Global patterns in excess body weight and the associated cancer burden.

The prevalence of excess body weight and the associated cancer burden have been rising over the past several decades globally. Between 1975 and 2016, the prevalence of excess body weight in adults-defined as a body mass index (BMI) ≥ 25 kg/m2 -increased from nearly 21% in men and 24% in women to approximately 40% in both sexes. Notably, the prevalence of obesity (BMI ≥ 30 kg/m2 ) quadrupled in men, from 3% to 12%, and more than doubled in women, from 7% to 16%. This change, combined with population growth, resulted in a more than 6-fold increase in the number of obese adults, from 100 to 671 million. The largest absolute increase in obesity occurred among men and boys in high-income Western countries and among women and girls in Central Asia, the Middle East, and North Africa. The simultaneous rise in excess body weight in almost all countries is thought to be driven largely by changes in the global food system, which promotes energy-dense, nutrient-poor foods, alongside reduced opportunities for physical activity. In 2012, excess body weight accounted for approximately 3.9% of all cancers (544,300 cases) with proportion varying from less than 1% in low-income countries to 7% or 8% in some high-income Western countries and in Middle Eastern and Northern African countries. The attributable burden by sex was higher for women (368,500 cases) than for men (175,800 cases). Given the pandemic proportion of excess body weight in high-income countries and the increasing prevalence in low- and middle-income countries, the global cancer burden attributable to this condition is likely to increase in the future. There is emerging consensus on opportunities for obesity control through the multisectoral coordinated implementation of core policy actions to promote an environment conducive to a healthy diet and active living. The rapid increase in both the prevalence of excess body weight and the associated cancer burden highlights the need for a rejuvenated focus on identifying, implementing, and evaluating interventions to prevent and control excess body weight.

The Global Incident Gastrointestinal Cancers Attributable to Suboptimal Diets From 1990 to 2018.

BACKGROUND & AIMS: The contribution of suboptimal diets to gastrointestinal (GI) cancer incidence globally remains unquantified, and we aimed to evaluate it. METHODS: Comprehensive meta-analyses and rigorous evidence-grading assessment identified the associations between suboptimal diets and 6 GI cancers and their subtypes. A comparative risk assessment model was used to estimate the proportional attributable burden and attributable rate of GI cancers to suboptimal diets by using the corroborative association estimates. In addition, correlation assessments with the Sociodemographic Index were carried out. RESULTS: In 2018, 21.5% (95% uncertainty interval, 19.1%-24.5%) of incident GI cancer cases globally were attributable to suboptimal diets, maintaining a relatively stable proportion since 1990 (22.4%; 19.7%-25.6%), whereas the absolute diet-attributable cases doubled from 580,862 (510,658-664,076) in 1990 to 1,039,877 (923,482-1,187,244) in 2018. Excessive processed meat consumption (5.9%; 4.2%-7.9%), insufficient fruit intake (4.8%; 3.8%-5.9%), and insufficient whole grain intake (3.6%; 2.8%-5.1%) were the most significant dietary risk factors in 2018, a shift from 1990 when the third major concern was insufficient nonstarchy vegetable intake. In addition, Central and Eastern Europe and Central Asia experienced the highest attributable burden across regions in both 1990 (31.6%; 27.0%-37.4%) and 2018 (31.6%; 27.3%-36.5%), and a positive correlation (P < .001) between the Sociodemographic Index and the attributable GI cancer incidence was observed. CONCLUSIONS: Although the proportional attributable GI incidence remains relatively stable, the doubling of absolute cases from 1990 to 2018, along with the discrepancies among urbanicity and countries/regions, informs dietary priorities and more targeted preventive measures.

An Empirical Dietary Pattern Associated With the Gut Microbial Features in Relation to Colorectal Cancer Risk.

BACKGROUND & AIMS: Epidemiologic evidence for dietary influence on colorectal cancer (CRC) risk through the gut microbiome remains limited. METHODS: Leveraging 307 men and 212 women with stool metagenomes and dietary data, we characterized and validated a sex-specific dietary pattern associated with the CRC-related gut microbial signature (CRC Microbial Dietary Score [CMDS]). We evaluated the associations of CMDS with CRC risk according to Fusobacterium nucleatum, pks+Escherichia coli, and enterotoxigenic Bacteroides fragilis status in tumor tissue using Cox proportional hazards regression in the Health Professionals Follow-Up Study (1986-2018), Nurses' Health Study (1984-2020), and Nurses' Health Study II (1991-2019). RESULTS: The CMDS was characterized by high industrially processed food and low unprocessed fiber-rich food intakes. In 259,200 participants, we documented 3854 incident CRC cases over 6,467,378 person-years of follow-up. CMDS was associated with a higher risk of CRC (Ptrend < .001), with a multivariable hazard ratio (HRQ5 vs Q1) of 1.25 (95% CI, 1.13-1.39). The association remained after adjusting for previously established dietary patterns, for example, the Western and prudent diets. Notably, the association was stronger for tumoral F nucleatum-positive (HRQ5 vs Q1, 2.51; 95% CI, 1.68-3.75; Ptrend < .001; Pheterogeneity = .03, positivity vs negativity), pks+E coli-positive (HRQ5 vs Q1, 1.68; 95% CI, 0.84-3.38; Ptrend = .005; Pheterogeneity = .01, positivity vs negativity), and enterotoxigenic Bacteroides fragilis-positive CRC (HRQ5 vs Q1, 2.06; 95% CI, 1.10-3.88; Ptrend = .016; Pheterogeneity = .06, positivity vs negativity), compared with their negative counterparts. CONCLUSIONS: CMDS was associated with increased CRC risk, especially for tumors with detectable F nucleatum, pks+E coli, and enterotoxigenic Bacteroides fragilis in tissue. Our findings support a potential role of the gut microbiome underlying the dietary effects on CRC.

The metabolic potential of inflammatory and insulinaemic dietary patterns and risk of type 2 diabetes.

AIMS/HYPOTHESIS: Diets with higher inflammatory and insulinaemic potential have been associated with an increased risk of type 2 diabetes. However, it remains unknown whether plasma metabolomic profiles related to proinflammatory/hyperinsulinaemic diets and to inflammatory/insulin biomarkers are associated with type 2 diabetes risk. METHODS: We analysed 6840 participants from the Nurses' Health Study and Health Professionals Follow-up Study to identify the plasma metabolome related to empirical dietary inflammatory pattern (EDIP), empirical dietary index for hyperinsulinemia (EDIH), four circulating inflammatory biomarkers and C-peptide. Dietary intakes were assessed using validated food frequency questionnaires. Plasma metabolomic profiling was conducted by LC-MS/MS. Metabolomic signatures were derived using elastic net regression. Multivariable Cox regression was used to examine associations of the metabolomic profiles with type 2 diabetes risk. RESULTS: We identified 27 metabolites commonly associated with both EDIP and inflammatory biomarker z score and 21 commonly associated with both EDIH and C-peptide. Higher metabolomic dietary inflammatory potential (MDIP), reflecting higher metabolic potential of both an inflammatory dietary pattern and circulating inflammatory biomarkers, was associated with higher type 2 diabetes risk. The HR comparing highest vs lowest quartiles of MDIP was 3.26 (95% CI 2.39, 4.44). We observed a strong positive association with type 2 diabetes risk for the metabolomic signature associated with EDIP-only (HR 3.75; 95% CI 2.71, 5.17) or inflammatory biomarkers-only (HR 4.07; 95% CI 2.91, 5.69). In addition, higher metabolomic dietary index for hyperinsulinaemia (MDIH), reflecting higher metabolic potential of both an insulinaemic dietary pattern and circulating C-peptide, was associated with greater type 2 diabetes risk (HR 3.00; 95% CI 2.22, 4.06); further associations with type 2 diabetes were HR 2.79 (95% CI 2.07, 3.76) for EDIH-only signature and HR 3.89 (95% CI 2.82, 5.35) for C-peptide-only signature. The diet scores were significantly associated with risk, although adjustment for the corresponding metabolomic signature scores attenuated the associations with type 2 diabetes, these remained significant. CONCLUSIONS/INTERPRETATION: The metabolomic signatures reflecting proinflammatory or hyperinsulinaemic diets and related biomarkers were positively associated with type 2 diabetes risk, supporting that these dietary patterns may influence type 2 diabetes risk via the regulation of metabolism.

Healthy dietary patterns and risk of prostate cancer in men at high genetic risk.

Prostate cancer has high heritability. Healthy lifestyle has been associated with lower lethal prostate cancer risk among men at increased genetic susceptibility, but the role of healthy dietary patterns remains unknown. We prospectively followed 10,269 genotyped men in the Health Professionals Follow-up Study (1993-2019). Genetic risk was quantified using an established polygenic risk score (PRS). Five dietary patterns were investigated: healthy eating index, Mediterranean, diabetes risk-reducing, hyperinsulinemic and inflammatory diet. Overall and lethal prostate cancer rates (metastatic disease/prostate cancer-specific death) were analyzed using multivariable Cox proportional hazards models. During 26 years of follow-up, 2133 overall and 253 lethal prostate cancer events were documented. In the highest PRS quartile, higher adherence to a diabetes risk-reducing diet was associated with lower rates of overall (top vs. bottom quintile HR [95% CI], 0.74 [0.58-0.94]) and lethal prostate cancer (0.43 [0.21-0.88]). A low insulinemic diet was associated with similar lower rates (overall, 0.76 [0.60-0.95]; lethal, 0.46 [0.23-0.94]). Other dietary patterns showed weaker, but similar associations. In the highest PRS quartile, men with healthy lifestyles based on body weight, physical activity, and low insulinemic diet had a substantially lower rate (0.26 [0.13-0.49]) of lethal prostate cancer compared with men with unhealthy lifestyles, translating to a lifetime risk of 3.4% (95% CI, 2.3%-5.0%) among those with healthy lifestyles and 9.5% (5.3%-16.7%) among those with unhealthy lifestyles. Our findings indicate that lifestyle modifications lowering insulin resistance and chronic hyperinsulinemia could be relevant in preventing aggressive prostate cancer among men genetically predisposed to prostate cancer.

Identifying modifiable risk factors to prevent aggressive colorectal cancer.

It remains unclear if pre-diagnostic factors influence the developmental pathways of colorectal cancer (CRC) that could enhance tumor aggressiveness. This study used prospective data from 205,489 cancer-free US health professionals to investigate the associations of 31 known or putative risk factors with the risk of aggressive CRC. Tumor aggressiveness was characterized by three endpoints: aggressive CRC (cancer that causes death within 5 years of diagnosis), fatal CRC, and tumor stage at diagnosis. The data augmentation method was used to assess the difference in the associations between risk factors and endpoints. We documented 3201 CRC cases, of which 899 were aggressive. The protective associations of undergoing lower endoscopy (hazard ratios [HR] 0.43, 95% confidence interval (CI) 0.37, 0.49 for aggressive versus HR 0.61, 95% CI 0.56, 0.67 for non-aggressive) and regular use of aspirin (HR 0.70, 95% CI 0.61, 0.81 versus HR 0.84, 95% CI 0.77, 0.92) were stronger for aggressive than non-aggressive CRC (pHeterogeneity <0.05). Lower intake of whole grains or cereal fiber and greater dietary inflammatory potential were associated with a higher risk of aggressive but not non-aggressive CRC. The remaining risk factors showed comparable associations with aggressive CRC and non-aggressive CRC. Aggressive cases were more likely to have KRAS-mutated tumors but less likely to have distal or MSI-high tumors (p < .007). Similar results were observed for fatal CRC and advanced tumor stages at diagnosis. These findings provide initial evidence for the role of pre-diagnostic risk factors in the pathogenesis of aggressive CRC and suggest research priorities for preventive interventions.

Pre-diagnostic plasma inflammatory proteins and risk of hepatocellular carcinoma in three population-based cohort studies from the United States and the United Kingdom.

Previous studies suggest a role for inflammation in hepatocarcinogenesis. However, no study has comprehensively evaluated associations between circulating inflammatory proteins and risk of hepatocellular carcinoma (HCC) among the general population. We conducted a nested case-control study in the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS) with 56 pairs of incident HCC cases and controls. External validation was performed in the UK Biobank (34 HCC cases and 48,471 non-HCC controls). Inflammatory protein levels were measured in pre-diagnostic plasma using the Olink® Inflammation Panel. We used conditional logistic regression to calculate multivariable odds ratios (ORs) with 95% confidence intervals (CIs) for associations between a 1-standard deviation (SD) increase in biomarker levels and HCC risk, considering a statistically significant threshold of false discovery rate (FDR)-adjusted p < .05. In the NHS/HPFS, among 70 analyzed proteins with call rates >80%, 15 proteins had significant associations with HCC risk (pFDR < .05). Two proteins (stem cell factor, OR per SD = 0.31, 95% CI = 0.16-0.58; tumor necrosis factor superfamily member 12, OR per SD = 0.51, 95% CI = 0.31-0.85) were inversely associated whereas 13 proteins were positively associated with risk of HCC; positive ORs per SD ranged from 1.73 for interleukin (IL)-10 to 2.35 for C-C motif chemokine-19. A total of 11 proteins were further replicated in the UK Biobank. Seven of the eight selected positively associated proteins also showed positive associations with HCC risk by enzyme-linked immunosorbent assay, with ORs ranging from 1.56 for IL-10 to 2.72 for hepatocyte growth factor. More studies are warranted to further investigate the roles of these observed inflammatory proteins in HCC etiology, early detection, risk stratification, and disease treatment.

Evaluating recommendation-based dietary and physical activity strategies for prostate cancer prevention: a target trial emulation in the Health Professionals Follow-up Study.

The 2018 World Cancer Research Fund/American Institute for Cancer Research recommends sustained strategies of physical activity and diet for cancer prevention, but evidence for long-term prostate cancer risk is limited. Using observational data from 27,859 men in the Health Professionals Follow-up Study, we emulated a target trial of recommendation-based physical activity and dietary strategies and 26-year risks of prostate cancer, adjusting for risk factors via the parametric g-formula. Compared with no intervention, limiting sugar-sweetened beverages showed a 0.4% (0.0-0.9%) lower risk of lethal (metastatic or fatal) disease and 0.5% (0.1-0.9%) lower risk of fatal disease. Restricting consumption of processed foods showed a 0.4-0.9% higher risk of all prostate cancer outcomes. Estimated risk differences for clinically significant disease were close to null for strategies involving fruits and non-starchy vegetables, whole grains and legumes, red meat, and processed meat, as well as under a joint strategy of physical activity and diet. Compared with a "low adherence" strategy, maintaining recommended physical activity levels showed a 0.4% (0.1-0.8%) lower risk of lethal and 0.5% (0.2-0.8%) lower risk of fatal disease. Adhering to specific components of current physical activity and dietary recommendations may help to prevent lethal and fatal prostate cancer over 26 years.

Post-diagnostic multivitamin supplement use and colorectal cancer survival: A prospective cohort study.

BACKGROUND: Use of multivitamin supplements has been associated with lower incidence of colorectal cancer (CRC). However, its influence on CRC survival remains unknown. METHODS: Among 2424 patients with stage I-III CRC who provided detailed information about multivitamin supplements in the Nurses' Health Study and Health Professionals Follow-up Study, the authors calculated multivariable hazard ratios (HRs) of multivitamin supplements for all-cause and CRC-specific mortality according to post-diagnostic use and dose of multivitamin supplements. RESULTS: During a median follow-up of 11 years, the authors documented 1512 deaths, among which 343 were of CRC. Compared to non-users, post-diagnostic users of multivitamin supplements at a dose of 3-5 tablets/week had lower CRC-specific mortality (HR, 0.55; 95% confidence interval [CI], 0.36-0.83, p = .005), and post-diagnostic users at doses of 3-5 and 6-9 tablets/week had lower all-cause mortality (HR, 0.81; 95% CI, 0.67-0.99, p = .04; HR, 0.79; 95% CI, 0.70-0.88), p < .001). The dose-response analysis showed a curvilinear relationship for both CRC-specific (pnonlinearity < .001) and all-cause mortality (pnonlinearity = .004), with the maximum risk reduction observed at 3-5 tablets/week and no further reduction at higher doses. Compared to non-users in both pre- and post-diagnosis periods, new post-diagnostic users at dose of <10 tablets/week had a lower all-cause mortality (HR, 0.81; 95% CI, 0.71-0.94, p = .005), whereas new users at a dose of ≥10 tablets/week (HR, 1.58; 95% CI, 1.07-2.33) and discontinued users (HR, 1.35; 95% CI, 1.14-1.59) had a higher risk of mortality. CONCLUSIONS: Use of multivitamin supplements at a moderate dose after a diagnosis of nonmetastatic CRC is associated with lower CRC-specific and overall mortality, whereas a high dose (≥10 tablets/week) use is associated with higher CRC-specific mortality.

Multivitamin use after diagnosis and prostate cancer survival among men with nonmetastatic prostate cancer.

BACKGROUND: Multivitamin use is common among cancer patients. Whether post-diagnostic multivitamin supplementation is beneficial for prostate cancer survival is largely unknown, and some evidence even suggests potential harm. METHODS: We prospectively assessed post-diagnostic multivitamin use in relation to prostate cancer survival among 4756 men with nonmetastatic prostate cancer at diagnosis in the Health Professionals Follow-up Study (1986-2016). Cox regression models were used to evaluate the association between post-diagnostic multivitamin use and frequency and risk of lethal prostate cancer (distant metastases or prostate cancer-specific death) and all-cause mortality. RESULTS: We observed 438 lethal prostate cancer and 2609 deaths during a median follow-up of 11 years. Compared to non-users, post-diagnostic multivitamin use was not associated with risk of lethal prostate cancer (HR [95% CI], 0.98 [0.74-1.30]) or all-cause mortality (1.00 [0.88-1.12]), after adjustment for potential confounders. Similarly, null associations were observed across various categories of use frequency. Compared to non-users, men who used multivitamins regularly (6-9 tablets/week) after cancer diagnosis had similar risk of lethal prostate cancer (0.96 [0.72-1.28]) and all-cause mortality (0.99 [0.88-1.12]). CONCLUSIONS: We found no evidence that post-diagnostic multivitamin use among men with nonmetastatic prostate cancer was associated with better or worse survival in a well-nourished population.

Association between weight cycling and risk of colorectal cancer: a prospective cohort study.

BACKGROUND: Weight cycling is the repeated episodes manifesting intentional weight loss and subsequent unintentional weight gain. Whether the frequency and magnitude of weight cycling is associated with colorectal cancer risk independent of body mass index (BMI) remains unknown. METHODS: Two prospective cohort studies, Nurses' Health Study I and Health Professionals Follow-up Study, followed 85,562 participants from 1992 to 2014. Participants completed a questionnaire regarding the frequency and magnitude of intentional weight loss in the past 4 years at the baseline. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazard model. RESULTS: We identified 1626 colorectal cancer cases during up to 22 years of follow-up. In the pooled analysis of HPFS and NHS, compared to non-weight cycling, moderate weight cycling (≥3 times of intentional weight loss of ≥2.3-4.4 kg) was associated with a reduced risk of colorectal cancer after adjustment for confounders, including attained BMI after weight cycling (HR = 0.82, 95% CI 0.69, 0.97). However, no significant association was observed in mild weight cyclers and in severe weight cyclers. CONCLUSIONS: Moderate weight cycling was associated with a lower risk of colorectal cancer independent of BMI. This finding needs further studies for replication and putative biological mechanisms.

A prospective study of birth weight and prostate cancer risk and mortality in the Health Professionals Follow-up Study.

BACKGROUND: Previous studies have observed inconsistent associations between birth weight and aggressive prostate cancer risk. This study aimed to prospectively analyse this association in the Health Professionals Follow-up Study (HPFS). METHODS: Birth weight was self-reported in 1994, and prostate cancer diagnoses were assessed biennially through January 2017 and confirmed by medical record review. Multivariable Cox proportional hazards regression was used to evaluate the association between birth weight and prostate cancer risk and mortality. RESULTS: Among 19,889 eligible men, 2520 were diagnosed with prostate cancer, including 643 with higher-grade/advanced stage, 296 with lethal, and 248 with fatal disease. Overall, no association was observed for increasing birth weight with risk of overall prostate cancer, lower-grade, and organ-confined disease. However, a borderline statistically significant positive trend was observed for increasing birth weight with risk of higher-grade and/or advanced-stage prostate cancer (adjusted hazard ratio [HRadj] per pound: 1.05; 95% confidence interval [CI]: 0.99-1.11; P-trend = 0.08), but no associations were observed with risk of lethal or fatal disease (HRadj: 0.99, 95% CI: 0.91-1.08; P-trend = 0.83; and HRadj: 0.99, 95% CI: 0.90-1.08; P-trend = 0.82, respectively). CONCLUSION: No consistent associations were observed between birth weight and prostate cancer risk or mortality in this 22-year prospective cohort study.

Appendectomy and Long-term Colorectal Cancer Incidence, Overall and by Tumor Fusobacterium nucleatum Status.

OBJECTIVE: To test hypotheses that appendectomy history might lower long-term colorectal cancer risk and that the risk reduction might be strong for tumors enriched with Fusobacterium nucleatum, bacterial species implicated in colorectal carcinogenesis. BACKGROUND: The absence of the appendix, an immune system organ and a possible reservoir of certain pathogenic microbes, may affect the intestinal microbiome, thereby altering long-term colorectal cancer risk. METHODS: Utilizing databases of prospective cohort studies, namely the Nurses' Health Study and the Health Professionals Follow-up Study, we examined the association of appendectomy history with colorectal cancer incidence overall and subclassified by the amount of tumor tissue Fusobacterium nucleatum​​ (Fusobacterium animalis). We used an inverse probability weighted multivariable-adjusted duplication-method Cox proportional hazards regression model. RESULTS: During the follow-up of 139,406 participants (2,894,060 person-years), we documented 2811 incident colorectal cancer cases, of which 1065 cases provided tissue F. nucleatum analysis data. The multivariable-adjusted hazard ratio of appendectomy for overall colorectal cancer incidence was 0.92 (95% CI, 0.84-1.01). Appendectomy was associated with lower F. nucleatum-positive cancer incidence (multivariable-adjusted hazard ratio, 0.53; 95% CI, 0.33-0.85; P=0.0079), but not F. nucleatum-negative cancer incidence (multivariable-adjusted hazard ratio, 0.98; 95% CI, 0.83-1.14), suggesting a differential association by F. nucleatum status (Pheterogeneity=0.015). This differential association appeared to persist in various participant/patient strata including tumor location and microsatellite instability status. CONCLUSIONS: Appendectomy likely lowers the future long-term incidence of F. nucleatum-positive (but not F. nucleatum-negative) colorectal cancer. Our findings do not support the existing hypothesis that appendectomy may increase colorectal cancer risk.

Smoking and Alcohol Consumption and Risk of Incident Diverticulitis in Women.

BACKGROUND & AIMS: Much of what is known about the effects of alcohol and tobacco use on diverticular disease derives from studies of asymptomatic diverticulosis or complicated diverticulitis. We examined smoking and alcohol consumption and risk of incident diverticulitis in a large cohort of women. METHODS: We conducted a prospective study of 84,232 women in the Nurses' Health Study II (NHS II) who were 39-52 years old and without known diverticulitis at baseline in 2003. Smoking was ascertained every 2 years and alcohol use every 4 years. We used Cox proportional hazards regression to estimate multivariable-adjusted hazards ratios (HRs) and 95% confidence intervals (CIs). RESULTS: During 1,139,660 person-years of follow up, we identified 3018 incident cases of diverticulitis. After adjustment for other risk factors, current (HR, 1.20; 95% CI, 1.04-1.39) and past smoking (HR, 1.20; 95% CI, 1.11-1.30) were associated with increased risk of diverticulitis when compared with never smokers. Women who consumed ≥30 g/d of alcohol had a multivariate HR of 1.26 (95% CI, 1.05-1.50) when compared with women who did not drink. A joint analysis of smoking and alcohol found that individuals who ever smoked and consumed ≥15 g/d of alcohol were at highest risk of diverticulitis (multivariate HR, 1.60; 95% CI, 1.16-2.21), compared with participants who never smoked and reported no alcohol use. CONCLUSIONS: In this large prospective study of women, smoking and alcohol consumption were associated with an increased risk of incident diverticulitis. These data highlight additional modifiable risk factors for diverticulitis that may aid in prevention.

All-cause and cause-specific mortality risk and loss in life expectancy associated with incident type 2 diabetes onset age and duration.

BACKGROUND: Evidence on type 2 diabetes onset age and duration on mortality risk has been limited by short follow-up, inadequate control for confounding, missing repeated measurements, and inability to cover the full range of onset age, duration, and major causes of death. Moreover, scarce data dissect how type 2 diabetes onset age and duration shape life expectancy. METHODS: We evaluate prospectively these topics based on 270,075 eligible participants in the Nurses' Health Studies and Health Professionals Follow-up Study, leveraging repeated measurements throughout up to 40 years of follow-up. Cox models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: In fully adjusted analyses, incident early onset type 2 diabetes (diagnosed <40 years of age) was associated with significantly higher mortality from all-causes (HR, 95% CI was 3.16, 2.64-3.79; vs. individuals without type 2 diabetes), cardiovascular disease (6.56, 4.27-10.1), respiratory disease (3.43, 1.38-8.51), neurodegenerative disease (5.13, 2.09-12.6), and kidney disease (8.55, 1.98-36.9). The relative risk elevations declined dramatically with each higher decade of age at diagnosis for deaths from most of these causes, though the absolute risk difference increased continuously. A substantially higher cumulative incidence of mortality and a greater loss in life expectancy were associated with younger age at type 2 diabetes diagnosis. Longer disease duration was associated with generally higher relative and absolute risk of mortality. CONCLUSION: Early onset of type 2 diabetes and longer disease duration are associated with substantially increased risk of all-cause and cause-specific mortality and greater loss in life expectancy.

Risk of colorectal cancer and adenoma after an appendectomy: results from three large prospective cohort studies and meta-analysis.

PURPOSE: The relationship between appendectomy and subsequent colorectal cancer risk remains unclear, and no study has examined its association with colorectal adenoma. METHODS: We used data from three prospective cohorts: Health Professionals Follow-up Study, Nurses' Health Study (NHS), and NHSII. Appendectomy history was self-reported at baseline. Colorectal cancer risk was analyzed with Cox proportional hazard models among 224,109 participants followed up to 32 years. Colorectal adenoma risk was evaluated among 157,490 participants with at least one lower gastrointestinal endoscopy during follow-up with logistic regression models accounting for repeated observations. We also performed a meta-analysis of cohort studies that examined association between appendectomy and colorectal cancer risk. RESULTS: We documented 3,384 colorectal cancers, 13,006 conventional adenomas, and 11,519 serrated polyps during the follow-up period. Compared to participants without appendectomy, those who reported appendectomy history were not at higher risk of colorectal (HR [95% CI], 0.92 [0.84-1.00]), colon (0.92 [0.83-1.01]), or rectal (0.85 [0.70-1.03]) cancer. Similarly, appendectomy history was not associated with higher risk of conventional adenoma (OR [95% CI], 1.00 [0.97-1.02]), serrated polyp (0.97 [0.94-1.00]), or high-risk adenoma (0.96 [0.92-1.01]). The meta-analysis showed appendectomy was associated with a higher risk of colorectal cancer within a short time after the procedure (1.68 [1.01-2.81]), while the long-term risk was slightly inverse (0.94 [0.90-0.97]). CONCLUSION: We found no evidence of an association between appendectomy history and long-term risk of colorectal cancer or its precursors. The observed higher risk of colorectal cancer right after appendectomy in the first few years is likely due to reverse causation.

Excess weight, weight gain, and prostate cancer risk and prognosis: the PROCA-life study.

BACKGROUND: Studies of excess weight and weight changes throughout adult life for prostate cancer (PCa) risk and prognosis have shown inconsistent results. METHODS: In a population-based cohort, the Prostate Cancer Study throughout life (PROCA-life), 16,960 healthy men from the prospective cohort Tromsø Study (1994-2016) were included. Body mass index (BMI) and weight were measured at all four attendings, and weight change was calculated as the difference between the first and last of either Tromsø4, Tromsø5 or Tromsø6. Overall, 904 men developed PCa during 16 years of follow-up, and Poisson regression with fractional polynomials was used to investigate trends in incidence. Cox proportional hazard and logistic regression models were used to study associations between measurements of BMI and weight change and PCa risk, severity, and mortality. RESULTS: At study entry, 46% of the participants (median age 44 years) were overweight, and 14% were obese (BMI > 30 kg/m2). We observed a 127% increase in overall age adjusted PCa incidence in the cohort during 1995 through 2019. No overall associations between BMI or weight change and PCa risk were observed. However, in sub-group analysis, weight gain among obese men was associated with a three-fold higher PCa risk (HR 3.03, 95% CI 1.39-6.58) compared with obese men with stable weight. Overweight was associated with lower risk of metastatic cancer (OR 0.48, 95% CI 0.30-0.75) at diagnosis. Men with obesity had higher risk of PCa-specific death (HR 1.72, 95% CI 1.03-2.88), while nonsmoking obese PCa cases had two times higher PCa-specific mortality compared with normal weighted PCa cases (HR 2.10, 95% CI 1.11-3.70). INTERPRETATION: In our cohort, weight gain among obese men was associated with higher risk of PCa, and obesity was associated with higher PCa-specific mortality, especially among nonsmokers. The relationship between weight and risk for PCa remains complicated, and future studies are needed to determine clinical implications.

Vitamin D and human health: evidence from Mendelian randomization studies.

We summarized the current evidence on vitamin D and major health outcomes from Mendelian randomization (MR) studies. PubMed and Embase were searched for original MR studies on vitamin D in relation to any health outcome from inception to September 1, 2022. Nonlinear MR findings were excluded due to concerns about the validity of the statistical methods used. A meta-analysis was preformed to synthesize study-specific estimates after excluding overlapping samples, where applicable. The methodological quality of the included studies was evaluated according to the STROBE-MR checklist. A total of 133 MR publications were eligible for inclusion in the analyses. The causal association between vitamin D status and 275 individual outcomes was examined. Linear MR analyses showed genetically high 25-hydroxyvitamin D (25(OH)D) concentrations were associated with reduced risk of multiple sclerosis incidence and relapse, non-infectious uveitis and scleritis, psoriasis, femur fracture, leg fracture, amyotrophic lateral sclerosis, anorexia nervosa, delirium, heart failure, ovarian cancer, non-alcoholic fatty liver disease, dyslipidemia, and bacterial pneumonia, but increased risk of Behçet's disease, Graves' disease, kidney stone disease, fracture of radium/ulna, basal cell carcinoma, and overall cataracts. Stratified analyses showed that the inverse association between genetically predisposed 25(OH)D concentrations and multiple sclerosis risk was significant and consistent regardless of the genetic instruments GIs selected. However, the associations with most of the other outcomes were only pronounced when using genetic variants not limited to those in the vitamin D pathway as GIs. The methodological quality of the included MR studies was substantially heterogeneous. Current evidence from linear MR studies strongly supports a causal role of vitamin D in the development of multiple sclerosis. Suggestive support for a number of other health conditions could help prioritize conditions where vitamin D may be beneficial or harmful.

Effects of vitamin D supplementation on liver fibrogenic factors, vitamin D receptor and liver fibrogenic microRNAs in metabolic dysfunction-associated steatotic liver disease (MASLD) patients: an exploratory randomized clinical trial.

BACKGROUND AND AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global metabolic problem which can lead to irreversible liver fibrosis. It has been shown that vitamin D and its receptors contribute to fibrogenic pathways in the liver. However, the effect of vitamin D supplementation on liver fibrosis related factors have not been examined. This double blinded placebo controlled clinical trial was designed to investigate the effects on vitamin D supplementation on serum levels of VDR, fibrogenic factors and fibrogenic MicroRNAs in MASLD patients. METHODS: Forty six MASLD patients after block matching for sex and BMI were randomly assigned to receive 4000 IU/d vitamin D or placebo for 12 weeks. Weight, height and waist circumference were measured. Serum fibrogenic microRNAs, laminin, collagen type IV, hyaluronic acid, vitamin D, VDR, PTH, blood fasting glucose, serum fasting insulin, lipid profile, ALT and AST were determined at the baseline and at the end of the trial. Insulin resistance and insulin sensitivity were calculated using the HOMA-IR and QUICKI equation. RESULTS: Supplementation with vitamin D for 12 weeks led to the significant increases in serum 25(OH) vitamin D, VDR and HDL-C compared to placebo (P < 0.001, P = 0.008 and P < 0.001). There were significant decreases in ALT, AST, FBS and LDL-C levels in the vitamin D group as compared to the placebo (P < 0.05). Laminin and hyaluronic acid concentrations were significantly decreased in the vitamin D group as compared to the placebo group, by -10.6 and - 28.7 ng/mL, respectively. Supplementation with vitamin D for 12 weeks resulted in a significant lower MiR-21 and MiR-122 gene expressions compared to the placebo group (P = 0.01 and P < 0.001, respectively). DISCUSSION: As the first randomized controlled trial on the effect of vitamin D supplementation on serum levels of VDR, fibrogenic factors and fibrogenic MicroRNAs in MASLD patients, we found a significant reduction in some liver fibrogenic factors, in liver transaminases and corresponding changes in some fibrosis-related MiRs and some metabolic factors. Further clinical trials with larger sample sizes and direct measures of liver fibrosis are needed to confirm these findings. TRIAL REGISTRATION NUMBER: (available at: http://www.irct.ir , identifier: IRCT201405251485N13), Registration date: 14-03-2017.

The global diet quality score as an indicator of adequate nutrient intake and dietary quality - a nation-wide representative study.

BACKGROUND: The Global Diet Quality Score (GDQS) was developed to be a simple, timely and cost-effective tool to track, simultaneously, nutritional deficiency and non-communicable disease risks from diet in diverse settings. The objective was to investigate the performance of GDQS as an indicator of adequate nutrient intake and dietary quality in a national-representative sample of the Brazilian population. METHODS: Nationally-representative data from 44,744 men and non-pregnant and non-lactating women aging ≥ 10 years, from the Brazilian National Dietary Survey were used. Dietary data were collected through two 24-h recalls (24HR). The GDQS was calculated and compared to a proxy indicator of nutrient adequate intake (the Minimum Dietary Diversity for Women-MDD-W) and to an indicator of high-risk diet for non-communicable diseases (caloric contribution from ultra-processed foods-UPF). To estimate the odds for overall nutrient inadequacy across MDD-W and GDQS quintiles, a multiple logistic regression was applied, and the two metrics' performances were compared using Wald's post-test. RESULTS: The mean GDQS for Brazilians was 14.5 (0-49 possible range), and only 1% of the population had a low-risk diet (GDQS ≥ 23). The GDQS mean was higher in women, elderly individuals and in higher-income households. An inverse correlation was found between the GDQS and UPF (rho (95% CI) = -0.20(-0.21;-0.19)). The odds for nutrient inadequacy were lower as quintiles of GDQS and MDD-W were higher (p-trend < 0.001), and MDD-W had a slightly better performance than GDQS (p-diff < 0.001). Having a low-risk GDQS (≥ 23) lowered the odds for nutrient inadequacy by 74% (95% CI:63%-81%). CONCLUSION: The GDQS is a good indicator of overall nutrient adequacy, and correlates well with UPF in a nationally representative sample of Brazil. Future studies must investigate the relationship between the GDQS and clinical endpoints, strengthening the recommendation to use this metric to surveillance dietary risks.