Using genome and transcriptome data from African-ancestry female participants to identify putative breast cancer susceptibility genes.

African-ancestry (AA) participants are underrepresented in genetics research. Here, we conducted a transcriptome-wide association study (TWAS) in AA female participants to identify putative breast cancer susceptibility genes. We built genetic models to predict levels of gene expression, exon junction, and 3' UTR alternative polyadenylation using genomic and transcriptomic data generated in normal breast tissues from 150 AA participants and then used these models to perform association analyses using genomic data from 18,034 cases and 22,104 controls. At Bonferroni-corrected P < 0.05, we identified six genes associated with breast cancer risk, including four genes not previously reported (CTD-3080P12.3, EN1, LINC01956 and NUP210L). Most of these genes showed a stronger association with risk of estrogen-receptor (ER) negative or triple-negative than ER-positive breast cancer. We also replicated the associations with 29 genes reported in previous TWAS at P < 0.05 (one-sided), providing further support for an association of these genes with breast cancer risk. Our study sheds new light on the genetic basis of breast cancer and highlights the value of conducting research in AA populations.

Genome-wide association analyses of breast cancer in women of African ancestry identify new susceptibility loci and improve risk prediction.

We performed genome-wide association studies of breast cancer including 18,034 cases and 22,104 controls of African ancestry. Genetic variants at 12 loci were associated with breast cancer risk (P < 5 × 10-8), including associations of a low-frequency missense variant rs61751053 in ARHGEF38 with overall breast cancer (odds ratio (OR) = 1.48) and a common variant rs76664032 at chromosome 2q14.2 with triple-negative breast cancer (TNBC) (OR = 1.30). Approximately 15.4% of cases with TNBC carried six risk alleles in three genome-wide association study-identified TNBC risk variants, with an OR of 4.21 (95% confidence interval = 2.66-7.03) compared with those carrying fewer than two risk alleles. A polygenic risk score (PRS) showed an area under the receiver operating characteristic curve of 0.60 for the prediction of breast cancer risk, which outperformed PRS derived using data from females of European ancestry. Our study markedly increases the population diversity in genetic studies for breast cancer and demonstrates the utility of PRS for risk prediction in females of African ancestry.

Associations of pre-diagnosis physical activity with treatment tolerance and treatment efficacy in breast cancer patients with neoadjuvant chemotherapy.

PURPOSE: Higher pre-diagnosis physical activity (PA) is associated with lower all-cause mortality in breast cancer (BCa) patients. However, the association with pathological complete response (pCR) is unclear. We investigated the association between pre-diagnosis PA level and chemotherapy completion, dose delay, and pCR in BCa patients receiving neoadjuvant chemotherapy (NACT). METHODS: 180 stage I-III BCa patients receiving NACT (mean [SD] age of diagnosis: 60.8 [8.8] years) in the Sister Study were included. Self-reported recreational and total PA levels were converted to metabolic equivalent of task-hours per week (MET-hrs/wk). The pCR was defined as no invasive or in situ residual in breast or lymph node (ypT0 ypN0). Multivariable logistic regression analyses estimated odds ratios (ORs) and 95% confidence intervals (CIs) for treatment outcomes. RESULTS: In this sample, 45 (25.0%) BCa patients achieved pCR. Higher pre-diagnosis recreational PA was not associated with lower likelihood of chemotherapy completion (highest vs. lowest tertile: OR = 0.87, 95% CI = 0.30-2.56; Ptrend = 0.84), greater dose delay (OR = 1.45, 95% CI = 0.54-3.92; Ptrend = 0.46), or greater odds of pCR (OR = 1.28, 95% CI = 0.49-3.34; Ptrend = 0.44). Associations were similar for pre-diagnosis total PA. Meeting the recommended level of recreational PA was not associated with pCR overall (≥ 7.5 vs. < 7.5 MET-hrs/wk: OR = 1.33, 95% CI = 0.59-3.01). CONCLUSIONS: Although small sample size and limited information on exercise closer to time of diagnosis limit interpretation, pre-diagnosis PA was not convincingly associated with treatment tolerance or treatment efficacy in BCa patients receiving NACT. Future investigations are needed to better understand the impact of pre-diagnosis PA on BCa treatment.

Describing Energy Expenditure in Children with a Chronic Disease: A Systematic Review.

Understanding energy expenditure in children with chronic disease is critical due to the impact on energy homeostasis and growth. This systematic review aimed to describe available literature of resting (REE) and total energy expenditure (TEE) in children with chronic disease measured by gold-standard methods of indirect calorimetry (IC) and doubly labeled water (DLW), respectively. A literature search was conducted using OVID Medline, Embase, CINAHL Plus, Cochrane, and Scopus until July 2023. Studies were included if the mean age of the participants was ≤18 y, participants had a chronic disease, and measurement of REE or TEE was conducted using IC or DLW, respectively. Studies investigating energy expenditure in premature infants, patients with acute illness, and intensive care patients were excluded. The primary outcomes were the type of data (REE, TEE) obtained and REE/TEE stratified by disease group. In total, 271 studies across 24 chronic conditions were identified. Over 60% of retrieved studies were published >10 y ago and conducted on relatively small population sizes (n range = 1-398). Most studies obtained REE samples (82%) rather than that of TEE (8%), with very few exploring both samples (10%). There was variability in the difference in energy expenditure in children with chronic disease compared with that of healthy control group across and within disease groups. Eighteen predictive energy equations were generated across the included studies. Quality assessment of the studies identified poor reporting of energy expenditure protocols, which may limit the validity of results. Current literature on energy expenditure in children with chronic disease, although extensive, reveals key future research opportunities. International collaboration and robust measurement of energy expenditure should be conducted to generate meaningful predictive energy equations to provide updated evidence that is reflective of emerging disease-modifying therapies. This study was registered in PROSPERO as CRD42020204690.

Metformin and feeding increase levels of the appetite-suppressing metabolite Lac-Phe in humans.

Metformin, a widely used first-line treatment for type 2 diabetes (T2D), is known to reduce blood glucose levels and suppress appetite. Here we report a significant elevation of the appetite-suppressing metabolite N-lactoyl phenylalanine (Lac-Phe) in the blood of individuals treated with metformin across seven observational and interventional studies. Furthermore, Lac-Phe levels were found to rise in response to acute metformin administration and post-prandially in patients with T2D or in metabolically healthy volunteers.

BMI and breast cancer risk around age at menopause.

BACKGROUND: A high body mass index (BMI, kg/m2) is associated with decreased risk of breast cancer before menopause, but increased risk after menopause. Exactly when this reversal occurs in relation to menopause is unclear. Locating that change point could provide insight into the role of adiposity in breast cancer etiology. METHODS: We examined the association between BMI and breast cancer risk in the Premenopausal Breast Cancer Collaborative Group, from age 45 up to breast cancer diagnosis, loss to follow-up, death, or age 55, whichever came first. Analyses included 609,880 women in 16 prospective studies, including 9956 who developed breast cancer before age 55. We fitted three BMI hazard ratio (HR) models over age-time: constant, linear, or nonlinear (via splines), applying piecewise exponential additive mixed models, with age as the primary time scale. We divided person-time into four strata: premenopause; postmenopause due to natural menopause; postmenopause because of interventional loss of ovarian function (bilateral oophorectomy (BO) or chemotherapy); postmenopause due to hysterectomy without BO. Sensitivity analyses included stratifying by BMI in young adulthood, or excluding women using menopausal hormone therapy. RESULTS: The constant BMI HR model provided the best fit for all four menopausal status groups. Under this model, the estimated association between a five-unit increment in BMI and breast cancer risk was HR=0.87 (95% CI: 0.85, 0.89) before menopause, HR=1.00 (95% CI: 0.96, 1.04) after natural menopause, HR=0.99 (95% CI: 0.93, 1.05) after interventional loss of ovarian function, and HR=0.88 (95% CI: 0.76, 1.02) after hysterectomy without BO. CONCLUSION: The BMI breast cancer HRs remained less than or near one during the 45-55 year age range indicating that the transition to a positive association between BMI and risk occurs after age 55.

Functional EPAS1/HIF2A missense variant is associated with hematocrit in Andean highlanders.

Hypoxia-inducible factor pathway genes are linked to adaptation in both human and nonhuman highland species. EPAS1, a notable target of hypoxia adaptation, is associated with relatively lower hemoglobin concentration in Tibetans. We provide evidence for an association between an adaptive EPAS1 variant (rs570553380) and the same phenotype of relatively low hematocrit in Andean highlanders. This Andean-specific missense variant is present at a modest frequency in Andeans and absent in other human populations and vertebrate species except the coelacanth. CRISPR-base-edited human cells with this variant exhibit shifts in hypoxia-regulated gene expression, while metabolomic analyses reveal both genotype and phenotype associations and validation in a lowland population. Although this genocopy of relatively lower hematocrit in Andean highlanders parallels well-replicated findings in Tibetans, it likely involves distinct pathway responses based on a protein-coding versus noncoding variants, respectively. These findings illuminate how unique variants at EPAS1 contribute to the same phenotype in Tibetans and a subset of Andean highlanders despite distinct evolutionary trajectories.

Whole genome sequencing reveals stepping-stone dispersal buffered against founder effects in a range expanding seabird.

Many species are shifting their ranges in response to climate-driven environmental changes, particularly in high-latitude regions. However, the patterns of dispersal and colonization during range shifting events are not always clear. Understanding how populations are connected through space and time can reveal how species navigate a changing environment. Here, we present a fine-scale population genomics study of gentoo penguins (Pygoscelis papua), a presumed site-faithful colonial nesting species that has increased in population size and expanded its range south along the Western Antarctic Peninsula. Using whole genome sequencing, we analysed 129 gentoo penguin individuals across 12 colonies located at or near the southern range edge. Through a detailed examination of fine-scale population structure, admixture, and population divergence, we inferred that gentoo penguins historically dispersed rapidly in a stepping-stone pattern from the South Shetland Islands leading to the colonization of Anvers Island, and then the adjacent mainland Western Antarctica Peninsula. Recent southward expansion along the Western Antarctic Peninsula also followed a stepping-stone dispersal pattern coupled with limited post-divergence gene flow from colonies on Anvers Island. Genetic diversity appeared to be maintained across colonies during the historical dispersal process, and range-edge populations are still growing. This suggests large numbers of migrants may provide a buffer against founder effects at the beginning of colonization events to maintain genetic diversity similar to that of the source populations before migration ceases post-divergence. These results coupled with a continued increase in effective population size since approximately 500-800 years ago distinguish gentoo penguins as a robust species that is highly adaptable and resilient to changing climate.

Outdoor air pollution exposure and uterine cancer incidence in the sister study.

BACKGROUND: Outdoor air pollution is a ubiquitous exposure that includes endocrine-disrupting and carcinogenic compounds that may contribute to the risk of hormone-sensitive outcomes such as uterine cancer. However, there is limited evidence about the relationship between outdoor air pollution and uterine cancer incidence. METHODS: We investigated the associations of residential exposure to particulate matter less than 2.5 µm in diameter (PM2.5) and nitrogen dioxide (NO2) with uterine cancer among 33,417 Sister Study participants with an intact uterus at baseline (2003-2009). Annual average air pollutant concentrations were estimated at participants' geocoded primary residential address(es) using validated spatiotemporal models. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between time-varying 12-month PM2.5 (µg/m3) and NO2 (ppb) averages and uterine cancer incidence. RESULTS: Over a median follow-up period of 9.8 years, 319 incident uterine cancer cases were identified. A 5-ppb increase in NO2 was associated with a 23% higher incidence of uterine cancer (HR = 1.23, 95% CI 1.04-1.46), especially among participants living in urban areas (HR = 1.53, 95% CI: 1.13-2.07). However, PM2.5 was not associated with increased uterine cancer incidence. CONCLUSION: In this large U.S. cohort, NO2, a marker of vehicular traffic exposure, was associated with a higher incidence of uterine cancer. These findings expand the scope of health effects associated with air pollution, supporting the need for policy and other interventions designed to reduce air pollutant exposure.

Seasonal patterns in trace elements assessed in toenails.

BACKGROUND: Seasonal patterns in measured exposure biomarkers can cause measurement error in epidemiological studies. There is little research about the seasonality of metals and trace elements when assessed in toenail samples. Adjusting for such patterns in models for estimating associations between long-term exposures and health outcomes can potentially improve precision and reduce bias. OBJECTIVES: Assess and describe seasonal patterns in toenail measurements of trace elements. METHODS: The Sister Study enrolled women residing in the US, including Puerto Rico, whose sister had been diagnosed with breast cancer. At the time of enrollment, participants removed nail polish and collected their toenail clippings, which were cleaned before analysis. We considered the following elements: iron, vanadium, aluminum, chromium, manganese, cobalt, nickel, copper, zinc, arsenic, selenium, molybdenum, cadmium, tin, antimony, mercury, and lead. For two subsamples of the cohort, we fit trigonometric regression models with toenail element measures as the outcome, using sine and cosine functions of the collection day (transformed to an angle) to capture seasonal patterns. These models can estimate the amplitude and timing of the peaks in measures. We evaluated the evidence for a seasonal effect by comparing for each measured element the trigonometric model to a model that was constant across time. RESULTS: There was a seasonal trend in toenail element concentration for iron, aluminum, vanadium, chromium, manganese, cobalt, arsenic, molybdenum, cadmium, tin, and lead, all of which peaked near mid-August. Seasonal patterns were concordant across two non-overlapping samples of women, analyzed in different labs. DISCUSSION: Given the evidence supporting seasonal patterns for 11 of the 17 elements measured in toenails, correcting for seasonality of toenail levels of those trace elements in models estimating the association between those exposures and health outcomes is important. The basis for higher concentrations in toenails collected during the summer remains unknown.

Personal Care Product Use during Puberty and Incident Breast Cancer among Black, Hispanic/Latina, and White Women in a Prospective US-Wide Cohort.

BACKGROUND: Some personal care products (PCPs) contain endocrine-disrupting chemicals that may affect breast cancer (BC) risk. Patterns of use vary by race and ethnicity. Use often starts in adolescence, when rapidly developing breast tissue may be more susceptible to environmental carcinogens. Few studies have examined associations of BC with PCP use during this susceptible window. OBJECTIVES: We characterized race and ethnicity-specific patterns of PCP use at 10-13 years of age and estimated associations of use with incident BC. METHODS: At enrollment (2003-2009), Sister Study participants (n=4,049 Black, 2,104 Latina, and 39,312 White women) 35-74 years of age reported use of 37 "everyday" PCPs during the ages of 10-13 y (did not use, sometimes, or frequently used). We conducted race and ethnicity-specific latent class analyses to separately identify groups of women with similar patterns of beauty, hair, and skincare/hygiene product use. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for associations of identified PCP classes and single products with incident BC using Cox proportional hazards regression. RESULTS: During a mean follow-up time of 10.8 y, 280 Black, 128 Latina, and 3,137 White women were diagnosed with BC. Classes of adolescent PCP use were not clearly associated with BC diagnosis among Black, Latina, or White women. HRs were elevated but imprecise for frequent nail product and perfume use in Black women (HR=1.34; 95% CI: 0.85, 2.12) and greater hair product use in Black (HR=1.28; 95% CI: 0.91, 1.80) and Latina (HR=1.42; 95% CI: 0.81, 2.48) women compared with lighter use. In single-product models, we observed higher BC incidence associated with frequent use of lipstick, nail products, pomade, perfume, makeup remover, and acne/blemish products in at least one group. DISCUSSION: This work provides some support for the hypothesis that PCP use during puberty is associated with BC risk. More research is needed to confirm these novel findings. https://doi.org/10.1289/EHP13882.

Circulating Leukocyte Subsets Before and After a Breast Cancer Diagnosis and Therapy.

Importance: Changes in leukocyte composition often precede chronic disease onset. Patients with a history of breast cancer (hereinafter referred to as breast cancer survivors) are at increased risk for subsequent chronic diseases, but the long-term changes in peripheral leukocyte composition following a breast cancer diagnosis and treatment remain unknown. Objective: To examine longitudinal changes in peripheral leukocyte composition in women who did and did not develop breast cancer and identify whether differences in breast cancer survivors were associated with specific treatments. Design, Setting, and Participants: In this prospective cohort study, paired blood samples were collected from 2315 women enrolled in The Sister Study, a US-nationwide prospective cohort study of 50 884 women, at baseline (July 2003 to March 2009) and follow-up (October 2013 to March 2015) home visits, with a mean (SD) follow-up interval of 7.6 (1.4) years. By design, approximately half of the included women had been diagnosed and treated for breast cancer after enrollment and before the second blood draw. A total of 410 women were included in the present study, including 185 breast cancer survivors and 225 who remained free of breast cancer over a comparable follow-up period. Data were analyzed from April 21 to September 9, 2022. Exposures: Breast cancer status and, among breast cancer survivors, cancer treatment type (chemotherapy, radiotherapy, endocrine therapy, or surgery). Main Outcomes and Measures: Blood DNA methylation data were generated in 2019 using a genome-wide methylation screening tool and deconvolved to estimate percentages of 12 circulating leukocyte subsets. Results: Of the 410 women included in the analysis, the mean (SD) age at enrollment was 56 (9) years. Compared with breast cancer-free women, breast cancer survivors had decreased percentages of circulating eosinophils (-0.45% [95% CI, -0.87% to -0.03%]; P = .03), total CD4+ helper T cells (-1.50% [95% CI, -2.56% to -0.44%]; P = .01), and memory B cells (-0.22% [95% CI, -0.34% to -0.09%]; P = .001) and increased percentages of circulating naive B cells (0.46% [95% CI, 0.17%-0.75%]; P = .002). In breast cancer survivor-only analyses, radiotherapy was associated with decreases in total CD4+ T cell levels, whereas chemotherapy was associated with increases in naive B cell levels. Surgery and endocrine therapy were not meaningfully associated with leukocyte changes. Conclusions and Relevance: In this cohort study of 410 women, breast cancer survivors experienced lasting changes in peripheral leukocyte composition compared with women who remained free of breast cancer. These changes may be related to treatment with chemotherapy or radiotherapy and could influence future chronic disease risk.

Vitamin D status and supplementation, calcium supplementation, and timing of natural menopause.

Vitamin D status has been inconsistently associated with ovarian reserve and menopause. We used data from the Sister Study cohort to examine the associations of vitamin D supplement use, total 25-hydroxyvitamin D (25OHD) level, and calcium supplement use with the timing of natural menopause. Vitamin D and calcium supplement use were assessed on a questionnaire at baseline (mean age: 46) and two follow-up time points, and characterized in multiple ways based on type, dose, and duration of use. Serum samples from a random subset of participants were analyzed for total 25OHD (25OHD3 + 25OHD2 + epi-25OHD3) using liquid chromatography-mass spectrometry. Menopause was assessed at each yearly follow-up with the question "Have you had a menstrual period in the past 12 months?"; if the response was "no", age at last menstrual period was recorded. We censored women at time of hysterectomy or medically induced menopause, death, loss to follow-up or October 2020. We used multivariable Cox proportional hazard models with age as the time scale to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs), adjusting for race/ethnicity, education, body mass index, alcohol use, smoking status, and physical activity. Among the 13,102 eligible premenopausal participants, 8897 experienced natural menopause during follow-up. Concomitant use of a multivitamin and a vitamin D supplement was associated with slightly earlier menopause (HR(CI): 1.10 (0.98, 1.24)). None of the remaining vitamin D or calcium supplement variables (alone or in combination) were meaningfully associated with timing of natural menopause. In a subsample with 25OHD measurements (n = 906), neither total 25OHD nor 25OHD3 was associated with timing of menopause. Our study includes, on average, 6 years of follow-up from an average age of 46 years and did not find associations between vitamin D or calcium supplement use and timing of menopause. Future studies should focus on a life course approach to this question and include 25OHD measures from early mid-life when examining menopause timing.

Association of Fibroids, Endometriosis, and Gynecologic Surgeries with Breast Cancer Incidence and Hormone Receptor Subtypes.

BACKGROUND: Fibroids and endometriosis are sex hormone-mediated and exhibit cancer-like behavior. Breast cancer may be more common in women who have had these conditions, but the literature is conflicting and does not always address factors like hysterectomy/oophorectomy status, race/ethnicity, menopause, and hormone receptor subtypes. METHODS: Data are from the Sister Study, a cohort of 50,884 U.S. women enrolled in 2003 to 2009 and followed through 2020. Cox proportional hazards models with time-varying exposures and covariates assessed the relationship of fibroids or endometriosis with breast cancer. Logistic regression examined the association with estrogen receptor (ER) status among cases. RESULTS: Fibroids (19,932 cases) were positively associated with breast cancer [fully adjusted HR: 1.07; 95% confidence interval (CI): 1.01-1.14], notably among Black participants (HR: 1.34; 95% CI: 1.07-1.69) and women who had a hysterectomy (HR: 1.18; 95% CI: 1.05-1.31). Endometriosis (3,970 cases) was not associated with breast cancer (HR: 0.99; 95% CI: 0.91-1.08). Among 4,419 breast cancer cases, fibroids were positively associated with ER+ subtypes (OR: 1.34; 95% CI: 1.10-1.65), while endometriosis was negatively associated with ER+ subtypes (OR: 0.78; 95% CI: 0.61-1.01). CONCLUSIONS: We observed a modest positive association between fibroids and breast cancer, particularly ER+ breast cancer. No relationship with endometriosis and breast cancer incidence was found. IMPACT: Fibroids, even in those with a family history of breast cancer, might modify breast cancer risk stratification tools. Future studies should further assess this link and interrogate shared risk factors.

Novel breast cancer susceptibility loci under linkage peaks identified in African ancestry consortia.

BACKGROUND: Expansion of genome-wide association studies across population groups is needed to improve our understanding of shared and unique genetic contributions to breast cancer. We performed association and replication studies guided by a priori linkage findings from African ancestry (AA) relative pairs. METHODS: We performed fixed-effect inverse-variance weighted meta-analysis under three significant AA breast cancer linkage peaks (3q26-27, 12q22-23, and 16q21-22) in 9241 AA cases and 10 193 AA controls. We examined associations with overall breast cancer as well as estrogen receptor (ER)-positive and negative subtypes (193,132 SNPs). We replicated associations in the African-ancestry Breast Cancer Genetic Consortium (AABCG). RESULTS: In AA women, we identified two associations on chr12q for overall breast cancer (rs1420647, OR = 1.15, p = 2.50×10-6; rs12322371, OR = 1.14, p = 3.15×10-6), and one for ER-negative breast cancer (rs77006600, OR = 1.67, p = 3.51×10-6). On chr3, we identified two associations with ER-negative disease (rs184090918, OR = 3.70, p = 1.23×10-5; rs76959804, OR = 3.57, p = 1.77×10-5) and on chr16q we identified an association with ER-negative disease (rs34147411, OR = 1.62, p = 8.82×10-6). In the replication study, the chr3 associations were significant and effect sizes were larger (rs184090918, OR: 6.66, 95% CI: 1.43, 31.01; rs76959804, OR: 5.24, 95% CI: 1.70, 16.16). CONCLUSION: The two chr3 SNPs are upstream to open chromatin ENSR00000710716, a regulatory feature that is actively regulated in mammary tissues, providing evidence that variants in this chr3 region may have a regulatory role in our target organ. Our study provides support for breast cancer variant discovery using prioritization based on linkage evidence.

Toenail and serum levels as biomarkers of iron status in pre- and postmenopausal women: correlations and stability over eight-year follow-up.

Iron status is often assessed in epidemiologic studies, and toenails offer a convenient alternative to serum because of ease of collection, transport, and storage, and the potential to reflect a longer exposure window. Very few studies have examined the correlation between serum and toenail levels for trace metals. Our aim was to compare iron measures using serum and toenails on both a cross-sectional and longitudinal basis. Using a subset of the US-wide prospective Sister Study cohort, we compared toenail iron measures to serum concentrations for iron, ferritin and percent transferrin saturation. Among 146 women who donated both blood and toenails at baseline, a subsample (59%, n = 86) provided specimens about 8 years later. Cross-sectional analyses included nonparametric Spearman's rank correlations between toenail and serum biomarker levels. We assessed within-woman maintenance of rank across time for the toenail and serum measures and fit mixed effects models to measure change across time in relation to change in menopause status. Spearman correlations at baseline (follow-up) were 0.08 (0.09) for serum iron, 0.08 (0.07) for transferrin saturation, and - 0.09 (- 0.17) for ferritin. The within-woman Spearman correlation for toenail iron between the two time points was higher (0.47, 95% CI 0.30, 0.64) than for serum iron (0.30, 95% CI 0.09, 0.51) and transferrin saturation (0.34, 95% CI 0.15, 0.54), but lower than that for ferritin (0.58, 95% CI 0.43, 0.73). Serum ferritin increased over time while nail iron decreased over time for women who experienced menopause during the 8-years interval. Based on cross-sectional and repeated assessments, our evidence does not support an association between serum biomarkers and toenail iron levels. Toenail iron concentrations did appear to be moderately stable over time but cannot be taken as a proxy for serum iron biomarkers and they may reflect physiologically distinct fates for iron.

International Pooled Analysis of Leisure-Time Physical Activity and Premenopausal Breast Cancer in Women From 19 Cohorts.

PURPOSE: There is strong evidence that leisure-time physical activity is protective against postmenopausal breast cancer risk but the association with premenopausal breast cancer is less clear. The purpose of this study was to examine the association of physical activity with the risk of developing premenopausal breast cancer. METHODS: We pooled individual-level data on self-reported leisure-time physical activity across 19 cohort studies comprising 547,601 premenopausal women, with 10,231 incident cases of breast cancer. Multivariable Cox regression was used to estimate hazard ratios (HRs) and 95% CIs for associations of leisure-time physical activity with breast cancer incidence. HRs for high versus low levels of activity were based on a comparison of risk at the 90th versus 10th percentiles of activity. We assessed the linearity of the relationship and examined subtype-specific associations and effect modification across strata of breast cancer risk factors, including adiposity. RESULTS: Over a median 11.5 years of follow-up (IQR, 8.0-16.1 years), high versus low levels of leisure-time physical activity were associated with a 6% (HR, 0.94 [95% CI, 0.89 to 0.99]) and a 10% (HR, 0.90 [95% CI, 0.85 to 0.95]) reduction in breast cancer risk, before and after adjustment for BMI, respectively. Tests of nonlinearity suggested an approximately linear relationship (Pnonlinearity = .94). The inverse association was particularly strong for human epidermal growth factor receptor 2-enriched breast cancer (HR, 0.57 [95% CI, 0.39 to 0.84]; Phet = .07). Associations did not vary significantly across strata of breast cancer risk factors, including subgroups of adiposity. CONCLUSION: This large, pooled analysis of cohort studies adds to evidence that engagement in higher levels of leisure-time physical activity may lead to reduced premenopausal breast cancer risk.

Dietitian and nutrition-related practices and resources in Australian and New Zealand PICUs: A clinician survey.

BACKGROUND: Recommendations to facilitate evidence-based nutrition provision for critically ill children exist and indicate the importance of nutrition in this population. Despite these recommendations, it is currently unknown how well Australian and New Zealand (ANZ) paediatric intensive care units (PICUs) are equipped to provide nutrition care. OBJECTIVES: The objectives of this project were to describe the dietitian and nutrition-related practices and resources in ANZ PICUs. METHODS: A clinician survey was completed as a component of an observational study across nine ANZ PICUs in June 2021. The online survey comprised 31 questions. Data points included reporting on dietetics resourcing, local feeding-related guidelines and algorithms, nutrition screening and assessment practices, anthropometry practices, and indirect calorimetry (IC) device availability and local technical expertise. Data are presented as frequency (%), mean (standard deviation), or median (interquartile range). RESULTS: Survey responses were received from all nine participating sites. Dietetics staffing per available PICU bed ranged from 0.01 to 0.07 full-time equivalent (median: 0.03 [interquartile range: 0.02-0.04]). Nutrition screening was established in three (33%) units, all of which used the Paediatric Nutrition Screening Tool. Dietitians consulted all appropriate patients (or where capacity allowed) in six (66%) units and on a request or referral basis only in three (33%) units. All units possessed a local feeding guideline or algorithm. An IC device was available in two (22%) PICUs and was used in one of these units. CONCLUSIONS: This is the first study to describe the dietitian and nutrition-related practices and resources of ANZ PICUs. Areas for potential improvement include dietetics full-time equivalent, routine nutrition assessment, and access to IC.

Use of personal care product mixtures and incident hormone-sensitive cancers in the Sister Study: A U.S.-wide prospective cohort.

BACKGROUND: Personal care products (PCPs), a source of endocrine-disrupting chemical exposure, may be associated with the risk of hormone-sensitive cancers. Few studies have investigated associations for PCP use with the incidence of hormone-sensitive cancers or considered the joint effect of multiple correlated PCPs. We examined associations between frequently used, or "everyday", PCPs and incident cancers of the breast, ovary, and uterus with a fucus on the joint effect of multiple product exposure. METHODS: Sister Study participants (n=49 899) self-reported frequency of use in the year before enrollment (2003-2009) for 41 PCPs. Using five-level frequency categories based on questionnaire options, hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for the associations between multiple PCP use and incident breast, ovarian, and uterine cancer using quantile-based g-computation with Cox proportional hazards regression as the underlying model. Multiple PCP use was examined using groupings (beauty, hygiene, and skincare products) determined by both a priori knowledge and Spearman correlation coefficients for co-occurring product use. Associations between individual PCPs and the three cancers were also examined using Cox proportional hazards models coupling with Benjamini-Hochberg procedure for multiple comparisons. RESULTS: Over an average of 11.6 years, 4 226 breast, 277 ovarian, and 403 uterine cancer cases were identified. Positive associations were observed between the hygiene mixture and ovarian cancer (HR=1.35, 95%CI=1.00, 1.83) and the beauty mixture with postmenopausal breast cancer (HR=1.08, 95%CI=1.01, 1.16). Additionally, we observed an inverse association between the skincare mixture and breast cancer (HR=0.91, 95%CI=0.83, 0.99). No significant associations were observed for individual products after corrected for multiple comparison. CONCLUSIONS: Findings from this multi-product, joint-effect approach contribute to the growing body of evidence for associations between PCPs and breast cancer and provides novel information on ovarian and uterine cancer.

Genomic Selection Signals in Andean Highlanders Reveal Adaptive Placental Metabolic Phenotypes That Are Disrupted in Preeclampsia.

BACKGROUND: The chronic hypoxia of high-altitude residence poses challenges for tissue oxygen supply and metabolism. Exposure to high altitude during pregnancy increases the incidence of hypertensive disorders of pregnancy and fetal growth restriction and alters placental metabolism. High-altitude ancestry protects against altitude-associated fetal growth restriction, indicating hypoxia tolerance that is genetic in nature. Yet, not all babies are protected and placental pathologies associated with fetal growth restriction occur in some Andean highlanders. METHODS: We examined placental metabolic function in 79 Andeans (18-45 years; 39 preeclamptic and 40 normotensive) living in La Paz, Bolivia (3600-4100 m) delivered by unlabored Cesarean section. Using a selection-nominated approach, we examined links between putatively adaptive genetic variation and phenotypes related to oxygen delivery or placental metabolism. RESULTS: Mitochondrial oxidative capacity was associated with fetal oxygen delivery in normotensive but not preeclamptic placenta and was also suppressed in term preeclamptic pregnancy. Maternal haplotypes in or within 200 kb of selection-nominated genes were associated with lower placental mitochondrial respiratory capacity (PTPRD [protein tyrosine phosphatase receptor-δ]), lower maternal plasma erythropoietin (CPT2 [carnitine palmitoyl transferase 2], proopiomelanocortin, and DNMT3 [DNA methyltransferase 3]), and lower VEGF (vascular endothelial growth factor) in umbilical venous plasma (TBX5 [T-box transcription factor 5]). A fetal haplotype within 200 kb of CPT2 was associated with increased placental mitochondrial complex II capacity, placental nitrotyrosine, and GLUT4 (glucose transporter type 4) protein expression. CONCLUSIONS: Our findings reveal novel associations between putatively adaptive gene regions and phenotypes linked to oxygen delivery and placental metabolic function in highland Andeans, suggesting that such effects may be of genetic origin. Our findings also demonstrate maladaptive metabolic mechanisms in the context of preeclampsia, including dysregulation of placental oxygen consumption.