Obesity risk in young adults from the Jerusalem Perinatal Study (JPS): the contribution of polygenic risk and early life exposure.

BACKGROUND/OBJECTIVES: The effects of early life exposures on offspring life-course health are well established. This study assessed whether adding early socio-demographic and perinatal variables to a model based on polygenic risk score (PRS) improves prediction of obesity risk. METHODS: We used the Jerusalem Perinatal study (JPS) with data at birth and body mass index (BMI) and waist circumference (WC) measured at age 32. The PRS was constructed using over 2.1M common SNPs identified in genome-wide association study (GWAS) for BMI. Linear and logistic models were applied in a stepwise approach. We first examined the associations between genetic variables and obesity-related phenotypes (e.g., BMI and WC). Secondly, socio-demographic variables were added and finally perinatal exposures, such as maternal pre-pregnancy BMI (mppBMI) and gestational weight gain (GWG) were added to the model. Improvement in prediction of each step was assessed using measures of model discrimination (area under the curve, AUC), net reclassification improvement (NRI) and integrated discrimination improvement (IDI). RESULTS: One standard deviation (SD) change in PRS was associated with a significant increase in BMI (ß = 1.40) and WC (ß = 2.45). These associations were slightly attenuated (13.7-14.2%) with the addition of early life exposures to the model. Also, higher mppBMI was associated with increased offspring BMI (ß = 0.39) and WC (ß = 0.79) (p < 0.001). For obesity (BMI ≥ 30) prediction, the addition of early socio-demographic and perinatal exposures to the PRS model significantly increased AUC from 0.69 to 0.73. At an obesity risk threshold of 15%, the addition of early socio-demographic and perinatal exposures to the PRS model provided a significant improvement in reclassification of obesity (NRI, 0.147; 95% CI 0.068-0.225). CONCLUSIONS: Inclusion of early life exposures, such as mppBMI and maternal smoking, to a model based on PRS improves obesity risk prediction in an Israeli population-sample.

Women's attitudes towards disclosure of genetic information in pregnancy with varying levels of penetrance.

BACKGROUND: Chromosomal-microarray-analysis (CMA) may reveal susceptibility-loci (SL) of varied penetrance for autism-spectrum-disorder (ASD) and other neurodevelopmental conditions. Attitudes of women/parents to disclosure of SL during pregnancy are understudied. METHODS: A multiple-choice questionnaire was distributed to postpartum women. Data were collected on women's interest to receive prenatal genetic information with various levels of penetrance. RESULTS: Women's (n = 941) disclosure choices were dependent on the magnitude of risk: approximately 70% supported disclosure of either full or 40% penetrance, 53% supported disclosure at a 20% risk threshold, and 40% supported disclosure at 10% or less. Although most women supported, rejected or were indecisive about disclosure consistently across all risk levels, nearly one-quarter (24%) varied their responses based on penetrance, and this was associated with religiosity, education, parity and concern about fetal health (p-values <0.04). Among those who varied their choices, the risk threshold was lower among secular women (20%) than among ultraorthodox women (40%). In a multivariable analysis, ultraorthodox women were much less likely to vary their choices on ASD disclosure compared with secular women (aOR = 0.37, p < 0.001). CONCLUSION: Women's attitudes toward disclosure are influenced by the level of risk and their individual characteristics. We therefore encourage engaging women/couples in disclosure decisions regarding uncertain and probabilistic results from prenatal genomic tests.

Efficient inference of parent-of-origin effect using case-control mother-child genotype data.

Parent-of-origin effect plays an important role in mammal development and disorder. Case-control mother-child pair genotype data can be used to detect parent-of-origin effect and is often convenient to collect in practice. Most existing methods for assessing parent-of-origin effect do not incorporate any covariates, which may be required to control for confounding factors. We propose to model the parent-of-origin effect through a logistic regression model, with predictors including maternal and child genotypes, parental origins, and covariates. The parental origins may not be fully inferred from genotypes of a target genetic marker, so we propose to use genotypes of markers tightly linked to the target marker to increase inference efficiency. A robust statistical inference procedure is developed based on a modified profile log-likelihood in a retrospective way. A computationally feasible expectation-maximization algorithm is devised to estimate all unknown parameters involved in the modified profile log-likelihood. This algorithm differs from the conventional expectation-maximization algorithm in the sense that it is based on a modified instead of the original profile log-likelihood function. The convergence of the algorithm is established under some mild regularity conditions. This expectation-maximization algorithm also allows convenient handling of missing child genotypes. Large sample properties, including weak consistency, asymptotic normality, and asymptotic efficiency, are established for the proposed estimator under some mild regularity conditions. Finite sample properties are evaluated through extensive simulation studies and the application to a real dataset.

Receiving uncertain results from prenatal chromosomal microarray analysis: Women's decisions on continuation or termination of pregnancy.

BACKGROUND: Chromosomal microarray analysis (CMA) may detect variants of uncertain clinical significance (VUS) and susceptibility loci (SL) with incomplete penetrance for neurodevelopmental disorders. This qualitative study provides empirical data on women's experiences with receiving such findings in pregnancy and their decisions regarding continuation or termination of the pregnancy. METHODS: Semi-structured interviews were conducted with women who received a VUS and/or SL from prenatal CMA in the last 2-4 years and were analyzed using Grounded Theory. RESULTS: The vast majority of women recalled being stressed by the findings. All women sought further advice and information to be able to decide whether to continue or terminate their pregnancy. The three pregnancies that were terminated have in common a de novo SL with a 10%-20% penetrance. Similar reasoning (coping with uncertainty, the quest for a perfect child, and a chance for recurrence in future pregnancies) led different women to contradicting conclusions regarding their pregnancies. All women felt satisfied with their decisions. CONCLUSION: Although uncertain/probabilistic information commonly involves a psychological burden, it may also be perceived as valuable and actionable. Pre-test parental choice regarding the disclosure of such information could allow personalized utilization of advanced genomic tests in pregnancy.

Covariate adjusted inference of parent-of-origin effects using case-control mother-child paired multilocus genotype data.

It is of great interest to identify parent-of-origin effects (POEs) since POEs play an important role in many human heritable disorders and human early life growth and development. POE is sometimes referred to as imprinting effect in the literature. Compared with the standard logistic regression analyses, retrospective likelihood-based statistical methods are more powerful in identifying POEs when data are collected from related individuals retrospectively. However, none of existing retrospective-based methods can appropriately incorporate covariates that should be adjusted for if they are confounding factors. In this paper, a novel semiparametric statistical method, M-HAP, is developed to detect POEs by fully exploring available information from multilocus genotypes of case-control mother-child pairs and covariates. Some large sample properties are established for M-HAP. Finite sample properties of M-HAP are illustrated by extensive simulation studies and real data applications to the Jerusalem Perinatal Study and the Danish National Birth Cohort study, which confirm the desired superiority of M-HAP over some existing methods. M-HAP has been implemented in the updated R package CCMO.

Postpartum women's attitudes to disclosure of adult-onset conditions in pregnancy.

BACKGROUND: Advanced prenatal genomic technologies can identify risks for adult-onset (AO) conditions in the fetus, challenging the traditional purpose of prenatal testing. Professional guidelines commonly support disclosure of high-penetrance AO actionable conditions, yet attitudes of women/parents to these findings and factors affecting their attitudes are understudied. METHODS: We explored 941 (77% response rate) postpartum women's attitudes towards receiving prenatal genetic information, and associations of sociodemographic, medical and psychological characteristics with their choices, focusing on AO conditions. RESULTS: Women largely support the disclosure of actionable AO findings (58.4%), in line with professional guidelines. A third of the women also supported the disclosure of non-actionable AO conditions. Stronger religious observance (p < 0.001) and higher psychological distress (p = 0.024) were associated with decreased interest in receiving actionable AO conditions, whereas higher concern for fetal health yielded increased interest (p = 0.032). Attitudes towards disclosure were strongly associated with women's perceived benefit of such information for their own, partner's, and future child's health. Termination of pregnancy based on such information received very little support. CONCLUSION: In-light of the demonstrated understanding of nuanced genetic information and the observed diversity in attitudes, a culturally competent opt-in/out policy could be considered. If full-disclosure is practiced, support should be provided to those expressing higher levels of distress.

Holocaust Experience and Mortality Patterns: 4-Decade Follow-up in a Population-Based Cohort.

Research on mortality associated with exposure to the Holocaust is relevant for a better understanding of the effects of genocides on survivors. To our knowledge, previous studies have not investigated the long-term cause-specific mortality of Holocaust survivors. We compared mortality rates among Israelis born in European countries controlled by the Nazis during World War II with those among Israelis of European descent who did not have this exposure. Records of 22,671 people (45% women; 5,042 survivors) from the population-based Jerusalem Perinatal Study (1964-1976) were linked to the Israeli Population Registry, which was updated through 2016. Cox models were used for analysis, with 2-sided tests of statistical significance. Risk of all-cause mortality was higher among exposed women (hazard ratio (HR) = 1.15, 95% confidence interval (CI): 1.05, 1.27) than in unexposed women. No association was found between Holocaust exposure and male all-cause mortality. In both sexes, survivors had higher cancer-specific mortality (HR = 1.17 (95% CI: 1.01, 1.35) in women and HR = 1.14 (95% CI: 1.01, 1.28) in men). Exposed men also had excess mortality due to coronary heart disease (HR = 1.39, 95% CI: 1.09, 1.77) and lower mortality from other known causes combined (HR = 0.86, 95% CI: 0.75, 0.99). In summary, experiencing the Holocaust was associated with excess all-cause and cancer-specific mortality in women and cancer- and coronary heart disease-specific mortality in men.

Clinicians' attitudes towards parental choice in the era of advanced genomic tests in pregnancy.

OBJECTIVE: Israel is one of the first countries to incorporate chromosomal microarray analysis into routine prenatal care. We explored attitudes of Israeli healthcare professionals (HCPs) towards the disclosure of challenging findings: variants of uncertain clinical significance (VUS), susceptibility loci (SL) for neurodevelopmental disorders and variants associated with adult-onset (AO) conditions. Particularly, we sought their views on providing parental choice regarding the disclosure of these findings. METHODS: Twenty-nine in-depth interviews were conducted with genetic counselors (n = 19), medical geneticists (n = 4), medical geneticists that are trained in and practice fetal medicine (n = 3), and fetal medicine experts (n = 3). RESULTS: Most participants (n = 24) supported parental choice regarding uncertain genetic information. Engaging parents in disclosure decisions allows avoidance from potentially anxiety-provoking information, practicing parental autonomy, and better preparation in cases where uncertain findings are identified. HCPs believed that given appropriate preparation, parents can make informed decisions. Four participants believed that disclosure should be based on professional judgment and one supported full-disclosure. Unlike VUS or SL, all interviewees agreed that in cases of medically actionable AO conditions, the benefit of disclosure outweighs the damage. CONCLUSION: HCPs attitudes are largely in-line with the Israeli practice of involving parents in disclosure decisions regarding uncertain information. This may mitigate disclosure dilemmas and allow personalized disclosure based on parents' views.

Birth Weight and Maternal Body Size as Determinants of Blood Pressure at Age 17: Results from the Jerusalem Perinatal Study Cohort.

OBJECTIVES: To investigate the effect of birth weight (BW) and maternal pre-pregnancy BMI (mBMI) on blood pressure (BP) in adolescence. METHODS: A Population-based cohort of 11,729 births in Jerusalem during 1974-1976, with archival data on maternal and birth characteristics was performed. Measurements at age 17 were assessed and linear regression models were used to evaluate the associations of birth characteristics with BP outcomes. RESULTS: BW was inversely associated with both systolic (SBP) and diastolic (DBP) BP at age 17 (SBP: B = - 0.829, p = 0.002; DBP: B = - 0.397, p = 0.033). The interaction term between BW and weight at age 17 was significant for DBP (p = 0.017) and pulse pressure (p = 0.005). mBMI yielded significant positive associations with BP, independent of BW. CONCLUSIONS FOR PRACTICE: Our findings indicate that there are at least two distinct pathways linking early life characteristics with subsequent BP: Intrauterine growth, as reflected by BW and other genetic or environmental factors, reflected by mBMI and maternal education, contribute to offspring adolescent BP. These results warrant replication in other birth cohorts and underline the need to explore specific mechanisms that account for these associations.

Early-life factors and adult anti-Müllerian hormone levels.

AIM: This study aims to examine whether early-life factors are associated with adult ovarian reserve, measured by anti-Müllerian hormone (AMH) levels. METHODS: The work is based on the Jerusalem Perinatal Study (JPS), an extensive birth cohort with detailed information on all pregnancies and deliveries in Jerusalem between 1974 and 1976. A subset of individuals participated in a follow-up study that took place between 2007 and 2009 in which they completed questionnaires and were physically examined at mean age of 32. A blood sample was additionally drawn from each participant, and AMH was measured in a sample of 239 women. The associations between each early-life factors, including birth weight, maternal pre-pregnancy weight, gestational weight gain (GWG), socioeconomic position at birth, and parental smoking during pregnancy, were assessed with AMH levels at the age of 32.Multivariable regression models were used to examine the associations with AMH, adjusting for potential confounders at birth and at the age of 32. RESULTS: Low birth weight was significantly associated with lower ovarian reserve reflected by lower levels of AMH at age 32 (range 30-36), independent of other early-life factors and after adjusting for confounders (ß = 0.180, p = 0.03). CONCLUSIONS: This prospective study demonstrates the association of birth weight and adult ovarian reserve. Underlying mechanisms are yet to be fully understood.

Higher BMI is associated with smaller regional brain volume in older adults with type 2 diabetes.

AIMS/HYPOTHESIS: There are established relationships between adiposity (obesity) and higher dementia risk, faster cognitive decline and associated neural injury. Type 2 diabetes is strongly linked to greater adiposity and has been consistently associated with neural injury and poor cognitive outcomes. However, although obesity is a major cause of type 2 diabetes, there is limited evidence on the association of adiposity with brain atrophy among individuals with type 2 diabetes. METHODS: We examined the association of BMI (a measure of adiposity), and of long-term trajectories of BMI (three empirically identified groups of trajectories-'normal', 'overweight' and 'obese'-using SAS macro PROC TRAJ), with regional brain volume, in a sample of older individuals (aged 64-84) with type 2 diabetes participating in the Israel Diabetes and Cognitive Decline Study (n = 198). RESULTS: Using linear regression, we found that greater BMI was associated with smaller volumes of the inferior frontal gyrus (IFG) (r = -0.25, p = 0.001) and the middle temporal gyrus (r = -0.19; p = 0.010) after adjusting for sociodemographic covariates and total intracranial volume. In addition, there were significant differences between BMI trajectory groups in IFG volume (F = 4.34, p = 0.014), such that a long-term trajectory of obesity was associated with a smaller volume. Additional adjustment for cardiovascular and diabetes-related potential confounders did not substantively alter the results. There were no associations of adiposity with superior frontal gyrus, middle frontal gyrus or total grey matter volumes. CONCLUSIONS/INTERPRETATION: In older adults with type 2 diabetes, long-term adiposity may have a detrimental impact on volume of brain regions relevant to cognitive functioning. Further studies to identify the underlying mechanisms are warranted. Graphical abstract.

Parent-of-Origin Effects of the APOB Gene on Adiposity in Young Adults.

Loci identified in genome-wide association studies (GWAS) of cardio-metabolic traits account for a small proportion of the traits' heritability. To date, most association studies have not considered parent-of-origin effects (POEs). Here we report investigation of POEs on adiposity and glycemic traits in young adults. The Jerusalem Perinatal Family Follow-Up Study (JPS), comprising 1250 young adults and their mothers was used for discovery. Focusing on 18 genes identified by previous GWAS as associated with cardio-metabolic traits, we used linear regression to examine the associations of maternally- and paternally-derived offspring minor alleles with body mass index (BMI), waist circumference (WC), fasting glucose and insulin. We replicated and meta-analyzed JPS findings in individuals of European ancestry aged ≤50 belonging to pedigrees from the Framingham Heart Study, Family Heart Study and Erasmus Rucphen Family study (total N≅4800). We considered p<2.7x10-4 statistically significant to account for multiple testing. We identified a common coding variant in the 4th exon of APOB (rs1367117) with a significant maternally-derived effect on BMI (ß = 0.8; 95%CI:0.4,1.1; p = 3.1x10-5) and WC (ß = 2.7; 95%CI:1.7,3.7; p = 2.1x10-7). The corresponding paternally-derived effects were non-significant (p>0.6). Suggestive maternally-derived associations of rs1367117 were observed with fasting glucose (ß = 0.9; 95%CI:0.3,1.5; p = 4.0x10-3) and insulin (ln-transformed, ß = 0.06; 95%CI:0.03,0.1; p = 7.4x10-4). Bioinformatic annotation for rs1367117 revealed a variety of regulatory functions in this region in liver and adipose tissues and a 50% methylation pattern in liver only, consistent with allelic-specific methylation, which may indicate tissue-specific POE. Our findings demonstrate a maternal-specific association between a common APOB variant and adiposity, an association that was not previously detected in GWAS. These results provide evidence for the role of regulatory mechanisms, POEs specifically, in adiposity. In addition this study highlights the benefit of utilizing family studies for deciphering the genetic architecture of complex traits.

Accounting for Life-Course Exposures in Epigenetic Biomarker Association Studies: Early Life Socioeconomic Position, Candidate Gene DNA Methylation, and Adult Cardiometabolic Risk.

Recent studies suggest that epigenetic programming may mediate the relationship between early life environment, including parental socioeconomic position, and adult cardiometabolic health. However, interpreting associations between early environment and adult DNA methylation may be difficult because of time-dependent confounding by life-course exposures. Among 613 adult women (mean age = 32 years) of the Jerusalem Perinatal Study Family Follow-up (2007-2009), we investigated associations between early life socioeconomic position (paternal occupation and parental education) and mean adult DNA methylation at 5 frequently studied cardiometabolic and stress-response genes (ABCA1, INS-IGF2, LEP, HSD11B2, and NR3C1). We used multivariable linear regression and marginal structural models to estimate associations under 2 causal structures for life-course exposures and timing of methylation measurement. We also examined whether methylation was associated with adult cardiometabolic phenotype. Higher maternal education was consistently associated with higher HSD11B2 methylation (e.g., 0.5%-point higher in 9-12 years vs. ≤8 years, 95% confidence interval: 0.1, 0.8). Higher HSD11B2 methylation was also associated with lower adult weight and total and low-density lipoprotein cholesterol. We found that associations with early life socioeconomic position measures were insensitive to different causal assumption; however, exploratory analysis did not find evidence for a mediating role of methylation in socioeconomic position-cardiometabolic risk associations.

Plasma vitamin D is associated with fasting insulin and homeostatic model assessment of insulin resistance in young adult males, but not females, of the Jerusalem Perinatal Study.

OBJECTIVE: To examine cross-sectional relationships between plasma vitamin D and cardiometabolic risk factors in young adults. DESIGN: Data were collected from interviews, physical examinations and biomarker measurements. Total plasma 25-hydroxyvitamin D (25(OH)D) was measured using LC-tandem MS. Associations between 25(OH)D and cardiometabolic risk factors were modelled using weighted linear regression with robust estimates of standard errors. SETTING: Individuals born in Jerusalem during 1974-1976. SUBJECTS: Participants of the Jerusalem Perinatal Study (n 1204) interviewed and examined at age 32 years. Participants were oversampled for low and high birth weight and for maternal pre-pregnancy obesity. RESULTS: Mean total 25(OH)D concentration among participants was 21·7 (sd 8·9) ng/ml. Among males, 25(OH)D was associated with homeostatic model assessment of insulin resistance (natural log-transformed, ß=-0·011, P=0·004) after adjustment for BMI. However, these associations were not present among females (P for sex interaction=0·005). CONCLUSIONS: We found evidence for inverse associations of 25(OH)D with markers of insulin resistance among males, but not females, in a healthy, young adult Caucasian population. Prospective studies and studies conducted on other populations investigating sex-specific effects of vitamin D on cardiometabolic risk factors are warranted.

Gum chewing and gastrointestinal function following caesarean delivery: a systematic review and meta-analysis.

AIMS AND OBJECTIVES: The aims of this systematic review and meta-analysis were to summarise current knowledge regarding gum chewing intervention for activation of the gastrointestinal (GI) system following caesarean delivery. BACKGROUND: GI symptoms such as nausea, vomiting and defecatory difficulties are bothersome for women following a caesarean delivery. There is category A recommendation to not withhold oral intake postoperatively. However, current practice guidelines vary widely on time to initiate oral feeding post caesarean delivery, and additional research is needed. Gum chewing has been shown to stimulate the GI system in other postoperative patient populations. DESIGN: A systematic review and meta-analysis. METHODS: An electronic review was undertaken using the following resources: PubMed (Medline), CINAHL, EMBASE and ClinicalTrials.gov databases. Key words used in various combinations included cesarean section; cesarean delivery; postoperative chewing gum; bowel movement; bowel function and complications. RESULTS: A total of 171 articles were found of which 166 were excluded: 157 were duplicates and the remainder did not meet the inclusion criteria. Five randomised control trials were included in the meta-analysis, focusing on gum chewing as an intervention as compared with a nongum chewing intervention, with a total of 846 participants. Compared with the nongum chewing group, gum chewing showed a beneficial impact on the major outcomes of digestive system activation, including bowel sound, gas passage and defecation. CONCLUSIONS: This meta-analysis supports the effectiveness of gum chewing post caesarean delivery as a noninvasive/nonpharmacological intervention for reactivation of bowel movement. RELEVANCE TO CLINICAL PRACTICE: Gum chewing in the immediate postoperative period following caesarean delivery may provide a socially acceptable, low-cost and safe intervention to reduce postcaesarean delivery GI complications and restore GI function.

Self-reported Prevalence of and Knowledge About Urinary Incontinence Among Community-Dwelling Israeli Women of Child-Bearing Age.

PURPOSE: The aim of this study was to examine the prevalence of urinary incontinence (UI) among parous women of child-bearing age and compare their level of knowledge regarding UI to those women without the condition. METHODS: A convenience sample of women aged 20 to 50 years who had given birth at least once completed questionnaires regarding (1) demographic information, (2) knowledge of UI (PIKQ-Prolapse and Incontinence Knowledge Quiz and PIKQ+), and (3) prevalence of UI (ICIQ-UI questionnaire-International Consultation on Incontinence Questionnaire-Urinary Incontinence short form). Women who were pregnant or 3 months or less postpartum were excluded from the analysis of the ICIQ-UI. RESULTS: Three hundred twenty-three women, representing 89.7% of those approached, participated in the study. Their mean age was 35.3 ±5.0 years (mean ± SD), all completed the knowledge questionnaire while 260 (80.5%) completed the UI questionnaire. Eighty-three (31.9%) suffered from UI, and most (67.5%) were between 31 and 40 years of age. Participants' level of knowledge about UI was found to be moderate (mean = 7.37 ± 3.6) on the PIKQ+. Knowledge level was correlated with age (P = .017) and with higher levels of education (P < .001). There was a significantly higher level of UI knowledge (PIKQ+ scores) among women with UI (mean = 8.6; SD = 3.01) as compared to those who did not report UI (mean = 7.6; SD =±3.75; P < .001). CONCLUSION: Approximately one-third of parous women aged 20 to 50 years reported UI. Knowledge related to the condition tends to be moderate, increasing with higher age and education.

A multi-locus likelihood method for assessing parent-of-origin effects using case-control mother-child pairs.

Parent-of-origin effects have been pointed out to be one plausible source of the heritability that was unexplained by genome-wide association studies. Here, we consider a case-control mother-child pair design for studying parent-of-origin effects of offspring genes on neonatal/early-life disorders or pregnancy-related conditions. In contrast to the standard case-control design, the case-control mother-child pair design contains valuable parental information and therefore permits powerful assessment of parent-of-origin effects. Suppose the region under study is in Hardy-Weinberg equilibrium, inheritance is Mendelian at the diallelic locus under study, there is random mating in the source population, and the SNP under study is not related to risk for the phenotype under study because of linkage disequilibrium (LD) with other SNPs. Using a maximum likelihood method that simultaneously assesses likely parental sources and estimates effect sizes of the two offspring genotypes, we investigate the extent of power increase for testing parent-of-origin effects through the incorporation of genotype data for adjacent markers that are in LD with the test locus. Our method does not need to assume the outcome is rare because it exploits supplementary information on phenotype prevalence. Analysis with simulated SNP data indicates that incorporating genotype data for adjacent markers greatly help recover the parent-of-origin information. This recovery can sometimes substantially improve statistical power for detecting parent-of-origin effects. We demonstrate our method by examining parent-of-origin effects of the gene PPARGC1A on low birth weight using data from 636 mother-child pairs in the Jerusalem Perinatal Study.

Signs of aging in midlife: physical function and sex differences in microbiota.

Microbiota composition has been linked to physical activity, health measures, and biological age, but a shared profile has yet to be shown. The aim of this study was to examine the associations between microbiota composition and measures of function, such as a composite measure of physical capacity, and biological age in midlife, prior to onset of age-related diseases. Seventy healthy midlife individuals (age 44.58 ± 0.18) were examined cross-sectionally, and their gut-microbiota profile was characterized from stool samples using 16SrRNA gene sequencing. Biological age was measured using the Klemera-Doubal method and a composition of blood and physiological biomarkers. Physical capacity was calculated based on sex-standardized functional tests. We demonstrate that the women had significantly richer microbiota, p = 0.025; however, microbiota diversity was not linked with chronological age, biological age, or physical capacity for either women or men. Men had slightly greater ß-diversity; however, ß-diversity was positively associated with biological age and with physical capacity for women only (p = 0.01 and p = 0.04; respectively). For women, an increase in abundance of Roseburia faecis and Collinsella aerofaciens, as well as genus Ruminococcus and Dorea, was significantly associated with higher biological age and lower physical capacity; an increase in abundance of Akkermansia muciniphila and genera Bacteroides and Alistipes was associated with younger biological age and increased physical capacity. Differentially abundant taxa were also associated with non-communicable diseases. These findings suggest that microbiota composition is a potential mechanism linking physical capacity and health status; personalized probiotics may serve as a new means to support health-promoting interventions in midlife. Investigating additional factors underlying this link may facilitate the development of a more accurate method to estimate the rate of aging.

Perinatal exposures and adolescence overweight: The role of shared maternal-offspring pathways.

BACKGROUND AND AIMS: Early life exposures affect offspring health across the life-course. We aimed to examine whether prevalent perinatal exposures and obstetric complications are independently associated with offspring overweight in adolescence. We then assessed whether shared maternal-offspring pathways drive the association of perinatal exposures with offspring overweight. METHODS: Using data from the Jerusalem Perinatal Study birth cohort, two perinatal scores were constructed: obstetric complications (OC) and prevalent perinatal exposures (PPE) scores. PPE score, generated by principal component analysis, included three primary components. Logistic regressions were used to assess associations of scores with offspring overweight, with and without adjustment for maternal life-course survival. RESULTS: OC and PPE scores were independently associated with offspring overweight (OROC = 1.15, 95%CI:1.07,1.25; ORPPE1- SEP and lifestyle = 0.85, 95%CI:0.79,0.91; ORPPE2- Maternal body size = 1.20, 95%CI: 1.13,1.28; ORPPE3-Fetal growth = 1.18, 95%CI:1.11,1.26). Maternal survival was associated with offspring overweight (OR = 1.38, 95%CI:1.08,1.76), yet introducing PPE score to the same model attenuated this association (OR = 1.16, 95%CI:0.90, 1.49). When OC score and maternal survival were included in the same model, their associations with offspring overweight remained unchanged. CONCLUSIONS: Mother-offspring shared factors, captured by maternal life-course survival, underlie the effect of prevalent perinatal exposures on offspring overweight. However, the effect of obstetric complications was independent, highlighting the contribution of additional pathways.

Mapping cell-to-tissue graphs across human placenta histology whole slide images using deep learning with HAPPY.

Accurate placenta pathology assessment is essential for managing maternal and newborn health, but the placenta's heterogeneity and temporal variability pose challenges for histology analysis. To address this issue, we developed the 'Histology Analysis Pipeline.PY' (HAPPY), a deep learning hierarchical method for quantifying the variability of cells and micro-anatomical tissue structures across placenta histology whole slide images. HAPPY differs from patch-based features or segmentation approaches by following an interpretable biological hierarchy, representing cells and cellular communities within tissues at a single-cell resolution across whole slide images. We present a set of quantitative metrics from healthy term placentas as a baseline for future assessments of placenta health and we show how these metrics deviate in placentas with clinically significant placental infarction. HAPPY's cell and tissue predictions closely replicate those from independent clinical experts and placental biology literature.