry, and discretionary fat. The covariate-adjusted association of DBS and mortality from all causes, cancer, and coronary heart disease was examined using Cox proportional hazards regression methods. Compared with those in the lowest one-fifth of DBS, the multivariate-adjusted relative risk of mortality in the highest one-fifth of the DBS was 0.75 (95% CI, 0.70-0.80) in women and 0.79 (95% CI, 0.75-0.83) in men (P-trend < 0.0001). The inverse association of DBS and mortality was significant in both genders in nearly all categories of covariates. Similar trends were observed for DBS associations with mortality from cancer and heart disease. Nearly 12% of the covariate-adjusted population risk of mortality was attributable to nonconformity with dietary recommendations. Adoption of recommended dietary behaviors was associated with lower mortality in both men and women independent of other lifestyle risk factors. [ABSTRACT FROM AUTHOR]

Increased physical activity has been associated with decreased lung cancer risk. However, no previous investigation has examined physical activity in relation to lung cancer histologic types by smoking status. The authors investigated these relations in the National Institutes of Health-AARP Diet and Health Study among 501,148 men and women aged 50-71 years at baseline in 1995-1996. During follow-up to 2003, 6,745 lung carcinomas occurred (14.8% small cell, 40.3% adenocarcinoma, 19.7% squamous cell, 6.1% undifferentiated large cell, 7.2% non-small cell not otherwise specified, and 11.8% carcinoma not otherwise specified). Among former smokers, the multivariate relative risks of small cell, adenocarcinoma, squamous cell, and undifferentiated large cell carcinomas comparing the highest with the lowest activity level (> or =5 times/week vs. inactive) were 0.93 (95% confidence interval (CI): 0.67, 1.28), 0.79 (95% CI: 0.67, 0.94), 0.73 (95% CI: 0.57, 0.93), and 0.61 (95% CI: 0.38, 0.98), respectively. Among current smokers, corresponding values were 0.77 (95% CI: 0.58, 1.02), 0.76 (95% CI: 0.61, 0.95), 0.85 (95% CI: 0.65, 1.11), and 1.10 (95% CI: 0.69, 1.78). In contrast, physical activity was unrelated to lung carcinoma among never smokers (P(interaction) between physical activity and smoking for total lung carcinomas = 0.002). The inverse findings among former and current smokers in combination with the null results for physical activity among never smokers may point toward residual confounding by cigarette smoking as an explanation for the relations observed. [ABSTRACT FROM AUTHOR]

Previous studies have provided limited evidence for a harmful effect of high glycemic index and dietary glycemic load on cancer. The authors analyzed associations among glycemic index, glycemic load, and risk of cancer in women and men in the National Institutes of Health-AARP Diet and Health Study. Published glycemic index values were assigned to 225 foods/food groups. Glycemic load was calculated by multiplying the glycemic index, carbohydrate content, and intake frequency of individual foods reported on a food frequency questionnaire. From 1995 through 2003, the authors identified 15,215 and 33,203 cancer cases in women and men, respectively. Cox proportional hazards models were used to estimate multivariate relative risks and 95% confidence intervals. For women and men, respectively, the relative risks for total cancer for high versus low glycemic index were 1.03 (P(trend)=0.217) and 1.04 (P(trend)=0.012) and, for glycemic load, were 0.90 (P(trend)=0.024) and 0.93 (P(trend)=0.01). Associations with total cancer held only among the overweight for glycemic index and among those of healthy weight for glycemic load. These findings suggest that glycemic index and glycemic load are not strong predictors of cancer incidence. The direction and small magnitude of associations might be explained by the manner in which high glycemic index and glycemic load track with overall diet and lifestyle patterns. [ABSTRACT FROM AUTHOR]

BACKGROUND: There is probable evidence that some types of fruit and vegetables provide protection against many cancers. OBJECTIVE: We hypothesized that fruit and vegetable intakes are inversely related to the incidence of total cancers among women and men aged >50 y. DESIGN: We performed a prospective study among the cohort of the National Institutes of Health-AARP Diet and Health Study. We merged the MyPyramid Equivalents Database (version 1.0) with food-frequency-questionnaire data to calculate cup equivalents for fruit and vegetables. From 1995 to 2003, we identified 15,792 and 35,071 cancer cases in 195,229 women and 288,109 men, respectively. We used Cox proportional hazards models to estimate multivariate relative risks (RRs) and 95% CIs associated with the highest compared with the lowest quintile (Q) of fruit and vegetable intakes. RESULTS: Fruit intake was not associated with the risk of total cancer among women (RR(Q5 vs Q1) = 0.99; 95% CI: 0.94, 1.05; P trend = 0.059) or men (RR(Q5 vs Q1) = 0.98; 95% CI: 0.95, 1.02; P for trend = 0.17). Vegetable intake was not associated with risk of total cancer among women (RR(Q5 vs Q1) = 1.04; 95% CI: 0.98, 1.09; P for trend = 0.084), but was associated with a significant decrease in risk in men (RR(Q5 vs Q1) = 0.94; 95% CI: 0.91, 0.97; P trend = 0.004). This significant finding among men was no longer evident when we limited the analysis to men who never smoked (RR(Q5 vs Q1) = 0.97; 95% CI: 0.91, 1.04; P for trend = 0.474). CONCLUSIONS: Intake of fruit and vegetables was generally unrelated to total cancer incidence in this cohort. Residual confounding by smoking is a likely explanation for the observed inverse association with vegetable intake among men. Copyright © 2009 American Society for Nutrition [ABSTRACT FROM AUTHOR]

Background: Smoking and high adiposity are strong independent health risk factors but are also interrelated. Smoking is related to a lower body mass index (BMI) but not necessarily with a smaller waist circumference. Smoking cessation is associated with increased body weight and a substantial increase in waist circumference. How this affects mortality risk is unknown.Objective: This study examined the combined relations of smoking status with BMI and waist circumference and smoking status to all-cause mortality.Design: Data were from 149 502 men and 88 184 women aged 51-72 y participating in the National Institutes of Health-AARP Diet and Health Study. All-cause mortality was assessed over 10 y of follow-up from 1996 to 2006.Results: Current smokers with a BMI (in kg/m[2]) <18.5 or >/=35 had a mortality risk 6-8 times that of persons within the normal BMI range who never smoked. Current smokers with a large waist circumference had a mortality risk about 5 times that of never smokers with a waist circumference in the second quintile.Conclusion: Both smoking and adiposity are independent predictors of mortality, but the combination of current or recent smoking with a BMI >/= 35 or a large waist circumference is related to an especially high mortality risk. © American Society for Nutrition [ABSTRACT FROM AUTHOR]

Few prospective studies of the relationship between intake of dairy foods, calcium, vitamin D, and lactose and ovarian cancer have been conducted, and results have been largely inconsistent. Two recent studies found significant increased risk with frequent dairy consumption and perhaps with high intakes of calcium or lactose. The authors investigated the association between these foods and nutrients and ovarian cancer risk among 31,925 subjects in the Breast Cancer Detection Demonstration Project follow-up cohort. Multivariable (MV) relative risks (RRs) adjusted for age, parity, and other factors were estimated using Cox proportional hazards models. Over an average follow-up of 8.3 yr, 146 incident ovarian cancer cases were confirmed. Higher intakes of total dairy food (comparing four or more servings per day vs. less than one serving per day) were associated with a statistically significant decreased risk of ovarian cancer, although the trend was not significant (MV RR = 0.42; 95% confidence interval (CI) = 0.20-0.89; P for trend = 0.07). Comparing extreme quartiles, we observed a statistically nonsignificant inverse association between high dietary calcium intake and ovarian cancer (RR = 0.67; 95% CI = 0.43, 1.04; P for trend = 0.08). No statistically significant relations were found for consumption of specific dairy foods, lactose, or vitamin D and ovarian cancer risk. The possibility of a decreased risk of ovarian cancer for dietary calcium merits further evaluation. [ABSTRACT FROM AUTHOR]

With the growing number of epidemiologic publications on the relation between dietary factors and cancer risk, pooled analyses that summarize results from multiple studies are becoming more common. Here, the authors describe the methods being used to summarize data on diet-cancer associations within the ongoing Pooling Project of Prospective Studies of Diet and Cancer, begun in 1991. In the Pooling Project, the primary data from prospective cohort studies meeting prespecified inclusion criteria are analyzed using standardized criteria for modeling of exposure, confounding, and outcome variables. In addition to evaluating main exposure-disease associations, analyses are also conducted to evaluate whether exposure-disease associations are modified by other dietary and nondietary factors or vary among population subgroups or particular cancer subtypes. Study-specific relative risks are calculated using the Cox proportional hazards model and then pooled using a random- or mixed-effects model. The study-specific estimates are weighted by the inverse of their variances in forming summary estimates. Most of the methods used in the Pooling Project may be adapted for examining associations with dietary and nondietary factors in pooled analyses of case-control studies or case-control and cohort studies combined. [ABSTRACT FROM AUTHOR]

Background: Monounsaturated and polyunsaturated fats act as inhibitors of cholesterol cholelithiasis in animal experiments.Objective: To examine the association between long-term intake of cis unsaturated fats and the incidence of gallstone disease in humans.Design: Prospective population-based cohort study.Setting: The Health Professional Follow-up Study.Participants: 45,756 men, age 40 to 75 years in 1986, who were free of gallstone disease.Measurements: Consumption of cis unsaturated fats was assessed starting in 1986 as part of the 131-item semi-quantitative food-frequency questionnaires. Questionnaires were mailed to participants every 2 years. The main outcome measure was self-reported newly diagnosed symptomatic gallstone disease.Results: During 14 years of follow-up, 2323 new cases of gallstone disease were documented. After adjustment for age and other potential risk factors, the relative risk for gallstone disease among men in the highest quintile of dietary intake of cis unsaturated fats compared with men in the lowest quintile was 0.82 (95% CI, 0.69 to 0.96; P for trend = 0.006). The relative risk among men in the highest quintile of polyunsaturated fat consumption compared with men in the lowest quintile was 0.84 (CI, 0.73 to 0.96; P for trend = 0.01), and the relative risk among men in the highest quintile of monounsaturated fat consumption compared with men in the lowest quintile was 0.83 (CI, 0.70 to 1.00; P for trend = 0.01).Limitations: Outcomes were restricted to men with cholecystectomy or diagnostically confirmed but unremoved symptomatic gallstones.Conclusions: A high intake of polyunsaturated and monounsaturated fats in the context of an energy-balanced diet is associated with a reduced risk for gallstone disease in men. For definitions of terms used in the text, see Glossary. [ABSTRACT FROM AUTHOR]

In animals, vegetable protein can inhibit gallstone formation. Epidemiologic studies of dietary protein in relation to gallstone disease are sparse, and the effects of dietary protein of different origins are not clear. The authors aimed to examine the relation between dietary protein intake and risk of cholecystectomy among participants in the Nurses' Health Study, a cohort study of US women in 11 states. During 20 years of follow-up (1980-2000), the authors documented 7,831 cases of cholecystectomy. After adjustment for age, other known or suspected risk factors, and specific fats in a multivariate model, the relative risk of cholecystectomy for women in the highest quintile of dietary total protein intake compared with women in the lowest quintile was 1.00 (95% confidence interval (CI): 0.93, 1.08; p for trend = 0.46). When extreme quintiles were compared, the relative risk for animal protein intake was 1.07 (95% CI: 0.98, 1.15; p for trend = 0.08), whereas the relative risk for vegetable protein intake was 0.79 (95% CI: 0.71, 0.88; p for trend < 0.0001), with a significant dose-response relation. Additional mutual adjustment between animal and vegetable proteins did not materially alter the risks. These results suggest that increased consumption of vegetable protein in the context of an energy-balanced diet can reduce the risk of cholecystectomy in women. [ABSTRACT FROM AUTHOR]

OBJECTIVES: This study examined the association between recreational physical activity and mortality in middle-aged and older women and the possibility that physical activity serves as an important marker of health. METHODS: Analyses were conducted among participants in the Nurses' Health Study. Levels of physical activity were assessed by questionnaire in 1980 and updated every 2 to 4 years. RESULTS: Levels of physical activity were inversely associated with mortality risk; however, each activity level above the reference level had approximately the same level of risk reduction (20%-30%). The inverse association was stronger for cardiovascular deaths than for cancer deaths and was strongest for respiratory deaths. Women who died of noncardiovascular, noncancer causes were more likely to have reported that poor health limited their physical activity than were women who died of other causes or who remained alive. CONCLUSIONS: Part of the link between physical activity and mortality risk is probably spurious and difficult to remove analytically; however, on the basis of epidemiologic evidence, much of the health benefit of activity is real. [ABSTRACT FROM AUTHOR]

Context: Coffee has several metabolic effects that could reduce the risk of gallstone formation.Objective: To examine the association between coffee consumption and the risk of symptomatic gallstone disease in men.Design and Setting: The Health Professionals Follow-up Study, a prospective cohort study, in which the consumption of coffee and other caffeinated drinks was assessed starting in 1986 as part of the 131-item food frequency questionnaire given to US male health professionals with follow-up through 1996.Participants: A total of 46008 men, aged 40 to 75 years in 1986, without history of gallstone disease.Main Outcome Measures: Newly symptomatic gallstone disease (diagnosed by ultrasonography or x-ray) or a cholecystectomy.Results: During 404 166 person-years of follow-up, 1081 subjects reported symptomatic gallstone disease, of whom 885 required cholecystectomy. After adjusting for other known or suspected risk factors, compared with men who did not consume regular coffee in 1986 and 1990, the adjusted relative risk (RR) for those who consistently drank 2 to 3 cups of regular coffee per day was 0.60 (95% confidence interval [CI], 0.42-0.86) and for those who drank 4 or more cups per day the RR was 0.55 (95% CI, 0.33-0.92). All coffee brewing methods showed a decreased risk. The risk of symptomatic gallstone disease also declined with increasing caffeine intake (P for trend = .005). After controlling for known or suspected risk factors, the RR for men in the highest category of caffeine intake (>800 mg/d) compared with men in the lowest category (< or =25 mg/d) was 0.55 (95% CI, 0.35-0.87). In contrast, decaffeinated coffee was not associated with a decreased risk.Conclusions: In this cohort of US men, coffee consumption may have helped to prevent symptomatic gallstone disease. [ABSTRACT FROM AUTHOR]

Background: Several epidemiologic studies have examined the association between physical activity and pancreatic cancer risk; however, the results of these studies are not consistent.Methods: This study examined the associations of total, moderate, and vigorous physical activity to pancreatic cancer in a cohort of 33,530 U.S. women enrolled in the Breast Cancer Detection Demonstration Project (BCDDP). At baseline (1987-1989), information on physical activity over the past year was obtained using a self-administered questionnaire. Cox proportional hazards regression was used to estimate relative risks (RR) and 95% confidence intervals of pancreatic cancer risk.Results: 70 incident cases of pancreatic cancer were ascertained during 284,639 person years of follow-up between 1987-1989 and 1995-1998. After adjustment for age, body mass index, smoking status, history of diabetes, and height, increased physical activity was related to a suggestively decreased risk of pancreatic cancer. The RRs for increasing quartiles of total physical activity were 1.0, 0.80, 0.66, 0.52 (95% CI = 0.26, 1.05; ptrend = 0.05). This association was consistent across subgroups defined by body mass index and smoking status. We also observed statistically non-significant reductions in pancreatic cancer risk for women in the highest quartile of moderate (RR = 0.57; 95% CI = 0.26, 1.26) and highest quartile of vigorous physical activity (RR = 0.63; 95% CI = 0.31, 1.28) compared to their least active counterparts.Conclusion: Our study provides evidence for a role of physical activity in protecting against pancreatic cancer. [ABSTRACT FROM AUTHOR]

Background: Obesity, defined by a body-mass index (BMI) (the weight in kilograms divided by the square of the height in meters) of 30.0 or more, is associated with an increased risk of death, but the relation between overweight (a BMI of 25.0 to 29.9) and the risk of death has been questioned.Methods: We prospectively examined BMI in relation to the risk of death from any cause in 527,265 U.S. men and women in the National Institutes of Health-AARP cohort who were 50 to 71 years old at enrollment in 1995-1996. BMI was calculated from self-reported weight and height. Relative risks and 95 percent confidence intervals were adjusted for age, race or ethnic group, level of education, smoking status, physical activity, and alcohol intake. We also conducted alternative analyses to address potential biases related to preexisting chronic disease and smoking status.Results: During a maximum follow-up of 10 years through 2005, 61,317 participants (42,173 men and 19,144 women) died. Initial analyses showed an increased risk of death for the highest and lowest categories of BMI among both men and women, in all racial or ethnic groups, and at all ages. When the analysis was restricted to healthy people who had never smoked, the risk of death was associated with both overweight and obesity among men and women. In analyses of BMI during midlife (age of 50 years) among those who had never smoked, the associations became stronger, with the risk of death increasing by 20 to 40 percent among overweight persons and by two to at least three times among obese persons; the risk of death among underweight persons was attenuated.Conclusions: Excess body weight during midlife, including overweight, is associated with an increased risk of death. [ABSTRACT FROM AUTHOR]

Background: Insufficient physical activity (PA) is a leading risk factor for non-communicable diseases posing a significant economic burden to healthcare systems and societies. The study aimed to examine the differences in healthcare and indirect costs between sufficient and insufficient PA and the cost differences between PA intensity groups., Methods: The cross-sectional analysis was based on data from 157,648 participants in the baseline examination of the German National Cohort (NAKO) study. Healthcare and indirect costs were calculated based on self-reported information on health-related resource use and productivity losses. PA in the domains leisure, transport, and work was assessed by the Global Physical Activity Questionnaire and categorized into sufficient/insufficient and intensity levels (very low/low/medium/high) based on PA recommendations of the World Health Organization. Two-part models adjusted for relevant covariates were used to estimate mean costs for PA groups., Results and Conclusion: Insufficiently active people had higher average annual healthcare costs (Δ €188, 95% CI [64, 311]) and healthcare plus indirect costs (Δ €482, 95% CI [262, 702]) compared to sufficiently active people. The difference was especially evident in the population aged 60 + years and when considering only leisure PA. An inverse association was observed between leisure PA and costs, whereas a direct association was found between PA at work and costs. Adjusting for the number of comorbidities reduced the differences between activity groups, but the trend persisted. The association between PA and costs differed in direction between PA domains. Future research may provide further insight into the temporal relationship between PA and costs., Competing Interests: Declarations. Competing interests: The authors declare that they have no competing interests., (© 2024. The Author(s).)

Observational studies suggest that child maltreatment increases the risk of externalizing spectrum disorders such as attention deficit hyperactivity disorder (ADHD), conduct disorder (CD), antisocial personality disorder (ASPD), and substance use disorder (SUD). Yet, only few of such associations have been investigated by approaches that provide strong evidence for causation, such as Mendelian Randomization (MR). Establishing causal inference is essential given the growing recognition of gene-environment correlations, which can confound observational research in the context of childhood maltreatment. Evaluating causality between child maltreatment and the externalizing phenotypes, we used genome-wide association study (GWAS) summary data for child maltreatment (143,473 participants), ADHD (20,183 cases; 35,191 controls), CD (451 cases; 256,859 controls), ASPD (381 cases; 252,877 controls), alcohol use disorder (AUD; 13,422 cases; 244,533 controls), opioid use disorder (OUD; 775 cases; 255,921 controls), and cannabinoid use disorder (CUD; 14,080 cases; 343,726 controls). We also generated a latent variable 'common externalizing factor' (EXT) using genomic structural equation modeling. Genetically predicted childhood maltreatment was consistently associated with ADHD (odds ratio [OR], 10.09; 95%-CI, 4.76-21.40; P = 1.63 × 10 -09 ), AUD (OR, 3.72; 95%-CI, 1.85-7.52; P = 2.42 × 10 -04 ), and the EXT (OR, 2.64; 95%-CI, 1.52-4.60; P = 5.80 × 10 -04 ) across the different analyses and pleiotropy-robust methods. A subsequent GWAS on childhood maltreatment and the externalizing dimension from Externalizing Consortium (EXT-CON) confirmed these results. Two of the top five genes with the strongest associations in EXT GWAS, CADM2 and SEMA6D, are also ranked among the top 10 in the EXT-CON. The present results confirm the existence of a common externalizing factor and an increasing vulnerability caused by child maltreatment, with crucial implications for prevention. However, the partly diverging results also indicate that specific influences impact individual phenotypes separately., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Physical activity supports weight regulation and metabolic health, but its timing in relation to obesity and diabetes remains unclear. We aimed to assess the diurnal timing of physical activity and its association with obesity and diabetes., Methods: We cross-sectionally analyzed hip-worn accelerometry data from 61,116 participants aged 20-75 in the German National Cohort between 2015 and 2019. We divided physical activity into sex- and age-standardized quartiles of total morning (06:00-11:59), afternoon (12:00-17:59), evening (18:00-23:59), and nighttime (00:00-06:00) physical activity. Using multivariable logistic regression, we estimated associations of physical activity timing with obesity (BMI ≥ 30.0 kg/m 2 ) and diabetes (self-reported or HbA1c ≥ 6.5%). We accounted for sex, age, study region, education, employment, risky alcohol use, smoking, night shift work, and sleep duration., Results: High afternoon (top vs. bottom quartile, OR: 0.36, 95% CI: 0.33-0.38) and evening physical activity (OR: 0.45, 95% CI: 0.42-0.48) showed lower obesity odds than high morning activity (OR: 0.71, 95% CI: 0.66-0.76), whereas nighttime activity increased obesity odds (OR: 1.58, 95% CI: 1.48-1.68). Associations were similar for diabetes, with the lowest odds for afternoon (OR: 0.47, 95% CI: 0.42-0.53), followed by evening (OR: 0.56, 95% CI: 0.50-0.62) and morning activity (OR: 0.80, 95% CI: 0.71-0.89), and higher odds for nighttime activity (OR: 1.43, 95% CI: 1.29-1.58). Findings were not modified by employment status, night shift work, and sleep duration., Conclusions: Our cross-sectional findings require longitudinal corroboration but suggest afternoon and evening activity provide greater metabolic health benefits than morning activity, while nighttime activity is discouraged., Competing Interests: Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: The NAKO obtained ethics approval from all local committees of the study centers (original ethics approval of the leading ethics committee of the Bayerische Landesaerztekammer with protocol code 13023). All participants provided written informed consent. This study was conducted in line with the Declaration of Helsinki and the Strengthening the Reporting of Observational studies in Epidemiology (STROBE) guideline for cross-sectional studies., (© 2025. The Author(s).)

Objective: Low body fat and high physical activity levels are key lifestyle factors in cancer prevention, but the interplay of abdominal obesity and physical activity on cancer risk remains unknown. We explored individual and joint associations of waist circumference and physical activity with cancer risk., Methods: Using UK Biobank data (n=315 457), we categorised individuals according to WHO guideline thresholds for waist circumference and self-reported physical activity levels. Multivariable-adjusted Cox regression was used to estimate HRs and 95% CIs of total cancer. The reference group comprised individuals with recommended levels of waist circumference (<88 cm for women and <102 cm for men) and physical activity (>10 metabolic equivalent of task hours/week). Furthermore, we estimated the proportion of cancers attributable to abdominal obesity and insufficient physical activity., Results: During a median follow-up period of 11 years (3 321 486 person-years), 29 710 participants developed any type of cancer. Participants not meeting the WHO guideline on waist circumference had increased cancer risk, even when sufficiently physically active according to the WHO (HR 1.11, 95% CI 1.08 to 1.15). Similarly, individuals not achieving the WHO guideline for physical activity showed an elevated risk, even if they were abdominally lean (HR 1.04, 95% CI 1.01 to 1.07). Not adhering to either guideline yielded the strongest increase in risk (HR 1.15, 95% CI 1.11 to 1.19). We estimated that abdominal obesity coupled with insufficient physical activity could account for 2.0% of UK Biobank cancer cases., Conclusion: Adherence to both WHO guidelines for waist circumference and physical activity is essential for cancer prevention; meeting just one of these guidelines is insufficient., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Individual traditional anthropometric measures such as body mass index and waist circumference may not fully capture the relation of adiposity to mortality. Investigating multitrait body shapes could overcome this limitation, deepening insights into adiposity and mortality., Methods: Using UK Biobank data from 462,301 adults (40-69 years at baseline: 2006-2010), we derived four body shapes from principal component analysis on body mass index, height, weight, waist and hip circumference, and waist-to-hip ratio. We then used multivariable-adjusted Cox proportional hazard models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between body shapes and mortality for principal component scores of +1 and -1., Results: During 6,114,399 person-years of follow-up, 28,807 deaths occurred. A generally obese body shape exhibited a U-shaped mortality association. A tall and centrally obese body shape showed increased mortality risk in a dose-response manner (comparing a score of +1 and 0: HR = 1.16, 95% CI = 1.14, 1.18). Conversely, tall and lean or athletic body shapes displayed no increased mortality risks when comparing a score of +1 and 0, with positive relations for the comparison between a score of -1 and 0 in these shapes (short and stout shape: HR = 1.12, 95% CI = 1.10, 1.14; nonathletic shape: HR = 1.15, 95% CI = 1.13, 1.17)., Conclusion: Four distinct body shapes, reflecting heterogeneous expressions of obesity, were differentially associated with all-cause and cause-specific mortality. Multitrait body shapes may refine our insights into the associations between different adiposity subtypes and mortality., Competing Interests: Disclosure: The authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Physical activity reduces colorectal cancer risk, yet the diurnal timing of physical activity in colorectal cancer etiology remains unclear., Methods: This study used 24-h accelerometry time series from UK Biobank participants aged 42 to 79 years to derive circadian physical activity patterns using functional principal component analysis. Multivariable Cox proportional hazard models were used to examine associations with colorectal cancer risk., Results: Among 86,252 participants (56% women), 529 colorectal cancer cases occurred during a median 5.3-year follow-up. We identified four physical activity patterns that explained almost 100% of the data variability during the day. A pattern of continuous day-long activity was inversely associated with colorectal cancer risk (hazard ratio (HR) = 0.94, 95% confidence interval (CI) = 0.89-0.99). A second pattern of late-day activity was suggestively inversely related to risk (HR = 0.93, 95% CI = 0.85-1.02). A third pattern of early- plus late-day activity was associated with decreased risk (HR = 0.89, 95% CI = 0.80-0.99). A fourth pattern of mid-day plus night-time activity showed no relation (HR = 1.02, 95% CI = 0.88-1.19). Our results were consistent across various sensitivity analyses, including the restriction to never smokers, the exclusion of the first 2 years of follow-up, and the adjustment for shift work., Conclusions: A pattern of early- plus late-day activity is related to reduced colorectal cancer risk, beyond the benefits of overall activity. Further research is needed to confirm the role of activity timing in colorectal cancer prevention., (© 2024. The Author(s).)

Background: Glioblastoma (GB) is the most common malignant primary brain tumor in adults and is associated with a poor prognosis. Current treatment guidelines outline the standard of care for patients with newly diagnosed GB; however, there is currently no well-established consensus for the treatment of progressive GB. With this systematic meta-analysis of recently published randomized controlled trials (RCTs), we aim to establish evidence on targeted agents in the treatment of patients with progressive GB., Material and Methods: We conducted searches across the Cochrane Library, Pubmed, MEDLINE (Ovid), ClinicalTrials.gov, WHO's International Clinical Trials Registry Platform and Google Scholar, encompassing the time span from 1954 to 2022, aiming to identify RCTs evaluating targeted therapies in patients with progressive GB. In order to perform a random-effects meta-analysis, we extracted hazard ratios (HRs) of overall survival (OS) and progression-free survival (PFS)., Results: We included 16 RCTs (n = 3025 patients) in the systematic meta-analysis. Formally, regorafenib (RR 0.50; 95% CI 0.33-0.75), Depatux-M + TMZ (RR 0.66; 95% CI 0.47-0.93) and rindopepimut + bevacizumab (RR 0.53; 95% CI 0.32-0.88) were associated with an improved OS compared to the control arm. The combination of bevacizumab + CCNU (RR = 0.49; 95% CI 0.35-0.69) and regorafenib (RR 0.65; 95% CI 0.44-0.95) were formally associated with improved PFS., Conclusions: The aim of this systematic meta-analysis was to establish evidence for the use of targeted therapies in progressive GB. While some studies demonstrated benefits for OS and/or PFS, those results have to be interpreted with caution as most studies had major methodological weaknesses, including potential differences in sample size, trial design, or the initial distribution of prognostic factors., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Sustainable diets are gaining interest as a possible approach to tackle climate change and the global extent of obesity. Yet, the association between sustainable diets and adiposity remains unclear. We performed a systematic review and meta-analysis, calculating summary relative risks and 95% confidence intervals (CI). We pooled maximally adjusted risk estimates, assessed heterogeneity and publication bias, calculated the E-value, and evaluated the risk of bias across the included studies. A total of eight studies were eligible for analysis. Comparing the highest versus the lowest levels of adherence to sustainable diets, the pooled effect estimate was 0.69 (95% CI = 0.62-0.76) for overweight and 0.61 (95% CI = 0.47-0.78) for obesity. These results suggest that sustainable diets may decrease the risk of overweight/obesity and therefore could serve as enablers for improving both public and planetary health. An agreed-upon clear definition of sustainable diets would enhance the comparability of future studies in this area., (© 2024 The Authors. Obesity Reviews published by John Wiley & Sons Ltd on behalf of World Obesity Federation.)

Background: Obesity is a worldwide health problem. We conducted detailed analyses of anthropometric measures in a comprehensive, population-based, current cohort in Germany., Methods: In the German National Cohort (NAKO), we analyzed cross-sectional data on body mass index (BMI), waist and hip circumference, subcutaneous (SAT) and visceral adipose tissue (VAT) as measured by ultrasound, and body fat percentage. The data were stratified by sex, age, and self-reported physicians' diagnoses of cardiovascular diseases (CVD), metabolic diseases (MetD), cardiometabolic diseases (CMD), and cancer., Results: Data were available from 204 751 participants (age, 49.9 ± 12.8 years; 50.5% women). Body size measures generally increased with age. Men had a higher BMI, larger waist circumference, and more VAT than women, while women had a larger hip circumference, more SAT, and a higher body fat percentage than men. For example, the mean BMI of participants over age 60 was 28.3 kg/m2 in men and 27.6 kg/m2 in women. CVD, MetD, and CMD were associated with higher anthropometric values, while cancer was not. For example, the mean BMI was 25.3 kg/m2 in healthy women, 29.4 kg/m2 in women with CMD, and 25.4 kg/m2 in women with cancer., Conclusion: Obesity is widespread in Germany, with notable differences between the sexes in anthro - pometric values. Obesity was more common in older participants and those with chronic diseases other than cancer. Elevated values were especially common in multimorbid individuals.

Large population-based cohort studies utilizing device-based measures of physical activity are crucial to close important research gaps regarding the potential protective effects of physical activity on chronic diseases. The present study details the quality control processes and the derivation of physical activity metrics from 100 Hz accelerometer data collected in the German National Cohort (NAKO). During the 2014 to 2019 baseline assessment, a subsample of NAKO participants wore a triaxial ActiGraph accelerometer on their right hip for seven consecutive days. Auto-calibration, signal feature calculations including Euclidean Norm Minus One (ENMO) and Mean Amplitude Deviation (MAD), identification of non-wear time, and imputation, were conducted using the R package GGIR version 2.10-3. A total of 73,334 participants contributed data for accelerometry analysis, of whom 63,236 provided valid data. The average ENMO was 11.7 ± 3.7 mg (milli gravitational acceleration) and the average MAD was 19.9 ± 6.1 mg. Notably, acceleration summary metrics were higher in men than women and diminished with increasing age. Work generated in the present study will facilitate harmonized analysis, reproducibility, and utilization of NAKO accelerometry data. The NAKO accelerometry dataset represents a valuable asset for physical activity research and will be accessible through a specified application process., (© 2024. The Author(s).)

Background: The benefit of physical activity (PA) for increasing longevity is well-established, however, the impact of diurnal timing of PA on mortality remains poorly understood. We aimed to derive circadian PA patterns and investigate their associations with all-cause mortality., Methods: We used 24 h PA time series from 96,351 UK Biobank participants aged between 42 and 79 years at accelerometry in 2013-2015. Functional principal component analysis (fPCA) was applied to obtain circadian PA patterns. Using multivariable Cox proportional hazard models, we related the loading scores of these fPCs to estimate risk of mortality., Results: During 6.9 years of follow-up, 2,850 deaths occurred. Four distinct fPCs accounted for 96% of the variation of the accelerometry data. Using a loading score of zero (i.e., average overall PA during the day) as the reference, a fPC1 score of + 2 (high overall PA) was inversely associated with mortality (Hazard ratio, HR = 0.91; 95% CI: 0.84-0.99), whereas a score of -2 (low overall PA) was associated with higher mortality (1.69; 95% CI: 1.57-1.81; p for non-linearity < 0.001). Significant inverse linear associations with mortality were observed for engaging in midday PA instead of early and late PA (fPC3) (HR for a 1-unit increase 0.88; 95% CI: 0.83-0.93). In contrast, midday and nocturnal PA instead of early and evening PA (fPC4) were positively associated with mortality (HR for a 1-unit increase 1.16; 95% CI: 1.08-1.25)., Conclusion: Our results suggest that it is less important during which daytime hours one is active but rather, to engage in some level of elevated PA for longevity., (© 2023. BioMed Central Ltd., part of Springer Nature.)