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IntroductionGestational weight gain (GWG) is associated with fetal and newborn health; however, data from sub-Saharan Africa are limited.MethodsWe used data from a prenatal micronutrient supplementation trial among a cohort of HIV-negative pregnant women in Dar es Salaam, Tanzania to estimate the relationships between GWG and newborn outcomes. GWG adequacy was defined as the ratio of the total observed weight gain over the recommended weight gain based on the Institute of Medicine body mass index (BMI)-specific guidelines. Newborn outcomes assessed were: stillbirth, perinatal death, preterm birth, low birthweight, macrosomia, small-for-gestational age (SGA), large-for-gestational age (LGA), stunting at birth, and microcephaly. Modified Poisson regressions with robust standard error were used to estimate the relative risk of newborn outcomes as a function of GWG adequacy.ResultsOf 7561 women included in this study, 51% had severely inadequate (ConclusionInterventions to support optimal gestational weight gain are needed and are likely to improve newborn outcomes.

Background Hypertensive disorders of pregnancy are important causes of maternal morbidity and mortality, as well as preterm birth, the leading cause of death for children under 5 years globally. The World Health Organization currently recommends that pregnant women receive high-dose calcium supplementation (1500–2000 mg elemental calcium) for prevention of preeclampsia in populations with low dietary calcium intake. Trials of low-dose calcium supplementation ( Methods/design We will conduct two independent trials in Bangalore, India (n = 11,000 pregnancies), and Dar es Salaam, Tanzania (n = 11,000 pregnancies). The trial designs are individually randomized, parallel group, quadruple-blind, non-inferiority trials of low-dose calcium supplementation (500 mg elemental calcium/day) as compared to standard high-dose calcium supplementation (1500 mg elemental calcium/day) among nulliparous pregnant women. Pregnant women will be enrolled in the trial before 20 weeks of gestation and will receive the randomized calcium regimen from randomization until the time of delivery. The co-primary outcomes are (i) preeclampsia and (ii) preterm birth; we will test non-inferiority of the primary outcomes for low-dose as compared to the standard high-dose supplementation regimen in each trial. The trials’ secondary outcomes include gestational hypertension, severe features of preeclampsia, pregnancy-related death, third trimester severe anemia, fetal death, stillbirth, low birthweight, small-for-gestational age birth, and infant death. Discussion The trials will provide causal evidence on the non-inferiority of low-dose as compared to the standard high-dose supplementation in India and Tanzania. A single tablet, low-dose calcium supplementation regimen may improve individual-level adherence, reduce programmatic costs, and ultimately expand implementation of routine calcium supplementation in pregnancy in populations with low dietary calcium intake. Trial registration ClinicalTrials.gov identifier: NCT03350516; registered on 22 November 2018. Clinical Trials Registry—India identifier: CTRI/2018/02/012119; registered on 23 February 2018. Tanzania Medicines and Medical Devices Authority Trials Registry identifier: TFDA0018/CTR/0010/5; registered on 20 December 2018.

Background Gestational weight gain (GWG) has critical implications for maternal and child health. Inflammation and angiogenesis are implicated in various aspects of maternal metabolism that may play a role in gestational weight gain. The associations of inflammatory, angiogenic, and metabolic pathways with GWG are yet to be elucidated. This study evaluated associations between a panel of inflammatory, angiogenic, and metabolic proteins measured in mid-pregnancy and gestational weight gain. Methods Pregnant women were enrolled from Dar es Salaam, Tanzania, between 2001 and 2004. The participants were enrolled at mid-pregnancy (12 to 27 weeks of gestation) and followed up until delivery. This analysis focused on a cohort of 1002 women who were primigravid, had singleton live births, had longitudinal measures of gestational weight, and whose mid-pregnancy plasma samples underwent analysis for 18 proteins. Results Higher plasma concentrations of leptin (mean difference in GWG percent adequacy comparing highest with lowest quartiles: 10.24; 95% CI 3.31, 17.16; p-trend = 0.003) and chitinase-3-like protein-1 (CH3L1) (mean difference in GWG percent adequacy comparing highest with lowest quartiles: 7.02; 95% CI 0.31, 13.72; p-trend = 0.007) were associated with greater GWG in a dose-response pattern. Higher leptin concentrations were associated with a lower risk of inadequate GWG (risk ratio comparing highest with lowest quartiles: 0.77; 95% CI 0.65, 0.91; p-trend = 0.001) and a higher risk of excessive GWG (risk ratio comparing highest with lowest quartiles: 1.57; 95% CI 1.03, 2.39; p-trend = 0.03). Higher CH3L1 concentrations were associated with a higher risk of excessive GWG (p-trend = 0.007). The associations of leptin and CH3L1 with inadequate GWG were stronger during the second than the third trimester. The other 16 proteins examined were not significantly associated with GWG. Conclusions Mid-pregnancy plasma leptin concentrations may be associated with GWG and have clinical predictive utility in identifying women at a higher risk of inadequate or excessive gestational weight gain.

BACKGROUND Although fruit and vegetable intake during adolescence, a potentially sensitive time period for prostate cancer (PCa) development, has been proposed to protect against PCa risk, few studies have investigated the role of adolescent plant product intake in PCa development. METHODS Intake of various vegetables, fruit, and grains by males at ages 12-13 y was examined in relation to later PCa risk and mortality in the NIH-AARP Diet and Health Study. Cox proportional hazards regression was used to calculate HRs and 95% CIs of nonadvanced (n = 14,238) and advanced (n = 2,170) PCa incidence and PCa mortality (n = 760) during 1,729,896 person-years of follow-up. RESULTS None of the plant products examined were associated consistently with all PCa outcomes. However, greater adolescent intakes of tomatoes (P-trend = 0.004) and nonstarch vegetables (P-trend = 0.025) were associated with reduced risk of nonadvanced PCa, and greater intakes of broccoli (P-trend = 0.050) and fruit juice (P-trend = 0.019-0.025) were associated with reduced risk of advanced PCa and/or PCa mortality. Positive trends were also observed for greater intakes of fruit juice (P-trend = 0.002), total fruit (P-trend = 0.014), and dark bread (P-trend = 0.035) with nonadvanced PCa risk and for greater intakes of legumes (P-trend

PURPOSE: The association between alcohol intake and glioma remains unclear. We evaluated the association between alcohol intake and incidence of glioma in three large, prospective cohort studies with repeated alcohol assessments. METHODS: We harnessed data from three studies with repeat alcohol assessment to compute hazard ratios (HR) and 95% confidence intervals (CI) for glioma by overall alcohol intake and intake from specific beverages using Cox proportional hazards regression, adjusted for age, cohort, body mass index, smoking status, and caloric intake. Analyses were conducted separately for glioma overall and for glioblastoma (GBM). RESULTS: We confirmed 554 incident glioma cases (362 GBM) among 237,505 participants with 6,216,378 person-years of follow up. Cumulative average alcohol intake was associated with reduced risk of glioma (HR=0.75, 95%CI:0.56–0.99 comparing >8–15 to ≤0.5 g/d; HR=0.71, 95%CI:0.53–0.96 comparing >15 g/d to ≤0.5 g/d). When stratified by sex, for the same comparisons, the HRs for men were 0.57 (95%CI:0.36–0.89) and 0.79 (0.53–1.16), and for women 0.90 (95%CI:0.62–1.30) and 0.62, 95%CI:0.39–0.97. Results were consistent when examining cumulative average, baseline, and recent intake, and with a 4 year lag. CONCLUSION: These results provide evidence against a positive association between alcohol intake and glioma risk. Alcohol intake was associated with reduced risk of glioma in both men and women.

BACKGROUND: Epidemiologic studies examining the relations between dairy product and calcium intakes and breast cancer have been inconclusive, especially for tumor subtypes. OBJECTIVE: To evaluate the associations between intakes of specific dairy products and calcium and risk of breast cancer overall and for subtypes defined by estrogen receptor (ER) status. METHOD: We pooled the individual-level data of over 1 million women who were followed for a maximum of 8–20 years across studies. Associations were evaluated for dairy product and calcium intakes and risk of incident invasive breast cancer overall (n = 37,861 cases) and by subtypes defined by ER status. Study-specific multivariable hazard ratios (HRs) were estimated and then combined using random-effects models. RESULTS: Overall, no clear association was observed between the consumption of specific dairy foods, dietary (from foods only) calcium, and total (from foods and supplements) calcium, and risk of overall breast cancer. Although each dairy product showed a null or very weak inverse association with risk of overall breast cancer (P, test for trend >0.05 for all), differences by ER status were suggested for yogurt and cottage/ricotta cheese with associations observed for ER-negative tumors only (pooled HR = 0.90, 95% CI: 0.83, 0.98 comparing ≥60 g/d with

Background: Patients with cancer are recommended to follow cancer prevention guidelines due to inadequate evidence for specific recommendations for cancer survivors. Methods: We examined whether diet and lifestyle scores measuring adherence to the 2018 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) cancer prevention guidelines were associated with colorectal cancer–specific and overall mortality among 1,491 patients with colorectal cancer in two prospective cohorts. Cox proportional hazards regression models were used to calculate the multivariable-adjusted HRs and 95% confidence intervals (CI). Results: During a median follow-up of 7.92 years, there were 641 deaths (179 colorectal cancer–specific deaths). Patients in the highest quartile of the post-diagnostic WCRF/AICR lifestyle score including diet, body mass index (BMI), and physical activity had a 24% lower risk (HR = 0.76, 95% CI: 0.49–1.18) of colorectal cancer–specific mortality and a 37% lower risk (HR = 0.63, 95% CI: 0.50–0.78) of overall mortality compared with the lowest quartile. When BMI was not included in the lifestyle score due to potential disease-related weight loss, stronger inverse associations were observed for both colorectal cancer–specific and overall mortality for the same comparison (colorectal cancer–specific: HR = 0.50, 95% CI: 0.32–0.79; overall: HR = 0.59, 95% CI: 0.47–0.75). The post-diagnostic WCRF/AICR diet score was not statistically significantly associated with either colorectal cancer–specific or overall mortality. Conclusions: Greater adherence to the WCRF/AICR cancer prevention recommendations was associated with improved survival in patients with colorectal cancer. Impact: This study provides support for patients with colorectal cancer to follow cancer prevention recommendations after diagnosis. Future studies on cancer survivors will continue to contribute to evidence-based diet and lifestyle recommendations for patients with cancer.

BACKGROUND: The influence of a high sugar diet on colorectal cancer (CRC) survival is unclear. METHODS: Among 1463 stage I–III CRC patients from the Nurses’ Health Study and Health Professionals Follow-up Study, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for CRC-specific and all-cause mortality in relation to intake of post-diagnosis sugar-sweetened beverages (SSB), artificially sweetened beverages (ASB), fruit juice, fructose and other sugars. RESULTS: Over a median 8.0 years, 781 cases died (173 CRC-specific deaths). Multivariable-adjusted HRs for post-diagnosis intake and CRC-specific mortality were 1.21 (95% CI: 0.87–1.68) per 1 serving SSBs per day (serving/day) and 1.24 (95% CI: 0.95–1.63) per 20 grams fructose per day. Significant positive associations for CRC-specific mortality were primarily observed ≤5 years from diagnosis (HR per 1 serving/day of SSBs = 1.59, 95% CI: 1.06–2.38). Significant inverse associations were observed between ASBs and CRC-specific and all-cause mortality (HR for ≥5 versus

Summary Colorectal cancer is a heterogeneous disease with diverse prognoses between left-sided and right-sided patients; therefore, it is necessary to precisely evaluate the survival probability of side-specific colorectal cancer patients. Here, we collected multi-omics data from The Cancer Genome Atlas program, including gene expression, DNA methylation and microRNA expression. Specificity measure and robust likelihood-based survival analysis were used to identify 6 left-sided and 28 right-sided prognostic biomarkers. Compared to the performance of clinical prognostic models, the addition of these biomarkers could significantly improve the discriminatory ability and calibration in predicting side-specific 5-year survival for colorectal cancer. Additional dataset derived from Gene Expression Omnibus was used to validate the prognostic value of side-specific genes. Finally, we constructed colorectal cancer side-specific molecular database (CoSMeD), a user-friendly interface for estimating side-specific colorectal cancer 5-year survival probability, which can lay the basis for personalized management of left-sided and right-sided colorectal cancer patients. Availability and implementation CoSMeD is freely available at https://mulongdu.shinyapps.io/cosmed. Supplementary information Supplementary data are available at Bioinformatics online.

Background Adolescent intake of animal products has been proposed to contribute to prostate cancer (PCa) development because of its potentially carcinogenic constituents and influence on hormone levels during adolescence. Methods We used data from 159,482 participants in the NIH-AARP Diet and Health Study to investigate associations for recalled adolescent intake of red meat (unprocessed beef and processed red meat), poultry, egg, canned tuna, animal fat and animal protein at ages 12-13 years with subsequent PCa risk and mortality over 14 years of follow-up. Cox proportional hazard regression was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) of total (n = 17,349), advanced (n = 2,297) and fatal (n = 804) PCa. Results Suggestive inverse trends were observed for adolescent unprocessed beef intake with risks of total, advanced and fatal PCa (multivariable-adjusted P-trends = 0.01, 0.02 and 0.04, respectively). No consistent patterns of association were observed for other animal products by PCa outcome. Conclusion We found evidence to suggest that adolescent unprocessed beef intake, or possibly a correlate of beef intake, such as early-life socioeconomic status, may be associated with reduced risk and mortality from PCa. Additional studies with further early-life exposure information are warranted to better understand this association.

Background Although colorectal cancer (CRC) incidence in the USA is declining overall, its incidence is increasing among those younger than 50 years of age. The reasons underlying the increasing trend are largely unknown, although behavioral changes, such as unhealthy diet and lifestyle factors, may be partially responsible. Design A prospective cohort study included 94 217 women aged 26-45 years at baseline. Validated anthropometric measures and lifestyle information were self-reported biennially. Exposures were four recommendation-based dietary indices—the prime diet quality score and three plant-based dietary indices; and two mechanism-based indices—the empirical dietary and lifestyle index for hyperinsulinemia (EDIH and ELIH). We calculated hazard ratios (HRs) and 95% confidence intervals (CIs) for overall CRC and for early-onset (before age 50) and after age 50 CRC separately. Results We documented 332 cases of CRC during 24 years of follow-up (2 113 655 person-years), with an average age of 52 ± 7 years at diagnosis. Hyperinsulinemic dietary and lifestyle patterns were associated with a higher risk of CRC. Multivariable-adjusted HRs (95% CIs) comparing participants in the highest versus lowest quartile were: 1.67 for EDIH (95% CI: 1.15-2.44, P-trend = 0.01) and 1.51 for ELIH (95% CI: 1.10-2.08, P-trend = 0.01). Moreover, per 75% increment in rank, ELIH appeared to be a stronger risk factor for early-onset CRC (HR = 1.86, 95% CI: 1.12-3.07) than after age 50 CRC (HR = 1.20, 95% CI: 0.83-1.73, P-heterogeneity = 0.16). The four recommendation-based indices were not significantly associated with overall, early-onset, or after age 50 CRC risk (per 75% increment in rank, HRs ranged from 0.75 to 1.28). Conclusion Dietary and lifestyle patterns contributing to hyperinsulinemia were associated with greater CRC risk in younger women. Moreover, the hyperinsulinemic lifestyle showed a suggestively stronger positive association with early-onset CRC risk, compared with after age 50 CRC. Our findings suggest that dietary and lifestyle interventions to reduce insulinemic potential may be effective for CRC prevention among younger women.

Background Osteoporosis and low bone density (LBD) may be associated with higher risk of hearing loss, but findings are inconsistent and longitudinal data are scarce. Bisphosphonates may influence risk, but the relation has not been studied in humans. We longitudinally investigated associations of osteoporosis and LBD, bisphosphonate use, vertebral fracture (VF), hip fracture (HF), and risk of self-reported moderate or worse hearing loss. Design Longitudinal cohort study. Setting The Nurses' Health Study (NHS) (1982-2016) and Nurses' Health Study II (NHS II) (1995-2017). Participants Participants included 60,821 NHS women, aged 36-61 years at baseline, and 83,078 NHS II women, aged 31-48 years at baseline (total n = 143,899). Measurements Information on osteoporosis, LBD, bisphosphonate use, VF, HF, and hearing status was obtained from validated biennial questionnaires. In a subcohort (n = 3749), objective hearing thresholds were obtained by audiometry. Multivariable-adjusted Cox proportional hazards models were used to examine independent associations between osteoporosis (NHS), osteoporosis/LBD (NHS II), and risk of hearing loss. Results The multivariable-adjusted relative risk (MVRR, 95% confidence interval) of moderate or worse hearing loss was higher among women with osteoporosis or LBD in both cohorts. In NHS, compared with women without osteoporosis, the MVRR was 1.14 (1.09, 1.19) among women with osteoporosis; in NHS II, the MVRR was 1.30 (1.21, 1.40) among women with osteoporosis/LBD. The magnitude of the elevated risk was similar among women who did and did not use bisphosphonates. VF was associated with higher risk (NHS: 1.31 [1.16, 1.49]; NHS II: 1.39 [1.13, 1.71]), but HF was not (NHS: 1.00 [0.86, 1.16];NHS II: 1.15 [0.75,1.74]). Among participants with audiometric measurements, compared with women without osteoporosis/LBD, the mean multivariable-adjusted hearing thresholds were higher (i.e., worse) among those with osteoporosis/LBD who used bisphosphonates. Conclusion Osteoporosis and LBD may be important contributors to aging-related hearing loss. Among women with osteoporosis, the risk of hearing loss was not influenced by bisphosphonate use.

Associations between anthropometric factors and breast cancer (BC) risk have varied inconsistently by estrogen and/or progesterone receptor (ER/PR) status. Associations between prediagnostic anthropometric factors and risk of premenopausal and postmenopausal BC overall and ER/PR status subtypes were investigated in a pooled analysis of 20 prospective cohorts, including 36,297 BC cases among 1,061,915 women, using multivariable Cox regression analyses, controlling for reproductive factors, diet and other risk factors. We estimated dose–response relationships and tested for nonlinear associations using restricted cubic splines. Height showed positive, linear associations for premenopausal and postmenopausal BC risk (6–7% RR increase per 5 cm increment), with stronger associations for receptor-positive subtypes. Body mass index (BMI) at cohort baseline was strongly inversely associated with premenopausal BC risk, and strongly positively—and nonlinearly—associated with postmenopausal BC (especially among women who never used hormone replacement therapy). This was primarily observed for receptor-positive subtypes. Early adult BMI (at 18–20 years) showed inverse, linear associations for premenopausal and postmenopausal BC risk (21% and 11% RR decrease per 5 kg/m2, respectively) with stronger associations for receptor-negative subtypes. Adult weight gain since 18–20 years was positively associated with postmenopausal BC risk, stronger for receptor-positive subtypes, and among women who were leaner in early adulthood. Women heavier in early adulthood generally had reduced premenopausal BC risk, independent of later weight gain. Positive associations between height, baseline (adult) BMI, adult weight gain and postmenopausal BC risk were substantially stronger for hormone receptor-positive versus negative subtypes. Premenopausal BC risk was positively associated with height, but inversely with baseline BMI and weight gain (mostly in receptor-positive subtypes). Inverse associations with early adult BMI seemed stronger in receptor-negative subtypes of premenopausal and postmenopausal BC. Electronic supplementary material The online version of this article (10.1007/s10654-020-00688-3) contains supplementary material, which is available to authorized users.

BACKGROUND Trimethylamine-N-oxide (TMAO) is a compound that is present in seafood and produced through human gut microbial metabolism of its precursors. Previous studies have suggested that elevated TMAO concentrations are associated with an increased risk of cardiovascular events. However, the association between diet and TMAO concentrations in free-living adult populations has not been adequately described. OBJECTIVES The objective of this study was to identify dietary predictors of plasma TMAO concentrations. METHODS TMAO concentrations were assessed in 2 fasting plasma samples collected 6 mo apart among 620 healthy men. Short-term and long-term dietary intakes were assessed during the same time-frame of blood collections via repeated 7-d dietary records (7DDRs) and a semiquantitative food-frequency questionnaire (SFFQ), respectively. We grouped individual food items into 21 groups and regressed against averaged TMAO concentrations. We also assessed the association between dietary scores and TMAO concentrations. RESULTS In models adjusted for demographic characteristics and mutually adjusted for food groups, SFFQ-assessments of fish and egg intakes were significantly associated with increased TMAO concentration (β = 0.082; 95% CI: 0.021, 0.14; P = 0.009 for fish; β = 0.065; 95% CI: 0.004, 0.13; P = 0.039 for egg). The positive association between fish consumption and TMAO concentration was replicated in the 7DDR-assessments (β = 0.12; 95% CI: 0.060, 0.18; P

Background: Higher total 25-hydroxyvitamin D [25(OH)D] levels are associated with improved survival among patients with colorectal cancer, but the relationships between circulating vitamin D binding protein (VDBP), and bioavailable or free 25(OH)D, and colorectal cancer survival remain unknown. Methods: We examined the associations between prediagnostic plasma levels of vitamin D–related markers and survival among 603 White participants diagnosed with colorectal cancer from two prospective U.S. cohorts. Plasma VDBP and total 25(OH)D were directly measured, while bioavailable and free 25(OH)D was calculated using a validated formula on the basis of total 25(OH)D, VDBP, and albumin levels. Cox proportional hazards regression was used to estimate HRs for overall and colorectal cancer–specific mortality, with adjustment for other prognostic markers and potential confounders. Results: Higher VDBP levels were associated with improved overall (Ptrend = 0.001) and colorectal cancer–specific survival (Ptrend = 0.02). Compared with patients in the lowest quartile, those in the highest quartile of VDBP had a multivariate HR of 0.58 [95% confidence interval (CI), 0.41–0.80] for overall mortality and 0.58 (95% CI, 0.37–0.91) for colorectal cancer–specific mortality. The results remained similar after further adjustment for total 25(OH)D levels. In contrast, neither bioavailable nor free 25(OH)D levels were associated with overall or colorectal cancer–specific mortality (all Ptrend > 0.15). Conclusions: Prediagnostic circulating concentrations of VDBP were positively associated with survival among patients with colorectal cancer. Impact: The clinical utility of VDBP as a prognostic marker warrants further exploration, as well as research into underlying mechanisms of action.

Low-dose aspirin is recommended by the U.S. Preventive Services Task Force for primary prevention of colorectal cancer in certain individuals. However, broader implementation will require improved precision prevention approaches to identify those most likely to benefit. The major urinary metabolite of PGE2, 11α-hydroxy-9,15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid (PGE-M), is a biomarker for colorectal cancer risk, but it is unknown whether PGE-M is modifiable by aspirin in individuals at risk for colorectal cancer. Adults (N = 180) who recently underwent adenoma resection and did not regularly use aspirin or NSAIDs were recruited to a double-blind, placebo-controlled, randomized trial of aspirin at 81 or 325 mg/day for 8–12 weeks. The primary outcome was postintervention change in urinary PGE-M as measured by LC/MS. A total of 169 participants provided paired urine samples for analysis. Baseline PGE-M excretion was 15.9 ± 14.6 (mean ± S.D, ng/mg creatinine). Aspirin significantly reduced PGE-M excretion (−4.7 ± 14.8) compared with no decrease (0.8 ± 11.8) in the placebo group (P = 0.015; mean duration of treatment = 68.9 days). Aspirin significantly reduced PGE-M levels in participants receiving either 81 (−15%; P = 0.018) or 325 mg/day (−28%; P < 0.0001) compared with placebo. In 40% and 50% of the individuals randomized to 81 or 325 mg/day aspirin, respectively, PGE-M reduction reached a threshold expected to prevent recurrence in 10% of individuals. These results support that aspirin significantly reduces elevated levels of PGE-M in those at increased colorectal cancer risk to levels consistent with lower risk for recurrent neoplasia and underscore the potential utility of PGE-M as a precision chemoprevention biomarker. The ASPIRED trial is registered as NCT02394769.

Progression-free survival (PFS), defined as the time from randomization to progression of disease or death, has been indicated as an endpoint to support accelerated approval of certain cancer drugs by the U.S. FDA. The standard Kaplan–Meier (KM) estimator of PFS, however, can result in significantly biased estimates. A major source for the bias results from the substitution of censored progression times with death times. Currently, to ameliorate this bias, several sensitivity analyses based on rather arbitrary definitions of PFS censoring are usually conducted. In addition, especially in the advanced cancer setting, patients with censored progression and observed death times have the potential to experience disease progression between those two times, in which case their true PFS time is actually between those times. In this paper, we present two alternative nonparametric estimators of PFS, which statistically incorporate survival data often available for those patients who are censored with respect to progression to obtain less biased estimates. Through extensive simulations, we show that these estimators greatly reduce the bias of the standard KM estimator and can also be utilized as alternative sensitivity analyses with a solid statistical basis in lieu of the arbitrarily defined analyses currently used. An example is also given using an ECOG-ACRIN Cancer Research Group advanced breast cancer study.

PURPOSE: Although a growing body of evidence supports an early-life contribution to prostate cancer (PCa) development, few studies have investigated early-life diet, and only three have examined early-life dairy product intake, a promising candidate risk factor because of its known/suspected influence on insulin-like growth factor levels and height. METHODS: We used recalled dietary data from 162,816 participants in the NIH-AARP Diet and Health Study to investigate associations for milk, cheese, ice cream, total dairy, and calcium intake at ages 12–13 years with incident total (n=17,729), advanced (n=2,348), and fatal PCa (n=827) over 14 years of follow-up. We calculated relative risks (RRs) and 95% confidence intervals (CIs) by Cox proportional hazards regression. RESULTS: We observed suggestive positive trends for milk, dairy, and calcium intake with total and/or advanced PCa (p-trends=0.016–0.148). These trends attenuated after adjustment for additional components of adolescent diet, particularly red meat and vegetables/potatoes. In contrast, suggestive inverse trends were observed for cheese and ice cream intake with total and/or advanced PCa (p-trends=0.043–0.153), and for milk, dairy, and calcium intake with fatal PCa (p-trend=0.045–0.117). CONCLUSION: Although these findings provide some support for a role of adolescent diet in increasing PCa risk, particularly for correlates of milk intake or overall dietary patterns, our protective findings for cheese and ice cream intake with PCa risk and mortality, and for all dairy products with PCa mortality suggest alternative explanations, such as the influence of early-life socioeconomic status, and increased PCa screening, earlier detection, and better PCa care.

Summary Background Observational data suggest that low vitamin D status is associated with an increased incidence of pulmonary tuberculosis and mortality among people living with HIV. The primary aims of this study were to assess the effect of vitamin D3 supplementation on the risk of mortality and incidence of pulmonary tuberculosis among adults initiating antiretroviral therapy (ART). Methods This was a randomised, double-blind, placebo-controlled trial of vitamin D3 supplementation among adults living with HIV who initiated ART and had serum 25-hydroxyvitamin D concentrations of less than 30 ng/mL at four large HIV care and treatment centres in Dar es Salaam, Tanzania. Patients were excluded if they were younger than 18 years, pregnant at the time of randomisation, or were enrolled in any other clinical trial. Patients were randomly assigned 1:1 to receive either weekly oral 50 000 IU vitamin D3 supplements (cholecalciferol) for the first month of ART followed by daily 2000 IU vitamin D3 supplements or a matching weekly and daily placebo regimen. The randomisation list was computer-generated by a non-study statistician with sequence blocks of ten that were stratified by study clinic. Complete allocation concealment was ensured and patients, field team, and investigators were masked to group assignment. The trial follow-up duration was 1 year and the primary efficacy outcomes were death and incident pulmonary tuberculosis. An intention-to-treat analysis was followed for all-cause mortality; participants diagnosed with or receiving treatment for pulmonary tuberculosis at randomisation, or suspected to have tuberculosis at randomisation and who later had that diagnosis confirmed, were excluded from analyses of pulmonary tuberculosis incidence. Safety was assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov , NCT01798680 , and is completed. Findings Between Feb 24, 2014, and Feb 24, 2017, 6250 adults initiating ART had serum 25-hydroxyvitamin D screening, 4000 of whom were enrolled in the trial and followed up for 1 year (follow-up of all participants was completed on March 7, 2018). 2001 patients were randomly assigned to the vitamin D3 supplementation group, and 1999 to the placebo group. 415 deaths were recorded: 211 in the vitamin D3 group and 204 in the placebo group. Among all randomly assigned participants, there was no overall effect of vitamin D3 supplementation on the risk of mortality (hazard ratio [HR] 1·04, 95% CI 0·85–1·25; p=0·73). There was also no difference in the overall incidence of pulmonary tuberculosis between the vitamin D3 (50 events in 1812 patients analysed) and placebo groups (64 events in 1827 patients; HR 0·78, 0·54–1·13; p=0·19). The vitamin D3 regimen did not increase the risk of hypercalcaemia (three events in the vitamin D3 group and two events in the placebo group; relative risk 1·25, 95% CI 0·43–3·66; Fisher's exact p=1·00). 101 hospital admissions were reported in the vitamin D3 group and 94 in the placebo group (incidence rate ratio 1·06, 95% CI 0·80–1·41; p=0·66). Interpretation Additional research is needed before vitamin D3 supplementation should be considered for implementation in HIV care and treatment programmes for the prevention of pulmonary tuberculosis or mortality. Funding National Institute of Diabetes and Digestive and Kidney Diseases.

CUL4B, which acts as a scaffold protein in CUL4B-RING ubiquitin ligase (CRL4B) complexes, participates in a variety of biological processes. Previous studies have shown that CUL4B is often overexpressed and exhibits oncogenic activities in a variety of solid tumors. However, the roles and the underlying mechanisms of CUL4B in bladder cancer (BC) were poorly understood. Here, we showed that CUL4B levels were overexpressed and positively correlated with the malignancy of BC, and CUL4B could confer BC cells increased motility, invasiveness, stemness, and chemoresistance. The PIK3CA/AKT pathway was identified as a critical downstream mediator of CUL4B-driven oncogenicity in BC cells. Furthermore, we demonstrated that CRL4B epigenetically repressed the transcription of miR-372/373, via catalyzing monoubiquitination of H2AK119 at the gene cluster encoding miR-372/373, leading to upregulation of PIK3CA and activation of AKT. Our findings thus establish a critical role for the CUL4B-miR-372/373-PIK3CA/AKT axis in the pathogenesis of BC and have important prognostic and therapeutic implications in BC.

Background The relation between sodium intake and cardiovascular disease remains controversial, owing in part to inaccurate assessment of sodium intake. Assessing 24-hour urinary excretion over a period of multiple days is considered to be an accurate method. Methods We included individual-participant data from six prospective cohorts of generally healthy adults; sodium and potassium excretion was assessed with the use of at least two 24-hour urine samples per participant. The primary outcome was a cardiovascular event (coronary revascularization or fatal or nonfatal myocardial infarction or stroke). We analyzed each cohort using consistent methods and combined the results using a random-effects meta-analysis. Results Among 10,709 participants, who had a mean (±SD) age of 51.5±12.6 years and of whom 54.2% were women, 571 cardiovascular events were ascertained during a median study follow-up of 8.8 years (incidence rate, 5.9 per 1000 person-years). The median 24-hour urinary sodium excretion was 3270 mg (10th to 90th percentile, 2099 to 4899). Higher sodium excretion, lower potassium excretion, and a higher sodium-to-potassium ratio were all associated with a higher cardiovascular risk in analyses that were controlled for confounding factors (P≤0.005 for all comparisons). In analyses that compared quartile 4 of the urinary biomarker (highest) with quartile 1 (lowest), the hazard ratios were 1.60 (95% confidence interval [CI], 1.19 to 2.14) for sodium excretion, 0.69 (95% CI, 0.51 to 0.91) for potassium excretion, and 1.62 (95% CI, 1.25 to 2.10) for the sodium-to-potassium ratio. Each daily increment of 1000 mg in sodium excretion was associated with an 18% increase in cardiovascular risk (hazard ratio, 1.18; 95% CI, 1.08 to 1.29), and each daily increment of 1000 mg in potassium excretion was associated with an 18% decrease in risk (hazard ratio, 0.82; 95% CI, 0.72 to 0.94). Conclusions Higher sodium and lower potassium intakes, as measured in multiple 24-hour urine samples, were associated in a dose-response manner with a higher cardiovascular risk. These findings may support reducing sodium intake and increasing potassium intake from current levels. (Funded by the American Heart Association and the National Institutes of Health.).

BACKGROUND Diet quality scores (DQSs) are frequently used to study diet-disease relationships but the validity of these scores derived from food frequency questionnaires (FFQs) has rarely been evaluated. OBJECTIVE To evaluate the validity and reproducibility of six commonly used DQSs derived from the FFQ, including the Alternate Healthy Eating Index-2010 (AHEI-2010), Dietary Approaches to Stop Hypertension (DASH) score, alternative Mediterranean Diet score (AMED), and three plant-based diet indices (overall, healthful, and unhealthful). DESIGN This analysis included 1,394 participants from the Men's (n = 652) and Women's (n = 742) Lifestyle Validation Studies. Participants completed a 152-item FFQ at the beginning of the study and one year later, and completed two weighed 7-day dietary records (7DDRs) and donated two blood samples six-month apart between FFQ assessments. The reproducibility of the FFQs was evaluated by rank intraclass correlation coefficients (ICC). The validity was assessed by comparing FFQ-derived DQSs to those from the average of two 7DDRs using Spearman rank correlation coefficients deattenuated for random measurement error in the 7DDRs (rs). Further, we calculated the correlations between DQSs and plasma biomarkers of diet including fatty acids, folate, carotenoids, retinol, and alpha-and gamma-tocopherol. RESULTS Six FFQ derived DQSs demonstrated moderate to high reproducibility (energy-adjusted ICCs = 0.61 to 0.84) and validity (energy-adjusted, deattenuated rs = 0.56 to 0.80) in both men and women. We consistently observed expected correlations between FFQ derived DQSs with plasma fatty acids, including long chain N-3 and trans fatty acids, most carotenoids, and gamma-tocopherol (rs>0.2). CONCLUSIONS Our study demonstrates the validity of the FFQ to evaluate overall diet quality using six commonly used DQSs. In addition, these DQSs have qualitatively demonstrated biological relevance as indicated by their correlations with circulating biomarkers.

Background: We hypothesized that the risk of colorectal cancer in night-shift workers might be different according to insulin receptor substrate status. Methods: Among 77,470 eligible women having night work assessed in the Nurses' Health Study, we documented a total of 1,397 colorectal cancer cases, of which 304 or 308 had available data on IRS1 and IRS2, respectively. We used duplication-method Cox proportional hazards regression analysis for competing risks to calculate HRs and 95% confidence intervals (CI) for each colorectal cancer subtype. We measured tumor IRS1 or IRS2 expression by immunohistochemistry (IHC). Results: Compared with women who never worked night shifts, those working ≥15 years night shifts had a marginal trend of increased overall risk of colorectal cancer (Ptrend = 0.06; multivariable HR = 1.20; 95% CI, 0.99–1.45). Longer duration of night-shift work was associated with a higher risk of IRS2-positive tumors (multivariable HR = 2.69; 95% CI, 1.48–4.89; Ptrend = 0.001, ≥15 years night shifts vs. never) but not with IRS2-negative tumors (multivariable HR = 0.90; 95% CI, 0.54–1.51; Ptrend = 0.72; Pheterogeneity for IRS2 = 0.008). Similarly, the corresponding multivariable HRs were 1.81 for IRS1-positive tumors (95% CI, 0.94–3.48; Ptrend = 0.06) and 1.13 for IRS1-negative tumors (95% CI, 0.71–1.80; Ptrend = 0.56; Pheterogeneity for IRS1 = 0.02). Conclusions: Our molecular pathologic epidemiology data suggest a potential role of IRS in mediating carcinogenesis induced by night-shift work. Impact: Although these findings need validation, rotating night shift might increase colorectal cancer risk in women with abnormal insulin receptor pathways.

Background Excess body weight is an established cause of postmenopausal breast cancer, but it is unknown if weight loss reduces risk. Methods Associations between weight change and risk of breast cancer were examined among women aged 50 years and older in the Pooling Project of Prospective Studies of Diet and Cancer. In 10 cohorts, weight assessed on three surveys was used to examine weight change patterns over approximately 10 years (interval 1 median = 5.2 years; interval 2 median = 4.0 years). Sustained weight loss was defined as no less than 2 kg lost in interval 1 that was not regained in interval 2. Among 180 885 women, 6930 invasive breast cancers were identified during follow-up. Results Compared with women with stable weight (±2 kg), women with sustained weight loss had a lower risk of breast cancer. This risk reduction was linear and specific to women not using postmenopausal hormones (>2–4.5 kg lost: hazard ratio [HR] = 0.82, 95% confidence interval [CI] = 0.70 to 0.96; >4.5– Conclusions These results suggest that sustained weight loss, even modest amounts, is associated with lower breast cancer risk for women aged 50 years and older. Breast cancer prevention may be a strong weight-loss motivator for the two-thirds of American women who are overweight or obese.

We conducted a prospective study of dietary patterns and longitudinal change in audiometric hearing thresholds among 3,135 women (mean age = 59 years) in the Nurses’ Health Study II (2012–2018). Diet adherence scores for the Dietary Approaches to Stop Hypertension (DASH) and Alternate Mediterranean (AMED) diets and the Alternate Healthy Eating Index 2010 (AHEI-2010) were calculated using validated food-frequency questionnaires. Baseline and 3-year follow-up hearing sensitivities were assessed by pure-tone audiometry at 19 US sites. We used multivariable-adjusted logistic regression models to examine independent associations between diet adherence scores and risk of ≥5 dB elevation in the pure-tone average (PTA) of low-frequency (LPTA0.5,1,2 kHz), mid-frequency (MPTA3,4 kHz), and high-frequency (HPTA6,8 kHz) hearing thresholds. Higher adherence scores were associated with lower risk of hearing loss. Compared with the lowest quintile of DASH score, the multivariable-adjusted odds ratios for mid-frequency and high-frequency threshold elevation in the highest quintile were 0.71 (95% confidence interval (CI): 0.55, 0.92; P for trend = 0.003) and 0.75 (95% CI: 0.59, 0.96; P for trend = 0.02); for AMED and AHEI scores, for mid-frequency threshold elevation, they were 0.77 (95% CI: 0.60, 0.99; P for trend = 0.02) and 0.72 (95% CI: 0.57, 0.92; P for trend = 0.002). Nonsignificant inverse associations were observed for high-frequency threshold elevation. There were no significant associations between adherence scores and low-frequency threshold elevation. Our findings indicate that eating a healthy diet might reduce the risk of acquired hearing loss.

Calcium intake has been associated with a lower risk of colorectal cancer. Calcium signaling may enhance T-cell proliferation and differentiation, and contribute to T-cell–mediated antitumor immunity. In this prospective cohort study, we investigated the association between calcium intake and colorectal cancer risk according to tumor immunity status to provide additional insights into the role of calcium in colorectal carcinogenesis. The densities of tumor-infiltrating T-cell subsets [CD3+, CD8+, CD45RO (PTPRC)+, or FOXP3+ cell] were assessed using IHC and computer-assisted image analysis in 736 cancer cases that developed among 136,249 individuals in two cohorts. HRs and 95% confidence intervals (CI) were calculated using Cox proportional hazards regression. Total calcium intake was associated with a multivariable HR of 0.55 (comparing ≥1,200 vs.

Objective Sustained hypertension is a major cause of heart failure in aging hypertensive patients. Salusin β, a novel bioactive peptide of 20 amino acids, has been reported to participate in various cardiovascular diseases, including hypertension. We therefore hypothesized that central knockdown of salusin β might be effective for hypertension-induced heart failure treatment. Methods and results Eighteen-month-old male aged spontaneously hypertensive rats (SHR) with heart failure and WKY rats were microinjected with either a specific adenoviral vector encoding salusin β shRNA (Ad-Sal-shRNA) or a scramble shRNA (Ad-Scr-shRNA) in the hypothalamic paraventricular nucleus (PVN) for 4 weeks. Radiotelemetry and echocardiography were used for measuring blood pressure and cardiac function, respectively. Blood samples and heart were harvested for evaluating plasma norepinephrine, tyrosine hydroxylase, and cardiac morphology, respectively. The mesenteric arteries were separated for measurement of vascular responses. The PVN was analyzed for salusin β, proinflammatory cytokines (PICs), mitogen-activated protein kinase (MAPK), NF-κB, and reactive oxygen species (ROS) levels. Compared with normotensive rats, aging SHR with heart failure had dramatically increased salusin β expression. Silencing salusin β with Ad-Sal-shRNA attenuated arterial pressure and improved autonomic function, cardiac and vascular dysfunction in aging SHR with heart failure, but not in aging WKY rats. Knockdown of salusin β significantly reduced paraventricular nucleus PICs levels, MAPK and NF-κB activity, and ROS levels in aging SHR with heart failure. Conclusion These data demonstrate that in aging SHR, the heart failure that was developed during the end stage of hypertension could be ameliorated by silencing salusin β.

Context The association between weight change and mortality among participants with incident type 2 diabetes (T2D) was unclear. Objective To examine above association and evaluate the impact of lifestyle on it. Methods This prospective analysis included 11 262 incident T2D patients from Nurses’ Health Study and Health Professionals Follow-up Study. We assessed weight change bracketing T2D diagnosis in relation to mortality. We also examined potential effect modification by a healthy lifestyle consisting of high-quality diet, regular physical activity, nonsmoking status, and moderate alcohol consumption. Results On average, T2D patients lost 2.3 kg during a 2-year time window spanning the T2D diagnosis, and body weight increased afterwards following a trajectory similar to that of nondiabetics. Compared with patients with a stable weight, T2D patients who lost ≥10% body weight had a 21% (95% CI, 9%-35%) increased all-cause mortality. Lifestyle significantly modified these associations: the hazard ratios (95% CIs) of all-cause mortality comparing ≥10% weight loss with stable weight were 1.63 (1.26-2.09) among participants with a deteriorated lifestyle, 1.27 (1.11-1.46) for a stable lifestyle, and 1.02 (0.81-1.27) for an improved lifestyle (Pinteraction < 0.001). Major weight loss was associated with increased cause-specific mortality and similar effect modifications by lifestyle were also observed. Conclusion Significant weight loss upon T2D incidence was associated with increased mortality, although improved lifestyle quality abolished these associations. These results highlight the role of adopting a healthy lifestyle for newly diagnosed T2D patients, especially among those who might lose weight unintentionally, and improving long-term survival.

Evidence regarding lignan consumption in relation to coronary heart disease (CHD) risk remains limited and mixed.The aim of this study was to prospectively examine associations between lignan intake and CHD risk in U.S. men and women.We prospectively followed 214,108 men and women in 3 cohorts who did not have cardiovascular disease or cancer at baseline. Diet was repeatedly assessed using a validated food frequency questionnaire every 2-4 years since baseline.During 5,517,225 person-years of follow-up, we documented 10,244 CHD cases, including 6,283 nonfatal myocardial infarction and 3,961 fatal CHD cases. In multivariable-adjusted analyses, comparing extreme quintiles, the pooled hazard ratios of CHD were 0.85 (95% CI: 0.79-0.92) for total lignans, 0.76 (95% CI: 0.71-0.82) for matairesinol, 0.87 (95% CI: 0.81-0.93) for secoisolariciresinol, 0.89 (95% CI: 0.83-0.95) for pinoresinol, and 0.89 (95% CI: 0.83-0.95) for lariciresinol (all P values for trend ≤0.003). Nonlinear relationships were found for total lignan, matairesinol, and secoisolariciresinol: the risk reduction plateaued at intakes above approximately 300 μg/d, 10 μg/d, and 100 μg/d, respectively (P 0.01 for all nonlinearity). The inverse associations for total lignan intake appeared to be more apparent among participants with higher total fiber intake (P = 0.04 for interaction). In addition, lignan intake was more strongly associated with plasma concentrations of enterolactone when fiber intake was higher.Increased long-term intake of lignans was associated with a significantly lower risk of total CHD in both men and women. Possible synergistic effects may exist between lignan and fiber intake in relation to CHD risk reduction, possibly through enhancing the production of enterolignans.

Background Biological evidence indicates that smoking can influence macrophage functions and polarization, thereby promoting tumor evolution. We hypothesized that the association of smoking with colorectal cancer incidence might differ by macrophage infiltrates. Methods Using the Nurses’ Health Study and the Health Professionals Follow-up Study, we examined the association of smoking with incidence of colorectal cancer subclassified by macrophage counts. Multiplexed immunofluorescence (for CD68, CD86, IRF5, MAF, and MRC1 [CD206]) combined with digital image analysis and machine learning was used to identify overall, M1-polarized, and M2-polarized macrophages in tumor. We used inverse-probability–weighted multivariable Cox proportional hazards regression models to control for potential confounders and selection bias because of tissue data availability. All statistical tests were 2-sided. Results During follow-up of 131 144 participants (3 648 370 person-years), we documented 3092 incident colorectal cancer cases, including 871 cases with available macrophage data. The association of pack-years smoked with colorectal cancer incidence differed by stromal macrophage densities (Pheterogeneity = .003). Compared with never smoking, multivariable-adjusted hazard ratios (95% confidence interval) for tumors with low macrophage densities were 1.32 (0.97 to 1.79) for 1-19 pack-years, 1.31 (0.92 to 1.85) for 20-39 pack-years, and 1.74 (1.26 to 2.41) for 40 or more pack-years (Ptrend = .004). In contrast, pack-years smoked was not statistically significantly associated with the incidence of tumors having intermediate or high macrophage densities (Ptrend > .009, with an α level of .005). No statistically significant differential association was found for colorectal cancer subclassified by M1-like or M2-like macrophages. Conclusions The association of smoking with colorectal cancer incidence is stronger for tumors with lower stromal macrophage counts. Our findings suggest an interplay of smoking and macrophages in colorectal carcinogenesis.

BACKGROUND & AIMS: Vitamin D has been implicated in colorectal cancer (CRC) pathogenesis, but it remains unknown whether total vitamin D intake is associated with early-onset CRC and precursors diagnosed before age 50. METHODS: We prospectively examined the association between total vitamin D intake and risks of early-onset CRC and precursors among women enrolled in the Nurses’ Health Study II. Multivariable-adjusted hazard ratio (HR) and 95% confidence interval (CI) for early-onset CRC were estimated with Cox proportional hazards model. Multivariable-adjusted odds ratio (OR) and 95% CI for early-onset conventional adenoma and serrated polyp were estimated with logistic regression model. RESULTS: We documented 111 incident cases of early-onset CRC during 1,250,560 person-years of follow-up (1991 to 2015). Higher total vitamin D intake was significantly associated with a reduced risk of early-onset CRC (HR for ≥450 IU/day vs

Tissue microarrays (TMAs) have been used in thousands of cancer biomarker studies. To what extent batch effects, measurement error in biomarker levels between slides, affects TMA-based studies has not been assessed systematically. We evaluated 20 protein biomarkers on 14 TMAs with prospectively collected tumor tissue from 1,448 primary prostate cancers. In half of the biomarkers, more than 10% of biomarker variance was attributable to between-TMA differences (range, 1–48%). We implemented different methods to mitigate batch effects (R package batchtma), tested in plasmode simulation. Biomarker levels were more similar between mitigation approaches compared to uncorrected values. For some biomarkers, associations with clinical features changed substantially after addressing batch effects. Batch effects and resulting bias are not an error of an individual study but an inherent feature of TMA-based protein biomarker studies. They always need to be considered during study design and addressed analytically in studies using more than one TMA.

Introduction: Identifying strategies to mitigate gradual long-term weight gain is critical for preventing obesity and its related chronic diseases, particularly for persons at high risk, such as women with a history of gestational diabetes mellitus (GDM). We prospectively examined the independent associations between lifestyle changes in mid-life with long-term weight change among women with and without a history of GDM. Hypothesis: We hypothesized that favorable improvements in lifestyle would be associated with less long-term weight gain, particularly among women with a history of GDM. Methods: We used data from the longitudinal Nurses’ Health Study II, with self-reported lifestyle, diet via food frequency questionnaire, and body weight updated every 2-4 years. We analyzed repeated 4-year changes of the following lifestyle factors among parous women after age 40: adherence to a healthy dietary pattern (Alternate Healthy Eating Index score [AHEI]), physical activity (MET-hrs/wk), moderate alcohol intake (servings/d), and non-smoking, in relation to concurrent 4-year change in body weight (lb). We used multivariable generalized estimating equation models to estimate the least-squares mean of 4-year weight change and 95% confidence interval (CI) for each lifestyle change category (e.g., decrease, remain stable, and increase). Results: Our analysis included 61,637 women, of which 3,444 (5.6%) had a history of GDM. Mean of repeated 4-year weight change after age 40 was 3.0 lb (SD=14.3). Improving diet was associated with favorable 4-year weight change, particularly among women with a history of GDM vs. without GDM (AHEI score change from low to high: -6.3 lb [CI: -9.3, -3.4] vs. -2.7 lb [CI: -3.2, -2.2], respectively; p-interaction=0.04). Increasing physical activity was associated with weight maintenance for GDM women only (MET-hrs/wk change from low to high: 0.6 lb [95% CI: -0.6, 1.7] vs. 2.0 lb [95% CI: 1.8, 2.2] for GDM vs. non-GDM, respectively; p-interaction=0.01). Reducing alcohol (decreased servings/d: 1.9 lb [95% CI: 1.2, 2.6] and 2.8 lb [95% CI: 2.6, 2.9] for GDM vs. non-GDM, respectively) and smoking cessation (recent quitter: 9.8 lb [95% CI: 7.1, 12.5] and 8.5 lb [95% CI: 8.0, 9.1] for GDM vs. non-GDM, respectively) were associated with similar patterns in weight change for women with and without prior GDM. Further, the joint association of improving both diet and physical activity from low to high was related to -12.3 lb (95% CI: -19.5, -5.0) and -6.1 lb (95% CI: -8.0, -4.2) of weight loss for GDM vs. non-GDM women, respectively. Conclusions: We observed that attainable improvements in diet quality and physical activity were associated with weight gain prevention. These findings support continued efforts to improve lifestyle as a beneficial strategy to prevent long-term weight gain, particularly among women with a history of GDM.

Background: Red and processed meat intake have been associated with higher risk of fatal coronary heart disease (CHD). However, very few studies have evaluated substitution of alternative protein sources for red and processed meat in relation to fatal CHD risk. Objective: We estimated the associations of substituting other animal and plant protein sources for total red meat, unprocessed red meat, and processed meat in relation to risk of fatal CHD. Methods: This pooled analysis was conducted within the Pooling Project of Prospective Studies of Diet and Cancer and included participants with no prior self-reported history of cardiovascular diseases or cancer. Diet was assessed by cohort-specific food frequency questionnaires collected at baseline. Total red meat included processed meat and unprocessed red meat. Animal protein sources included seafood, poultry, eggs, and low- and high-fat dairy products; plant protein sources included nuts and beans. After adjusting for dietary and non-dietary factors, study-specific relative risks (RR) and 95% confidence intervals (CI) were calculated using Cox proportional hazard models and then pooled using a random effects model. Isocaloric dietary substitution was evaluated by differences in coefficients in models including red meat and all alternative protein sources described above as continuous variables. Results: In preliminary analyses of 16 prospective cohorts including 1,364,211 participants (40% men and mean age of 57 ± 10 years) followed for a maximum of 32 years across studies, we identified 51,176 fatal CHD cases. A 100g/day increment in total red meat intake was associated with a 7% higher risk of fatal CHD, RR=1.07 (95% CI 1.04, 1.10). Substitutions of 200 kcal/day from nuts, low- and high-fat dairy products, and poultry for 200 kcal/d from total red meat were associated with 6-14% lower risks of fatal CHD. These associations were stronger when substituting the alternative protein sources for processed meat, especially among women (n=14,888 cases, 17-24% lower risk). Substituting 200 kcal/day from eggs for 200 kcal/day from total red meat and unprocessed red meat was associated with 8 and 14% higher risk of fatal CHD, respectively; this substitution for processed meat was weaker and not significant (4%). Results were similar after excluding the first 4 years of follow-up. Conclusions: Preliminary results from this international pooled analysis of 16 cohort studies provide more evidence about the risks of red and processed meat consumption. Replacement of red and processed meat with nuts, dairy products, or poultry may reduce the risk of fatal CHD.

Estrogen receptor-α36 (ER-α36), a subtype of the estrogen receptor, is reported to play roles in tumorigenesis and tamoxifen resistance in several tumors, especially breast cancer. However, the role of ER-α36 in glioma proliferation and invasion remains unknown. Here, we explored the function of ER-α36 in glioma cells, using U87 and U251 cell lines. We found that ER-α36 was upregulated in glioma tissues compared to adjacent nontumor tissues. In U87 and U251 glioma cell lines, inhibition of ER-α36 expression by shRNA suppressed cell proliferation and invasion. In addition, the expression of an epithelial marker, ZO-1, was upregulated while that of one mesenchymal marker, N-cadherin, was downregulated with ER-α36 knockdown. We also found that inhibition of ER-α36 inactivated both PI3K/AKT and MEK/ERK signals. Taken together, these data indicated that overexpression of ER-α36 is associated with glioma proliferation and progression but that inhibition of ER-α36 leads to suppressed invasion and the epithelial-to-mesenchymal transition via PI3K/AKT and MEK/ERK pathway inactivation in glioma cells.

Hongying Shi,1,2 Tianyi Huang,3,4 Yanan Ma,5 A Heather Eliassen,2,3 Qi Sun,2– 4 Molin Wang2,3,6 1Department of Epidemiology and Health Statistics, School of Public Health and Management, Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 2Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; 3Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA; 4Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA; 5Department of Biostatistics and Epidemiology, School of Public Health, China Medical University, Shenyang, Liaoning, People’s Republic of China; 6Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USACorrespondence: Molin WangDepartment of Epidemiology, Harvard T.H. Chan School of Public Health, 665 Huntington Avenue, Boston, MA, 02115, USATel +1 617 525 2202Email mwang@hsph.harvard.eduQi SunDepartment of Nutrition, Harvard T.H. Chan School of Public Health, 665 Huntington Avenue, Boston, MA, 02115, USATel +1 617 432 7490Email qisun@hsph.harvard.eduPurpose: Both short and long sleep durations are associated with higher mortality. This study examined the association between sleep duration and overall health among those who survive to older ages.Participants and Methods: In the Nurses’ Health Study, participants without major chronic diseases in 1986 and survived to age 70 years or older in 1995– 2001 were included. Habitual sleep duration and snoring were self-reported in 1986. Healthy aging was defined as being free of 11 major chronic diseases and having no cognitive impairment, physical impairment, or mental health limitations. Logistic regression was used to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) for healthy aging.Results: Of the 12,304 participants, 1354 (11.0%) achieved healthy aging. We observed a non-linear association between sleep duration and the odds of achieving healthy aging. Compared with women sleeping 7 hours per day, women with longer sleep duration were less likely to achieve healthy aging; there was also a suggestion of lower odds of healthy aging for shorter sleepers, although the associations did not reach statistical significance: the multivariate-adjusted ORs (95% CIs) of healthy aging for those sleeping ≤ 5, 6, 8, and ≥ 9 hours were 0.94 (0.70, 1.27), 0.88 (0.76, 1.02), 0.83 (0.72, 0.96), and 0.60 (0.43, 0.84), respectively. Similar non-linear associations were consistently observed for individual dimensions of healthy aging. Regular snoring was associated with 31% lower odds of healthy aging (95% CI: 0.54, 0.88), which was primarily due to lower odds of having no major chronic diseases.Conclusion: Both short and long sleep durations as well as regular snoring at midlife were associated with lower odds of healthy aging in later life.Keywords: sleep, healthy aging, prospective studies, Nurses’ Health Study, snoring

Despite heightened interest in early-onset colorectal cancer (CRC) diagnosed before age 50, little is known on immune cell profiles of early-onset CRC. It also remains to be studied whether CRCs diagnosed at or shortly after age 50 are similar to early-onset CRC. We therefore hypothesized that immune cell infiltrates in CRC tissue might show differential heterogeneity patterns between three age groups (

Tamoxifen (TAM) resistance is a significant clinical challenge in endocrine therapies for estrogen receptor (ER)-positive breast cancer patients. Cullin 4B (CUL4B), which acts as a scaffold protein in CUL4B-RING ubiquitin ligase complexes (CRL4B), is frequently overexpressed in cancer and represses tumor suppressors through diverse epigenetic mechanisms. However, the role and the underlying mechanisms of CUL4B in regulating drug resistance remain unknown. Here, we showed that CUL4B promotes TAM resistance in breast cancer cells through a miR-32-5p/ER-α36 axis. We found that upregulation of CUL4B correlated with decreased TAM sensitivity of breast cancer cells, and knockdown of CUL4B or expression of a dominant-negative CUL4B mutant restored the response to TAM in TAM-resistant MCF7-TAMR and T47D-TAMR cells. Mechanistically, we demonstrated that CUL4B renders breast cancer cells TAM-resistant by upregulating ER-α36 expression, which was mediated by downregulation of miR-32-5p. We further showed that CRL4B epigenetically represses the transcription of miR-32-5p by catalyzing monoubiquitination at H2AK119 and coordinating with PRC2 and HDAC complexes to promote trimethylation at H3K27 at the promoter of miR-32-5p. Pharmacologic or genetic inhibition of CRL4B/PRC2/HDAC complexes significantly increased TAM sensitivity in breast cancer cells in vitro and in vivo. Taken together, our findings thus establish a critical role for the CUL4B-miR-32-5p-ER-α36 axis in the regulation of TAM resistance and have important therapeutic implications for combined application of TAM and the inhibitors of CRL4B/PRC2/HDAC complex in breast cancer treatment. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Objectives Tinnitus and hearing loss commonly coexist, however, the temporal relation between tinnitus and hearing loss is complex and not fully understood. Our objective was to examine the longitudinal association between persistent tinnitus, bothersome tinnitus, and 3-year elevation of audiometric hearing thresholds. Design We conducted a longitudinal cohort study among 3106 women (mean age 59 years) who were participants in the Nurses' Health Study II (2012-2018). Information on tinnitus was obtained from biennial questionnaires. Longitudinal changes in air conduction thresholds (0.5 to 8 kHz) were assessed by pure-tone audiometry conducted by licensed audiologists at 19 audiology testing sites across the United States. Logistic regression was used to estimate multivariable-adjusted odds ratios (MVORs, 95% confidence interval [CI]) and evaluate the relations of persistent tinnitus (several days per week or more), bothersome tinnitus (interferes with work, sleep, or daily activities), and risk of 3-year elevation of hearing thresholds. Results Persistent tinnitus was associated with higher risk of 3-year elevation of hearing thresholds across a broad range of frequencies. Compared with women without tinnitus, the MVORs (95% CI) for ≥5-dB threshold elevation among women with persistent tinnitus were 1.01 (0.81, 1.25) at 0.5 kHz, 1.45 (1.17, 1.81) at 1 kHz, 1.25 (1.00, 1.56) at 2 kHz, 1.34 (1.07, 1.69) at 3 kHz, 1.34 (1.06, 1.70) at 4 kHz, 1.49 (1.16, 1.91) at 6 kHz, and 1.63 (1.25, 2.12) at 8 kHz. The magnitudes of the associations for ≥10-dB threshold elevation were similar. The magnitudes of the associations were substantially greater among women with bothersome tinnitus. For example, compared with women without tinnitus, the MVORs (95% CI) for a ≥5- and ≥10-dB elevation of hearing thresholds at 4 kHz were 2.97 (1.50, 5.89) and 2.79 (1.38, 5.65), respectively. The risk was elevated even among women with tinnitus who had clinically normal hearing thresholds at baseline. In analyses that examined the association of tinnitus and elevation of low-, mid- and high-frequency pure-tone average (PTA) hearing thresholds, the results were similar. Compared with women without tinnitus, the MVORs (95% CI) for ≥5-dB PTA elevation among women with persistent tinnitus were 1.29 (0.99,1.67) for LPTA(0.5,1,2 kHz); 1.44 (1.16, 1.78) for MPTA(3,4 kHz); and 1.38 (1.11, 1.71) for HPTA(6,8 kHz). For ≥10-dB elevation, the MVORs were 2.85 (1.55, 5.23), 1.52 (1.10, 2.09), and 1.41 (1.10, 1.82), respectively. Conclusion Persistent tinnitus was associated with substantially higher risk of 3-year hearing threshold elevation, even among women with clinically normal baseline hearing. The magnitudes of the associations were greater among those with bothersome tinnitus. Monitoring hearing sensitivities may be indicated in patients with tinnitus, including those without audiometric evidence of hearing impairment.

Immunotherapy targeting the CD274 (PD-L1)/PDCD1 (PD-1) immune checkpoint axis has emerged as a promising treatment strategy for various cancers. Experimental evidence suggests that phosphatidylinositol-4,5-bisphosphonate 3-kinase (PI3K) signaling may upregulate CD274 expression. Thus, we hypothesized that PIK3CA mutation, PTEN loss, or their combined status might be associated with CD274 overexpression in colorectal carcinoma. We assessed tumor CD274 and PTEN expression by immunohistochemistry and assessed PIK3CA mutation by pyrosequencing in 753 patients among 4,465 incident rectal and colon cancer cases that had occurred in two U.S.-wide prospective cohort studies. To adjust for potential confounders and selection bias due to tissue availability, inverse probability weighted multivariable ordinal logistic regression analyses used the 4,465 cases and tumoral data including microsatellite instability, CpG island methylator phenotype, KRAS and BRAF mutations. PIK3CA mutation and loss of PTEN expression were detected in 111 of 753 cases (15%) and 342 of 585 cases (58%), respectively. Tumor CD274 expression was negative in 306 (41%), low in 195 (26%), and high in 252 (33%) of 753 cases. PTEN loss was associated with CD274 overexpression [multivariable odds ratio (OR) 1.83; 95% confidence interval (CI), 1.22–2.75; P = .004]. PIK3CA mutation was statistically-insignificantly (P = .036 with the stringent alpha level of 0.005) associated with CD274 overexpression (multivariable OR, 1.54; 95% CI, 1.03–2.31). PIK3CA-mutated PTEN-lost tumors (n = 33) showed higher prevalence of CD274-positivity (82%) than PIK3CA-wild-type PTEN-lost tumors (n = 204; 70% CD274-positivity) and PTEN-expressed tumors (n = 147; 50% CD274-positivity) (P = .003). Our findings support the role of PI3K signaling in the CD274/PDCD1 pathway.