Maternal Mortality in the United States: Trends and Opportunities for Prevention.

Maternal mortality is unusually high in the United States compared to other wealthy nations and is characterized by major disparities in race/ethnicity, geography, and socioeconomic factors. Similar to other developed nations, the United States has seen a shift in the underlying causes of pregnancy-related death, with a relative increase in mortality resulting from diseases of the cardiovascular system and preexisting medical conditions. Improved continuity of care aimed at identifying reproductive-age women with preexisting conditions that may heighten the risk of maternal death, preconception management of risk factors for major adverse pregnancy outcomes, and primary care visits within the first year after delivery may offer opportunities to address gaps in medical care contributing to the unacceptable rates of maternal mortality in the United States.

2024 Guideline for the Primary Prevention of Stroke: A Guideline From the American Heart Association/American Stroke Association.

AIM: The "2024 Guideline for the Primary Prevention of Stroke" replaces the 2014 "Guidelines for the Primary Prevention of Stroke." This updated guideline is intended to be a resource for clinicians to use to guide various prevention strategies for individuals with no history of stroke. METHODS: A comprehensive search for literature published since the 2014 guideline; derived from research involving human participants published in English; and indexed in MEDLINE, PubMed, Cochrane Library, and other selected and relevant databases was conducted between May and November 2023. Other documents on related subject matter previously published by the American Heart Association were also reviewed. STRUCTURE: Ischemic and hemorrhagic strokes lead to significant disability but, most important, are preventable. The 2024 primary prevention of stroke guideline provides recommendations based on current evidence for strategies to prevent stroke throughout the life span. These recommendations align with the American Heart Association's Life's Essential 8 for optimizing cardiovascular and brain health, in addition to preventing incident stroke. We also have added sex-specific recommendations for screening and prevention of stroke, which are new compared with the 2014 guideline. Many recommendations for similar risk factor prevention were updated, new topics were reviewed, and recommendations were created when supported by sufficient-quality published data.

The Impact of Sex and Gender on Stroke.

Women face a disproportionate burden of stroke mortality and disability. Biologic sex and sociocultural gender both contribute to differences in stroke risk factors, assessment, treatment, and outcomes. There are substantial differences in the strength of association of stroke risk factors, as well as female-specific risk factors. Moreover, there are differences in presentation, response to treatment, and stroke outcomes in women. This review outlines current knowledge of impact of sex and gender on stroke, as well as delineates research gaps and areas for future inquiry.

Differences in Metabolomic Profiles Between Black and White Women and Risk of Coronary Heart Disease: an Observational Study of Women From Four US Cohorts.

BACKGROUND: Racial differences in metabolomic profiles may reflect underlying differences in social determinants of health by self-reported race and may be related to racial disparities in coronary heart disease (CHD) among women in the United States. However, the magnitude of differences in metabolomic profiles between Black and White women in the United States has not been well-described. It also remains unknown whether such differences are related to differences in CHD risk. METHODS: Plasma metabolomic profiles were analyzed using liquid chromatography-tandem mass spectrometry in the WHI-OS (Women's Health Initiative-Observational Study; 138 Black and 696 White women), WHI-HT trials (WHI-Hormone Therapy; 156 Black and 1138 White women), MESA (Multi-Ethnic Study of Atherosclerosis; 114 Black and 219 White women), JHS (Jackson Heart Study; 1465 Black women with 107 incident CHD cases), and NHS (Nurses' Health Study; 2506 White women with 136 incident CHD cases). First, linear regression models were used to estimate associations between self-reported race and 472 metabolites in WHI-OS (discovery); findings were replicated in WHI-HT and validated in MESA. Second, we used elastic net regression to construct a racial difference metabolomic pattern (RDMP) representing differences in the metabolomic patterns between Black and White women in the WHI-OS; the RDMP was validated in the WHI-HT and MESA. Third, using conditional logistic regressions in the WHI (717 CHD cases and 719 matched controls), we examined associations of metabolites with large differences in levels by race and the RDMP with risk of CHD, and the results were replicated in Black women from the JHS and White women from the NHS. RESULTS: Of the 472 tested metabolites, levels of 259 (54.9%) metabolites, mostly lipid metabolites and amino acids, significantly differed between Black and White women in both WHI-OS and WHI-HT after adjusting for baseline characteristics, socioeconomic status, lifestyle factors, baseline health conditions, and medication use (false discovery rate <0.05); similar trends were observed in MESA. The RDMP, composed of 152 metabolites, was identified in the WHI-OS and showed significantly different distributions between Black and White women in the WHI-HT and MESA. Higher RDMP quartiles were associated with an increased risk of incident CHD (odds ratio=1.51 [0.97-2.37] for the highest quartile comparing to the lowest; Ptrend=0.02), independent of self-reported race and known CHD risk factors. In race-stratified analyses, the RDMP-CHD associations were more pronounced in White women. Similar patterns were observed in Black women from the JHS and White women from the NHS. CONCLUSIONS: Metabolomic profiles significantly and substantially differ between Black and White women and may be associated with CHD risk and racial disparities in US women.

Differences in metabolomic profiles between Black and White women in the U.S.: Analyses from two prospective cohorts.

There is growing interest in incorporating metabolomics into public health practice. However, Black women are under-represented in many metabolomics studies. If metabolomic profiles differ between Black and White women, this under-representation may exacerbate existing Black-White health disparities. We therefore aimed to estimate metabolomic differences between Black and White women in the U.S. We leveraged data from two prospective cohorts: the Nurses' Health Study (NHS; n = 2077) and Women's Health Initiative (WHI; n = 2128). The WHI served as the replication cohort. Plasma metabolites (n = 334) were measured via liquid chromatography-tandem mass spectrometry. Observed metabolomic differences were estimated using linear regression and metabolite set enrichment analyses. Residual metabolomic differences in a hypothetical population in which the distributions of 14 risk factors were equalized across racial groups were estimated using inverse odds ratio weighting. In the NHS, Black-White differences were observed for most metabolites (75 metabolites with observed differences ≥ |0.50| standard deviations). Black women had lower average levels than White women for most metabolites (e.g., for N6, N6-dimethlylysine, mean Black-White difference = - 0.98 standard deviations; 95% CI: - 1.11, - 0.84). In metabolite set enrichment analyses, Black women had lower levels of triglycerides, phosphatidylcholines, lysophosphatidylethanolamines, phosphatidylethanolamines, and organoheterocyclic compounds, but higher levels of phosphatidylethanolamine plasmalogens, phosphatidylcholine plasmalogens, cholesteryl esters, and carnitines. In a hypothetical population in which distributions of 14 risk factors were equalized, Black-White metabolomic differences persisted. Most results replicated in the WHI (88% of 272 metabolites available for replication). Substantial differences in metabolomic profiles exist between Black and White women. Future studies should prioritize racial representation.

Developing and evaluating the construct validity of a dietary pattern predictive of plasma TMAO and choline.

BACKGROUND AND AIMS: The metabolism of choline (highly present in animal products) can produce trimethylamine N-oxide (TMAO), a metabolite with atherosclerotic effects; however, dietary fiber may suppress this metabolic pathway. This study aimed to develop a dietary pattern predictive of plasma TMAO and choline concentrations using reduced rank regression (RRR) and to evaluate its construct validity. METHODS AND RESULTS: Diet and plasma concentrations of choline (µmol/L) and TMAO (µmol/L) were assessed in 1724 post-menopausal women who participated in an ancillary study within the Women's Health Initiative Observational Study (1993-1998). The TMAO dietary pattern was developed using RRR in half of the sample (Training Sample) and applied to the other half of the sample (Validation Sample) to evaluate its construct validity. Energy-adjusted food groups were the predictor variables and plasma choline and TMAO, the response variables. ANCOVA and linear regression models were used to assess associations between each biomarker and the dietary pattern score. Discretionary fat, potatoes, red meat, and eggs were positively associated with the dietary pattern, while yogurt, fruits, added sugar, and starchy vegetables were inversely associated. Mean TMAO and choline concentrations significantly increased across increasing quartiles of the dietary pattern in the Training and Validation samples. Positive associations between the biomarkers and the TMAO dietary pattern were also observed in linear regression models (Validation Sample: TMAO, adjusted beta-coefficient = 0.037 (p-value = 0.0088); Choline, adjusted beta-coefficient = 0.011 (p-value = 0.0224). CONCLUSION: We established the TMAO dietary pattern, a dietary pattern reflecting the potential of the diet to contribute to plasma concentrations of TMAO and choline.

Metabolomic profiles of chronic distress are associated with cardiovascular disease risk and inflammation-related risk factors.

BACKGROUND: Chronic psychological distress is associated with increased risk of cardiovascular disease (CVD) and investigators have posited inflammatory factors may be centrally involved in these relationships. However, mechanistic evidence and molecular underpinnings of these processes remain unclear, and data are particularly sparse among women. This study examined if a metabolite profile linked with distress was associated with increased CVD risk and inflammation-related risk factors. METHODS: A plasma metabolite-based distress score (MDS) of twenty chronic psychological distress-related metabolites was developed in cross-sectional, 1:1 matched case-control data comprised of 558 women from the Nurses' Health Study (NHS; 279 women with distress, 279 controls). This MDS was then evaluated in two other cohorts: the Women's Health Initiative Observational Cohort (WHI-OS) and the Prevención con Dieta Mediterránea (PREDIMED) trial. We tested the MDS's association with risk of future CVD in each sample and with levels of C-reactive protein (CRP) in the WHI-OS. The WHI-OS subsample included 944 postmenopausal women (472 CHD cases; mean time to event = 5.8 years); the PREDIMED subsample included 980 men and women (224 CVD cases, mean time to event = 3.1 years). RESULTS: In the WHI-OS, a 1-SD increase in the plasma MDS was associated with a 20% increased incident CHD risk (odds ratio [OR] = 1.20, 95% CI: 1.04 - 1.38), adjusting for known CVD risk factors excluding total and HDL cholesterol. This association was attenuated after including total and HDL cholesterol. CRP mediated an average 12.9% (95% CI: 4.9% - 28%, p < 10-15) of the total effect of MDS on CHD risk when adjusting for matching factors. This effect was attenuated after adjusting for known CVD risk factors. Of the metabolites in the MDS, tryptophan and threonine were inversely associated with incident CHD risk in univariate models. In PREDIMED, each one SD increase in the MDS was associated with an OR of 1.19 (95% CI: 1.00 - 1.41) for incident CVD risk, after adjusting all risk factors. Similar associations were observed in men and women. Four metabolites in the MDS were associated with incident CVD risk in PREDIMED in univariate models. Biliverdin and C36:5 phosphatidylcholine (PC) plasmalogen had inverse associations; C16:0 ceramide and C18:0 lysophosphatidylethanolamine(LPE) each had positive associations with CVD risk. CONCLUSIONS: Our study points to molecular alterations that may underlie the association between chronic distress and subsequent risk of cardiovascular disease in adults.

Validation of parental recall questionnaire to classify preterm delivery subtypes: Spontaneous preterm labour, preterm premature rupture of membranes and clinician-initiated preterm delivery.

BACKGROUND: Preterm delivery (PTD) includes three main presenting subtypes: spontaneous preterm labour (sPTL), preterm premature rupture of membranes (pPROM) and clinician-initiated preterm delivery (ciPTD). PTD subtype data are rarely available from birth registries and are onerous to derive from medical records. OBJECTIVES: To develop and test the validity of a questionnaire to classify PTD subtype based on birthing parent recall of labour and delivery events. METHODS: The questionnaire was sent in 2022 to 581 patients with PTD history documented in the LIFECODES study, a hospital-based birth cohort in Boston, Massachusetts. Eighty-two respondents reported 94 PTDs that could be linked to medical records. Data on PTD subtype were extracted from medical records as the reference standard. RESULTS: Medical records indicated 47 spontaneous (24 sPTL, 23 pPROM) and 47 ciPTD deliveries occurring a median eight years earlier. The sensitivity and specificity of the recall questionnaire were 88% (95% confidence interval: 68, 97%) and 89% (79, 95%) for sPTL; 96% (78, 100%) and 94% (86, 98%) for pPROM; and 83% (69, 92%) and 100% (92, 100%) for ciPTD, respectively. Greater time since pregnancy did not degrade the sensitivity or specificity of the parental recall questionnaire. CONCLUSIONS: Although derived from a modest sample, the moderate-to-high sensitivity and specificity of the parental recall questionnaire to classify sPTL, pPROM and ciPTD demonstrates its potential for large studies of PTD and for correction of misclassification bias. Future studies are required to test the questionnaire in a variety of populations.

Assault-related anoxia and neck injuries in US emergency departments.

BACKGROUND: Early identification of non-fatal strangulation in the context of intimate partner violence (IPV) is crucial due to its severe physical and psychological consequences for the individual experiencing it. This study investigates the under-reported and underestimated burden of IPV-related non-fatal strangulation by analysing assault-related injuries leading to anoxia and neck injuries. METHODS: An IRB-exempt, retrospective review of prospectively collected data were performed using the National Electronic Injury Surveillance System All Injury Programme data from 2005 to 2019 for all assaults resulting in anoxia and neck injuries. The type and mechanism of assault injuries resulting in anoxia (excluding drowning, poisoning and aspiration), anatomical location of assault-related neck injuries and neck injury diagnosis by morphology, were analysed using statistical methods accounting for the weighted stratified nature of the data. RESULTS: Out of a total of 24 493 518 assault-related injuries, 11.6% (N=2 842 862) resulted from IPV (defined as perpetrators being spouses/partners). Among 22 764 cases of assault-related anoxia, IPV accounted for 40.4%. Inhalation and suffocation were the dominant mechanisms (60.8%) of anoxia, with IPV contributing to 41.9% of such cases. Neck injuries represented only 3.0% of all assault-related injuries, with IPV accounting for 21% of all neck injuries and 31.9% of neck contusions. CONCLUSIONS: The study reveals a significant burden of IPV-related anoxia and neck injuries, highlighting the importance of recognising IPV-related strangulation. Comprehensive screening for IPV should be conducted in patients with unexplained neck injuries, and all IPV patients should be screened for strangulation events.

Host and gut microbial tryptophan metabolism and type 2 diabetes: an integrative analysis of host genetics, diet, gut microbiome and circulating metabolites in cohort studies.

OBJECTIVE: Tryptophan can be catabolised to various metabolites through host kynurenine and microbial indole pathways. We aimed to examine relationships of host and microbial tryptophan metabolites with incident type 2 diabetes (T2D), host genetics, diet and gut microbiota. METHOD: We analysed associations between circulating levels of 11 tryptophan metabolites and incident T2D in 9180 participants of diverse racial/ethnic backgrounds from five cohorts. We examined host genome-wide variants, dietary intake and gut microbiome associated with these metabolites. RESULTS: Tryptophan, four kynurenine-pathway metabolites (kynurenine, kynurenate, xanthurenate and quinolinate) and indolelactate were positively associated with T2D risk, while indolepropionate was inversely associated with T2D risk. We identified multiple host genetic variants, dietary factors, gut bacteria and their potential interplay associated with these T2D-relaetd metabolites. Intakes of fibre-rich foods, but not protein/tryptophan-rich foods, were the dietary factors most strongly associated with tryptophan metabolites. The fibre-indolepropionate association was partially explained by indolepropionate-associated gut bacteria, mostly fibre-using Firmicutes. We identified a novel association between a host functional LCT variant (determining lactase persistence) and serum indolepropionate, which might be related to a host gene-diet interaction on gut Bifidobacterium, a probiotic bacterium significantly associated with indolepropionate independent of other fibre-related bacteria. Higher milk intake was associated with higher levels of gut Bifidobacterium and serum indolepropionate only among genetically lactase non-persistent individuals. CONCLUSION: Higher milk intake among lactase non-persistent individuals, and higher fibre intake were associated with a favourable profile of circulating tryptophan metabolites for T2D, potentially through the host-microbial cross-talk shifting tryptophan metabolism toward gut microbial indolepropionate production.

Adverse Pregnancy Outcomes and Cardiovascular Disease Risk: Unique Opportunities for Cardiovascular Disease Prevention in Women: A Scientific Statement From the American Heart Association.

This statement summarizes evidence that adverse pregnancy outcomes (APOs) such as hypertensive disorders of pregnancy, preterm delivery, gestational diabetes, small-for-gestational-age delivery, placental abruption, and pregnancy loss increase a woman's risk of developing cardiovascular disease (CVD) risk factors and of developing subsequent CVD (including fatal and nonfatal coronary heart disease, stroke, peripheral vascular disease, and heart failure). This statement highlights the importance of recognizing APOs when CVD risk is evaluated in women, although their value in reclassifying risk may not be established. A history of APOs is a prompt for more vigorous primordial prevention of CVD risk factors and primary prevention of CVD. Adopting a heart-healthy diet and increasing physical activity among women with APOs, starting in the postpartum setting and continuing across the life span, are important lifestyle interventions to decrease CVD risk. Lactation and breastfeeding may lower a woman's later cardiometabolic risk. Black and Asian women experience a higher proportion APOs, with more severe clinical presentation and worse outcomes, than White women. More studies on APOs and CVD in non-White women are needed to better understand and address these health disparities. Future studies of aspirin, statins, and metformin may better inform our recommendations for pharmacotherapy in primary CVD prevention among women who have had an APO. Several opportunities exist for health care systems to improve transitions of care for women with APOs and to implement strategies to reduce their long-term CVD risk. One proposed strategy includes incorporation of the concept of a fourth trimester into clinical recommendations and health care policy.

Ten-Year Differences in Women's Awareness Related to Coronary Heart Disease: Results of the 2019 American Heart Association National Survey: A Special Report From the American Heart Association.

BACKGROUND: High awareness that cardiovascular disease is the leading cause of death (LCOD) among women is critical to prevention. This study evaluated longitudinal trends in this awareness among women. METHODS AND RESULTS: Online surveys of US women (≥25 years of age) were conducted in January 2009 and January 2019. Data were weighted to the US population distribution of sociodemographic characteristics. Multivariable logistic regression was used to evaluate knowledge of the LCOD. In 2009, awareness of heart disease as the LCOD was 65%, decreasing to 44% in 2019. In 2019, awareness was greater with older age and increasing education and lower among non-White women and women with hypertension. The 10-year awareness decline was observed in all races/ethnicities and ages except women ≥65 years of age. The greatest declines were among Hispanic women (odds ratio of awareness comparing 2019 to 2009, 0.14 [95% CI, 0.07-0.28]), non-Hispanic Black women (odds ratio, 0.31 [95% CI, 0.19-0.49]), and 25- to 34-year-olds (odds ratio, 0.19 [95% CI, 0.10-0.34]). In 2019, women were more likely than in 2009 to incorrectly identify breast cancer as the LCOD (odds ratio, 2.59 [95% CI, 1.86-3.67]), an association that was greater in younger women. Awareness of heart attack symptoms also declined. CONCLUSIONS: Awareness that heart disease is the LCOD among women declined from 2009 to 2019, particularly among Hispanic and non-Hispanic Black women and in younger women (in whom primordial/primary prevention may be most effective). An urgent redoubling of efforts by organizations interested in women's health is required to reverse these trends.

Laparoscopically Confirmed Endometriosis and Risk of Incident Stroke: A Prospective Cohort Study.

BACKGROUND: Prior research suggests that women with endometriosis are at greater risk of coronary heart disease. Therefore, our objective was to prospectively investigate the association between laparoscopically confirmed endometriosis and risk of incident stroke during 28 years of follow-up. METHODS: Participants in the NHSII cohort study (Nurses' Health Study II) were followed from 1989 when they were between the ages of 25 to 42 until 2017 for development of incident stroke (ischemic and hemorrhagic). Cox proportional hazard models were used to calculate hazard ratios and 95% CI, with adjustment for potential confounding variables (alcohol intake, body mass index at age 18, current body mass index, age at menarche, menstrual cycle pattern in adolescence, current menstrual cycle pattern, parity, oral contraceptive use history, smoking history, diet quality, physical activity, NSAID use, aspirin use, race/ethnicity, and income). We estimated the proportion of the total association mediated by history of hypertension, hypercholesterolemia, hysterectomy/oophorectomy, and hormone therapy. We also tested for effect modification by age (<50, ≥50 years), infertility history, body mass index (<25, ≥25 kg/m2), and menopausal status. RESULTS: We documented 893 incident cases of stroke during 2 770 152 person-years of follow-up. Women with laparoscopically confirmed endometriosis had a 34% greater risk of stroke in multivariable-adjusted models (hazard ratio, 1.34 [95% CI, 1.10-1.62]), compared to those without a history of endometriosis. Of the total association of endometriosis with risk of stroke, the largest proportion was attributed to hysterectomy/oophorectomy (39% mediated [95% CI, 14%-71%]) and hormone therapy (16% mediated [95% CI, 5%-40%]). We observed no differences in the relationship between endometriosis and stroke by age, infertility history, body mass index, or menopausal status. CONCLUSIONS: We observed that women with endometriosis were at elevated risk of stroke. Women and their health care providers should be aware of endometriosis history, maximize primary cardiovascular prevention, and discuss signs and symptoms of cardiovascular disease.

Plasma Metabolomic Signature of Early Abuse in Middle-Aged Women.

OBJECTIVE: Metabolomic profiling may provide insights into biological mechanisms underlying the strong epidemiologic links observed between early abuse and cardiometabolic disorders in later life. METHODS: We examined the associations between early abuse and midlife plasma metabolites in two nonoverlapping subsamples from the Nurses' Health Study II, comprising 803 (mean age = 40 years) and 211 women (mean age = 61 years). Liquid chromatography-tandem mass spectrometry assays were used to measure metabolomic profiles, with 283 metabolites consistently measured in both subsamples. Physical and sexual abuse before age 18 years was retrospectively assessed by validated questions integrating type/frequency of abuse. Analyses were conducted in each sample and pooled using meta-analysis, with multiple testing adjustment using the q value approach for controlling the positive false discovery rate. RESULTS: After adjusting for age, race, menopausal status, body size at age 5 years, and childhood socioeconomic indicators, more severe early abuse was consistently associated with five metabolites at midlife (q value < 0.20 in both samples), including lower levels of serotonin and C38:3 phosphatidylethanolamine plasmalogen and higher levels of alanine, proline, and C40:6 phosphatidylethanolamine. Other metabolites potentially associated with early abuse (q value < 0.05 in the meta-analysis) included triglycerides, phosphatidylcholine plasmalogens, bile acids, tyrosine, glutamate, and cotinine. The association between early abuse and midlife metabolomic profiles was partly mediated by adulthood body mass index (32% mediated) and psychosocial distress (13%-26% mediated), but not by other life-style factors. CONCLUSIONS: Early abuse was associated with distinct metabolomic profiles of multiple amino acids and lipids in middle-aged women. Body mass index and psychosocial factors in adulthood may be important intermediates for the observed association.

Primary Care Physician Gender and Electronic Health Record Workload.

BACKGROUND: Prior research indicates that female physicians spend more time working in the electronic health record (EHR) than do male physicians. OBJECTIVE: To examine gender differences in EHR usage among primary care physicians and identify potential causes for those differences. DESIGN: Retrospective study of EHR usage by primary care physicians (PCPs) in an academic hospital system. PARTICIPANTS: One hundred twenty-five primary care physicians INTERVENTIONS: N/A MAIN MEASURES: EHR usage including time spent working and volume of staff messages and patient messages. KEY RESULTS: After adjusting for panel size and appointment volume, female PCPs spend 20% more time (1.9 h/month) in the EHR inbasket and 22% more time (3.7 h/month) on notes than do their male colleagues (p values 0.02 and 0.04, respectively). Female PCPs receive 24% more staff messages (9.6 messages/month), and 26% more patient messages (51.5 messages/month) (p values 0.03 and 0.004, respectively). The differences in EHR time are not explained by the percentage of female patients in a PCP's panel. CONCLUSIONS: Female physicians spend more time working in their EHR inbaskets because both staff and patients make more requests of female PCPs. These differential EHR burdens may contribute to higher burnout rates in female PCPs.

Associations of depression status with plasma levels of candidate lipid and amino acid metabolites: a meta-analysis of individual data from three independent samples of US postmenopausal women.

Recent animal and small clinical studies have suggested depression is related to altered lipid and amino acid profiles. However, this has not been examined in a population-based sample, particularly in women. We identified multiple metabolites associated with depression as potential candidates from prior studies. Cross-sectional data from three independent samples of postmenopausal women were analyzed, including women from the Women's Health Initiative-Observational Study (WHI-OS, n = 926), the WHI-Hormone Trials (WHI-HT; n = 1,325), and the Nurses' Health Study II Mind-Body Study (NHSII-MBS; n = 218). Positive depression status was defined as having any of the following: elevated depressive symptoms, antidepressant use, or depression history. Plasma metabolites were measured using liquid chromatography-tandem mass spectrometry (21 phosphatidylcholines (PCs), 7 lysophosphatidylethanolamines, 5 ceramides, 3 branched chain amino acids, and 9 neurotransmitters). Associations between depression status and metabolites were evaluated using multivariable linear regression; results were pooled by random-effects meta-analysis with multiple testing adjustment using the false discovery rate (FDR). Prevalence rates of positive depression status were 24.4% (WHI-OS), 25.7% (WHI-HT), and 44.7% (NHSII-MBS). After multivariable adjustment, positive depression status was associated with higher levels of glutamate and PC 36 : 1/38 : 3, and lower levels of tryptophan and GABA-to-glutamate and GABA-to-glutamine ratio (FDR-p < 0.05). Positive associations with LPE 18 : 0/18 : 1 and inverse associations with valine and serotonin were also observed, although these associations did not survive FDR adjustment. Associations of positive depression status with several candidate metabolites including PC 36 : 1/38 : 3 and amino acids involved in neurotransmission suggest potential depression-related metabolic alterations in postmenopausal women, with possible implications for later chronic disease.

Duration and Life-Stage of Antibiotic Use and Risks of All-Cause and Cause-Specific Mortality: Prospective Cohort Study.

Rationale: The overuse of antibiotics has been an important clinical issue, and antibiotic exposure is linked to alterations in gut microbiota, which has been related to risks of various chronic diseases such as cardiovascular disease and cancer. Also, duration of antibiotic exposure may be a risk factor of premature death. Objective: We investigated associations of life-stage and duration of antibiotic use during adulthood with risks of all-cause and cause-specific mortality. Methods and Results: This prospective cohort study included 37 516 women aged ≥60 years who were free of cardiovascular disease or cancer from the Nurses' Health Study. Participants reported a total amount of time they used antibiotics (none, <15 days, 15 days to <2 months, or ≥2 months) in the middle- (age, 40-59) and late adulthood (age, 60 or older). We estimated hazard ratios for all-cause mortality and deaths from cardiovascular disease or cancer over 10 years according to duration of antibiotic use. During 355 918 person-years of follow-up, we documented 4536 deaths from any cause (including 728 cardiovascular deaths and 1206 cancer deaths). As compared with women who did not use antibiotics, those who used them for ≥2 months in late adulthood had increased risks of all-cause mortality (hazard ratio, 1.16 [95% CI, 1.01-1.33]) and cardiovascular mortality (hazard ratio, 1.49 [95% CI, 1.04-2.13]), but not cancer mortality (hazard ratio, 0.85 [95% CI, 0.65-1.12]) after adjustment for chronic metabolic diseases, antibiotic use during middle adulthood, indication for use, demographic factors, and lifestyle/dietary factors. The association was more evident among women who also used antibiotics in middle-adulthood than among those who did not use during this life-stage. Conclusions: Long-term use of antibiotics in late adulthood may be a risk factor for all-cause and cardiovascular mortality. The unfavorable effect of antibiotic exposure for subsequent risks of deaths due to chronic diseases needs to be considered.

Ten-year changes in plasma L-carnitine levels and risk of coronary heart disease.

PURPOSE: L-Carnitine is abundant in animal source foods, particularly red meat, and circulating L-carnitine may be related to the incidence of coronary heart disease (CHD). We investigated whether long-term changes in plasma L-carnitine over 10 years were associated with the CHD incidence and also examined joint associations of carnitine-rich red meat consumption and L-carnitine changes on the subsequent risk of CHD. METHODS: This prospective nested case-control study included 772 healthy women at baseline (386 incident CHD cases and 386 healthy controls). Plasma L-carnitine levels were measured both at the first (1989-90) and second blood collections (2000-02). Incident cases of CHD were prospectively followed from the date of the second blood collection through 2016. RESULTS: Overall, a greater increase in L-carnitine from the first to the second time point was related to a higher risk of CHD, regardless of the initial L-carnitine levels (relative risk: 1.36 (95% CI 0.999, 1.84) per 1-SD increase). The 10-year changes in L-carnitine were positively associated with red meat consumption over time, and women with higher red meat intake (≥ 36 g/day) and with greater increases in L-carnitine had a 1.86 (95% CI 1.13, 3.09) times increased risk of CHD, as compared to those with lower red meat intake and lesser increases in L-carnitine. CONCLUSION: Long-term increases in L-carnitine levels were associated with the subsequent incidence of CHD, especially among women with higher intake of red meat. Our results suggest the importance of atherogenic L-carnitine changes and dietary intakes over time in the prevention of CHD.

Long-term aircraft noise exposure and risk of hypertension in the Nurses' Health Studies.

BACKGROUND: Aircraft noise can affect populations living near airports. Chronic exposure to aircraft noise has been associated with cardiovascular disease, including hypertension. However, previous studies have been limited in their ability to characterize noise exposures over time and to adequately control for confounders. OBJECTIVES: The aim of this study was to examine the association between aircraft noise and incident hypertension in two cohorts of female nurses, using aircraft noise exposure estimates with high spatial resolution over a 20-year period. METHODS: We obtained contour maps of modeled aircraft noise levels over time for 90 U.S. airports and linked them with geocoded addresses of participants in the Nurses' Health Study (NHS) and Nurses' Health Study II (NHS II) to assign noise exposure for 1994-2014 and 1995-2013, respectively. We used time-varying Cox proportional hazards models to estimate hypertension risk associated with time-varying noise exposure (dichotomized at 45 and 55 dB(A)), adjusting for fixed and time-varying confounders. Results from both cohorts were pooled via random effects meta-analysis. RESULTS: In meta-analyses of parsimonious and fully-adjusted models with aircraft noise dichotomized at 45 dB(A), hazard ratios (HR) for hypertension incidence were 1.04 (95% CI: 1.00, 1.07) and 1.03 (95% CI: 0.99, 1.07), respectively. When dichotomized at 55 dB(A), HRs were 1.10 (95% CI: 1.01, 1.19) and 1.07 (95% CI: 0.98, 1.15), respectively. After conducting fully-adjusted sensitivity analyses limited to years in which particulate matter (PM) was obtained, we observed similar findings. In NHS, the PM-unadjusted HR was 1.01 (95% CI: 0.90, 1.14) and PM-adjusted HR was 1.01 (95% CI: 0.89, 1.14); in NHS II, the PM-unadjusted HR was 1.08 (95% CI: 0.96, 1.22) and the PM-adjusted HR was 1.08 (95% CI: 0.95, 1.21). Overall, in these cohorts, we found marginally suggestive evidence of a positive association between aircraft noise exposure and hypertension.

Self-reported history of comorbidities and markers of ovarian reserve among subfertile women.

PURPOSE: To investigate whether history of comorbidities is associated with markers of ovarian reserve among subfertile women. METHODS: This observational study includes 645 women seeking fertility care at the Massachusetts General Hospital who enrolled in the Environment and Reproductive Health (EARTH) study (2005-2019). Women completed a comprehensive questionnaire including medical diagnosis of comorbidities. Ovarian reserve markers including antral follicle count (AFC), assessed by transvaginal ultrasound, and circulating serum levels of day 3 FSH and AMH, are assessed by immunoassays. We fit linear regression models to evaluate the association between history of comorbidities and markers of ovarian reserve while adjusting for confounders. RESULTS: Self-reported history of hypertension, cancer, and neurological disorders was negatively associated with AFC in unadjusted models and in adjusted models for age, smoking, physical activity, comorbidity count, and BMI. Adjusted mean AFC (95% CI) was lower among women with history of hypertension, compared to women with no self-reported history of hypertension (11.5 vs 15.6, p value 0.0001). In contrast, day 3 FSH levels were positively related to history of eating disorders in both unadjusted and adjusted models (10.8 vs. 7.43 IU/L, p value ≤ 0.0001). Self-reported history of other comorbidities was unrelated to AFC, day 3 FSH, and AMH levels. CONCLUSIONS: History of hypertension, cancer, and neurological disorders was negatively associated with AFC, and eating disorders were positively related to day 3 FSH levels. The prevention of common comorbidities among women in reproductive age may help increase women's fertility given the declining birth rates and increasing use of assisted reproductive technologies in the past years.