Offspring Study Research Articles

Generalizing the Prediction of Bipolar Disorder Onset Across High-Risk Populations

Risk calculators (RC) to predict clinical outcomes are gaining interest. An RC to estimate risk of bipolar spectrum disorders (BPSD) could help reduce the duration of undiagnosed BPSD and improve outcomes. Our objective was to adapt an RC previously validated in the Pittsburgh Bipolar Offspring Study (BIOS) sample to achieve adequate predictive ability in both familial high-risk and clinical high-risk youths. Participants (aged 6-12 years at baseline) from the Longitudinal Assessment of Manic Symptoms (LAMS) study (N= 473) were evaluated semi-annually. Evaluations included a Kiddie Schedule for Affective Disorders (K-SADS) interview. After testing an RC that closely approximated the original, we made modifications to improve model prediction. Models were trained in the BIOS data, which included biennial K-SADS assessments, and tested in LAMS. The final model was then trained in LAMS participants, including family history of BPSD as a predictor, and tested in the familial high-risk sample. Over follow-up, 65 youths newly met criteria for BPSD. The original RC identified youths who developed BPSD only moderately well (area under the curve [AUC]= 0.67). Eliminating predictors other than the K-SADS screening items for mania and depression improved accuracy (AUC= 0.73) and generalizability. The model trained in LAMS, including family history as a predictor, performed well in the BIOS sample (AUC= 0.74). The clinical circumstances under which the assessment of symptoms occurs affects RC accuracy; focusing on symptoms related to the onset of BPSD improved generalizability. Validation of the RC under clinically realistic circumstances will be an important next step.

The Israel Registry for Alzheimer’s Prevention (IRAP) Study: Design and Baseline Characteristics

Family history of Alzheimer's disease (AD) is associated with increased dementia-risk. The Israel Registry for Alzheimer's Prevention (IRAP) is a prospective longitudinal study of asymptomatic middle-aged offspring of AD patients (family history positive; FH+) and controls (whose parents have aged without dementia; FH-) aimed to unravel the contribution of midlife factors to future cognitive decline and dementia. Here we present the study design, methods, and baseline characteristics. Participants are members of the Maccabi Health Services, 40-65 years of age, with exquisitely detailed laboratory, medical diagnoses and medication data available in the Maccabi electronic medical records since 1998. Data collected through IRAP include genetic, sociodemographic, cognitive, brain imaging, lifestyle, and health-related characteristics at baseline and every three years thereafter. Currently IRAP has 483 participants [mean age 54.95 (SD = 6.68) and 64.8% (n = 313) women], 379 (78.5%) FH+, and 104 (21.5%) FH-. Compared to FH-, FH+ participants were younger (p = 0.011), more often males (p = 0.003) and with a higher prevalence of the APOE E4 allele carriers (32.9% FH+, 22% FH-; p = 0.040). Adjusting for age, sex, and education, FH+ performed worse than FH-in global cognition (p = 0.027) and episodic memory (p = 0.022). Lower cognitive scores and higher rates of the APOE E4 allele carriers among the FH+ group suggest that FH ascertainment is good. The combination of long-term historical health-related data available through Maccabi with the multifactorial information collected through IRAP will potentially enable development of dementia-prevention strategies already in midlife, a critical period in terms of risk factor exposure and initiation of AD-neuropathology.

Neurological, neuropsychiatric and neurodevelopmental complications of COVID-19.

Although COVID-19 is predominantly a respiratory disease, it is known to affect multiple organ systems. In this article, we highlight the impact of SARS-CoV-2 (the coronavirus causing COVID-19) on the central nervous system as there is an urgent need to understand the longitudinal impacts of COVID-19 on brain function, behaviour and cognition. Furthermore, we address the possibility of intergenerational impacts of COVID-19 on the brain, potentially via both maternal and paternal routes. Evidence from preclinical models of earlier coronaviruses has shown direct viral infiltration across the blood–brain barrier and indirect secondary effects due to other organ pathology and inflammation. In the most severely ill patients with pneumonia requiring intensive care, there appears to be additional severe inflammatory response and associated thrombophilia with widespread organ damage, including the brain. Maternal viral (and other) infections during pregnancy can affect the offspring, with greater incidence of neurodevelopmental disorders, such as autism, schizophrenia and epilepsy. Available reports suggest possible vertical transmission of SARS-CoV-2, although longitudinal cohort studies of such offspring are needed. The impact of paternal infection on the offspring and intergenerational effects should also be considered. Research targeted at mechanistic insights into all aspects of pathogenesis, including neurological, neuropsychiatric and haematological systems alongside pulmonary pathology, will be critical in informing future therapeutic approaches. With these future challenges in mind, we highlight the importance of national and international collaborative efforts to gather the required clinical and preclinical data to effectively address the possible long-term sequelae of this global pandemic, particularly with respect to the brain and mental health.

Race and Sex-Specific Population Attributable Fractions for Incident Heart Failure: Lifetime Risk Pooling Project

Objective Despite race- and sex-specific differences in risk of heart failure (HF), there are limited data comparing the contribution of major modifiable risk factors to the population burden of HF in each race-sex group. In addition, studies have not used a competing risk framework to account for death in the absence of HF, to provide a more accurate risk estimate for each risk factor. We determined the contribution of modifiable risk factors, specifically hypertension, diabetes, obesity, current smoking, and hyperlipidemia, to the population burden of HF, as measured by population attributable fraction (PAF), stratified by race and sex. Methods A pooled cohort was created using harmonized data from six longitudinal US-based cohorts (Atherosclerosis Risk in Communities Study, Coronary Artery Risk Development in Young Adults Study, Cardiovascular Health Study, Framingham Heart Study starting from 1970, Framingham Offspring Study, and the Multi-Ethnic Study of Atherosclerosis). Baseline measurements of the risk factors were used to determine prevalence. Relative risk of incident HF for each risk factor was determined using a piecewise constant hazards model adjusted for age, education, other modifiable risk factors, and the competing risk of non-HF death. PAF for HF was then calculated for each risk factor in each race-sex group. Results Hypertension had the highest adjusted PAF in black men (28.3%, 95% CI 18.7, 36.7%) and black women (25.8%, 95% CI 16.3, 34.2%). In contrast, obesity had the highest adjusted PAF in white men (21.0%, 95% CI 14.6, 27.0%) and white women (17.9%, 95% CI 12.8, 22.6%). Diabetes disproportionately contributed to HF in black women (PAF 16.4%, 95% CI 12.7, 19.9%). Current smoking made a modest contribution and hyperlipidemia contributed minimally to HF risk. The cumulative PAF for all risk factors was highest in black women (51.9%, 95% CI 39.3, 61.8%) and lowest in white women (39.3%, 95% CI 33.9, 44.4%). Conclusions Our findings extend insights into the contribution of modifiable risk factors to population HF burden by using a competing risk model and providing race and sex-specific contemporary PAF estimates (Figure 1). Our results highlight the growing impact of hypertension and diabetes on HF burden, especially in black women. These results can guide public health policies aimed at reducing the population burden of HF. Despite race- and sex-specific differences in risk of heart failure (HF), there are limited data comparing the contribution of major modifiable risk factors to the population burden of HF in each race-sex group. In addition, studies have not used a competing risk framework to account for death in the absence of HF, to provide a more accurate risk estimate for each risk factor. We determined the contribution of modifiable risk factors, specifically hypertension, diabetes, obesity, current smoking, and hyperlipidemia, to the population burden of HF, as measured by population attributable fraction (PAF), stratified by race and sex. A pooled cohort was created using harmonized data from six longitudinal US-based cohorts (Atherosclerosis Risk in Communities Study, Coronary Artery Risk Development in Young Adults Study, Cardiovascular Health Study, Framingham Heart Study starting from 1970, Framingham Offspring Study, and the Multi-Ethnic Study of Atherosclerosis). Baseline measurements of the risk factors were used to determine prevalence. Relative risk of incident HF for each risk factor was determined using a piecewise constant hazards model adjusted for age, education, other modifiable risk factors, and the competing risk of non-HF death. PAF for HF was then calculated for each risk factor in each race-sex group. Hypertension had the highest adjusted PAF in black men (28.3%, 95% CI 18.7, 36.7%) and black women (25.8%, 95% CI 16.3, 34.2%). In contrast, obesity had the highest adjusted PAF in white men (21.0%, 95% CI 14.6, 27.0%) and white women (17.9%, 95% CI 12.8, 22.6%). Diabetes disproportionately contributed to HF in black women (PAF 16.4%, 95% CI 12.7, 19.9%). Current smoking made a modest contribution and hyperlipidemia contributed minimally to HF risk. The cumulative PAF for all risk factors was highest in black women (51.9%, 95% CI 39.3, 61.8%) and lowest in white women (39.3%, 95% CI 33.9, 44.4%). Our findings extend insights into the contribution of modifiable risk factors to population HF burden by using a competing risk model and providing race and sex-specific contemporary PAF estimates (Figure 1). Our results highlight the growing impact of hypertension and diabetes on HF burden, especially in black women. These results can guide public health policies aimed at reducing the population burden of HF.

Intrauterine exposure to diabetes and risk of cardiovascular disease in adolescence and early adulthood: a population-based birth cohort study.

It is unclear whether intrauterine exposure to maternal diabetes is associated with risk factors for cardiovascular disease and related end points in adulthood. We examined this potential association in a population-based birth cohort followed up to age 35 years. We performed a cohort study of offspring born between 1979 and 2005 (n = 293 546) and followed until March 2015 in Manitoba, Canada, using registry-based administrative data. The primary exposures were intrauterine exposure to gestational diabetes and type 2 diabetes mellitus. The primary outcome was a composite measure of incident cardiovascular disease events, and the secondary outcome was a composite of risk factors for cardiovascular disease in offspring followed up to age 35 years. The cohort provided 3 628 576 person-years of data (mean age at latest follow-up 20.5 [standard deviation 6.4] years, 49.3% female); 2765 (0.9%) of the offspring experienced a cardiovascular disease end point, and 12 673 (4.3%) experienced a cardiovascular disease risk factor. After propensity score matching, the hazard for cardiovascular disease end points was elevated in offspring exposed to gestational diabetes (adjusted hazard ratio [HR] 1.42, 95% confidence interval [CI] 1.12-1.79) but not type 2 diabetes (adjusted HR 1.40, 95% CI 0.98-2.01). A similar association was observed for cardiovascular disease risk factors (gestational diabetes: adjusted HR 1.92, 95% CI 1.75-2.11; type 2 diabetes: adjusted HR 3.40, 95% CI 3.00-3.85). Intrauterine exposure to maternal diabetes was associated with higher morbidity and risk related to cardiovascular disease among offspring up to 35 years of age.

Eicosanoid Inflammatory Mediators Are Robustly Associated With Blood Pressure in the General Population.

BackgroundEpidemiological and animal studies have associated systemic inflammation with blood pressure (BP). However, the mechanistic factors linking inflammation and BP remain unknown. Fatty acid–derived eicosanoids serve as mediators of inflammation and have been suggested to regulate renal vascular tone, peripheral resistance, renin‐angiotensin system, and endothelial function. We hypothesize that specific proinflammatory and anti‐inflammatory eicosanoids are linked with BP.Methods and ResultsWe studied a population sample of 8099 FINRISK 2002 participants randomly drawn from the Finnish population register (53% women; mean age, 48±13 years) and, for external validation, a sample of 2859 FHS (Framingham Heart Study) Offspring study participants (55% women; mean age, 66±9 years). Using nontargeted liquid chromatography–mass spectrometry, we profiled 545 distinct high‐quality eicosanoids and related oxylipin mediators in plasma. Adjusting for conventional hypertension risk factors, we observed 187 (34%) metabolites that were significantly associated with systolic BP (P<Bonferroni‐corrected threshold of 0.05/545). We used forward selection linear regression modeling in FINRISK to define a general formula for individual eicosanoid risk score. Individuals of the top risk score quartile in FINRISK had a 9.0 (95% CI, 8.0–10.1) mm Hg higher systolic BP compared with individuals in the lowest quartile in fully adjusted models. Observed metabolite associations were consistent across FINRISK and FHS.ConclusionsPlasma eicosanoids demonstrate strong associations with BP in the general population. As eicosanoid compounds affect numerous physiological processes that are central to BP regulation, they may offer new insights about the pathogenesis of hypertension, as well as serve as potential targets for therapeutic intervention.

Metabolic Architecture of Acute Exercise Response in Middle-Aged Adults in the Community.

Whereas regular exercise is associated with lower risk of cardiovascular disease and mortality, mechanisms of exercise-mediated health benefits remain less clear. We used metabolite profiling before and after acute exercise to delineate the metabolic architecture of exercise response patterns in humans. Cardiopulmonary exercise testing and metabolite profiling was performed on Framingham Heart Study participants (age 53±8 years, 63% women) with blood drawn at rest (n=471) and at peak exercise (n=411). We observed changes in circulating levels for 502 of 588 measured metabolites from rest to peak exercise (exercise duration 11.9±2.1 minutes) at a 5% false discovery rate. Changes included reductions in metabolites implicated in insulin resistance (glutamate, -29%; P=1.5×10-55; dimethylguanidino valeric acid [DMGV], -18%; P=5.8×10-18) and increases in metabolites associated with lipolysis (1-methylnicotinamide, +33%; P=6.1×10-67), nitric oxide bioavailability (arginine/ornithine + citrulline, +29%; P=2.8×10-169), and adipose browning (12,13-dihydroxy-9Z-octadecenoic acid +26%; P=7.4×10-38), among other pathways relevant to cardiometabolic risk. We assayed 177 metabolites in a separate Framingham Heart Study replication sample (n=783, age 54±8 years, 51% women) and observed concordant changes in 164 metabolites (92.6%) at 5% false discovery rate. Exercise-induced metabolite changes were variably related to the amount of exercise performed (peak workload), sex, and body mass index. There was attenuation of favorable excursions in some metabolites in individuals with higher body mass index and greater excursions in select cardioprotective metabolites in women despite less exercise performed. Distinct preexercise metabolite levels were associated with different physiologic dimensions of fitness (eg, ventilatory efficiency, exercise blood pressure, peak Vo2). We identified 4 metabolite signatures of exercise response patterns that were then analyzed in a separate cohort (Framingham Offspring Study; n=2045, age 55±10 years, 51% women), 2 of which were associated with overall mortality over median follow-up of 23.1 years (P≤0.003 for both). In a large sample of community-dwelling individuals, acute exercise elicits widespread changes in the circulating metabolome. Metabolic changes identify pathways central to cardiometabolic health, cardiovascular disease, and long-term outcome. These findings provide a detailed map of the metabolic response to acute exercise in humans and identify potential mechanisms responsible for the beneficial cardiometabolic effects of exercise for future study.

Longitudinal dimensions of alcohol consumption and dietary intake in the Framingham Heart Study Offspring Cohort (1971-2008).

Existing studies addressing alcohol consumption have not captured the multidimensionality of drinking patterns, including drinking frequency, binge drinking, beverage preference and changes in these measures across the adult life course. We examined longitudinal trends in drinking patterns and their association with diet over four decades in ageing US adults from the Framingham Offspring Study (n 4956; baseline mean age 36·2 years). Alcohol intake (drinks/week, drinking frequency, beverage-specific consumption, drinks/occasion) was assessed quadrennially from examinations 1 to 8. Participants were classified as binge drinkers, moderate drinkers or heavy drinkers (4+ and 5+ drinks/occasion; ≤1 and ≤2 drinks/d and >7 and >14 drinks/week for women and men, respectively). Dietary data were collected by a FFQ from examinations 5 to 8 (1991-2008). We evaluated trends in drinking patterns using linear mixed effect models and compared dietary intake across drinking patterns using heterogeneous variance models. Alcohol consumption decreased from 1971 to 2008 (3·7 v. 2·2 oz/week; P < 0·05). The proportion of moderate (66 v. 59·3 %), heavy (18·4 v. 10·5 %) and binge drinkers (40·0 v. 12·3 %) declined (P < 0·05). While average wine consumption increased (1·4 v. 2·2 drinks/week), beer (3·4 v. 1·5 drinks/week) and cocktail intake (2·8 v. 1·2 drinks/week) decreased. Non-binge drinkers consumed less sugary drinks and more whole grains than binge drinkers, and the latter consumed more total fat across all examinations (P < 0·05). There was a significant difference in consumption trends of total grains by drinking level (P < 0·05). In conclusion, alcohol drinking patterns are unstable throughout adulthood. Higher intakes were generally associated with poorer diets. These analyses support the nuanced characterisation of alcohol consumption in epidemiological studies.

Health outcomes in offspring born to survivors of childhood cancers following assisted reproductive technologies

PurposeAn increasing number of childhood cancer survivors are using assisted reproductive technologies (ART) to overcome treatment-related fertility impairment. We report perinatal and health outcomes of offspring born to survivors following ART.MethodsThe FeCt Multicenter Offspring Study surveyed the health of offspring of childhood cancer survivors. Health outcomes in offspring born to survivors following ART (n = 57, 4.6%) or after spontaneous conception (n = 1182) were assessed in the German cohort (n = 1239) using bivariate analysis. Findings were put into the context of the general German population by health outcome assessment in 1:1 matched-pair analysis (n = 2478).ResultsNearly twice the survivors used ART compared with numbers reported for the German general population (4.6% vs. 2.6%). Successful pregnancies were achieved after a median of two cycles, mainly using non-cryopreserved oocytes/sperm. Multiple sibling births (p < 0.001, 28.1% vs. 3.0%) and low birth weight (p = 0.008; OR = 2.659, 95% CI = 1.258–5.621) occurred significantly more often in offspring born to survivors who utilized ART than spontaneously conceived children, whereas similar percentages were born preterm or too small for their gestational age. ART did not increase the prevalence of childhood cancer or congenital malformations in offspring born to survivors.ConclusionART use by childhood cancer survivors was successful with both fresh and cryopreserved oocytes/sperm, and did not influence perinatal health or health outcomes when known confounders were taken into account.Implications for Cancer SurvivorsOncofertility is an important component of patient care. Our study implicates that the utilization of ART by adult survivors of childhood cancer does not put offspring at additional risk for adverse perinatal or health outcomes.

Database of Families of Workers Chronically Exposed to Radiation: Data and Biospecimen Resources.

Animal experiment findings suggest that high doses of ionizing radiation exposure (>1.0 Gy) may cause genetic and epigenetic effects in offspring. However, epidemiological studies of offspring of radiation-exposed parents did not find increased risks of any health effects. Findings of cellular/experimental investigations and studies of human health effects are contradicting, and further investigations are needed to help resolve ambiguities using updated and/or improved data. This paper provides a detailed description of a database of families of workers of the first Russian nuclear facility, Mayak Production Association, located in the Southern Urals in the Chelyabinsk region close to Ozyorsk city, which started its operation in 1948 and today consists of reactors, radiochemical and plutonium production plants, and auxiliary facilities. The Mayak worker cohort includes 22,377 individuals (25% females) who were hired at one of the main Mayak PA facilities between 1948 and 1982 and were externally or internally exposed to ionizing radiation over prolonged periods. Advantages of the cohort include its large size, extensive follow-up period (70 y), individually measured doses from external and internal exposure and the wide range of these doses, heterogeneity by gender/age/ethnicity/initial health status, complete data on vital status and causes of death, available medical information on morbidity and reproduction, available data on non-radiation factors, and stored biological specimens donated by more than one-third of the cohort members. Based on medical and dosimetry database "Clinics" containing raw data on workers of the study cohort, the Mayak workers' family and offspring database was created. To date, it comprises 12,195 family couples (a husband and a wife) and 16,585 offspring. Biological specimens are available for more than 1,000 family triads (a husband, a wife, and their child). Stages of assembling the database and its descriptive characteristics are presented in this paper. Examples of potential applications of the database for investigations of non-targeted and transgenerational radiation effects in offspring of exposed parents are discussed.

Relations between plasma microRNAs, echocardiographic markers of atrial remodeling, and atrial fibrillation: Data from the Framingham Offspring study.

BackgroundCirculating microRNAs may reflect or influence pathological cardiac remodeling and contribute to atrial fibrillation (AF).ObjectiveThe purpose of this study was to identify candidate plasma microRNAs that are associated with echocardiographic phenotypes of atrial remodeling, and incident and prevalent AF in a community-based cohort.MethodsWe analyzed left atrial function index (LAFI) of 1788 Framingham Offspring 8 participants. We quantified expression of 339 plasma microRNAs. We examined associations between microRNA levels with LAFI and prevalent and incident AF. We constructed pathway analysis of microRNAs’ predicted gene targets to identify molecular processes involved in adverse atrial remodeling in AF.ResultsThe mean age of the participants was 66 ± 9 years, and 54% were women. Five percent of participants had prevalent AF at the initial examination and 9% (n = 157) developed AF over a median 8.6 years of follow-up (IQR 8.1–9.2 years). Plasma microRNAs were associated with LAFI (N = 73, p<0.0001). Six of these plasma microRNAs were significantly associated with incident AF, including 4 also associated with prevalent AF (microRNAs 106b, 26a-5p, 484, 20a-5p). These microRNAs are predicted to regulate genes involved in cardiac hypertrophy, inflammation, and myocardial fibrosis.ConclusionsCirculating microRNAs 106b, 26a-5p, 484, 20a-5p are associated with atrial remodeling and AF.

Maternal Stress During Pregnancy Predicts Infant Infectious and Noninfectious Illness

To examine the association between prenatal stress and infant physical health in the first year of life within an understudied, racially and ethnically diverse, highly stressed community sample. We expected that greater stress exposure would predict higher rates of infant illness. Low-income, racially/ethnically diverse, overweight women with low medical risk pregnancies were recruited (2011-2014) during pregnancy. Pregnancy Stressful Life Events were assessed retrospectively (mean, 11.88months postpartum). Perceived stress was assessed twice during pregnancy (at a mean of 17.4weeks and again at a mean of 25.6weeks) and at 6months postpartum. Women with live births (n=202) were invited; 162 consented to the offspring study. Medical records from pediatric clinics and emergency departments for 148 infants were abstracted for counts of total infectious illnesses, total noninfectious illness, and diversity of illnesses over the first year of life. The final analytic sample included 109 women (mean age, 28.08years) and their infants. In covariate-adjusted negative binomial models, maternal perceptions of stress across pregnancy were positively associated with infant illness. Each 1-point increase in average stress was associated with a 38% increase in incidence of infant infections (Incidence rate ratio, 1.38; 95% CI, 1.01-1.88; P<.05), a 73% increase in noninfectious illness (IRR, 1.73; 95% CI, 1.34-2.23; P<.05), and a 53% increase in illness diversity (IRR, 1.53; 95% CI, 1.25, 1.88; P<.01); effect sizes were larger for perceived stress later in pregnancy. Stressful life events count and postnatal stress were not uniquely associated with illness. In line with recommendations from the American Academy of Pediatrics to screen for maternal perinatal depression, screening and support for stress reduction during pregnancy may benefit both maternal and child health.

In utero exposure to genistein decreased intranasal house dust mite-induced respiratory allergy in middle-aged male B6C3F1 offspring

Despite many hypothesized benefits of dietary isoflavone genistein (GEN) deriving from soy-based products, questions surrounding GEN’s developmental effects are increasing. To understand if in utero GEN exposure modulated postnatal respiratory allergies in the middle age, we conducted a time course study in the B6C3F1 offspring (PND 240-330) using a common household allergen (house dust mites: HDM; 10 μg/mouse for PND 240 and 290, and 50 μg/mouse for PND 330, a middle age in mice) following intranasal instillation, a physiological route of allergen exposure. GEN was administered to dams by gavage from gestational day 14 to parturition at a physiologically relevant dose (20 mg/kg body weight). Female and male offspring were sensitized with HDM allergens beginning about one month prior to sacrifice followed by challenges with three weekly dosings of HDM extracts, and they were euthanized at day 3 following the final HDM exposure. In utero exposure to GEN decreased HDM allergen-induced respiratory allergy in male B6C3F1 offspring at PND 330 as reflected by decreases in airway hyperresponsiveness (e.g., Penh value), HDM-specific IgG1 (a Th2 type Ab) and the activity of eosinophil peroxidase in the lung (an indication of eosinophil recruitment to the lungs). However, in utero exposure to GEN had minimal effects on HDM allergen-induced respiratory allergy in the middle-aged female offspring. Changes in serum total IgE, HDM-specific IgE, and lung histopathology scores in both male and female offspring were not biologically significant. Overall, in utero GEN exposure exerted a protective effect on respiratory allergy in the middle-aged male, but not female, B6C3F1 offspring following later-life HDM exposures.

MiRNA Mechanisms Underlying the Association of Beta Blocker Use and Bone Mineral Density.

Osteoporosis is a debilitating and costly disease that causes fractures in 33% of women and 20% of men over the age of 50 years. Recent studies have shown that beta blocker (BB) users have higher bone mineral density (BMD) and decreased risk of fracture compared with non-users. The mechanism underlying this association is thought to be due to suppression of adrenergic signaling in osteoblasts, which leads to increased BMD in rodent models; however, the mechanism in humans is unknown. Also, several miRNAs are associated with adrenergic signaling and BMD in separate studies. To investigate potential miRNA mechanisms, we performed a cross-sectional analysis using clinical data, dual-energy X-ray absorptiometry (DXA) scans, and miRNA and mRNA profiling of whole blood from the Framingham Study's Offspring Cohort. We found nine miRNAs associated with BB use and increased BMD. In parallel network analyses, we discovered a subnetwork associated with BMD and BB use containing two of these nine miRNAs, miR-19a-3p and miR-186-5p. To strengthen this finding, we showed that these two miRNAs had significantly higher expression in individuals without incident fracture compared with those with fracture in an external data set. We also noted a similar trend in association between these miRNA and Z-score as calculated from heel ultrasound measures in two external cohorts (SOS-Hip and SHIP-TREND). Because miR-19a directly targets the ADRB1 mRNA transcript, we propose BB use may downregulate ADRB1 expression in osteoblasts through increased miR-19a-3p expression. We used enrichment analysis of miRNA targets to find potential indirect effects through insulin and parathyroid hormone signaling. This analysis provides a starting point for delineating the role of miRNA on the association between BB use and BMD. © 2020 American Society for Bone and Mineral Research (ASBMR).

Comparing Methods from the National Cancer Institute vs Multiple Source Method for Estimating Usual Intake of Nutrients in the Hispanic Community Health Study/Study of Latino Youth

BackgroundThe Multiple Source Method (MSM) and the National Cancer Institute (NCI) method estimate usual dietary intake from short-term dietary assessment instruments, such as 24-hour recalls. Their performance varies according to sample size and nutrients distribution. A comparison of these methods among a multiethnic youth population, for which nutrient composition and dietary variability may differ from adults, is a gap in the literature. ObjectiveTo compare the performance of the NCI method relative to MSM in estimating usual dietary intakes in Hispanic/Latino adolescents. DesignData derived from the cross-sectional population-based Hispanic Community Health Study/Study of Latino Youth, an ancillary study of offspring of participants in the adult Hispanic Community Health Study/Study of Latino Youth cohort. Dietary data were obtained by two 24-hour recalls. Participants/settingOne thousand four hundred fifty-three Hispanic/Latino youth (aged 8 to 16 years) living in four urban US communities (Bronx, NY; Chicago, IL; Miami, FL; and San Diego, CA) during 2012 through 2014. Main outcome measuresThe NCI method and the MSM were applied to estimate usual intake of total energy, macronutrients, minerals and vitamins, added sugar, and caffeine. Statistical analysesMean, standard deviation, minimum and maximum values, coefficient of variation, variance ratio, and differences between NCI and MSM methods and the 2-day mean were estimated in several percentiles of the distribution, as well as concordance correlation coefficients and Bland-Altman plot analysis. ResultsThe distributions of all nutrients studied were very similar between NCI and MSM. The correlation between NCI and MSM was >0.80 for all nutrients (P<0.001), except dietary cholesterol, vitamin C, and n-3 fatty acids. In individual estimations, NCI method predicted higher estimates and lower variance than the MSM. The lowest level of agreement was observed in the values at the tails of the distribution, and for nutrients with high variance ratio. ConclusionsOverall, both MSM and NCI method provided acceptable estimates of the usual intake distribution using 24-hour recall, and they better represented the usual intake compared with 2-day mean, correcting for intraindividual variability.

Patterns of urinary albumin and IgM associate with markers of vascular ageing in young to middle-aged individuals in the Malm\xf6 offspring study

BackgroundIncreased urinary excretion of IgM and low-grade albuminuria are associated with increased risk of cardiovascular morbidity and mortality. The objective of this study was to investigate the association between urinary IgM, albuminuria, and vascular parameters reflecting arterial structure and function.MethodsSubjects of the present study were from the Malmö Offspring study (MOS) cohort, and included 1531 offspring (children and grand-children) to first-generation subjects that participated in the Malmö Diet Cancer-Cardiovascular Arm study cohort. At baseline, technical measurements of arterial stiffness (carotid-femoral pulse wave velocity; c-f PWV), carotid arterial morphology, 24-h ambulatory blood pressure recordings, ankle-brachial-index (ABI), and evaluation of endothelial function (reactive hyperemia index, RHI) were performed. Urinary (U) IgM, U-albumin, and U-creatinine were measured. Multivariate adjusted logistic regression was used to test whether U-IgM excretion and increasing urinary albumin excretion were related to vascular parameters.ResultsDetectable U-IgM was independently associated with higher systolic blood pressure, odds ratio (OR) 1.021, 95% confidence interval (CI, 1.003–1.039), p = 0.025 and lower ABI; ABI dx: OR 0.026, 95% CI (0.002–0.381), p = 0.008, ABI sin: OR 0.040, 95% CI (0.003–0.496), p = 0.012. Low-grade albuminuria was independently associated with systolic and diastolic blood pressure, aortic blood pressure, the c-f PWV and the number of carotid intima plaques (p < 0.05).ConclusionsIn young to middle-aged, mostly healthy individuals, increased U-IgM excretion and low-grade albuminuria are associated with adverse vascular parameters. Increased U-IgM excretion may reflect subclinical peripheral atherosclerosis, whereas increased U-albumin excretion is associated with a wide range of cardiovascular abnormalities. This may reflect different pathophysiological mechanisms.

Generational Differences in the 10-year Incidence of Impaired Contrast Sensitivity

ABSTRACT Purpose To determine if incidence of contrast sensitivity (CS) impairment differs by generation and identify factors to explain these differences. Methods The Beaver Dam Eye Study (BDES) and Beaver Dam Offspring Study (BOSS) are cohort studies of aging adults in Beaver Dam, Wisconsin. Baseline examinations occurred from 1993 to 1995 (BDES) and 2005–2008 (BOSS). Follow-up examinations occurred in five-year intervals. CS testing was conducted with Pelli-Robson letter sensitivity charts; Incident impairment was a log CS score <1.55 in either eye at follow-up. Associations of incidence with generation were investigated using estimated hazard ratios (HR) with 95% confidence intervals (CI). Results Participants (N = 3185) had a mean age of 51.9 years at baseline (standard deviation = 9.9) and 51.9% were female. Ten-year cumulative incidence of CS impairment was 40.1%, was higher among women (41.7%) than men (38.8%), and increased by age group. The risk of incident CS impairment decreased by 39% per generation. In multivariable models, the Baby Boom Generation (HR = 0.42, 95%CI = 0.31, 0.58) and Generation X (HR = 0.56, 95%CI = 0.34, 0.91) had a significantly decreased risk of CS impairment compared to the Greatest Generation. Results were similar in sensitivity analyses excluding those with cataract, age-related macular degeneration, or visual acuity impairment. Conclusion The risk of incident CS impairment decreased by birth cohort, with the greatest reduction in the Baby Boom Generation. The difference in risk suggests that there are unknown modifiable risk factors that may help to further explain the etiology of CS impairment and provide potential pathways for prevention in the future.

The gut microbiota-related metabolite phenylacetylglutamine associates with increased risk of incident coronary artery disease.

The gut microbiota is increasingly being implicated in cardiovascular health. Metabolites produced by bacteria have been suggested to be mediators in the bacterial action on cardiovascular health. We aimed to identify gut microbiota-related plasma metabolites and test whether these metabolites associate with future risk of coronary artery disease (CAD). Nontargeted metabolomics was performed using liquid chromatography-mass spectrometry in order to measure 1446 metabolite features in the Malmö Offspring Study (MOS) (N = 776). The gut microbiota was characterized using 16S rRNA sequencing. Gut bacteria-related metabolites were measured in two independent prospective cohorts, the Malmö Diet and Cancer - Cardiovascular Cohort (MDC-CC) (N = 3361) and the Malmö Preventive Project (MPP) (N = 880), in order to investigate the associations between gut bacteria-related metabolites and risk of CAD. In MOS, 33 metabolite features were significantly (P < 4.8e-7) correlated with at least one operational taxonomic unit. Phenylacetylglutamine (PAG) was associated with an increased risk of future CAD, using inverse variance weighted meta-analysis of age and sex-adjusted logistic regression models in MDC-CC and MPP. PAG remained significantly associated with CAD (OR = 1.17, 95% CI = 1.06-1.29, P = 1.9e-3) after adjustments for cardiovascular risk factors. The levels of 33 plasma metabolites were correlated with the gut microbiota. Out of these, PAG was associated with an increased risk of future CAD independently of other cardiovascular risk factors. Our results highlight a link between the gut microbiota and CAD risk and should encourage further studies testing if modification of PAG levels inhibits development of CAD.

Animal protein intake reduces risk of functional impairment and strength loss in older adults

Protein intake has been shown to lower risk of aging-related functional decline. The goal of this study was to assess long-term effects of weight-adjusted animal (AP) and plant protein (PP) intakes on aging-related change in functional status and grip strength. Framingham Offspring Study participants (n=1896, 891 men and 1005 women), ≥age 50, were followed for an average of 14.4 years. Protein intake derived from two sets of 3-day diet records (exams 3 and 5) was expressed as both weight-adjusted intake (from residuals) and per kilogram of body weight (g/kg/d). Seven tasks from two standardized assessments (Nagi and the Rosow-Breslau scales) were selected to determine functional status at exams 5-9. Functional impairment was defined as failure to complete (or having a lot of difficulty completing) a given task. Grip strength was assessed by dynamometer at exams 7-9. Participants with higher (vs. lower) weight-adjusted intakes of AP and PP maintained higher functional scores (p=0.001 and p<0.001, respectively). After accounting for baseline skeletal muscle mass (SMM) and physical activity, only AP was linked with lower risks of functional impairment. Higher AP intake among sedentary individuals led to 29% (95% CI: 0.51-1.00) reduced risks of impairment; among subjects with lower SMM, higher AP was associated with 30% (95% CI: 0.49-0.98) reduced risks. Physical activity and SMM were independently associated with reduced risks of functional impairment, regardless of protein intake. Finally, higher AP intake led to 34% and 48% greater preservation of grip strength in men (p=0.012) and women (p=0.034). Results were similar for protein intake expressed as g/kg/d. Higher AP intake and higher levels of physical activity and SMM were independently associated with lower risks of functional impairment and greater preservation of grip strength in adults over the age of 50 years.

Adult offspring of lesbian parents: How do they relate to their sperm donors?

To study how adult offspring in planned lesbian-parent families relate to their unknown or known donors. Qualitative analyses of the sixth wave of online surveys from a longitudinal study of adult offspring in planned lesbian families, enrolled at conception. Community-based United States national study. The 76 participants were 25-year-old donor insemination (DI) offspring whose lesbian parent(s) enrolled in a prospective longitudinal study when these offspring were conceived. None. Offspring were asked about donor type, feelings about permanently unknown donor, satisfaction with and role of known donor, whether relationship with known donor was ongoing, and age of meeting open-identity donor. This cohort (n = 76) of DI offspring with lesbian parents was among the first generation to reach adulthood. Thirty participants had permanently unknown donors and most participants felt comfortable about not knowing them. Sixteen participants had open-identity donors they had not met. Thirty had currently known donors-met in childhood (n = 22) or after open-identity donor disclosure (n = 8)-of whom two thirds had ongoing relationships with donors, half considered their donors as acquaintances, and nearly half had good feelings about their relationship, although a minority expressed conflicted feelings. This study of adult DI offspring from planned lesbian families shows that those who knew their donors mainly felt positively about these relationships. Qualitative analyses offered insight into offspring-donor relationships, whose numbers are increasing due to historical and demographic trends.