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Background and Purpose: Previous studies have shown that physical inactivity and obesity are risk factors for the development of colorectal cancer. However, controversy exists regarding the influence of these factors on survival in colorectal cancer patients. We evaluated the impact of recreational physical activity and body mass index (BMI) before and after colorectal cancer diagnosis on disease-specific mortality and all-cause mortality.Patients and Methods: This prospective cohort study included 1,339 women enrolled in the Women's Health Initiative study who were diagnosed with colorectal cancer subsequent to study enrollment. BMI and recreational physical activity were measured before cancer diagnosis at study entry (pre-diagnostic) and after diagnosis at study follow-up interviews (post-diagnostic). We used Cox regression to estimate the association between pre- and post-diagnostic exposures and survival after colorectal cancer diagnosis.Results: Among women diagnosed with colorectal cancer, 265 (13 %) deaths occurred during a median study follow-up of 11.9 years, of which 171 (65 %) were attributed to colorectal cancer. Compared with women reporting no pre-diagnostic recreational physical activity, those reporting activity levels of ≥18 MET-h/week had significantly lower colorectal cancer-specific mortality (hazard ratio (HR) = 0.68; 95 % confidence interval (CI): 0.41-1.13) and all-cause mortality (HR = 0.63; 95 % CI: 0.42-0.96). Similar inverse associations were seen for post-diagnostic recreational physical activity. Neither pre- nor post-diagnostic BMI were associated with mortality after colorectal cancer diagnosis.Conclusion: Recreational physical activity before and after colorectal cancer diagnosis, but not BMI, is associated with more favorable survival. [ABSTRACT FROM AUTHOR]

Background: To develop a positive aging phenotype, we undertook analyses to describe multiple dimensions of positive aging and their relationships to one another in women 65 years of age and older and evaluate the performance of individual indicators and composite factors of this phenotype as predictors of time to death, years of healthy living, and years of independent living.Methods: Data from Women's Health Initiative clinical trial and observational study participants ages 65 years and older at baseline, including follow-up observations up to 8 years later, were analyzed using descriptive statistics and principal components analysis to identify the factor structure of a positive aging phenotype. The factors were used to predict time to death, years of healthy living (without hospitalization or diagnosis of a serious health condition), and years of independent living (without nursing home admission or use of special services).Results: We identified a multidimensional phenotype of positive aging that included two factors: Physical-Social Functioning and Emotional Functioning. Both factors were predictive of each of the outcomes, but Physical-Social Functioning was the strongest predictor. Each standard deviation of increase in Physical-Social Functioning was accompanied by a 23.7% reduction in mortality risk, a 19.4% reduction in risk of major health conditions or hospitalizations, and a 26.3% reduction in risk of dependent living.Conclusions: Physical-Social Functioning and Emotional Functioning constitute important components of a positive aging phenotype. Physical-Social Functioning was the strongest predictor of outcomes related to positive aging, including years of healthy living, years of independent living, and time to mortality. [ABSTRACT FROM AUTHOR]

Background: Endogenous sex hormone levels are associated with risks of breast cancer overall and estrogen receptor (ER)-positive breast tumors; however, their associations with ER-negative tumors remain unclear.Methods: In a case-cohort study within the Women's Health Initiative Observational Study among postmenopausal women aged 50-79 years, we examined associations between endogenous testosterone and estradiol levels and the risks of ER-negative and ER-positive breast cancers. Serum levels of bioavailable testosterone and estradiol were assessed at the baseline visit in 317 invasive breast cancer case subjects and in a subcohort of 594 women. Bioavailable sex hormone levels were calculated using the total hormone level and the sex hormone-binding globulin concentration (measured by radioimmunoassays and a chemiluminescent immunoassay, respectively). Cox proportional hazards regression was used for statistical analysis. All statistical tests were two-sided.Result: The unadjusted absolute rates of ER-negative breast cancer for testosterone quartiles 1-4 were 0.34, 0.20, 0.23, and 0.21 per 10,000 person-years, respectively. Compared with women in the lowest quartile of testosterone level, those in quartile 2 had a 56% lower risk of ER-negative cancer (hazard ratio [HR] = 0.44, 95% confidence interval [CI] = 0.23 to 0.85), those in quartile 3 had a 45% lower risk (HR = 0.55, 95% CI = 0.30 to 1.01), and those in quartile 4 had a 49% lower risk (HR = 0.51, 95% CI = 0.28 to 0.94), independent of other risk factors. Estradiol level was not associated with ER-negative breast cancer. ER-positive breast cancer risk increased with higher testosterone levels (P(trend) = .04), but this trend was not statistically significant after adjustment for estradiol (P(trend) = .15). ER-positive cancer risk was approximately twofold higher in women with estradiol levels in quartiles 2-4 compared with women in quartile 1, independent of risk factors.Conclusion: Higher serum levels of bioavailable testosterone are associated with lower risks of ER-negative breast cancer in postmenopausal women. [ABSTRACT FROM AUTHOR]

Background: Cognitive function and physical performance are associated, but the common sequence of cognitive and physical decline remains unclear.Methods: In the Women's Health Initiative Memory Study (WHIMS) clinical trial, we examined associations at baseline and over a 6-year follow-up period between the Modified Mini-Mental State (3MS) Examination and three physical performance measures (PPMs): gait speed (meters/second), chair stands (number of stands in 15 seconds), and grip strength (kilograms). Using mixed models, we examined the baseline 3MS as predictor of change in PPM, change in the 3MS as predictor of change in PPM, and baseline PPM as predictors of 3MS change.Results: Among 1,793 women (mean age = 70.3 years, 89% white, and mean 3MS score = 95.1), PPM were weakly correlated with 3MS-gait speed: r = .06, p = .02; chair stands: r = .09, p < .001; and grip strength: r = .10, p < .001. Baseline 3MS score was associated with subsequent PPM decline after adjustment for demographics, comorbid conditions, medications, and lifestyle factors. For every SD (4.2 points) higher 3MS score, 0.04 SD (0.04 m/s) less gait speed and 0.05 SD (0.29 kg) less grip strength decline is expected over 6 years (p Conclusions: Baseline global cognitive function and change in global cognitive function were associated with physical performance change, but baseline physical performance was not associated with cognitive change in this cohort. These analyses support the hypothesis that cognitive decline on average precedes or co-occurs with physical performance decline. [ABSTRACT FROM AUTHOR]

Context: The Women's Health Initiative Memory Study (WHIMS) previously found increased risk for dementia and no effect on mild cognitive impairment (MCI) in women treated with conjugated equine estrogens (CEE) plus medroxyprogesterone acetate (MPA).Objective: To determine the effects of CEE alone and CEE plus MPA on incidence of probable dementia and MCI in older women.Design, Setting, and Participants: Randomized, double-blind, placebo-controlled clinical trials of CEE (estrogen-alone trial) or CEE plus MPA (estrogen plus progestin trial) in community-dwelling women aged 65 to 79 years, conducted from June 1995 to July 8, 2002 (estrogen plus progestin; n = 4532), or to February 29, 2004 (estrogen-alone; n = 2947), in 39 of the 40 WHI clinical centers.Interventions: In the estrogen-alone trial, 1 daily tablet containing either 0.625 mg/d of CEE vs matching placebo; in the estrogen plus progestin trial, 1 daily tablet containing CEE (0.625 mg/d) plus MPA (2.5 mg/d) vs matching placebos.Main Outcome Measures: Probable dementia and MCI.Results: In the estrogen-alone trial, 47 participants were diagnosed with probable dementia, of whom 28 were assigned to CEE and 19 to placebo (hazard ratio [HR], 1.49; 95% confidence interval [CI], 0.83-2.66). Incidence rates for probable dementia in the estrogen-alone trial were statistically similar to those in the estrogen plus progestin trial (45 vs 22 per 10 000 person-years for CEE plus MPA vs placebo, respectively; P =.11). When data were pooled per the original WHIMS protocol, the overall HR for probable dementia was 1.76 (95% CI, 1.19-2.60; P =.005). After excluding participants with baseline Modified Mini-Mental State Examination scores at or below the screening cut point, the HR was 1.77 (95% CI, 0.74-4.23; P =.20) in the estrogen-alone trial and 2.19 (95% CI, 1.25-3.84; P =.006) in the pooled trials. In the estrogen-alone trial, 76 participants were diagnosed with MCI in the CEE group vs 58 in the placebo group (HR, 1.34; 95% CI, 0.95-1.89). In the combined trial data, the HR was similar (1.25; 95% CI, 0.97-1.60). In the estrogen-alone trial, 93 participants receiving CEE were diagnosed with either probable dementia or MCI vs 69 receiving placebo (HR, 1.38; 95% CI, 1.01-1.89; P =.04).Conclusions: Estrogen therapy alone did not reduce dementia or MCI incidence and increased the risk for both end points combined. Pooling data for estrogen alone and estrogen plus progestin resulted in increased risks for both end points. Use of hormone therapy to prevent dementia or cognitive decline in women 65 years of age or older is not recommended. [ABSTRACT FROM AUTHOR]

Understanding risk perceptions for breast cancer among women smokers is important because smokers tend to underutilize breast cancer screening. Perceptions of the relative importance of a variety of factors which may increase breast cancer risk and the benefits/barriers of mammography, were examined among women who were current (n = 185), ex- (n = 632) and never (n = 623) smokers. Participants were a subset of women taking part in a project to increase mammography utilization among women aged 50 and over. Current smokers, but not ex-smokers, were significantly less likely than never smokers to agree that health risk behaviors most frequently seen in smokers (e.g., smoking cigarettes, high-fat diet, low intake of fruits and vegetables, physical inactivity, drinking alcohol) may increase risk for breast cancer. Current smokers, but not ex-smokers, perceived more barriers and fewer benefits of mammography, than never smokers. [ABSTRACT FROM AUTHOR]

Objective. To describe the outcomes of breast biopsy recommendations for women screened through a mobile mammography van. Methods. Data on all women screened through the Mobile Mammography Program in Suffolk County, Long Island, NY, from 1990 to 1994 were analyzed to determine biopsy recommendation rates, biopsy rates, positive biopsy rates, and cancer detection rates. Follow-up information was obtained from the women's physicians. Results. The breast cancer detection rate for women screened through the Mobile Mammography Program averaged 0.33% over a five-year period. The biopsy recommendation rate based on abnormal mammograms remained stable, at about 1% to 2%, over a five-year period, as did the rate of positive biopsies among women having biopsies (36.8% to 44.4%). For women ages 50 and older, the cancer rate in 1994 was 0.36%, while for women younger than age 50, the cancer rate was 0.25% (0.32% for all ages). Conclusions. These findings show that a breast cancer screening program using a mobile van can have comparable cancer detection rates to national figures and a fairly stable biopsy recommendation rate from which follow-up resource needs can be estimated. [ABSTRACT FROM AUTHOR]

Purpose: Menopausal hormone therapy's influence on ovarian and endometrial cancers remains unsettled. Therefore, we assessed the long-term influence of conjugated equine estrogen (CEE) plus medroxyprogesterone acetate (MPA) and CEE-alone on ovarian and endometrial cancer incidence and mortality in the Women's Health Initiative randomized, placebo-controlled clinical trials., Materials and Methods: Postmenopausal women, age 50-79 years, were entered on two randomized clinical trials evaluating different menopausal hormone therapy regimens. In 16,608 women with a uterus, 8,506 were randomly assigned to once daily 0.625 mg of CEE plus 2.5 mg once daily of MPA and 8,102 placebo. In 10,739 women with previous hysterectomy, 5,310 were randomly assigned to once daily 0.625 mg of CEE-alone and 5,429 placebo. Intervention was stopped for cause before planned 8.5-year intervention after 5.6 years (CEE plus MPA) and after 7.2 years (CEE-alone). Outcomes include incidence and mortality from ovarian and endometrial cancers and deaths after these cancers., Results: After 20-year follow-up, CEE-alone, versus placebo, significantly increased ovarian cancer incidence (35 cases [0.041%] v 17 [0.020%]; hazard ratio [HR], 2.04 [95% CI, 1.14 to 3.65]; P = .014) and ovarian cancer mortality ( P = .006). By contrast, CEE plus MPA, versus placebo, did not increase ovarian cancer incidence (75 cases [0.051%] v 63 [0.045%]; HR, 1.14 [95% CI, 0.82 to 1.59]; P = .44) or ovarian cancer mortality but did significantly lower endometrial cancer incidence (106 cases [0.073%] v 140 [0.10%]; HR, 0.72 [95% CI, 0.56 to 0.92]; P = .01)., Conclusion: In randomized clinical trials, CEE-alone increased ovarian cancer incidence and ovarian cancer mortality, while CEE plus MPA did not. By contrast, CEE plus MPA significantly reduced endometrial cancer incidence.

Background: While the Breast Cancer Risk Assessment Tool (BCRAT) predicts breast cancer incidence, the model's performance, re-purposed to predict breast cancer mortality, is uncertain. Therefore, we examined whether the BCRAT model predicts breast cancer mortality in postmenopausal women in the Women's Health Initiative (WHI)., Methods: BCRAT 5-year breast cancer incidence risk estimates were calculated for 145,408 women (aged 50-79 years) enrolled in the WHI at 40 US clinical centers to examine associations of BCRAT risk groups (< 1%, 1-< 3%, ≥ 3%) with breast cancer mortality using Cox proportional regression modeling in all participants and in those with incident breast cancer., Results: Women with BCRAT ≥ 3% risk, compared to women with BCRAT < 1% risk, were older (age 70-79 years: 38.3% versus 5.3%), less commonly Black (1.1% versus 40.2%), and had stronger breast cancer family history. With 20-years follow-up, considering all participants, with 8,849 breast cancers and 1,076 breast cancer deaths, breast cancer mortality in BCRAT group ≥ 3% was not higher versus BCRAT group < 1% (Hazard Ratio [HR] 1.06 95% Confidence Interval [CI] 0.80-1.40): percent without 20-year breast cancer mortality; 99.4% [group < 1%] and 98.8% [group ≥ 3%]. Considering women with incident breast cancer, breast cancer mortality was also not higher in BCRAT group ≥ 3% versus BCRAT group < 1% (HR 1.07 95% CI 0.79-1.45)., Conclusions: The BCRAT model, at ≥ 3% 5-year incidence risk (US guideline threshold for chemoprevention), does not identify women with higher breast cancer mortality risk, with implications for breast cancer prevention strategies., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Although infertility (i.e., failure to conceive after ≥ 12 months of trying) is strongly correlated with established breast cancer risk factors (e.g., nulliparity, number of pregnancies, and age at first pregnancy), its association with breast cancer incidence is not fully understood. Previous studies were primarily small clinic-based or registry studies with short follow-up and predominantly focused on premenopausal breast cancer. The objective of this study was to assess the relationship between infertility and postmenopausal breast cancer risk among participants in the Women's Health Initiative (analytic sample = 131,784; > 25 years of follow-up)., Methods: At study entry, participants were asked about their pregnancy history, infertility history, and diagnosed reasons for infertility. Incident breast cancers were self-reported with adjudication by trained physicians reviewing medical records. Cox proportional hazards models were used to estimate risk of incident postmenopausal breast cancer for women with infertility (overall and specific infertility diagnoses) compared to parous women with no history of infertility. We examined mediation of these associations by parity, age at first term pregnancy, postmenopausal hormone therapy use at baseline, age at menopause, breastfeeding, and oophorectomy., Results: We observed a modest association between infertility (n = 23,406) and risk of postmenopausal breast cancer (HR = 1.07; 95% CI 1.02-1.13). The association was largely mediated by age at first term pregnancy (natural indirect effect: 46.4% mediated, CI 12.2-84.3%)., Conclusion: These findings suggest that infertility may be modestly associated with future risk of postmenopausal breast cancer due to age at first pregnancy and highlight the importance of incorporating reproductive history across the life course into breast cancer analyses., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Although calcium and vitamin D (CaD) supplementation may affect chronic disease in older women, evidence of long-term effects on health outcomes is limited., Objective: To evaluate long-term health outcomes among postmenopausal women in the Women's Health Initiative CaD trial., Design: Post hoc analysis of long-term postintervention follow-up of the 7-year randomized intervention trial of CaD. (ClinicalTrials.gov: NCT00000611)., Setting: A multicenter ( n = 40) trial across the United States., Participants: 36 282 postmenopausal women with no history of breast or colorectal cancer., Intervention: Random 1:1 assignment to 1000 mg of calcium carbonate (400 mg of elemental calcium) with 400 IU of vitamin D 3 daily or placebo., Measurements: Incidence of colorectal, invasive breast, and total cancer; disease-specific and all-cause mortality; total cardiovascular disease (CVD); and hip fracture by randomization assignment (through December 2020). Analyses were stratified on personal supplement use., Results: For women randomly assigned to CaD versus placebo, a 7% reduction in cancer mortality was observed after a median cumulative follow-up of 22.3 years (1817 vs. 1943 deaths; hazard ratio [HR], 0.93 [95% CI, 0.87 to 0.99]), along with a 6% increase in CVD mortality (2621 vs. 2420 deaths; HR, 1.06 [CI, 1.01 to 1.12]). There was no overall effect on other measures, including all-cause mortality (7834 vs. 7748 deaths; HR, 1.00 [CI, 0.97 to 1.03]). Estimates for cancer incidence varied widely when stratified by whether participants reported supplement use before randomization, whereas estimates on mortality did not vary, except for CVD mortality., Limitation: Hip fracture and CVD outcomes were available on only a subset of participants, and effects of calcium versus vitamin D versus joint supplementation could not be disentangled., Conclusion: Calcium and vitamin D supplements seemed to reduce cancer mortality and increase CVD mortality after more than 20 years of follow-up among postmenopausal women, with no effect on all-cause mortality., Primary Funding Source: National Heart, Lung, and Blood Institute of the National Institutes of Health., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M23-2598.

Although cancer has been the second leading cause of death for close to 100 years, progress has been made in reducing cancer mortality and morbidity, with the adoption of high-quality screening tests and treatment advances delivered at earlier stages of diagnosis. To achieve the high cancer screening rates demonstrated by some practices, proven effective strategies need to be broadly adopted at both the patient and population levels. Factors affecting cancer screening test completion and approaches to improvement are described both generally and for breast, lung, cervical, colorectal, and prostate cancers. Closing the racial disparity gap is a critical component of reaching cancer screening and prevention goals., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Evidence suggests that birth weight may be associated with colorectal cancer (CRC) risk later in life. Whether the association is mediated by adult body size remains unexamined., Method: Cox proportional hazards models (Hazard Ratio (HR) and 95 % Confidence Intervals (CI)) were used to evaluate the association between self-reported birth weight (<6 lbs, 6-<8 lbs, ≥8 lbs) and CRC risk among 70,397 postmenopausal women from the Women's Health Initiative. Further, we assessed whether this association was mediated by adult body size using multiple mediation analyses., Results: Compared with birth weights of 6-< 8 lbs, birth weight ≥ 8 lbs was associated with higher CRC risk in postmenopausal women (HR = 1.31, 95 % CI 1.16-1.48). This association was significantly mediated by adult height (proportion mediated =11.4 %), weight (11.2 %), waist circumference (10.9 %), and body mass index at baseline (4.0 %). The joint effect of adult height and weight explained 21.6 % of this positive association., Conclusion: Our data support the hypothesis that the intrauterine environment and fetal development may be related to the risk of developing CRC later in life. While adult body size partially explains this association, further investigation is required to identify other factors that mediate the link between birth weight and CRC., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Purpose: We investigated the association of coffee and caffeine with breast cancer (BCa) risk, overall and by ER/PR status. We also examined potential interactions of coffee and caffeine with postmenopausal hormone use., Methods: Our study included 77,688 postmenopausal participants from the Women's Health Initiative observational study cohort without a history of any cancer at baseline (except non-melanoma skin) and with valid Food Frequency Questionnaire data and complete data on dietary caffeine. Regular coffee (none, 1, 2-3, 4-5, and ≥ 6 cups/day) and caffeine (tertiles) were assessed at baseline. Information on BCa risk factors was collected at baseline. The associations were examined using survival analysis, accounting for death as a competing risk., Results: The median follow-up time for our cohort was 18.3 years. During the follow-up, 5005 women developed invasive breast cancer. In multivariable analysis, coffee was not associated with the overall invasive BCa risk. Higher caffeine intake was mildly associated with increased BCa risk (2nd vs. 1st tertile SHR = 1.10, 95% CI 1.03-1.18, 3rd vs. 1st tertile SHR-1.05, 95% CI 0.98-1.13, overall p = 0.03). We found no interaction of coffee/caffeine with postmenopausal hormone use (p interaction = 0.44 and 0.42, respectively). In the exploratory analysis by ER/PR status, we found a positive association of caffeine with ER+ /PR+ BCa (2nd vs. 1st tertile SHR = 1.17, 95% CI 1.07-1.28, 3rd vs. 1st tertile SHR = 1.13, 95% CI 1.03-1.24, overall p = 0.002); no associations were observed for ER-/PR- tumors. Coffee was not associated with the risk of ER+ /PR+ or ER-/PR- tumors., Conclusion: We found no associations of coffee with BCa risk, overall and for ER/PR-defined tumor subtypes. The higher caffeine consumption was mildly and positively associated with the overall BCa risk and with ER+ /PR+ tumors., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: Although adherence to the American Cancer Society (ACS) Guidelines on Nutrition and Physical Activity for Cancer Prevention associates with lower risk of obesity-related cancer (ORC) incidence and mortality, evidence in Black and Latina women is limited. This association was examined in Black and Latina participants in the Women's Health Initiative (WHI)., Methods: Semi-Markov multistate model examined the association between ACS guideline adherence and ORC incidence and mortality in the presence of competing events, combined and separately, for 9301 Black and 4221 Latina postmenopausal women. Additionally, ACS guideline adherence was examined in a subset of less common ORCs and potential effect modification by neighborhood socioeconomic status and smoking., Results: Over a median of 11.1, 12.5, and 3.7 years of follow-up for incidence, nonconditional mortality, and conditional mortality, respectively, 1191 ORCs (Black/Latina women: 841/269), 1970 all-cause deaths (Black/Latina women: 1576/394), and 341 ORC-related deaths (Black/Latina women: 259/82) were observed. Higher ACS guideline adherence was associated with lower ORC incidence for both Black (cause-specific hazard ratio [CSHR] highvs.low : 0.72; 95% CI, 0.55-0.94) and Latina (CSHR highvs.low : 0.58, 95% CI, 0.36-0.93) women; but not conditional all-cause mortality (Black hazard ratio [HR] highvs.low : 0.86; 95% CI, 0.53-1.39; Latina HR highvs.low : 0.81; 95% CI, 0.32-2.06). Higher adherence was associated with lower incidence of less common ORC (P trend  = .025), but conditional mortality events were limited. Adherence and ORC-specific deaths were not associated and there was no evidence of effect modification., Conclusions: Adherence to the ACS guidelines was associated with lower risk of ORCs and less common ORCs but was not for conditional ORC-related mortality., Lay Summary: Evidence on the association between the American Cancer Society Guidelines on Nutrition and Physical Activity for Cancer Prevention and cancer remains scarce for women of color. Adherence to the guidelines and risk of developing one of 13 obesity-related cancers among Black and Latina women in the Women's Health Initiative was examined. Women who followed the lifestyle guidelines had 28% to 42% lower risk of obesity-related cancer. These findings support public health interventions to reduce growing racial/ethnic disparities in obesity-related cancers., (© 2022 American Cancer Society.)

Granulomas are the hallmark of Mycobacterium tuberculosis (Mtb) infection. Cytokine-mediated signaling can modulate immune function; thus, understanding the cytokine milieu in granulomas is critical for understanding immunity in tuberculosis (TB). Interferons (IFNs) are important immune mediators in TB, and while type 1 and 2 IFNs have been extensively studied, less is known about type 3 IFNs (IFNλs) in TB. To determine if IFNλs are expressed in granulomas, which cells express them, and how granuloma microenvironments influence IFNλ expression, we investigated IFNλ1 and IFNλ4 expression in macaque lung granulomas. We identified IFNλ expression in granulomas, and IFNλ levels negatively correlated with bacteria load. Macrophages and neutrophils expressed IFNλ1 and IFNλ4, with neutrophils expressing higher levels of each protein. IFNλ expression varied in different granuloma microenvironments, with lymphocyte cuff macrophages expressing more IFNλ1 than epithelioid macrophages. IFNλ1 and IFNλ4 differed in their subcellular localization, with IFNλ4 predominantly localizing inside macrophage nuclei. IFNλR1 was also expressed in granulomas, with intranuclear localization in some cells. Further investigation demonstrated that IFNλ signaling is driven in part by TLR2 ligation and was accompanied by nuclear translocation of IFNλR1. Our data indicate that IFNλs are part of the granuloma cytokine milieu that may influence myeloid cell function and immunity in TB., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Talukdar, Junecko, Lane, Maiello and Mattila.)

A relatively high healthy lifestyle index (HLI) score, representing a healthy diet, participation in moderate to vigorous physical exercise, no smoking, low to no alcohol intake and a normal body mass index, has been associated with a reduced risk of invasive breast cancer. However, no study has shown an association between the HLI and the risk of ductal carcinoma in situ of the breast (DCIS), which is considered to be a nonobligate precursor of invasive breast cancer. We evaluated this association in a prospective cohort of 132 230 postmenopausal women, aged 50 to 79 years, recruited between 1993 and 1998 across the United States and enrolled in the Women's Health Initiative study. The HLI score was created and categorized into quartiles. During an average follow-up of 15.4 years, 2035 DCIS cases were ascertained. Multivariable-adjusted Cox regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association of HLI with the risk of DCIS. Women in the highest HLI quartile had a lower DCIS risk than those in the lowest quartile (HR 4thQT  = 0.80, 95% CI, 0.70-0.92) and this association was stronger in women with a family history of breast cancer (HR 4thQT  = 0.70, 95% CI, 0.52-0.93), and for ER+/PR+ DCIS (HR 4thQT  = 0.66, 95% CI, 0.52-0.83). These findings suggest that there is an inverse association between HLI and risk of DCIS, and suggest that the adoption of a healthy lifestyle might lower the risk of DCIS., (© 2022 UICC.)

Background: Results of observational studies of the association between dietary fat and risk of invasive breast cancer have been inconsistent. In the Women's Health Initiative dietary modification (DM) randomized trial designed to lower fat intake, the intervention was not associated with a statistically significant reduction of overall breast cancer risk. However, the DM association with risk of ductal carcinoma in situ (DCIS) of the breast, a putative breast cancer precursor, has not been reported., Methods: A total of 48,835 postmenopausal women, ages 50-79 years at enrollment, with no breast cancer history and ≥32% of total energy intake from fat, were randomly assigned either to a dietary intervention ( n = 19,541) designed to reduce total fat intake to 20% of energy and to increase vegetable, fruit, and grain consumption, or to a comparison group ( n = 29,294). Cox proportional hazards models were used to estimate HRs and 95% confidence intervals for the association between the intervention and DCIS risk., Results: During 18.7 years (median) cumulative follow-up, including intervention (∼8.7 years) and post-intervention phases (∼13.0 years), 817 DCIS cases were ascertained. No evidence of an association between the DM intervention and DCIS risk was observed overall, or by trial phase (intervention and post-intervention). Similarly, no associations were found in subgroups defined by potential risk factors for DCIS., Conclusions: DM aiming to reduce fat intake was not associated with altered risk of DCIS., Impact: These results do not provide evidence of an association between dietary fat reduction and the risk of DCIS among postmenopausal women., (©2021 American Association for Cancer Research.)

Social endorsement cues (SEC) offer information about how online users have engaged and evaluated online content. Some view that SEC thus can serve as useful heuristics when users evaluate the credibility of news content on social media. At the same time, SEC can be manipulated by a variety of commercial and political actors on social media. This study examines whether SEC influence individuals' credibility judgments of political news on social media, and how the salience of concerns that SEC can be manipulated by others can undermine the perceived credibility. Using an experiment, we found that SEC had a negative influence on news credibility, regardless of whether or not SEC manipulability concerns were primed. An independent effect of SEC manipulability concerns was also found, such that priming thoughts about the manipulability of SEC led participants to rate the news post as less credible, regardless of whether that post included SEC. These results suggest a spillover effect whereby concerns over the manipulation of SEC can create doubt about the authenticity of other cues from the news (e.g., source and message), and lead to perceptions that news shared on social media can be manipulated more generally.

Context: Preventive medicine residents must train in population medicine (including analytics and population health) and clinical preventive medicine (including screening, behavioral counseling, and chemoprophylaxis). Yet, opportunities to perform both functions concurrently for the same population are scarce. Residents must also master the art of preventive medicine, but they often lack an established community of practice that provides a continuous forum to do so. This project explored Population Health Rounds as a novel vehicle to optimize preventive medicine residency training., Program Description: Modeled after traditional medical rounds, Population Health Rounds consist of a 1-hour weekly meeting engaging preventive medicine residents and supervising attendings at Stony Brook Medicine in both population medicine and clinical preventive medicine concurrently, including patient case discussions and targeted population health analytics., Evaluation and Results: Because of the pandemic, the rounds have predominantly focused on COVID-19 and its effects on the hospital employee population. In addition to providing direct patient care to COVID-19-positive and exposed employees, residents have analyzed data on this population and made recommendations to hospital leadership based on COVID-19's institutional epidemiology, including incidence, prevalence, and predictive factors. A formative qualitative survey of resident perceptions offers insights on the value and learning outcomes of this new model., Discussion and Conclusion: Factors that may impact the implementation, sustainability, and feasibility of this model are discussed. The preventive medicine residency program is commissioned to address gaps in clinical preventive services for the patient-centered medical home tied to the sponsoring institution's family medicine practice. Additional plans are underway to expand the rounds to other clinical contexts, such as lifestyle medicine in the occupational setting, and for targeted populations, such as the underserved. Replication of the Population Health Rounds model is recommended to determine its effectiveness., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Use of angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) has been postulated to reduce cancer risk by inhibition of tumor progression, vascularization, and metastasis. The renin-angiotensin system is upregulated in colorectal cancers; however, the association of ACEi and ARB use with colorectal cancer risk is not well understood., Methods: The study population was 142,812 Women's Health Initiative participants free of colorectal cancer who reported on ACEi and ARB use at baseline; 2,216 incident colorectal cancers were diagnosed during 10 years of follow-up. Cox regression models estimated adjusted HRs and 95% confidence intervals for associations relative to nonuse among normotensive women, untreated hypertensive women, and hypertensive women treated with other antihypertensive medications., Results: HRs among women who used any ACEi or ARB compared with nonuse in the three referent groups ranged between 0.97 and 1.01. Findings were similar for increased ACEi/ARB duration and for medications examined as separate classes or individually., Conclusions: In this large prospective study of women, no associations of ACEi or ARB use with colorectal cancer risk were observed., Impact: Choice of drug in the large population of aging women who will be prescribed ACEi and ARB should be made without factoring in any benefit on colorectal cancer risk., (©2021 American Association for Cancer Research.)

Background: Laboratory and animal studies suggest an inverse association between chocolate consumption and the risk of cancer. Epidemiological studies have yielded inconsistent evidence., Objective: To assess the association of chocolate candy consumption with incident, invasive total, breast, colorectal, and lung cancers in a large cohort of postmenopausal American women., Design: Prospective cohort study with a mean 14.8-year follow-up. Chocolate candy intake was assessed by food frequency questionnaire. Invasive cancer events were assessed by physician adjudication., Participants/setting: The Women's Health Initiative Study enrolled 161,808 postmenopausal women at 40 clinical centers nationwide between 1993 and 1998. Of these women, 114,281 with plausible food frequency or biometric data and no missing data on chocolate candy exposure were selected for analysis., Main Outcome Measures: Cancer risk in quartiles of chocolate candy consumption with the first quartile as referent., Statistical Analyses: Multivariable Cox regression was used to calculate hazard ratios and 95% confidence intervals., Results: There were 16,164 documented incident invasive cancers, representing an incidence rate of 17.0 per 100 participants and 12.3 per 1000 person years during follow-up among participants without any preexisting cancers or missing outcome data. There were no statistically significant associations for total invasive cancer (P-linear = .47, P-curvature = .14), or invasive breast cancer (P-linear = .77, P-curvature = .26). For colorectal cancer P-linear was .02, P-curvature was .03, and compared with women eating a 1 oz (28.4 g) chocolate candy serving <1 time per month, the hazard ratio for ≥1.5 times/wk was 1.18 (95% confidence interval: 1.04-1.35). This result may be attributable to the excess adiposity associated with frequent chocolate candy consumption., Conclusions: In the Women's Health Initiative, there was no significant association between chocolate candy consumption and invasive total or breast cancer. There was a modest 18% higher risk of invasive colorectal cancer for women who ate chocolate candy at least 1.5 times/wk. These results require confirmation., (Copyright © 2021 Academy of Nutrition and Dietetics. Published by Elsevier Inc. All rights reserved.)

The pandemonium from the 2020 pandemic calls for a greater emphasis on prevention, public health and population health. Yet the role of preventive medicine specialists, ideally qualified to lead this charge, remains difficult to situate within the houses of medicine and public health. To overcome this challenge to its identity and evolve to better tackle novel and on-going public health and population health problems, the authors propose that the specialty of preventive medicine should assert 3 core functions within preventive care; expand and modernize its knowledge base; and enhance its residency training accordingly. The authors also propose 10 essential services, not otherwise systematically provided by other specialties, that the preventive medicine specialty can optimally fulfill as its unique contributions within medicine and public health., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Physical activity is associated with decreased risk for many cancers. Studies on the association between physical activity and risk of bladder cancer are limited, and findings are inconsistent. Postmenopausal women (mean age = 63.3) were recruited into the Women's Health Initiative from 1993 to 1998. Self-reported baseline information on physical activity and other covariates were available in 141 288 participants. Incident bladder cancer cases were collected through 2018 and centrally adjudicated. Hazard ratios (HRs) and 95% confidence intervals (CIs) were determined by Cox proportional hazard regression models. Effect modification due to smoking was assessed. During an average of 18.5 years of follow-up, 817 bladder cancer cases were identified. Compared to physically inactive women, those who engaged in ≥15 MET-hours/week of total physical activity, ≥8.75 MET-hours/week of walking or ≥11.25 MET-hours/week of moderate to vigorous physical activity had lower risk of bladder cancer (HR = 0.74, 95% CI: 0.59-0.94, P for linear trend = .02; HR = 0.79, 95% CI: 0.63-0.98, P for linear trend = .03; and HR = 0.76, 95% CI: 0.61-0.94, P for linear trend = .02, respectively). No effect modification was found by smoking status (P for interaction = .06, 0.91 and 0.27, respectively). We found that total physical activity, walking and moderate to vigorous physical activity were inversely associated with bladder cancer incidence among postmenopausal women in a dose-response manner. Physical activity may play a potential role in the primary prevention of bladder cancer. Further studies with objective measurements of physical activity are needed to confirm these findings., (© 2020 UICC.)

Purpose: Observational studies of dietary fat intake and breast cancer have reported inconsistent findings. This topic was addressed in additional analyses of the Women's Health Initiative (WHI) Dietary Modification (DM) clinical trial that evaluated a low-fat dietary pattern influence on breast cancer incidence., Methods: In the WHI DM trial, 48,835 postmenopausal women, ages 50-79 years, with no prior breast cancer, and a dietary fat intake of ≥ 32% of energy were randomly assigned at 40 US centers to a usual diet comparison group (60%) or dietary intervention group (40%). The goals were to reduce fat intake to 20% of energy and increase vegetable, fruit, and grain intake. Breast cancers were confirmed after central medical record review and serial National Death Index linkages to enhance mortality findings., Results: During 8.5 years of dietary intervention, breast cancer incidence and deaths as a result of breast cancer were nonsignificantly lower in the intervention group, while deaths after breast cancer were statistically significantly lower both during intervention and through a 16.1-year (median) follow-up. Now, after a long-term, cumulative 19.6-year (median) follow-up, the significant reduction in deaths after breast cancer persists (359 [0.12%] v 652 [0.14%] deaths; hazard ratio [HR], 0.85; 95% CI, 0.74 to 0.96; P = .01), and a statistically significant reduction in deaths as a result of breast cancer (breast cancer followed by death attributed to the breast cancer) emerged (132 [0.037%, annualized risk] v 251 [0.047%] deaths, respectively; HR, 0.79; 95% CI, 0.64 to 0.97; P = .02)., Conclusion: Adoption of a low-fat dietary pattern associated with increased vegetable, fruit, and grain intake, demonstrably achievable by many, may reduce the risk of death as a result of breast cancer in postmenopausal women.

Background: We evaluated associations between perceived social support, social integration, living alone, and colorectal cancer (CRC) outcomes in postmenopausal women., Methods: The study included 1431 women from the Women's Health Initiative who were diagnosed from 1993 through 2017 with stage I through IV CRC and who responded to the Medical Outcomes Study Social Support survey before their CRC diagnosis. We used proportional hazards regression to evaluate associations of social support (tertiles) and types of support, assessed up to 6 years before diagnosis, with overall and CRC-specific mortality. We also assessed associations of social integration and living alone with outcomes also in a subset of 1141 women who had information available on social ties (marital/partner status, community and religious participation) and living situation., Results: In multivariable analyses, women with low (hazard ratio [HR], 1.52; 95% CI, 1.23-1.88) and moderate (HR, 1.21; 95% CI, 0.98-1.50) perceived social support had significantly higher overall mortality than those with high support (P [continuous] < .001). Similarly, women with low (HR, 1.42; 95% CI, 1.07-1.88) and moderate (HR, 1.28; 95% CI, 0.96-1.70) perceived social support had higher CRC mortality than those with high social support (P [continuous] = .007). Emotional, informational, and tangible support and positive interaction were all significantly associated with outcomes, whereas affection was not. In main-effects analyses, the level of social integration was related to overall mortality (P for trend = .02), but not CRC mortality (P for trend = .25), and living alone was not associated with mortality outcomes. However, both the level of social integration and living alone were related to outcomes in patients with rectal cancer., Conclusions: Women with low perceived social support before diagnosis have higher overall and CRC-specific mortality., (© 2020 American Cancer Society.)

Background: Understanding how older patients with chronic illnesses use the internet to obtain health information is relevant for the design of digital interventions aimed at improving the health and well-being of adults aged 65 years and older; this cohort represents the sickest, most expensive, and fastest-growing segment of the US population., Objective: The objective of our study was to describe online health information-seeking behavior among older patients with chronic illnesses and to compare the characteristics of patients who report using the internet to obtain health information with those who do not., Methods: The study population included 72,806 women aged 65 years and older enrolled in the Women's Health Initiative (WHI), a national cohort study, who completed a 2014 supplemental questionnaire assessing everyday technology use and internet use for researching health conditions. Comparisons were made between participants with and without a history of chronic illness and between users and nonusers of online sources for health information. Multivariate logistic regression was used to estimate odds ratios (ORs) and 95% CIs., Results: Of the total, 59% (42,887/72,806) of older women used the internet for health information. Compared with women who did not use the internet to obtain health information, those who used the internet were younger (median age: 76 vs 81 years), more likely to be non-Hispanic white (90% [38,481/42,887] vs 87% [26,017/29,919]), earned a higher income (over $US 50,000: 55% [23,410/42,887] vs 33% [9991/29,919]), achieved a higher educational level (more than high school: 87% [37,493/42,887] vs 75% [22,377/29,919]), and were more likely to live with a partner (52% [22,457/42,887] vs 36% [10,759/29,919]) (all P<.001). Women with Alzheimer disease were least likely to report online health information-seeking compared to those without the disease (OR 0.41, 95% CI 0.38-0.43). In contrast, women with a recent diagnosis of cancer, within the previous 2 years (OR 1.23, 95% CI 1.11-1.36) or 2-5 years ago (OR 1.09, 95% CI 1.00-1.19), were most likely to use the internet for health information., Conclusions: Nearly 6 in 10 older women participating in the WHI reported using the internet to obtain health information. Patients recently diagnosed with cancer are more likely to be looking for health information online, even after adjustment for age, suggesting that these patients may have a greater need for digital health resources., (©Mina S Sedrak, Enrique Soto-Perez-De-Celis, Rebecca A Nelson, Jennifer Liu, Molly E Waring, Dorothy S Lane, Electra D Paskett, Rowan T Chlebowski. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 09.04.2020.)

Background: Most studies demonstrating an association between excess adiposity and postmenopausal breast cancer have used anthropometric measures, particularly body mass index (BMI). However, more direct body fat measures may more accurately determine the relationship between body fat distribution and breast cancer risk., Methods: Cox proportional hazards regression models were created to examine the associations of dual-energy x-ray absorptiometry (DXA) body fat measures (at baseline and during follow-up) with breast cancer risk among 10 931 postmenopausal women from the Women's Health Initiative cohort. A total of 639 incident invasive breast cancer cases (including 484 estrogen receptor positive (ER+) cases) were ascertained after a median follow-up of 15.0 years., Results: Excess whole body fat mass and trunk fat mass were positively associated with risk invasive breast cancer risk. These associations persisted even after additional adjustment for standard anthropometric measures. In time-dependent analyses, we observed that both whole body fat mass and trunk fat mass, in the highest versus lowest category, were associated with a doubling of risk of invasive breast cancer overall (HR: 2.17; 95% CI: 1.54-3.05 and 2.20; 1.55-3.14, respectively) and of ER+ breast cancer (2.05; 1.37-3.05 and 2.03; 1.34-3.07, respectively). The remaining DXA measures were also positively associated with breast cancer risk in baseline and time-dependent analyses., Conclusion: These findings suggest that DXA-derived body fat measures are positively associated with breast cancer risk after adjustment for BMI and other conventional breast cancer risk factors., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)