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BackgroundWe investigated the associations of reproductive factors known to influence breast cancer risk with the expression of breast stem cell markers CD44, CD24, and ALDH1A1 in benign breast biopsy samples.MethodsWe included 439 cancer-free women with biopsy-confirmed benign breast disease within the Nurses’ Health Study (NHS) and NHSII. The data on reproductive and other breast cancer risk factors were obtained from biennial questionnaires. Immunohistochemistry (IHC) was performed on tissue microarrays. For each core, the IHC expression was assessed using a semi-automated platform and expressed as % of cells that stained positive for a specific marker out of the total cell count. Generalized linear regression was used to examine the associations of reproductive factors with a log-transformed expression of each marker (in epithelium and stroma), adjusted for other breast cancer risk factors.ResultsIn multivariate analysis, the time between menarche and age at first birth was inversely associated with CD44 in epithelium (β per 5 years = −0.38, 95% CI −0.69; −0.06). Age at first birth and the time between menarche and age at first birth were inversely associated with ALDH1A1 (stroma: β per 5 years = −0.43, 95% CI −0.76; −0.10 and β = −0.47, 95% CI −0.79; −0.15, respectively; epithelium: β = −0.15, 95% CI −0.30; −0.01 and β = −0.17, 95% CI −0.30; −0.03, respectively). Time since last pregnancy was inversely associated with stromal ALDH1A1 (β per 5 years = −0.55, 95% CI −0.98; −0.11). No associations were found for CD24. The observed associations were similar in premenopausal women. In postmenopausal women, lifetime duration of breastfeeding was inversely associated with stromal ALDH1A1 expression (β for ≥24 vs. 0 to

Abstract Background Epidemiologic and medical studies often rely on evaluators to obtain measurements of exposures or outcomes for study participants, and valid estimates of associations depends on the quality of data. Even though statistical methods have been proposed to adjust for measurement errors, they often rely on unverifiable assumptions and could lead to biased estimates if those assumptions are violated. Therefore, methods for detecting potential ‘outlier’ evaluators are needed to improve data quality during data collection stage. Methods In this paper, we propose a two-stage algorithm to detect ‘outlier’ evaluators whose evaluation results tend to be higher or lower than their counterparts. In the first stage, evaluators’ effects are obtained by fitting a regression model. In the second stage, hypothesis tests are performed to detect ‘outlier’ evaluators, where we consider both the power of each hypothesis test and the false discovery rate (FDR) among all tests. We conduct an extensive simulation study to evaluate the proposed method, and illustrate the method by detecting potential ‘outlier’ audiologists in the data collection stage for the Audiology Assessment Arm of the Conservation of Hearing Study, an epidemiologic study for examining risk factors of hearing loss in the Nurses’ Health Study II. Results Our simulation study shows that our method not only can detect true ‘outlier’ evaluators, but also is less likely to falsely reject true ‘normal’ evaluators. Conclusions Our two-stage ‘outlier’ detection algorithm is a flexible approach that can effectively detect ‘outlier’ evaluators, and thus data quality can be improved during data collection stage.

BackgroundWe examined associations between dog ownership, morning dog walking and its timing and duration, and depression risk in female nurses, exploring effect modification by chronotype. We hypothesized that dog ownership and morning walking with the dog are associated with lower odds of depression, and that the latter is particularly beneficial for evening chronotypes by helping them to synchronize their biological clock with the solar system.Methods26,169 depression-free US women aged 53-72 from the Nurses' Health Study 2 (NHS2) were prospectively followed from 2017-2019. We used age- and multivariable-adjusted logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (95%CIs) for depression according to dog ownership, and morning dog walking, duration, and timing.ResultsOverall, there was no association between owning a dog (ORvs_no_pets = 1.12, 95%CI = 0.91-1.37), morning dog walking (ORvs_not = 0.87, 95%CI = 0.64-1.18), or the duration (OR>30min vs. ≤15mins = 0.68, 95%CI = 0.35-1.29) or timing of morning dog walks (ORafter9am vs. before7am = 1.06, 95%CI = 0.54-2.05) and depression. Chronotype of dog owners appeared to modify these associations. Compared to women of the same chronotype but without pets, dog owners with evening chronotypes had a significantly increased odds of depression (OR = 1.60, 95%CI = 1.12-2.29), whereas morning chronotypes did not (OR = 0.94, 95%CI = 0.71-1.23). Further, our data suggested that evening chronotypes benefited more from walking their dog themselves in the morning (OR = 0.75, 95%CI = 0.46-1.23, Pintx = 0.064;) than morning chronotypes.ConclusionsOverall, dog ownership was not associated with depression risk though it was increased among evening chronotypes. Walking their dog in the morning might help evening chronotypes to lower their odds of depression, though more data are needed to confirm this finding.

Abstract Delirium is an acute confusional state and a common postoperative morbidity. Prevalent in older adults, delirium occurs at other ages but it is unclear whether the pathophysiology and biomarkers for the condition are independent of age. We quantified expression of 273 plasma proteins involved in inflammation and cardiovascular or neurologic conditions in 34 middle-aged and 42 older patients before and one day after elective spine surgery. Delirium was identified by the 3D-CAM and comprehensive chart review. Protein expression was measure by Proximity Extension Assay and results were analyzed by logistic regression, gene set enrichment, and protein–protein interactions. Twenty-two patients developed delirium postoperatively (14 older; 8 middle-aged) and 89 proteins in pre- or 1-day postoperative plasma were associated with delirium. A few proteins (IL-8, LTBR, TNF-R2 postoperatively; IL-8, IL-6, LIF, ASGR1 by pre- to postoperative change) and 12 networks were common to delirium in both age groups. However, there were marked differences in the delirium proteome by age; older patients had many more delirium-associated proteins and pathways than middle-aged subjects even though both had the same clinical syndrome. Therefore, there are age-dependent similarities and differences in the plasma proteomic signature of postoperative delirium, which may signify age differences in pathogenesis of the syndrome.

The area under the true ROC curve (AUC) is routinely used to determine how strongly a given model discriminates between the levels of a binary outcome. Standard inference with the AUC requires that outcomes be independent of each other. To overcome this limitation, a method was developed for the estimation of the variance of the AUC in the setting of two-level hierarchical data using probit-transformed prediction scores generated from generalized estimating equation models, thereby allowing for the application of inferential methods. This manuscript presents an extension of this approach so that inference for the AUC may be performed in a three-level hierarchical data setting (e.g., eyes nested within persons and persons nested within families). A method that accounts for the effect of tied prediction scores on inference is also described. The performance of 95% confidence intervals around the AUC was assessed through the simulation of three-level clustered data in multiple settings, including ones with tied data and variable cluster sizes. Across all settings, the actual 95% confidence interval coverage varied from 0.943 to 0.958, and the ratio of the theoretical variance to the empirical variance of the AUC varied from 0.920 to 1.013. The results are better than those from existing methods. Two examples of applying the proposed methodology are presented.

Abstract Background We investigated the associations of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) with breast cancer risk by the status of COX-2 protein expression. Methods This study included 421 cases and 3,166 controls from a nested case–control study within the Nurses’ Health Study (NHS) and Nurses’ Health Study II (NHSII) cohorts. Information on medication use was first collected in 1980 (NHS) and 1989 (NHSII) and was updated biennially. Medication use was defined as none, past or current; average cumulative dose and frequency were calculated for all past or current users using data collected from all biannual questionnaires preceding the reference date. Immunochemistry for COX-2 expression was performed using commercial antibody (Cayman Chemical and Thermo Fisher Scientific). We used polychotomous logistic regression to quantify associations of aspirin and NSAIDs with the risk of COX2+ and COX2− breast cancer tumors, while adjusting for known breast cancer risk factors. All tests of statistical significance were two-sided. Results In multivariate analysis, we found no differences in associations of the aspirin exposures and NSAIDs with breast cancer risk by COX2 expression status. In stratified analyses by COX2 status, significant associations of these medications with breast cancer risk were observed for dosage of aspirin among current users in COX2- tumors (OR for > 5 tablets per week vs. none 1.71, 95% CI 1.01–2.88, p-trend 0.04). Regular aspirin use was marginally associated with the risk of COX2- tumors (p-trend = 0.06). Conclusions Our findings suggested no differences in associations of aspirin and other NSAIDs with COX2+ and COX2− tumors.

Background and objectivesCrossover designs are frequently used to assess treatments for patients with Parkinson’s disease. Typically, two-period two-treatment trials include a washout period between the 2 periods and assume that the washout period is sufficiently long to eliminate carryover effects. A complementary strategy might be to jointly model carryover and treatment effects, though this has rarely been done in Parkinson’s disease crossover studies. The primary objective of this research is to demonstrate a modeling approach that assesses treatment and carryover effects in one unified mixed model analysis and to examine how it performs in a simulation study and a real data analysis example, as compared to other data analytic approaches used in Parkinson’s disease crossover studies.MethodsWe examined how three different methods of analysis (standard crossover t-test, mixed model with a carryover term included in model statement, and mixed model with no carryover term) performed in a simulation study and illustrated the methods in a real data example in Parkinson’s disease.ResultsThe simulation study based on the presence of a carryover effect indicated that mixed models with a carryover term and an unstructured correlation matrix provided unbiased estimates of treatment effect and appropriate type I error. The methods are illustrated in a real data example involving Parkinson’s disease. Our literature review revealed that a majority of crossover studies included a washout period but did not assess whether the washout was sufficiently long to eliminate the possibility of carryover.DiscussionWe recommend using a mixed model with a carryover term and an unstructured correlation matrix to obtain unbiased estimates of treatment effect.

Purpose: To evaluate associations between rare dysfunctional complement factor I (CFI) genetic variant status and progression to advanced age-related macular degeneration (AAMD), geographic atrophy (GA), and neovascular disease (NV). Design: Prospective, longitudinal study Participants: Patients aged 55 to 80 years at baseline identifying as White with non-AAMD in 1 or both eyes at baseline were included. Follow-up grades were assigned as early, intermediate, or AAMD (GA or NV). CFI variants were categorized using genotyping and sequencing platforms. Methods: Analyses were performed using the Seddon Longitudinal Cohort Study (N = 2116 subjects, 3901 eyes, and mean follow-up of 8.3 years) and the Age-Related Eye Disease Study (N = 2837 subjects, 5200 eyes, and mean follow-up of 9.2 years). CFI rare variants associated with low serum factor I (FI) protein levels and decreased FI function (type 1), other AMD genetic variants, and demographic, behavioral, and ocular factors were evaluated. Generalized estimating equations methods were used to assess the association between CFI rare variants and progression, independent of other genetic variants and covariates. Main Outcome Measures: Progression to AAMD, GA, or NV. Results: In the prospective cohort of 4953 subjects (9101 eyes with non-AAMD at baseline), 1% were type 1 rare CFI carriers. Over 12 years, progression to AAMD was 44% for carriers and 20% for noncarriers (P < 0.001), 30% of carriers versus 10% of noncarriers progressed to GA (P

Abstract Background Epidemiological studies have demonstrated a favorable association of whole grain intake with coronary heart disease (CHD) risk, although whether such an inverse association holds true for individual whole grain foods that have various nutritional profiles has not been examined. Methods We followed 74,244 women from Nurses’ Health Study since 1986, 91,430 women from Nurses’ Health Study II since 1991, and 39,455 men from the Health Professionals Follow-Up Study since 1984, who did not have a history of cardiovascular disease or cancer at baseline. Intake of seven individual whole grain foods was repeatedly assessed using a validated semi-quantitative food frequency questionnaire every 2–4 years since baseline. CHD diagnoses were ascertained through review of medical records or death certificates. Results We documented 9461 CHD cases during an average of 25.8 years’ follow-up. In the multivariable-adjusted model, the pooled hazard ratio (HR) (95% CI) of CHD risk corresponding to each one serving/day consumption of total whole grains was 0.93 (0.90–0.95; p trend

BackgroundThe data on the expression of stem cell markers CD44, CD24, and ALDH1A1 in the breast tissue of cancer-free women is very limited and no previous studies have explored the agreement between pathologist and computational assessments of these markers. We compared the immunohistochemical (IHC) expression assessment for CD44, CD24, and ALDH1A1 by an expert pathologist with the automated image analysis results and assessed the homogeneity of the markers across multiple cores pertaining to each woman.MethodsWe included 81 cancer-free women (399 cores) with biopsy-confirmed benign breast disease in the Nurses’ Health Study (NHS) and NHSII cohorts. IHC was conducted with commercial antibodies [CD44 (Dako, Santa Clara, CA, USA) 1:25 dilution; CD24 (Invitrogen, Waltham, MA, USA) 1:200 dilution and ALDH1A1 (Abcam, Cambridge, United Kingdom) 1:300 dilution]. For each core, the percent positivity was quantified by the pathologist and Definiens Tissue Studio. Correlations between pathologist and computational scores were evaluated with Spearman correlation (for categorical positivity: 0, >0–10–50, and >50%) and sensitivity/specificity (for binary positivity defined with 1 and 10% cut-offs), using the pathologist scores as the gold standard. Expression homogeneity was examined with intra-class correlation (ICC). Analyses were stratified by core [normal terminal duct-lobular units (TDLUs), benign lesions] and tissue type (epithelium, stroma).ResultsSpearman correlation between pathologist and Definiens ranged between 0.40–0.64 for stroma and 0.66–0.68 for epithelium in normal TDLUs cores and between 0.24–0.60 for stroma and 0.61–0.64 for epithelium in benign lesions. For stroma, sensitivity and specificity ranged between 0.92–0.95 and 0.24–0.60, respectively, with 1% cut-off and between 0.43–0.88 and 0.73–0.85, respectively, with 10% cut-off. For epithelium, 10% cut-off resulted in better estimates for both sensitivity and specificity. ICC between the cores was strongest for CD44 for both stroma and epithelium in normal TDLUs cores and benign lesions (range 0.74–0.80). ICC for CD24 and ALDH1A ranged between 0.42–0.63 and 0.44–0.55, respectively.ConclusionOur findings show that computational assessments for CD44, CD24, and ALDH1A1 exhibit variable correlations with manual assessment. These findings support the use of computational platforms for IHC evaluation of stem cell markers in large-scale epidemiologic studies. Pilot studies maybe also needed to determine appropriate cut-offs for defining staining positivity.

Abstract Background In many applications of instrumental variable (IV) methods, the treatments of interest are intrinsically time-varying and outcomes of interest are failure time outcomes. A common example is Mendelian randomization (MR), which uses genetic variants as proposed IVs. In this article, we present a novel application of g-estimation of structural nested cumulative failure models (SNCFTMs), which can accommodate multiple measures of a time-varying treatment when modelling a failure time outcome in an IV analysis. Methods A SNCFTM models the ratio of two conditional mean counterfactual outcomes at time k under two treatment strategies which differ only at an earlier time m. These models can be extended to accommodate inverse probability of censoring weights, and can be applied to case-control data. We also describe how the g-estimates of the SNCFTM parameters can be used to calculate marginal cumulative risks under nondynamic treatment strategies. We examine the performance of this method using simulated data, and present an application of these models by conducting an MR study of alcohol intake and endometrial cancer using longitudinal observational data from the Nurses’ Health Study. Results Our simulations found that estimates from SNCFTMs which used an IV approach were similar to those obtained from SNCFTMs which adjusted for confounders, and similar to those obtained from the g-formula approach when the outcome was rare. In our data application, the cumulative risk of endometrial cancer from age 45 to age 72 under the “never drink” strategy (4.0%) was similar to that under the “always ½ drink per day” strategy (4.3%). Conclusions SNCFTMs can be used to conduct MR and other IV analyses with time-varying treatments and failure time outcomes.

Inadequate sleep is a global health concern. Sleep is multidimensional and complex; new multi-ingredient agents are needed. This study assessed the comparative effects of two multi-ingredient supplements on sleep relative to placebo. Adults (N = 620) seeking better sleep were randomly assigned to receive one of three study products. Sleep A (contained lower (0.35 mg THC and higher levels of botanicals (75 mg each hops oil and valerian oil), Sleep B (contained higher THC (0.85 mg) and lower botanicals (20 mg each hops oil and valerian oil) or placebo) for 4 weeks. Sleep disturbance was assessed at baseline and weekly using NIH’s Patient-Reported Outcomes Measurement Information System (PROMIS™) Sleep Disturbance SF 8A survey. Anxiety, stress, pain, and well-being were assessed using validated measures at baseline and weekly. A linear mixed-effects regression model was used to assess the change in health outcome score between active product groups and the placebo. There was a significant difference in sleep disturbance, anxiety, stress, and well-being between Sleep A and placebo. There was no significant difference in any health parameter between Sleep B and placebo. Side effects were mild or moderate. There were no significant differences in the frequency of side effects between the study groups. A botanical blend containing a low concentration of THC improved sleep disturbance, anxiety, stress, and well-being in healthy individuals that reported better sleep as a primary health concern.

Abstract Background We investigated the associations of reproductive factors with the percentage of epithelium, stroma, and fat tissue in benign breast biopsy samples. Methods This study included 983 cancer-free women with biopsy-confirmed benign breast disease (BBD) within the Nurses’ Health Study and Nurses’ Health Study II cohorts. The percentage of each tissue type (epithelium, stroma, and fat) was measured on whole-section images with a deep-learning technique. All tissue measures were log-transformed in all the analyses to improve normality. The data on reproductive variables and other breast cancer risk factors were obtained from biennial questionnaires. Generalized linear regression was used to examine the associations of reproductive factors with the percentage of tissue types, while adjusting for known breast cancer risk factors. Results As compared to parous women, nulliparous women had a smaller percentage of epithelium (β = − 0.26, 95% confidence interval [CI] − 0.41, − 0.11) and fat (β = − 0.34, 95% CI − 0.54, − 0.13) and a greater percentage of stroma (β = 0.04, 95% CI 0.01, 0.08). Among parous women, the number of children was inversely associated with the percentage of stroma (β per child = − 0.01, 95% CI − 0.02, − 0.00). The duration of breastfeeding of ≥ 24 months was associated with a reduced proportion of fat (β = − 0.30, 95% CI − 0.54, − 0.06; p-trend = 0.04). In a separate analysis restricted to premenopausal women, older age at first birth was associated with a greater proportion of epithelium and a smaller proportion of stroma. Conclusions Our findings suggest that being nulliparous as well as having a fewer number of children (both positively associated with breast cancer risk) is associated with a smaller proportion of epithelium and a greater proportion of stroma, potentially suggesting the importance of epithelial-stromal interactions. Future studies are warranted to confirm our findings and to elucidate the underlying biological mechanisms.

Wilcoxon rank-based tests are distribution-free alternatives to the popular two-sample and paired t tests. For independent data, they are available in several R packages such as stats and coin. For clustered data, in spite of the recent methodological developments, there did not exist an R package that makes them available at one place. We present a package clusrank where the latest developments are implemented and wrapped under a unified user-friendly interface. With different methods dispatched based on the inputs, this package offers great flexibility in rank-based tests for various clustered data. Exact tests based on permutations are also provided for some methods. Details of the major schools of different methods are briefly reviewed. Usages of the package clusrank are illustrated with simulated data as well as a real dataset from an ophthalmological study. The package also enables convenient comparison between selected methods under settings that have not been studied before and the results are discussed.

Abstract Adolescent drinking is associated with higher risks of proliferative benign breast disease (BBD) and invasive breast cancer (BC). Furthermore, adolescent nut and fiber consumptions are associated with lower risks of benign lesions and premenopausal BC. We hypothesize that diet (nuts, fiber) may mitigate the elevated BBD risk associated with alcohol. A prospective cohort of 9031 females, 9–15 years at baseline, completed questionnaires in 1996–2001, 2003, 2005, 2007, 2010, 2013, and 2014. Participants completed food frequency questionnaires in 1996–2001. In 2005, participants (>=18 years) began reporting biopsy-confirmed BBD (N = 173 cases). Multivariable logistic regression estimated associations between BBD and cross-classified intakes (14–17 years) of alcohol and peanut butter/nuts (separately, total dietary fiber). Only 19% of participants drank in high school; drinking was associated with elevated BBD risk (OR = 1.75, 95% CI: 1.20–2.56; p = 0.004) compared to nondrinkers. Participants consuming any nuts/butter had lower BBD risk (OR = 0.64, 95% CI: 0.45–0.90; p = 0.01) compared to those consuming none. Participants in top 75% fiber intake had lower risk (OR = 0.57, 95% CI: 0.40–0.81; p = 0.002) compared to bottom quartile. Testing our hypothesis that consuming nuts/butter mitigates the elevated alcohol risk, analyzing alcohol and nuts combined found that those who consumed both had lower risk (RR = 0.47, 95% CI: 0.24–0.89; p = 0.02) compared to drinkers eating no nuts. Our analysis of alcohol and fiber together did not demonstrate risk mitigation by fiber. For high school females who drink, their BBD risk may be attenuated by consuming nuts. Due to modest numbers, future studies need to replicate our findings in adolescent/adult females. However, high school students may be encouraged to eat nuts and fiber, and to avoid alcohol, to reduce risk of BBD and for general health benefits.

Objective: Blood pressure (BP) references for Brazilian adolescents are lacking in the literature. This study aims to investigate the normal range of office BP in a healthy, non‐overweight Brazilian population of adolescents. Method: The Brazilian Study of Cardiovascular Risks in Adolescents (Portuguese acronym “ERICA”) is a national school‐based study that included adolescents (aged 12 through 17 years), enrolled in public and private schools, in cities with over 100,000 inhabitants, from all five Brazilian macro‐regions. Adolescents’ height and body mass index (BMI) were classified in percentiles according to age and gender, and reference curves from the World Health Organization were adopted. Three consecutive office BP measurements were taken with a validated oscillometric device using the appropriate cuff size. The mean values of the last two readings were used for analysis. Polynomial regression models relating BP, age, and height were applied. Results: Among 73,999 adolescents, non‐overweight individuals represented 74.5% (95% CI: 73.3–75.6) of the total, with similar distribution across ages. The majority of the non‐overweight sample was from public schools 84.2% (95% CI: 79.9–87.7) and sedentary 54.8% (95% CI: 53.7–55.8). Adolescents reporting their skin color as brown (48.8% [95% CI: 47.4–50.1]) or white (37.8% [95% CI: 36.1–39.5]) were most frequently represented. BP increased by both age and height percentile. Systolic BP growth patterns were more marked in males when compared to females, along all height percentiles. The same pattern was not observed for diastolic BP. Conclusions: Blood pressure references by sex, age, and height percentiles for Brazilian adolescents are provided. Resumo: Objetivo: Referências de pressão arterial (PA) para adolescentes brasileiros estão ausentes na literatura. Este estudo tem como objetivo investigar a variação normal da pressão arterial no consultório em uma população brasileira saudável de adolescentes sem sobrepeso. Método: O Estudo dos Riscos Cardiovasculares em Adolescentes (ERICA) é um estudo brasileiro, de âmbito nacional e de base escolar, que incluiu adolescentes (12 a 17 anos) matriculados em escolas públicas e privadas, em cidades com mais de 100.000 habitantes, de todas as cinco macrorregiões brasileiras. A altura e o índice de massa corporal (IMC) dos adolescentes foram classificados em percentis de acordo com a idade e o sexo, sendo adotadas as curvas de referência da Organização Mundial de Saúde. Foram realizadas três medidas consecutivas de PA no consultório com um dispositivo oscilométrico validado, utilizando o manguito de tamanho apropriado. Os valores médios das duas últimas leituras foram utilizados nas análises. Modelos de regressão polinomial relacionando PA, idade e estatura foram aplicados. Resultados: Entre os 73.999 adolescentes, os indivíduos sem sobrepeso representaram 74,5% (IC95%: 73,3‐75,6) do total, com distribuição similar entre as idades. A maior parte da amostra sem sobrepeso originava‐se das escolas públicas, com 84,2% (IC95%: 79,9‐87,7), e os sedentários 54,8% (IC95%: 53,7‐55,8). Os adolescentes que relataram sua cor de pele como parda (48,8% [IC95%: 47,4‐50,1]) e branca (37,8%: [IC 95% 36,1‐39,5]) foram os mais representados. A PA aumentou tanto com a idade, quanto com o percentil de altura. Os padrões de aumento sistólico da PA foram mais acentuados no sexo masculino quando comparados ao sexo feminino, em todos os percentis de altura. O mesmo padrão não foi observado para a PA diastólica. Conclusões: São fornecidas referências de pressão arterial por sexo, idade e percentil de altura para adolescentes brasileiros. Keywords: Pediatric, Office blood pressure, Hypertension, Blood pressure measurement/monitoring, Diagnostic method, Palavras‐chave: Pediátrico, Pressão arterial no consultório, Hipertensão, Mensuração/monitorização da pressão arterial, Método diagnóstico

In low- and middle-income countries (LMIC), measurement of symphysis fundal height (SFH) is often the only available method of estimating gestational age (GA) in pregnancy. This systematic review aims to summarize methods of SFH measurement and assess the accuracy of SFH for the purpose of GA estimation. We searched PubMed, EMBASE, Cochrane, Web of Science, POPLINE, and WHO Global Health Libraries from January 1980 through November 2021. For SFH accuracy, we pooled the variance of the mean difference between GA confirmed by ultrasound versus SFH. Of 1,003 studies identified, 37 studies were included. Nineteen different SFH measurement techniques and 13 SFH-to-GA conversion methods were identified. In pooled analysis of five studies (n = 5838 pregnancies), 71% (95% CI: 66-77%) of pregnancies dated by SFH were within ±14 days of ultrasound confirmed dating. Using the 1 cm SFH = 1wk assumption, SFH underestimated GA compared with ultrasound-confirmed GA (mean bias: -14.0 days) with poor accuracy (95% limits of agreement [LOA]: ±42.8 days; n = 3 studies, 2447 pregnancies). Statistical modeling of three serial SFH measurements performed better, but accuracy was still poor (95% LOA ±33 days; n = 4 studies, 4391 pregnancies). In conclusion, there is wide variation in SFH measurement and SFH-to-GA conversion techniques. SFH is inaccurate for estimating GA and should not be used for GA dating. Increasing access to quality ultrasonography early in pregnancy should be prioritized to improve gestational age assessment in LMIC.

Abstract Background Epidemiologic data suggest that parity increases risk of hormone receptor-negative breast cancer and that breastfeeding attenuates this association. Prospective data, particularly on the joint effects of higher parity and breastfeeding, are limited. Methods We investigated parity, breastfeeding, and breast cancer risk by hormone-receptor (estrogen (ER) and progesterone receptor (PR)) and molecular subtypes (luminal A, luminal B, HER2-enriched, and basal-like) in the Nurses’ Health Study (NHS; 1976–2012) and NHSII (1989–2013). A total of 12,452 (ER+ n = 8235; ER− n = 1978) breast cancers were diagnosed among 199,514 women. We used Cox proportional hazards models, adjusted for breast cancer risk factors, to calculate hazard ratios (HR) and 95% confidence intervals (CI). Results Parous women had lower risk of ER+ breast cancer (vs. nulliparous, HR = 0.82 [0.77–0.88]); no association was observed for ER− disease (0.98 [0.84–1.13]; P het = 0.03). Among parous women, breastfeeding was associated with lower risk of ER− (vs. never 0.82 [0.74–0.91]), but not ER+, disease (0.99 [0.94–1.05]; P het

In epidemiological studies, samples are often collected long before disease onset or outcome assessment. Understanding the long-term stability of biomarkers measured in these samples is crucial. We estimated within-person stability over 10 years of metabolites and metabolite features (n = 5938) in the Nurses’ Health Study (NHS): the primary dataset included 1880 women with 1184 repeated samples donated 10 years apart while the secondary dataset included 1456 women with 488 repeated samples donated 10 years apart. We quantified plasma metabolomics using two liquid chromatography mass spectrometry platforms (lipids and polar metabolites) at the Broad Institute (Cambridge, MA, USA). Intra-class correlations (ICC) were used to estimate long-term (10 years) within-person stability of metabolites and were calculated as the proportion of the total variability (within-person + between-person) attributable to between-person variability. Within-person variability was estimated among participants who donated two blood samples approximately 10 years apart while between-person variability was estimated among all participants. In the primary dataset, the median ICC was 0.43 (1st quartile (Q1): 0.36; 3rd quartile (Q3): 0.50) among known metabolites and 0.41 (Q1: 0.34; Q3: 0.48) among unknown metabolite features. The three most stable metabolites were N6,N6-dimethyllysine (ICC = 0.82), dimethylguanidino valerate (ICC = 0.72), and N-acetylornithine (ICC = 0.72). The three least stable metabolites were palmitoylethanolamide (ICC = 0.05), ectoine (ICC = 0.09), and trimethylamine-N-oxide (ICC = 0.16). Results in the secondary dataset were similar (Spearman correlation = 0.87) to corresponding results in the primary dataset. Within-person stability over 10 years is reasonable for lipid, lipid-related, and polar metabolites, and varies by metabolite class. Additional studies are required to estimate within-person stability over 10 years of other metabolites groups.

ObjectiveTo improve the accuracy of the prediction of gestational age (GA) before birth with the standardised measurement of symphysis-fundal height (SFH), estimation of uterine volume, and statistical modelling including maternal anthropometrics and other factors.DesignProspective pregnancy cohort study.SettingRural communities in Sylhet, Bangladesh.Participants1516 women with singleton pregnancies with early pregnancy ultrasound dating (37 weeks gestation. An estimated uterine volume (EUV) was calculated from these measures. Data on pregnancy characteristics and other maternal anthropometrics were also collected.Primary outcome measureGA at subsequent ANC visits, as defined by early ultrasound dating.Results1486 (98%) women had at least one subsequent ANC visit, 1102 (74%) women had two subsequent ANC visits, and 748 (50%) had three visits. Using the common clinical practice of approximating the GA (in weeks) with the SFH measurement (cm), SFH systematically underestimated GA in late pregnancy (mean difference −4.4 weeks, 95% limits of agreement −12.5 to 3.7). For the classification of GA

Inflammation and B-cell hyperactivation have been associated with non-Hodgkin lymphoma development. This prospective analysis aimed to further elucidate pre-diagnosis plasma immune marker profiles associated with non-Hodgkin lymphoma risk. We identified 598 incident lymphoma cases and 601 matched controls in Nurses’ Health Study and Health Professionals Follow-up Study participants with archived pre-diagnosis plasma samples and measured 13 immune marker levels with multiplexed immunoassays. Using multivariable logistic regression we calculated Odds Ratios (OR) and 95% Confidence Intervals (CI) per standard deviation unit increase in biomarker concentration for risk of non-Hodgkin lymphoma and major histological subtype, stratifying additional models by years (

Industrial fortification of wheat flour is a potentially effective strategy for addressing micronutrient deficiencies in Mongolia, given its ubiquitous consumption and centralized production. However, Mongolia has not mandated fortification of any foods except for salt with iodine. This study modeled the effectiveness and safety of mandatory industrial fortification of wheat flour alone and in combination with edible oil and milk in reducing the prevalence of multiple micronutrient intake deficiencies among healthy non-pregnant adults in Mongolia. Six days of diet records (3 summer, 3 winter) were collected from 320 urban and rural adults across the country and analyzed for food and nutrient consumption using a purpose-built food composition table, and the Intake Monitoring and Planning Program (IMAPP) was used to project the effects of fortification on summer and winter bioavailable micronutrient intake and intake deficiency under different fortification guidelines within population subgroups defined by urban or rural locality and sex. Projections showed that flour fortification would be effective in reducing intake deficiencies of thiamin and folate, while marginal benefits of fortification with iron and riboflavin would be smaller given these nutrients' higher baseline consumption, and fortification with zinc, niacin, and vitamin B12 may be unnecessary. Fortification of flour, oil, and milk with vitamins A, D, and E at levels suggested by international guidelines would substantially reduce vitamin A intake deficiency and would increase vitamin D intake considerably, with the greatest benefits elicited by flour fortification and smaller benefits by additionally fortifying oil and milk. These results support mandatory industrial fortification of wheat flour, edible oil, and milk with iron, thiamin, riboflavin, folate, and vitamins A, D, and E in Mongolia. Considerations will be necessary to ensure the fortification of these nutrients is also effective for children, for whom the potential benefit of zinc, niacin, and vitamin B12 fortification should be assessed.

Dietary diversity scores (DDS) are considered as metrics for monitoring the implementation of the UN's Sustainable Development Goals, but they need to be rigorously evaluated.To examine two DDS, the Food Groups Index (FGI), and the Minimum Dietary Diversity-Women (MDD-W), alongside two dietary quality scores, the Alternate Healthy Eating Index (AHEI-2010) and the Prime Diet Quality Score (PDQS), with risks of gestational diabetes mellitus (GDM) and hypertensive disorders of pregnancy (HDPs).The analysis included 21,312 (GDM) and 19,917 (HDPs) singleton births reported in the Nurses' Health Study II cohort (1991-2001), among women without major chronic disease or GDM/HDPs. Scores were derived using prepregnancy diet collected by a comprehensive food frequency questionnaire. Multivariable models were utilized to calculate relative risks (RR) and confidence intervals (95%CIs).Incident GDM (n = 916) and HDPs (n = 1,421) were reported. The MDD-W and FGI were not associated with risk of GDM or HDPs, but the AHEI-2010 and PDQS were associated with a lower risk of GDM and marginally lower risk of HDP. The RR's of GDM comparing the highest vs. lowest quintiles were 1.00 (95%CI: 0.79, 1.27; p-trend = 0.82) for MDD-W, 0.96 (95%CI: 0.76, 1.22; p-trend = 0.88) for FGI, 0.63 (95%CI: 0.50, 0.81; p-trend

BackgroundAlthough the timing of menarche and menopause may be associated with cardiovascular disease (CVD), the entire reproductive life span has not been considered comprehensively as risk for CVD. We investigate the associations of reproductive life span duration and ages at menarche and menopause, induced by natural means or surgical bilateral oophorectomy, with incident CVD in women. Methods and ResultsProspective cohort study of 73 814 Nurses' Health Study following participants without CVD, defined as incident coronary heart disease or stroke, from 1980 through 2012. Duration of reproductive life span was generated by subtracting age at menarche from age at menopause. A shorter reproductive life span was associated with a higher risk of incident CVD after multivariable adjustment (relative risk, 1.32 [95% confidence interval, 1.16–1.49] comparing duration

Household consumption and expenditure surveys are frequently conducted around the world and they usually include data on household food consumption, but their applicability to nutrition research is limited by their collection at the household level. Using data from Mongolia, this study evaluated four approaches for estimating diet from household surveys: direct inference from per-capita household consumption; disaggregation of household consumption using a statistical method and the “adult male equivalent” method, and direct prediction of dietary intake. Per-capita household consumption overestimated dietary energy in single- and multi-person households by factors of 2.63 and 1.89, respectively. Performance of disaggregation methods was variable across two household surveys analyzed, while the statistical method exhibited less bias in estimating intake densities (per 100 kcal) of most dietary components in both of the surveys. Increasingly complex prediction models explained 54% to 72% of in-sample variation in dietary energy, with consistent benefits incurred by inclusion of basic dietary measurements. In conclusion, in Mongolia and elsewhere, differences in how household and dietary measurements are recorded make their comparison challenging. Validity of disaggregation methods depends on household survey characteristics and the dietary components that are considered. Relatively precise prediction models of dietary intake can be achieved by integrating basic dietary assessment into household surveys.

To assess the independent impact of new genetic variants on conversion to advanced stages of AMD, controlling for established risk factors, and to determine the contribution of genes in predictive models.In this prospective longitudinal study of 2765 individuals, 777 subjects progressed to neovascular disease (NV) or geographic atrophy (GA) in either eye over 12 years. Recently reported genetic loci were assessed for their independent effects on incident advanced AMD after controlling for 6 established loci in 5 genes, and demographic, behavioral, and macular characteristics. New variants which remained significantly related to progression were then added to a final multivariate model to assess their independent effects. The contribution of genes to risk models was assessed using reclassification tables by determining risk within cross-classified quintiles for alternative models.THREE NEW GENETIC VARIANTS WERE SIGNIFICANTLY RELATED TO PROGRESSION: rare variant R1210C in CFH (hazard ratio (HR) 2.5, 95% confidence interval [CI] 1.2-5.3, P = 0.01), and common variants in genes COL8A1 (HR 2.0, 95% CI 1.1-3.5, P = 0.02) and RAD51B (HR 0.8, 95% CI 0.60-0.97, P = 0.03). The area under the curve statistic (AUC) was significantly higher for the 9 gene model (.884) vs the 0 gene model (.873), P = .01. AUC's for the 9 vs 6 gene models were not significantly different, but reclassification analyses indicated significant added information for more genes, with adjusted odds ratios (OR) for progression within 5 years per one quintile increase in risk score of 2.7, P

Breast, endometrial, and ovarian cancers share some hormonal and epidemiologic risk factors. While several models predict absolute risk of breast cancer, there are few models for ovarian cancer in the general population, and none for endometrial cancer.Using data on white, non-Hispanic women aged 50+ y from two large population-based cohorts (the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial [PLCO] and the National Institutes of Health-AARP Diet and Health Study [NIH-AARP]), we estimated relative and attributable risks and combined them with age-specific US-population incidence and competing mortality rates. All models included parity. The breast cancer model additionally included estrogen and progestin menopausal hormone therapy (MHT) use, other MHT use, age at first live birth, menopausal status, age at menopause, family history of breast or ovarian cancer, benign breast disease/biopsies, alcohol consumption, and body mass index (BMI); the endometrial model included menopausal status, age at menopause, BMI, smoking, oral contraceptive use, MHT use, and an interaction term between BMI and MHT use; the ovarian model included oral contraceptive use, MHT use, and family history or breast or ovarian cancer. In independent validation data (Nurses' Health Study cohort) the breast and ovarian cancer models were well calibrated; expected to observed cancer ratios were 1.00 (95% confidence interval [CI]: 0.96-1.04) for breast cancer and 1.08 (95% CI: 0.97-1.19) for ovarian cancer. The number of endometrial cancers was significantly overestimated, expected/observed = 1.20 (95% CI: 1.11-1.29). The areas under the receiver operating characteristic curves (AUCs; discriminatory power) were 0.58 (95% CI: 0.57-0.59), 0.59 (95% CI: 0.56-0.63), and 0.68 (95% CI: 0.66-0.70) for the breast, ovarian, and endometrial models, respectively.These models predict absolute risks for breast, endometrial, and ovarian cancers from easily obtainable risk factors and may assist in clinical decision-making. Limitations are the modest discriminatory ability of the breast and ovarian models and that these models may not generalize to women of other races. Please see later in the article for the Editors' Summary.

Background. Thyroid status may influence tumorigenesis of gynecologic cancers, yet epidemiologic studies of this relationship are limited and inconsistent. Methods. We evaluated the association of self-reported history of physician-diagnosed hypothyroidism and hyperthyroidism with medical-record confirmed endometrial (EC; all invasive adenocarcinomas) and ovarian cancer (OC; epithelial ovarian or peritoneal cancers) in Nurses' Health Study (NHS) from 1976 to 2010 and NHSII from 1989 to 2011. Cox proportional hazard models were used to estimate multivariable rate ratios (RRs) and 95% confidence intervals based on pooled cohort data. Results. We confirmed 1314 incident cases of EC and 1150 cases of OC. Neither a history of hypothyroidism nor hyperthyroidism was significantly associated with risk of EC or OC. However, having a history of hypothyroidism for 8+ years (median) was nonsignificantly inversely associated with EC (RR = 0.81; 95% CI = 0.63–1.04; P-trend with history duration = 0.11) and OC (RR = 0.87, 95% CI = 0.66–1.15; P-trend = 0.13). Having a history of hyperthyroidism for 6+ years (median) was non-significantly positively associated with EC (RR = 1.69; 95% CI = 0.86–3.30; P-trend = 0.12) but not OC (RR = 1.12; 95% CI = 0.46–2.72; P-trend = 0.95). Conclusions. A history of hypothyroidism or hyperthyroidism was not significantly associated with risk of EC or OC.

Abnormal one-carbon metabolism may lead to general genomic (global) hypomethylation, which may predispose an individual to the development of colorectal neoplasia.We evaluated the association between pre-diagnostic leukocyte genomic DNA methylation level and the risk of colorectal cancer in a nested case-control study of 358 colorectal cancer cases and 661 matched controls within the all-female cohort of the Nurses' Health Study (NHS). Among control subjects, we further examined major plasma components in the one-carbon metabolism pathway in relation to genomic DNA methylation level. Liquid chromatography/tandem mass spectrometry was used to examine leukocyte genomic DNA methylation level. We calculated odds ratios (ORs) and 95% confidence intervals (95% CIs) using logistic regression.Overall genomic DNA methylation level was not associated with the risk of colorectal cancer (p for trend, 0.45). Compared with women in the lowest quintile of methylation, the multivariate OR of colorectal cancer risk was 1.32 (95% CI, 0.82-2.13) for those in the highest quintile. We did not find significant associations between major plasma components of one-carbon metabolism or risk factors for colorectal cancer and genomic DNA methylation level (all p for trend >0.05). Also, neither one-carbon metabolism-related plasma components nor well-known risk factors for colorectal cancer modified the association between genomic DNA methylation level and the risk of colorectal cancer (all p for interaction >0.05).We found no evidence that hypomethylation of leukocyte genomic DNA increases risk of colorectal cancer among women. Additional studies are needed to investigate the association between pre-diagnostic genomic DNA methylation level and colorectal cancer risk among diverse populations.

BackgroundA recent randomized controlled trial in critical-care units revealed that the elimination of extended-duration work shifts (> or =24 h) reduces the rates of significant medical errors and polysomnographically recorded attentional failures. This raised the concern that the extended-duration shifts commonly worked by interns may contribute to the risk of medical errors being made, and perhaps to the risk of adverse events more generally. Our current study assessed whether extended-duration shifts worked by interns are associated with significant medical errors, adverse events, and attentional failures in a diverse population of interns across the United States.Methods and findingsWe conducted a Web-based survey, across the United States, in which 2,737 residents in their first postgraduate year (interns) completed 17,003 monthly reports. The association between the number of extended-duration shifts worked in the month and the reporting of significant medical errors, preventable adverse events, and attentional failures was assessed using a case-crossover analysis in which each intern acted as his/her own control. Compared to months in which no extended-duration shifts were worked, during months in which between one and four extended-duration shifts and five or more extended-duration shifts were worked, the odds ratios of reporting at least one fatigue-related significant medical error were 3.5 (95% confidence interval [CI], 3.3-3.7) and 7.5 (95% CI, 7.2-7.8), respectively. The respective odds ratios for fatigue-related preventable adverse events, 8.7 (95% CI, 3.4-22) and 7.0 (95% CI, 4.3-11), were also increased. Interns working five or more extended-duration shifts per month reported more attentional failures during lectures, rounds, and clinical activities, including surgery and reported 300% more fatigue-related preventable adverse events resulting in a fatality.ConclusionsIn our survey, extended-duration work shifts were associated with an increased risk of significant medical errors, adverse events, and attentional failures in interns across the United States. These results have important public policy implications for postgraduate medical education.