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Background: Recent advances in metabolomic studies have shown promise in elucidating the biological pathways underpinning aging processes and mortality in animal models, but data in humans are lacking. We aimed to evaluate the associations between metabolite profiles, all-cause and cause-specific mortality, and longevity. Methods: Within three prospective cohorts (Nurses’ Health Study [NHS], NHSII, and Health Professional’s Follow-up Study), we measured plasma metabolites from 11,523 participants (mean age 54 years, 86% female) using high-throughput liquid chromatography-mass spectrometry. Participants were free of cardiovascular disease and cancer at blood collection. Metabolome-wide association analyses were conducted for all-cause, cardiovascular, and cancer mortality using Cox proportional hazards regression and longevity (attaining 85 years of age) using logistic regression. Both pre-defined and data-driven metabolite groups were also evaluated. We further developed a multi-metabolite profile score for all-cause mortality using an elastic-net regularized Cox model and assessed its associations with mortality and longevity. Results for all-cause mortality were replicated among 1878 participants (mean age 67 years, 58% female) from the PREDIMED trial. Results: We documented 4252 deaths (including 864 cardiovascular deaths and 1070 cancer deaths) and 3048 achieving longevity over a median follow-up of 22.6 years in the NHS/NHSII/HPFS, and 126 deaths during a follow-up of 4.7 years in the PREDIMED. Higher levels of three nucleosides (N2,N2-dimethylguanosine, pseudouridine, and N4-acetylcytidine), 4-acetamidobutanoic acid, triacylglycerols with ≤56 carbons and ≤3 double bonds, and several other lipids were associated with increased risk of all-cause mortality and corresponding decreased likelihood of longevity; whereas L-serine, L-glutamine, and TAGs with >56 carbons or >3 double bonds were associated with lower mortality risk and higher odds of achieving longevity. A multi-metabolite profile score comprising 73 metabolites was positively associated with all-cause (HR per 1-SD increment=1.25 [95% CI: 1.21, 1.30] in NHS/NHSII/HPFS and 1.47 [95% CI: 1.22, 1.78] in PREDIMED), cardiovascular (HR=1.34 [95% CI:1.24, 1.45]), and cancer mortality (HR=1.15 [95% CI:1.08, 1.24]) and inversely associated with longevity (OR=0.79 [95% CI: 0.74, 0.86]). Conclusions: We identified multiple metabolites associated with mortality and longevity. Our findings provide insights into the biological pathways that lead to death and open up new avenues to incorporate these metabolomic markers in clinical and research settings.

ObjectiveTo identify pre-diagnostic plasma metabolomic biomarkers associated with risk of exfoliation glaucoma (XFG).MethodsWe conducted a metabolomic study using a 1:1 matched nested case-control study design within the Nurses’ Health Study (NHS) and Health Professionals Follow-up Study (HPFS). Participants provided blood samples in 1989-’90 (NHS) and 1993-’95 (HPFS); we identified 205 participants who newly developed XFG during follow-up to 2018 (average time to diagnosis from blood draw =11.8 years); XFG was confirmed with medical record review. We profiled plasma metabolites using liquid chromatography- mass spectrometry and identified 379 known metabolites that passed quality control checks. Metabolites were transformed using probit scores for normality. We used multivariable-adjusted logistic regression adjusting for matching factors (such as age, residential latitude, season and time of blood draw), glaucoma family history and other covariates. Metabolite Set Enrichment Analysis was used to identify metabolite classes associated with risk of XFG. Number of effective tests (NEF) and False Discovery Rate (FDR) were used to adjust for multiple comparisons.ResultsMean age of cases (n=205) at diagnosis was 71 years; 84% were women and >99% were Caucasian; matched controls (n=205) all reported eye exams as of the matched cases’ index date. A total of 33 metabolites were nominally significantly associated with XFG risk (p°N latitude), age (< or ≥60 years), sex or glaucoma family history.ConclusionsFour broad classes of metabolites (including steroids such as cortisone and 3 lipid classes) in pre-diagnostic plasma collected almost a decade before diagnosis were associated with XFG risk; these results should be confirmed in future studies.

Background Recent studies suggest an intergenerational influence of stress such that maternal exposure even before pregnancy could impact offspring health outcomes later in life. In humans, investigations on the impact of maternal stressors on offspring health outcomes, including stress-sensitive biomarkers, have largely been limited to extreme stressors. Prior studies have not addressed more moderate maternal stressors, such as rotating night shift work, on offspring stress markers in young adulthood. Methods We investigated the association between maternal rotating night shift work before conception and offspring salivary cortisol and alpha amylase (sAA) patterns in young adulthood among mothers enrolled in the Nurses' Health Study II (NHSII) and their offspring participating in the Growing Up Today Study 2 (GUTS2). Our sample included over 300 mother-child pairs where, between 2011 and 2014, the children provided 5 saliva samples over the course of one day. We used piecewise linear mixed models to compare awakening responses, overall slopes as well as several other diurnal patterns of cortisol and sAA between offspring born to shift working versus non-shift working mothers. Results Offspring born to shift working mothers had a flattened late decline in cortisol (percent differences in slope (%D): 2.1%; 95%CI: 0.3, 3.8) and their sAA awakening response was steeper (%D -37.4%; 95%CI: −59.0, −4.4), whereas sAA increase before bedtime appeared less pronounced (%D -35.9%; 95%CI: −55.3, −8.3), compared to offspring born to mothers without shift work. For cortisol, we observed a significant difference in the Area Under the Curve (AUC) (%D 1.5%; 95%CI: 0.3, 2.7) with higher AUC for offspring of mothers who worked rotating night shifts. In offspring-sex-stratified analyses we found differences primarily among males. Conclusion Our results provide some – albeit modest - evidence that maternal rotating night shift work—a moderate stressor—influences offspring stress markers. Future studies with larger samples sizes, more detailed exposure assessment (particularly during maternal pregnancy), and multiple offspring biomarker assessments at different developmental stages are needed to further investigate these associations.

BackgroundCopy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data.ResultsGene burden tests detected the strongest association for deletions in BRCA1 (P= 3.7E-18). Nine other genes were associated with a p-value < 0.01 including known susceptibility genes CHEK2 (P= 0.0008), ATM (P= 0.002) and BRCA2 (P= 0.008). Outside the known genes we detected associations with p-values < 0.001 for either overall or subtype-specific breast cancer at nine deletion regions and four duplication regions. Three of the deletion regions were in established common susceptibility loci.ConclusionsThis is the first genome-wide analysis of rare CNVs in a large breast cancer case-control dataset. We detected associations with exonic deletions in established breast cancer susceptibility genes. We also detected suggestive associations with non-coding CNVs in known and novel loci with large effects sizes. Larger sample sizes will be required to reach robust levels of statistical significance.

Background: Plant-based diets have been associated with a lower risk of type 2 diabetes. However, the underlying mechanisms are not completely understood, and the evidence using objective approaches to assess the adherence of plant-based diets is limited. Methods: In the Nurses’ Health Study (NHS), NHSII, and Health Professionals Follow-Up Study, we characterized the plasma metabolome related to plant-based diets and examined its association with the incidence of type 2 diabetes among 10 699 participants. Plasma metabolomic profiling was conducted by liquid chromatography-tandem mass spectrometry. Adherence to plant-based diets was assessed by three plant-based diet indices derived from the food frequency questionnaire: an overall plant-based diet index (PDI), a healthful PDI (hPDI), and an unhealthful PDI (uPDI). Metabolomic signatures reflecting the adherence to plant-based diets were created using elastic net regression, and their associations with risk of type 2 diabetes were subsequently evaluated using multivariable Cox proportional hazards regression. Results: Among 263 metabolites measured, nearly half were significantly associated with PDI (41.4%, 109 of 263), hPDI (51.7%, 136 of 263), and uPDI (40.3%, 106 of 263) after Bonferroni correction. We developed a metabolomic signature comprising 53 metabolites for PDI, 76 metabolites for hPDI, and 88 metabolites for uPDI, each robustly correlated with the corresponding diet index (r=0.34-0.36 for PDI, 0.43-0.44 for hPDI, and 0.36-0.37 for uPDI). We observed an inverse association of PDI metabolomic signature (HR 0.86, 95% CI 0.79-0.93 per one standard deviation) and hPDI metabolomic signature (0.79, 0.72-0.86) with type 2 diabetes risk after adjustment for body mass index and other potential confounders. These two inverse associations remained significant even further adjusting for the corresponding diet index PDI and hPDI. The metabolomic signature for uPDI was not associated with type 2 diabetes risk (1.00, 0.93-1.09). Conclusion: Plasma metabolome can robustly reflect adherence and metabolic response to plant-based diets. Metabolomic signatures reflecting greater adherence to an overall plant-based diet, especially a healthful plant-based diet, were associated with a lower risk of type 2 diabetes. These findings support and provide mechanistic insights on the important role of healthful plant-based diets in diabetes prevention.

Anti-Müllerian hormone (AMH) is expressed by antral stage ovarian follicles in women. Consequently, circulating AMH levels are detectable until menopause. Variation in age-specific AMH levels has been associated with breast cancer and polycystic ovary syndrome (PCOS), amongst other diseases. Identification of genetic variants underlying variation in AMH levels could provide clues about the physiological mechanisms that explain these AMH-disease associations. To date, only one variant in MCM8 has been identified to be associated with circulating AMH levels in women. We aimed to identify additional variants for AMH through a GWAS meta-analysis including data from 7049 premenopausal women of European ancestry, which more than doubles the sample size of the largest previous GWAS. We identified four loci associated with AMH levels at p < 5×10−8: the previously reported MCM8 locus and three novel signals in or near AMH, TEX41, and CDCA7. The strongest signal was a missense variant in the AMH gene (rs10417628). Most prioritized genes at the other three identified loci were involved in cell cycle regulation. Genetic correlation analyses indicated a strong positive correlation among SNPs for AMH levels and for age at menopause (rg= 0.82, FDR=0.003). Exploratory Mendelian randomization analyses did not support a causal effect of AMH on breast cancer or PCOS risk, but should be interpreted with caution as they may be underpowered and the validity of genetic instruments could not be extensively explored. In conclusion, we identified a variant in the AMH gene and three other loci that may affect circulating AMH levels in women.

Circulating branched chain amino acid (BCAA) levels reflect metabolic health as well as dietary intake and have been linked to some cancers. Associations with breast cancer are unclear.We evaluated the association between circulating BCAA levels and risk of breast cancer in a prospective nested case-control study (1,997 cases, 1,997 controls) within the Nurses’ Health Study (NHS) and NHSII. Two-thirds of women in NHS (592 cases) donated two blood samples collected 10 years apart. We used conditional logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) of breast cancer risk in multivariable models which included BMI at age 18 and adulthood weight gain, in addition to other risk factors. We conducted an external validation with secondary analyses in the Women’s Health Study (WHS) (1,297 cases).Among NHSII participants (predominantly premenopausal at blood collection), elevated circulating BCAA levels were associated with suggestively lower breast cancer risk (e.g., isoleucine highest vs. lowest quartile, multivariable OR (95% CI)= 0.86 (0.65-1.13), p-trend=0.20), with significant linear trends among fasting samples (e.g., isoleucine OR (95% CI)=0.74 (0.53-1.05), p-trend=0.05). In contrast, among postmenopausal women, proximate measures (within 10y from blood draw) were associated with increased breast cancer risk (e.g., isoleucine highest vs. lowest quartile multivariable OR (95% CI)=1.63 (1.12-2.39), p-trend=0.01), with slightly stronger associations among fasting samples (OR (95% CI)=1.73 (1.15-2.61), p-trend=0.01). Distant measures (10-20y since blood draw) were not statistically significantly associated with risk (OR (95% CI)=1.15 (0.87-1.52), p-trend=0.35). We did not observe significant heterogeneity by ER status or BMI. In the WHS, a suggestive positive association was observed for distant measures of leucine among postmenopausal women: OR (95% CI)=1.31 (0.97-1.75), p-trend=0.05.Although elevated circulating BCAA levels were associated with lower breast cancer risk among premenopausal NHSII women and higher risk of postmenopausal breast cancer in NHS when assessed within 10 years of diagnosis, independent of established risk factors, including adiposity, results were not validated in WHS. Additional independent studies are needed to reassess and understand the complex relationship between BCAAs, menopausal status and timing, and risk of breast cancer.Statement of significanceElevated circulating BCAA levels were associated with lower breast cancer risk among premenopausal NHSII women and higher risk of postmenopausal breast cancer in NHS when assessed within 10 years of diagnosis, independent of established risk factors, including adiposity.

STUDY QUESTION How are rotating night shift schedules associated with age at menopause among a large, national cohort of shift working nurses? SUMMARY ANSWER Our findings suggest that working rotating night shifts with sufficient frequency may modestly accelerate reproductive senescence among women who may already be predisposed to earlier menopause. WHAT IS KNOWN ALREADY Younger age at menopause has been associated with increased risk of adverse health outcomes, particularly those linked to reproduction. Night work has been associated with reproductive dysfunction, including disruption of menstrual cycle patterns. STUDY DESIGN, SIZE, DURATION This cohort study was conducted among 80 840 women of the Nurses’ Health Study 2 (NHS2), with prospective follow-up from 1991 through 2013. Loss-to-follow-up of the NHS2 is estimated to be PARTICIPANTS/MATERIALS, SETTING, METHODS We assessed the association between cumulative and current rotating night shift work and age at natural menopause over 22 years of follow-up (1991–2013). Cox proportional hazards models were used to estimate hazard ratios (HR) for menopause, adjusted for age, smoking status, body mass index, physical activity, alcohol consumption, reproductive factors and exogenous hormone use. MAIN RESULTS AND THE ROLE OF CHANCE Over follow-up, 27 456 women (34%) reached natural menopause. Women who worked 20 or more months of rotating night shifts in the prior 2-year had an increased risk of earlier menopause (multivariable-adjusted (MV)-HR = 1.09, 95% CI: 1.02–1.16) compared to women without rotating night shift work. This risk was stronger among women undergoing menopause or otherwise censored under age 45 years (MV-HR = 1.25, 95% CI: 1.08–1.46), than it was for those continuing in the study when >45 years old (MV-HR = 1.05, 95% CI: 0.99–1.13). Working 10 or more years of cumulative rotating night work was also associated with higher risk of menopause among women reaching menopause under age 45 (MV-HR10–19 years = 1.22, 95% CI: 1.03–1.44; MV-HR≥20 years = 1.73, 95% CI: 0.90–3.35), though not over the age of 45 years (MV-HR10–19 years = 1.04, 95% CI: 0.99–1.10; MV-HR≥20 years = 1.01, 95% CI: 0.89–1.15). LIMITATIONS, REASONS FOR CAUTION The degree to which observed effects of rotating night shifts on age at natural menopause are due to circadian disruption, rather than fatigue and stress associated with working more demanding schedules, is uncertain due to potential residual confounding by these factors. WIDER IMPLICATIONS OF THE FINDINGS This is the first study to assess the effects of night work on menopausal timing among a larger national cohort of shift working women. Women already prone to earlier menopause may further truncate their reproductive lifetime by working schedules comprising day as well as night shifts. STUDY FUNDING/COMPETING INTEREST(s) This study was supported by Center for Disease Control and Prevention/The National Institute for Occupational Safety and Health Grant 5R01OH009803 (PI: Schernhammer E), as well as UM1 CA176726 from the National Institute of Health. The funding sources had no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the article; and decision to submit the article for publication. The authors have no conflicts of interest.

Background: Modified median and subgroup-specific gene centering are two essential preprocessing methods to assign breast cancer molecular subtypes by PAM50. We evaluated the PAM50 subtypes derived from both methods in a subset of Nurses' Health Study (NHS) and NHSII participants; correlated tumor subtypes by PAM50 with IHC surrogates; and characterized the PAM50 subtype distribution, proliferation scores, and risk of relapse with proliferation and tumor size weighted (ROR-PT) scores in the NHS/NHSII. Methods: PAM50 subtypes, proliferation scores, and ROR-PT scores were calculated for 882 invasive breast tumors and 695 histologically normal tumor-adjacent tissues. Cox proportional hazards models evaluated the relationship between PAM50 subtypes or ROR-PT scores/groups with recurrence-free survival (RFS) or distant RFS. Results: PAM50 subtypes were highly comparable between the two methods. The agreement between tumor subtypes by PAM50 and IHC surrogates improved to fair when Luminal subtypes were grouped together. Using the modified median method, our study consisted of 46% Luminal A, 18% Luminal B, 14% HER2-enriched, 15% Basal-like, and 8% Normal-like subtypes; 53% of tumor-adjacent tissues were Normal-like. Women with the Basal-like subtype had a higher rate of relapse within 5 years. HER2-enriched subtypes had poorer outcomes prior to 1999. Conclusions: Either preprocessing method may be utilized to derive PAM50 subtypes for future studies. The majority of NHS/NHSII tumor and tumor-adjacent tissues were classified as Luminal A and Normal-like, respectively. Impact: Preprocessing methods are important for the accurate assignment of PAM50 subtypes. These data provide evidence that either preprocessing method can be used in epidemiologic studies.

Prior epidemiologic studies suggest that regular use of analgesics may decrease risk of breast and ovarian cancer. We explored possible hormone-mediated mechanisms for these associations by examining the relationship between use of aspirin, nonaspirin nonsteroidal anti-inflammatory drugs (NSAID), and acetaminophen and sex steroid hormone concentrations among 740 postmenopausal women in the Nurses' Health Study. All women reported their analgesic use in 1988 or 1990 and provided a blood sample in 1989 to 1990. We calculated adjusted geometric mean estrogen and androgen levels for each category of analgesic use and calculated the P value for trend with increasing frequency of use. There was no association between days of use per month of aspirin, nonaspirin NSAIDs, or acetaminophen in 1990 and hormone levels (all Ptrend ≥ 0.09). However, we observed significant inverse trends between the estimated number of aspirin tablets per month in 1988 and concentrations of estrone (Ptrend = 0.04) and estrone sulfate (Ptrend = 0.03). In analyses of total (aspirin and nonaspirin) NSAID use in 1990, women who used NSAIDs at least 15 days per month had significantly lower levels of estradiol compared with women with no NSAID use (Ptrend = 0.03). Frequency of use of all analgesics (aspirin, nonaspirin NSAIDs, and acetaminophen) in 1990 was inversely associated with concentrations of estradiol (Ptrend = 0.001), free estradiol (Ptrend = 0.01), estrone sulfate (Ptrend = 0.03), and the ratio of estradiol to testosterone (Ptrend = 0.04). Among postmenopausal women, regular users of aspirin and other analgesics may have lower estrogen levels than nonusers, which could contribute to a decreased risk of breast or ovarian cancer among analgesic users. Cancer Epidemiol Biomarkers Prev; 19(4); 1033–41. ©2010 AACR.

Background Pharmacogenetic testing is used to uncover genetic causes for variations in drug response. Documentation of the method's usefulness in a clinical setting is scarce. The aim of the study was to systematically categorize the experience from routine CYP2D6 genotyping in a diagnostic laboratory. Material and methods All samples submitted to our laboratory for CYP2D6 genotyping in the period 29.06.98-28.12.09 were examined retrospectively. The samples were classified into three indication groups based on clinical information given in the request form. All samples, and a control group consisting of 100 healthy blood donors, were tested for the four most prevalent non-functional CYP2D6 alleles in the European population, and for ultrarapid metabolizer-associated duplications of the gene. Results 325 samples were included. The proportion of ultrarapid metabolizers was significantly higher in the patient group (4.0 %, p = 0.045) than in the control group (0 %), with the highest proportion among those patients that used a known CYP2D6 substrate. The percentage of poor metabolizers was not significantly higher in the patient group (8.3 %) than in the control group (6.0 %) (p = 0.528). Interpretation The CYP2D6 analysis could rarely explain the patients' side effects or lack of drug response, even though the study group was selected because of clinical problems due to drugs they were using. Two explanations may be that the indication(s) for genetic testing is not clearly defined and that the CYP2D6 genotype is only one of many factors that determine individual drug response.

Background: Although overall mortality rates from CHD in the U.S. have continued to decline in recent decades, the CHD mortality rate among women 35 to 54 years old has been increasing on average by 1.5% per year since 1997. This unfavorable trend may be explained, in part, by adverse lifestyle habits among younger adults. The purpose of this analysis was to estimate the burden of CHD among younger women that can be attributed to lack of adherence to a healthy lifestyle. Methods and Results: We conducted a prospective analysis among 93,161 women, 27-44 years of age at baseline, enrolled in the Nurses’ Health Study II cohort and followed from 1991 to 2009. Lifestyle factors were assessed repeatedly during follow-up by questionnaire. Healthy lifestyle was defined as not currently smoking, having a BMI of 18.5 [[Unable to Display Character: –]] 24.9 kg/m 2 , engaging in at least 2.5 hours/week of moderate to vigorous-intensity physical activity, having a diet in the top 40% of Alternative Healthy Eating Index-2010, and consuming 5 [[Unable to Display Character: –]] 30g/day of alcohol. To estimate the proportion of CHD that could be attributed to poor adherence to a healthy lifestyle, we calculated the population attributable risk percent. During follow-up, we documented 441 new cases of non-fatal MI and fatal CHD. After adjustment for other CVD risk factors, non-smoking, healthy BMI, exercise, and healthy diet were independently and significantly associated with lower CHD risk. Compared to women with 0 healthy lifestyle factors, the hazard ratio (HR) for CHD was 0.07 (95% CI, 0.03, 0.17) for women with all 5 healthy lifestyle factors (4% of the study population). Approximately 67% (95% CI 28%, 87%) of CHD cases in this population were attributable to poor adherence to a healthy lifestyle. Among non-smokers, 59% (95% CI 13%, 84%) of CHD cases were attributable to poor adherence to the other four healthy lifestyle factors. Conclusions: Primordial prevention through maintenance or adoption of a healthy lifestyle may lower incidence of CHD and potentially reverse the unfavorable trend in CHD mortality in younger women.

Background: The majority of studies on the association between physical activity and coronary heart disease (CHD) risk have been conducted in middle-aged and older populations. Although physical activity has been shown to lower risk of CHD in women by approximately 30%, evidence for the benefits of exercise for CHD in young women is very limited. Methods and Results: We conducted a prospective cohort study among 114 054 women, 25–42 years of age at baseline, enrolled in the Nurses’ Health Study II and followed from 1989 to 2009. Leisure-time physical activity was assessed at baseline and during follow-up through a series of questions on the specific type of activity and the average time per week spent on the activity over the previous year. Additionally, at baseline, women were asked the number of months per year they participated in strenuous exercise or sports during high school and ages 18–22. During 20 years of follow-up, we documented 518 new cases of non-fatal MI and fatal CHD. After adjusting for age and other cardiovascular risk factors, the rate ratios (RR) (95% confidence intervals [CI]) corresponding to 0, 0.1 – 3.5, 3.6 – 8.8, 8.9 – 21.0, and > 21 MET-hours/week of physical activity were 1.0, 0.93 (0.71, 1.21), 0.73 (0.56, 0.95), 0.67 (0.52, 0.88), and 0.63 (0.49, 0.83) (p for trend = 0.001). There was no evidence of effect modification by age or body mass index. Specifically in women less than 50 years of age, the corresponding RR were 1.0, 0.97 (0.70, 1.35), 0.75 (0.53, 1.04), 0.69 (0.50, 0.96), and 0.63 (0.45, 0.88) (p for trend = 0.008). Brisk walking alone was also associated with significant reductions in CHD risk. In contrast to physical activity during adulthood, frequency of participation in strenuous activity in high school or during ages 18–22 was not associated with risk of CHD when adjusted for current physical activity. Conclusions: These prospective data suggest that physical activity is associated with substantial risk reductions in the incidence of coronary heart disease in young women.

Pharmacogenetic testing is used to uncover genetic causes for variations in drug response. Documentation of the method's usefulness in a clinical setting is scarce. The aim of the study was to systematically categorize the experience from routine CYP2D6 genotyping in a diagnostic laboratory.All samples submitted to our laboratory for CYP2D6 genotyping in the period 29.06.98-28.12.09 were examined retrospectively. The samples were classified into three indication groups based on clinical information given in the request form. All samples, and a control group consisting of 100 healthy blood donors, were tested for the four most prevalent non-functional CYP2D6 alleles in the European population, and for ultrarapid metabolizer-associated duplications of the gene.325 samples were included. The proportion of ultrarapid metabolizers was significantly higher in the patient group (4.0 %, p = 0.045) than in the control group (0 %), with the highest proportion among those patients that used a known CYP2D6 substrate. The percentage of poor metabolizers was not significantly higher in the patient group (8.3 %) than in the control group (6.0 %) (p = 0.528).The CYP2D6 analysis could rarely explain the patients' side effects or lack of drug response, even though the study group was selected because of clinical problems due to drugs they were using. Two explanations may be that the indication(s) for genetic testing is not clearly defined and that the CYP2D6 genotype is only one of many factors that determine individual drug response.

"I do not hesitate to say that, if three fourths of the time, energy, and money spent during the last fifteen years in carrying through elaborate pro grams of curriculum revision had been spent in a determined effort to raise the standards of selecting teachers, a far more significant contribution would have been made to the improvement of American education/'1 Dr. Bagley's keen analysis of the situation ?ve years ago, is even more true today. A similar statement from Syracuse University is quoted in a cur rent article

Prospective Teachers and their advisers are often searching for information regarding the extent to which a specific subject is taught in high schools, the degree to which it is combined with other subjects, and what those other subjects are. It was the purpose or this study to bring together such reported findings relative to the teaching of mathematics.

With the rapid development of extra-curriculum activities in the American secondary school, teachers are in most cases expected to assume some responsibility in directing these activities. To the extent that they are trained for such participation, their opportunities for securing employment are increased. An Ohio study' indicated that the chances were more than four to one that beginning teachers would be responsible for extra-curriculum duties requiring considerable time and planning. Cole" reported that 73 per cent of the secondary-school teachers of North Dakota supervised extra-curriculum activities. Similarly, the Commonwealth Teacher-Training Study3 found that the so-called "extra-curriculum activities" were prominent among the many duties of the teacher. The writer made a survey of approximately fifteen hundred recent teaching graduates of Ohio State University and found that about two-thirds of these graduates performed extra-curriculum duties in addition to their teaching. The activities of these teachers were classified and studied with respect to the prevalence with which they supervised extra-curriculum duties, the time consumed in such duties, and the previous training for these extra responsibilities. The types of activities were also analyzed according to the frequency with which each college major group directed them.

SummaryBackgroundAssociations between circulating concentrations of oestrogens, progesterone, and androgens with breast cancer and related risk factors in premenopausal women are not well understood. We aimed to characterise these associations with a pooled analysis of data from seven studies.MethodsIndividual participant data for prediagnostic sex hormone and sex hormone-binding globulin (SHBG) concentrations were contributed from seven prospective studies. We restricted analyses to women who were premenopausal and younger than 50 years at blood collection, and to women with breast cancer diagnosed before age 50 years. We estimated odds ratios (ORs) with 95% CIs for breast cancer associated with hormone concentrations by conditional logistic regression in cases and controls matched for age, date of blood collection, and day of cycle, with stratification by study and further adjustment for cycle phase. We examined associations of hormones with risk factors for breast cancer in control women by comparing geometric mean hormone concentrations in categories of these risk factors, adjusted for study, age, phase of menstrual cycle, and body-mass index (BMI). All statistical tests were two-sided.FindingsWe included data for up to 767 women with breast cancer and 1699 controls in the risk analyses. Breast cancer risk was associated with a doubling in concentrations of oestradiol (OR 1·19, 95% CI 1·06–1·35), calculated free oestradiol (1·17, 1·03–1·33), oestrone (1·27, 1·05–1·54), androstenedione (1·30, 1·10–1·55), dehydroepiandrosterone sulphate (1·17, 1·04–1·32), testosterone (1·18, 1·03–1·35), and calculated free testosterone (1·08, 0·97–1·21). Breast cancer risk was not associated with luteal phase progesterone (doubling in concentration OR 1·00, 95% CI 0·92–1·09), and adjustment for other factors had little effect on any of these ORs. Cross-sectional analyses in control women showed several associations of sex hormones with breast cancer risk factors.InterpretationCirculating oestrogens and androgens are positively associated with the risk for breast cancer in premenopausal women.FundingCancer Research UK.

REPORTS dealing with teacher supply and demand published during the years 1943, 1944, and 1945 included two doctors' dissertations (29, 57), one nationwide investigation (36), one regional study (65), seven state studies (1, 19, 23, 29, 56, 67, 76), many reports of state departments of education, estimates of future shortage (33, 52, 56, 57, 64, 89), and remedies tried or recommended (26, 68, 69). Several reports were limited to one specific area of teaching such as college (3, 4), secondary (78), elementary (7, 12, 62), rural (86, 95), industrial arts (13), home economics (23), physical education (33), vocational agriculture (32), and preschool (80). Considerable attention was given to the immediate effects of the war on teacher supply and demand (8, 9, 25, 42, 58, 93, 96). Extensive state surveys were reported in Georgia (1), California (56), Iowa (23), and Missouri (29). An investigation in 1945 by Elder (36\ was based upon current reports from thirty-seven state departments of education. A regional study covering nineteen states was made by Maul (65) for the North Central Association. Mead and his associates investigated technics of meeting teacher shortage (26, 68, 69).

REPORTS PUBLISHED in 1941, 1942, and 1943, include three doctor's dissertations (22, 27, 44), one master's thesis (7), eight statements made by representatives of state departments of education, including statistics for their respective states (3, 4, 8, 16, 30, 31, 32, 33), seven studies made by teacher associations or teacher groups (2, 20, 21, 25, 26, 36, 39), three individual investigations of statewide nature (6, 9, 22), four reviews of the literature (1, 14, 15, 19), three analyses of population trends (11, 40, 44), a report from the Wartime Commission of the U. S. Office of Education (43), one study concerned with vocational agriculture on a national scale (42), one analysis of vocational teacher supply (37), one survey of rural teachers (10), one audit of enrolments in teachers colleges (45), one list of factors to be considered in supply-demand accounting (23), and one presentation of technics for making statewide studies of teacher supply and demand (28). A number of reports somewhat general in character were included because of important statistics and recommendations. Annual reports of college placement offices are becoming so numerous that they are not listed in the bibliography.

A LERT leaders in higher education have for some time advocated re-evaluation and renovation of the program of the liberal-arts college. As a result, there are some interesting developments in the so-called progressive colleges. Even the more conservative leaders have at least mended their fences. A review of programs and procedures in higher institutions today, therefore, presents many degrees of newness from complete overhauling to minor repairs. Almost anyone interested in higher education knows something about "new" college plans such as those of the University of Chicago, Antioch, Bennington, and others. While these are undoubtedly among the most significant college plans, it is surprising to learn the extent to which other less publicized institutions are experimenting with curriculums and methods. To discover these more obscure college experiments, a large number of college catalogues were studied to obtain information concerning interesting programs. This survey has not attempted to be all inclusive, and it is possible that a firsthand study of many programs would reveal many inconsistencies between print and practice. There is no unanimity about aims and purposes among these schools. One group of large public-supported institutions is defending and encouraging mass education through the establishment of two-year junior or general colleges. This is in line with the suggestion of a famous college president who has said that in these days of serious unemployment facing our youth, about the only alternatives to education are idleness, prison, or the navy. Many private colleges, on the other hand, are making their student bodies more selective and defending the principle of a mental aristocracy as a fundamental need in a democracy. A few colleges are stressing a new emphasis on the cultures and ideas of the past, while many others are increasingly planning programs that shall grow out of current needs and problems of young people in contemporary life. Some institutions are emphasizing more prescription of courses, whereas, at the other extreme, efforts are made increasingly to encourage student initiative, self-direction, and self-education. To a student of higher education this may suggest the predicament of Stephen Leacock's horseman. Before attempting to start off in all directions at once it might be well to consider a few trends. There is, first of all, the tendency toward the extension and refinement