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In this placebo-controlled trial involving patients with recently diagnosed adenomas, daily supplementation with vitamin D 3 (1000 IU), calcium (1200 mg), or both did not reduce the risk of recurrent colorectal adenomas over 3 to 5 years. Vitamin D, an essential nutrient that is important for bone mineralization and calcium homeostasis, 1 also has effects beyond bone and calcium. Many studies have shown it to be antineoplastic, particularly in the colorectum. In in vitro studies, vitamin D and its analogues have been shown to inhibit proliferation, induce differentiation, inhibit angiogenesis, and promote apoptosis in epithelial tissues. 2 , 3 High vitamin D intake inhibits experimental carcinogenesis, 2 , 3 even in animals that are vitamin D–replete. 4 Observational studies of vitamin D intake 5 – 7 and serum levels of 25-hydroxyvitamin D 8 – 10 have shown inverse associations between these measures and the risk of colorectal . . .

Racial/ethnic minorities have been disproportionately impacted by COVID-19. The effects of COVID-19 on the long-term mental health of minorities remains unclear. To evaluate differences in odds of screening positive for depression and anxiety among various racial and ethnic groups during the latter phase of the COVID-19 pandemic, we performed a cross-sectional analysis of 691,473 participants nested within the prospective smartphone-based COVID Symptom Study in the United States (U.S.) and United Kingdom (U.K). from February 23, 2021 to June 9, 2021. In the U.S. ( n =57,187), compared to White participants, the multivariable odds ratios (ORs) for screening positive for depression were 1·16 (95% CI: 1·02 to 1·31) for Black, 1·23 (1·11 to 1·36) for Hispanic, and 1·15 (1·02 to 1·30) for Asian participants, and 1·34 (1·13 to 1·59) for participants reporting more than one race/other even after accounting for personal factors such as prior history of a mental health disorder, COVID-19 infection status, and surrounding lockdown stringency. Rates of screening positive for anxiety were comparable. In the U.K. ( n =643,286), racial/ethnic minorities had similarly elevated rates of positive screening for depression and anxiety. These disparities were not fully explained by changes in leisure time activities. Racial/ethnic minorities bore a disproportionate mental health burden during the COVID-19 pandemic. These differences will need to be considered as health care systems transition from prioritizing infection control to mitigating long-term consequences.

Preterm birth, defined as birth at <37 weeks of gestation, is the leading cause of neonatal death globally and the second leading cause of infant mortality in the United States. There is mounting evidence that COVID-19 infection during pregnancy is associated with an increased risk of preterm birth; however, data remain limited by trimester of infection. The ability to study COVID-19 infection during the earlier stages of pregnancy has been limited by available sources of data. The objective of this study was to use self-reports in large-scale social media data to assess the association between the trimester of COVID-19 infection and preterm birth. In this retrospective cohort study, we used natural language processing and machine learning, followed by manual validation, to identify self-reports of pregnancy on Twitter and to search these users' collection of publicly available tweets for self-reports of COVID-19 infection during pregnancy and, subsequently, a preterm birth or term birth outcome. Among the users who reported their pregnancy on Twitter, we also identified a 1:1 age-matched control group, consisting of users with a due date before January 1, 2020-that is, without COVID-19 infection during pregnancy. We calculated the odds ratios (ORs) with 95% CIs to compare the frequency of preterm birth for pregnancies with and without COVID-19 infection and by the timing of infection: first trimester (1-13 weeks), second trimester (14-27 weeks), or third trimester (28-36 weeks). Through August 2022, we identified 298 Twitter users who reported COVID-19 infection during pregnancy, a preterm birth or term birth outcome, and maternal age: 94 (31.5%) with first-trimester infection, 110 (36.9%) with second-trimester infection, and 95 (31.9%) with third-trimester infection. In total, 26 (8.8%) of these 298 users reported preterm birth: 8 (8.5%) with first-trimester infection, 7 (6.4%) with second-trimester infection, and 12 (12.6%) with third-trimester infection. In the 1:1 age-matched control group, 13 (4.4%) of the 298 users reported preterm birth. Overall, the odds of preterm birth were significantly higher for pregnancies with COVID-19 infection compared to those without (OR 2.08, 95% CI 1.06-4.28; P=.046). In particular, the odds of preterm birth were significantly higher for pregnancies with COVID-19 infection during the third trimester (OR 3.16, 95% CI 1.36-7.29; P=.007). The odds of preterm birth were not significantly higher for pregnancies with COVID-19 infection during the first trimester (OR 2.05, 95% CI 0.78-5.08; P=.12) or second trimester (OR 1.50, 95% CI 0.54-3.82; P=.44) compared to those without infection. Based on self-reports in large-scale social media data, the results of our study suggest that COVID-19 infection particularly during the third trimester is associated with higher odds of preterm birth.

Constipation, a low fiber diet, sedentary lifestyle and gravidity are commonly assumed to increase the risk of hemorrhoids. However, evidence regarding these factors is limited. We examined the association between commonly cited risk factors and the prevalence of hemorrhoids. We performed a cross sectional study of participants who underwent a colonoscopy in a colorectal adenoma prevention trial and who had a detailed assessment of bowel habits, diet and activity. The presence of hemorrhoids was extracted from the subjects' colonoscopy reports. We used logistic regression to estimate odds ratios and 95% confidence intervals while adjusting for age and sex. The study included 2,813 participants. Of these, 1,074 had hemorrhoids recorded. Constipation was associated with an increased prevalence of hemorrhoids (OR 1.43, 95% CI 1.11, 1.86). Of the fiber subtypes, high grain fiber intake was associated with a reduced risk (OR for quartile 4 versus quartile 1 = 0.78, 95% CI 0.62, 0.98). We found no association when comparing gravid and nulligravida women (OR 0.93, 95% CI 0.62-1.40). Sedentary behavior was associated with a reduced risk (OR 0.80, 95% CI 0.65-0.98), but not physical activity (OR 0.83, 95% CI 0.66-1.03). Neither being overweight nor obese was associated with the presence of hemorrhoids (OR 0.89, 95% CI 0.72-1.09 and OR 0.86, 95% CI 0.70-1.06). Constipation is associated with an increased risk of hemorrhoids. Gravidity and physical activity do not appear to be associated. High grain fiber intake and sedentary behavior are associated with a decreased risk of hemorrhoids.

Background Gallbladder disease (GBD) is a highly prevalent condition; however, little is known about potential differences in risk factors by sex and ethnicity/race. Our aim was to evaluate dietary, reproductive and obesity-related factors and GBD in multiethnic populations. Methods We performed a prospective analysis from the Multiethnic Cohort study who self-identified as non-Hispanic White ( n  = 32,103), African American ( n  = 30,209), Japanese ( n  = 35,987), Native Hawaiian ( n  = 6942) and Latino ( n  = 39,168). GBD cases were identified using Medicare and California hospital discharge files (1993–2012) and self-completed questionnaires. We used exposure information on the baseline questionnaire to identify exposures of interest. Associations were estimated by hazard ratios and 95% confidence intervals using Cox models adjusted for confounders. Result After a median 10.7 years of follow-up, there were 13,437 GBD cases. BMI over 25 kg/m 2 , diabetes, past and current smoking, red meat consumption, saturated fat and cholesterol were significant risk factors across ethnic/racial populations (p-trends < 0.01). Protective factors included vigorous physical activity, alcohol use, fruits, vegetables and foods rich in dietary fiber (p-trends < 0.01). Carbohydrates were inversely associated with GBD risk only among women and Latinos born in South America/Mexico (p-trend < 0.003). Parity was a significant risk factor among women; post-menopausal hormones use was only associated with an increased risk among White women (estrogen-only: HR = 1.24; 95% CI = 1.07–1.43 and estrogen + progesterone: HR = 1.23; 95% CI = 1.06–1.42). Conclusion Overall, dietary, reproductive and obesity-related factors are strong risk factors for GBD affecting men and women of different ethnicities/races; however some risk factors appear stronger in women and certain ethnic groups.

This study examines the value of risk stratification by documented diagnosis of diabetes and objectively measured height and weight (BMI) in COVID-19 severity and mortality in a large sample of patients in an urban hospital located in Southern California. Data from a retrospective cohort study of COVID-19 patients treated at Cedars-Sinai Medical Center between March 8, 2020, and January 25, 2021, was analyzed. Sociodemographic characteristics and pre-existing conditions were extracted from electronic medical records. Univariable and multivariable logistic regression models identified associated risk factors, and a regression causal mediation analysis examined the role of diabetes in the association between obesity and illness severity. All analyses were stratified by age (<65 and ≥65). Among individuals <65yo, diabetes accounted for 19-30% of the associations between obesity and COVID-19 illness severity. Among patients ≥65yo, having a BMI <18.5 was a risk factor for mortality regardless of diabetes history. Our findings have clinical implications in documenting which patients may be at elevated risk for adverse outcomes. More in-depth prospective studies are needed to capture how glycemic regulation may influence prognosis.

Background Fatty acid binding protein 4 (FABP-4) is a lipid-binding adipokine upregulated in obesity, which may facilitate fatty acid supply for tumor growth and promote insulin resistance and inflammation and may thus play a role in colorectal cancer (CRC) development. We aimed to investigate the association between circulating FABP-4 and CRC and to assess potential causality using a Mendelian randomization (MR) approach. Methods The association between pre-diagnostic plasma measurements of FABP-4 and CRC risk was investigated in a nested case-control study in 1324 CRC cases and the same number of matched controls within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. A two-sample Mendelian randomization study was conducted based on three genetic variants (1 cis, 2 trans) associated with circulating FABP-4 identified in a published genome-wide association study (discovery n  = 20,436) and data from 58,131 CRC cases and 67,347 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry. Results In conditional logistic regression models adjusted for potential confounders including body size, the estimated relative risk, RR (95% confidence interval, CI) per one standard deviation, SD (8.9 ng/mL) higher FABP-4 concentration was 1.01 (0.92, 1.12) overall, 0.95 (0.80, 1.13) in men and 1.09 (0.95, 1.25) in women. Genetically determined higher FABP-4 was not associated with colorectal cancer risk (RR per FABP-4 SD was 1.10 (0.95, 1.27) overall, 1.03 (0.84, 1.26) in men and 1.21 (0.98, 1.48) in women). However, in a cis-MR approach, a statistically significant association was observed in women (RR 1.56, 1.09, 2.23) but not overall (RR 1.23, 0.97, 1.57) or in men (0.99, 0.71, 1.37). Conclusions Taken together, these analyses provide no support for a causal role of circulating FABP-4 in the development of CRC, although the cis-MR provides some evidence for a positive association in women, which may deserve to be investigated further.

Background Physical activity and BMI have been individually associated with cancer survivorship but have not yet been studied in combinations in colorectal cancer patients. Here, we investigate individual and combined associations of physical activity and BMI groups with colorectal cancer survival outcomes. Methods Self-reported physical activity levels (MET hrs/wk) were assessed using an adapted version of the International Physical Activity Questionnaire (IPAQ) at baseline in 931 patients with stage I-III colorectal cancer and classified into ‘highly active’ and’not-highly active’(≥ / < 18 MET hrs/wk). BMI (kg/m 2 ) was categorized into ‘normal weight’, ‘overweight’, and ‘obese’. Patients were further classified into combined physical activity and BMI groups. Cox-proportional hazard models with Firth correction were computed to assess associations [hazard ratio (HR), 95% profile HR likelihood confidence interval (95% CI) between individual and combined physical activity and BMI groups with overall and disease-free survival in colorectal cancer patients. Results ‘Not-highly active’ compared to ‘highly active’ and ‘overweight’/ ‘obese’ compared to ‘normal weight’ patients had a 40–50% increased risk of death or recurrence (HR: 1.41 (95% CI: 0.99–2.06), p  = 0.03; HR: 1.49 (95% CI: 1.02–2.21) and HR: 1.51 (95% CI: 1.02–2.26), p  = 0.04, respectively). ‘Not-highly active’ patients had worse disease-free survival outcomes, regardless of their BMI, compared to ‘highly active/normal weight’ patients. ‘Not-highly active/obese’ patients had a 3.66 times increased risk of death or recurrence compared to ‘highly active/normal weight’ patients (HR: 4.66 (95% CI: 1.75–9.10), p  = 0.002). Lower activity thresholds yielded smaller effect sizes. Conclusion Physical activity and BMI were individually associated with disease-free survival among colorectal cancer patients. Physical activity seems to improve survival outcomes in patients regardless of their BMI.

Background Observational studies have linked childhood obesity with elevated risk of colorectal cancer; however, it is unclear if this association is causal or independent from the effects of obesity in adulthood on colorectal cancer risk. Methods We conducted Mendelian randomization (MR) analyses to investigate potential causal relationships between self-perceived body size (thinner, plumper, or about average) in early life (age 10) and measured body mass index in adulthood (mean age 56.5) with risk of colorectal cancer. The total and independent effects of body size exposures were estimated using univariable and multivariable MR, respectively. Summary data were obtained from a genome-wide association study of 453,169 participants in UK Biobank for body size and from a genome-wide association study meta-analysis of three colorectal cancer consortia of 125,478 participants. Results Genetically predicted early life body size was estimated to increase odds of colorectal cancer (odds ratio [OR] per category change: 1.12, 95% confidence interval [CI]: 0.98–1.27), with stronger results for colon cancer (OR: 1.16, 95% CI: 1.00–1.35), and distal colon cancer (OR: 1.25, 95% CI: 1.04–1.51). After accounting for adult body size using multivariable MR, effect estimates for early life body size were attenuated towards the null for colorectal cancer (OR: 0.97, 95% CI: 0.77–1.22) and colon cancer (OR: 0.97, 95% CI: 0.76–1.25), while the estimate for distal colon cancer was of similar magnitude but more imprecise (OR: 1.27, 95% CI: 0.90–1.77). Genetically predicted adult life body size was estimated to increase odds of colorectal (OR: 1.27, 95% CI: 1.03, 1.57), colon (OR: 1.32, 95% CI: 1.05, 1.67), and proximal colon (OR: 1.57, 95% CI: 1.21, 2.05). Conclusions Our findings suggest that the positive association between early life body size and colorectal cancer risk is likely due to large body size retainment into adulthood.

Genome-wide association studies have suggested numerous colorectal cancer (CRC) susceptibility genes, but their causality and therapeutic potential remain unclear. To prioritise causal associations between gene expression/splicing and CRC risk (52,775 cases; 45,940 controls), we perform a transcriptome-wide association study (TWAS) across six tissues with Mendelian randomisation and colocalisation, integrating sex- and anatomical subsite-specific analyses. Here we reveal 37 genes with robust causal links to CRC risk, ten of which have not previously been reported by TWAS. Most likely causal genes with evidence of cancer cell dependency show elevated expression linked to risk, suggesting therapeutic potential. Notably, SEMA4D , encoding a protein targeted by an investigational CRC therapy, emerges as a key risk gene. We also identify a female-specific association with CRC risk for CCM2 expression and subsite-specific associations, including LAMC1 with rectal cancer risk. These findings offer valuable insights into CRC molecular mechanisms and support promising therapeutic avenues. Transcriptome-wide association studies (TWAS) have identified colorectal cancer (CRC) susceptibility genes. Here, the authors combine two multi-tissue TWAS methods, Mendelian randomisation, and genetic colocalization to identify 37 likely causal CRC susceptibility genes.