Placental IGFBP1 levels during early pregnancy and the risk of insulin resistance and gestational diabetes.

Reduced insulin sensitivity (insulin resistance) is a hallmark of normal physiology in late pregnancy and also underlies gestational diabetes mellitus (GDM). We conducted transcriptomic profiling of 434 human placentas and identified a positive association between insulin-like growth factor binding protein 1 gene (IGFBP1) expression in the placenta and insulin sensitivity at ~26 weeks gestation. Circulating IGFBP1 protein levels rose over the course of pregnancy and declined postpartum, which, together with high gene expression levels in our placenta samples, suggests a placental or decidual source. Higher circulating IGFBP1 levels were associated with greater insulin sensitivity (lesser insulin resistance) at ~26 weeks gestation in the same cohort and in two additional pregnancy cohorts. In addition, low circulating IGFBP1 levels in early pregnancy predicted subsequent GDM diagnosis in two cohorts of pregnant women. These results implicate IGFBP1 in the glycemic physiology of pregnancy and suggest a role for placental IGFBP1 deficiency in GDM pathogenesis.

Placental RNA sequencing implicates IGFBP1 in insulin sensitivity during pregnancy and in gestational diabetes.

Reduced insulin sensitivity (or greater insulin resistance) is a hallmark of normal physiology in late pregnancy and also underlies gestational diabetes mellitus (GDM) pathophysiology. We conducted transcriptomic profiling of 434 human placentas and identified a strong positive association between insulin-like growth factor binding protein 1 gene (IGFBP1) expression in the placenta and insulin sensitivity at ~ 26 weeks' gestation. Circulating IGFBP1 protein levels rose over the course of pregnancy and declined postpartum, which together with high placental gene expression levels, suggests a placental source. Higher circulating IGFBP1 levels were strongly associated with greater insulin sensitivity (lesser insulin resistance) at ~ 26 weeks' gestation in the same cohort and two additional pregnancy cohorts. In addition, low circulating IGFBP1 levels in early pregnancy predicted subsequent GDM diagnosis in two cohorts. These results implicate IGFBP1 in the glycemic physiology of pregnancy and suggest a role for placental IGFBP1 deficiency in GDM pathogenesis.

Genome-wide association study of placental weight identifies distinct and shared genetic influences between placental and fetal growth.

A well-functioning placenta is essential for fetal and maternal health throughout pregnancy. Using placental weight as a proxy for placental growth, we report genome-wide association analyses in the fetal (n = 65,405), maternal (n = 61,228) and paternal (n = 52,392) genomes, yielding 40 independent association signals. Twenty-six signals are classified as fetal, four maternal and three fetal and maternal. A maternal parent-of-origin effect is seen near KCNQ1. Genetic correlation and colocalization analyses reveal overlap with birth weight genetics, but 12 loci are classified as predominantly or only affecting placental weight, with connections to placental development and morphology, and transport of antibodies and amino acids. Mendelian randomization analyses indicate that fetal genetically mediated higher placental weight is causally associated with preeclampsia risk and shorter gestational duration. Moreover, these analyses support the role of fetal insulin in regulating placental weight, providing a key link between fetal and placental growth.

Analysis of DNA methylation at birth and in childhood reveals changes associated with season of birth and latitude.

BACKGROUND: Seasonal variations in environmental exposures at birth or during gestation are associated with numerous adult traits and health outcomes later in life. Whether DNA methylation (DNAm) plays a role in the molecular mechanisms underlying the associations between birth season and lifelong phenotypes remains unclear. METHODS: We carried out epigenome-wide meta-analyses within the Pregnancy And Childhood Epigenetic Consortium to identify associations of DNAm with birth season, both at differentially methylated probes (DMPs) and regions (DMRs). Associations were examined at two time points: at birth (21 cohorts, N = 9358) and in children aged 1-11 years (12 cohorts, N = 3610). We conducted meta-analyses to assess the impact of latitude on birth season-specific associations at both time points. RESULTS: We identified associations between birth season and DNAm (False Discovery Rate-adjusted p values < 0.05) at two CpGs at birth (winter-born) and four in the childhood (summer-born) analyses when compared to children born in autumn. Furthermore, we identified twenty-six differentially methylated regions (DMR) at birth (winter-born: 8, spring-born: 15, summer-born: 3) and thirty-two in childhood (winter-born: 12, spring and summer: 10 each) meta-analyses with few overlapping DMRs between the birth seasons or the two time points. The DMRs were associated with genes of known functions in tumorigenesis, psychiatric/neurological disorders, inflammation, or immunity, amongst others. Latitude-stratified meta-analyses [higher (≥ 50°N), lower (< 50°N, northern hemisphere only)] revealed differences in associations between birth season and DNAm by birth latitude. DMR analysis implicated genes with previously reported links to schizophrenia (LAX1), skin disorders (PSORS1C, LTB4R), and airway inflammation including asthma (LTB4R), present only at birth in the higher latitudes (≥ 50°N). CONCLUSIONS: In this large epigenome-wide meta-analysis study, we provide evidence for (i) associations between DNAm and season of birth that are unique for the seasons of the year (temporal effect) and (ii) latitude-dependent variations in the seasonal associations (spatial effect). DNAm could play a role in the molecular mechanisms underlying the effect of birth season on adult health outcomes.

Maternal glycemia in pregnancy is longitudinally associated with blood DNAm variation at the FSD1L gene from birth to 5 years of age.

BACKGROUND: In utero exposure to maternal hyperglycemia has been associated with an increased risk for the development of chronic diseases in later life. These predispositions may be programmed by fetal DNA methylation (DNAm) changes that persist postnatally. However, although some studies have associated fetal exposure to gestational hyperglycemia with DNAm variations at birth, and metabolic phenotypes in childhood, no study has yet examined how maternal hyperglycemia during pregnancy may be associated with offspring DNAm from birth to five years of age. HYPOTHESIS: Maternal hyperglycemia is associated with variation in offspring DNAm from birth to 5 years of age. METHODS: We estimated maternal hyperglycemia using the area under the curve for glucose (AUCglu) following an oral glucose tolerance test conducted at 24-30 weeks of pregnancy. We quantified DNAm levels in cord blood (n = 440) and peripheral blood at five years of age (n = 293) using the Infinium MethylationEPIC BeadChip (Illumina). Our total sample included 539 unique dyads (mother-child) with 194 dyads having DNAm at both time-points. We first regressed DNAm M-values against the cell types and child age for each time-point separately to account for the difference by time of measurement for these variables. We then used a random intercept model from the linear mixed model (LMM) framework to assess the longitudinal association between maternal AUCglu and the repeated measures of residuals of DNAm. We adjusted for the following covariates as fixed effects in the random intercept model: maternal age, gravidity, smoking status, child sex, maternal body mass index (BMI) (measured at first trimester of pregnancy), and a binary variable for time-point. RESULTS: In utero exposure to higher maternal AUCglu was associated with lower offspring blood DNAm levels at cg00967989 located in FSD1L gene (ß = - 0.0267, P = 2.13 × 10-8) in adjusted linear regression mixed models. Our study also reports other CpG sites for which DNAm levels were suggestively associated (P < 1.0 × 10-5) with in utero exposure to gestational hyperglycemia. Two of these (cg12140144 and cg07946633) were found in the promotor region of PRDM16 gene (ß: - 0.0251, P = 4.37 × 10-07 and ß: - 0.0206, P = 2.24 × 10-06, respectively). CONCLUSION: Maternal hyperglycemia is associated with offspring DNAm longitudinally assessed from birth to 5 years of age.

Genetic effects on the timing of parturition and links to fetal birth weight.

The timing of parturition is crucial for neonatal survival and infant health. Yet, its genetic basis remains largely unresolved. We present a maternal genome-wide meta-analysis of gestational duration (n = 195,555), identifying 22 associated loci (24 independent variants) and an enrichment in genes differentially expressed during labor. A meta-analysis of preterm delivery (18,797 cases, 260,246 controls) revealed six associated loci and large genetic similarities with gestational duration. Analysis of the parental transmitted and nontransmitted alleles (n = 136,833) shows that 15 of the gestational duration genetic variants act through the maternal genome, whereas 7 act both through the maternal and fetal genomes and 2 act only via the fetal genome. Finally, the maternal effects on gestational duration show signs of antagonistic pleiotropy with the fetal effects on birth weight: maternal alleles that increase gestational duration have negative fetal effects on birth weight. The present study provides insights into the genetic effects on the timing of parturition and the complex maternal-fetal relationship between gestational duration and birth weight.

Associations of maternal insulin sensitivity during pregnancy with childhood central adiposity in the Genetics of Glucose regulation in Gestation and Growth (Gen3G) cohort.

BACKGROUND: Childhood obesity has been associated with prenatal exposure to maternal hyperglycaemia, but we lack understanding about maternal insulin physiologic components that contribute to this association. OBJECTIVES: Evaluate the association between maternal insulin sensitivity during pregnancy and adiposity measures in childhood. METHODS: In 422 mother-child pairs, we tested associations between maternal insulin sensitivity measures at ~26 weeks of pregnancy and child adiposity measures, including dual-energy X-ray absorptiometry body composition and anthropometry (body mass index and waist circumference) at ~5 years. We used linear regression analyses to adjust for maternal age, ethnicity, gravidity, first-trimester body mass index, and child sex and age at mid-childhood. RESULTS: In early pregnancy, maternal mean age was 28.6 ± 4.3 years and median body mass index was 24.1 kg/m2 . Lower maternal insulin sensitivity indices were correlated with greater child adiposity based on anthropometry measures and on dual-energy X-ray absorptiometry total and trunk % fat in univariate associations (r = -0.122 to -0.159). Lower maternal insulin sensitivity was specifically associated with higher dual-energy X-ray absorptiometry trunk % fat (n = 359 for Matsuda; ß = -0.034 ± 0.013; p = 0.01) after adjustment for covariates, including maternal body mass index. CONCLUSIONS: Maternal insulin sensitivity during pregnancy may contribute to increased risk for higher offspring central adiposity in middle childhood.

SERPINE1 DNA Methylation Levels Quantified in Blood Cells at Five Years of Age Are Associated with Adiposity and Plasma PAI-1 Levels at Five Years of Age.

Plasminogen activator inhibitor (PAI-1) expression has been associated with a higher risk of development of obesity. DNA methylation (DNAm) is an epigenetic mechanism regulating gene transcription and likely involved in the fetal programming of childhood obesity. Our study aimed to assess the associations between PAI-1 gene (SERPINE1) DNAm, plasma PAI-1 levels, and adiposity at five years of age. We analyzed DNAm and anthropometric data from 146 girls and 177 boys from the Gen3G prospective birth cohort. We assessed adiposity using BMI z-scores, waist circumference, total skinfolds, and percentages of total, android, and trunk fat measured by dual-energy radiography (DXA). We estimated blood cell DNAm levels at 15 CpG sites within SERPINE1 using the methylationEPIC array. After correction for multiple testing, we found that lower DNAm in SERPINE1 intron 3 (cg11353706) was associated with greater adiposity levels in girls (waist circumference: r = −0.258, p = 0.002; skinfolds: r = −0.212, p = 0. 013; android fat: r = −0.215, p = 0.015; BMI z-score: r = −0.278, p < 0.001) and that lower DNAm in the SERPINE1 promoter (cg19722814) was associated with higher plasma PAI-1 levels in boys (r = −0.178, p = 0.021). Our study suggests that DNAm levels at the SERPINE1 gene locus are negatively correlated with adiposity, but not with plasma PAI-1 levels, in young girls only.

Exercise Capacity and Perceived Exertion on Treadmill Stress Test Performed While Wearing vs Without a Surgical Mask: A Randomized Clinical Trial in Healthy Adults.

Background: The graded exercise treadmill stress test (GXT) is among the most frequently performed tests in cardiology. The COVID-19 pandemic led many healthcare facilities to require patients to wear a mask during the test. This study evaluated the effect of wearing a surgical face mask on exercise capacity and perceived exertion. Methods: In this prospective, randomized crossover trial, 35 healthy adults performed a GXT using the Bruce protocol while wearing a surgical mask, and without a mask. The primary outcome was exercise capacity in metabolic equivalents (MET), and the secondary outcome was exercise perception on the modified Borg scale (from 0 to 10). Effort duration, heart rate, oxygen saturation, and blood pressure were also analyzed. Results: Exercise capacity was reduced by 0.4 MET (95% confidence interval [CI] -0.7 to -0.2) during the GXT with a mask (11.8 ± 2.7 vs 12.3 ± 2.5 MET, P = 0.001), and the final perceived effort increased by 0.5 points (95% CI 0.2 to 0.8; 8.4 ± 1.3 vs 7.9 ± 1.6, P = 0.004). Effort duration was cut down by 24 seconds (CI -0:39 to -0:09; 10:03 ± 2:30 vs 10:27 ± 2:16 [minutes:seconds], P = 0.003). Oxygen saturation was slightly lower at the end of the test when participants wore a mask. No significant differences occurred in heart rate or blood pressure during the test. Conclusion: Wearing a surgical mask causes a statistically significant decrease in exercise capacity and increase in perceived exertion. This small effect is not clinically significant for the interpretation of test results.

Introduction: L'épreuve d'effort gradué sur tapis roulant (GXT, de l'anglais graded exercise test) compte parmi les épreuves les plus fréquemment réalisées en cardiologie. La pandémie de COVID-19 a poussé de nombreux établissements de soins de santé à exiger aux patients le port du masque durant l'épreuve. La présente étude portait sur l'évaluation des effets du port du masque chirurgical sur la capacité à l'effort et l'effort perçu. Méthodes: Dans cet essai croisé prospectif, 35 adultes en bonne santé ont réalisé une GXT selon le protocole de Bruce, avec le port du masque chirurgical et sans le port du masque. Le principal critère d'évaluation était la capacité à l'effort exprimée en équivalents métaboliques (MET, de l'anglais Metabolic Equivalent of Task), et le critère secondaire était la perception de l'effort selon l'échelle de Borg modifiée (de 0 à 10). La durée de l'effort, la fréquence cardiaque, la saturation en oxygène et la pression artérielle ont également fait l'objet de l'analyse. Résultats: La capacité à l'effort était réduite de 0,4 MET (intervalle de confiance [IC] à 95 % de ­0,7 à ­0,2) durant la GXT réalisée avec le port du masque (11,8 ± 2,7 vs 12,3 ± 2,5 MET, P = 0,001), et l'effort perçu final avait augmenté de 0,5 point (IC à 95 % de 0,2 à 0,8 ; 8,4 ± 1,3 vs 7,9 ± 1,6, P = 0,004). La durée de l'effort était réduite de 24 secondes (IC à 95 % de ­0:39 à ­0:09 ; 10:03 ± 2:30 vs 10:27 ± 2:16 [minutes:secondes], P = 0,003). La saturation en oxygène était légèrement plus faible à la fin de l'épreuve lorsque les participants portaient le masque. Aucune différence significative de la fréquence cardiaque et de la pression artérielle n'est apparue durant l'épreuve. Conclusion: Le port du masque chirurgical entraîne une diminution statistiquement significative de la capacité à l'effort et une augmentation de l'effort perçu. Cet effet minime n'est pas cliniquement significatif pour l'interprétation des résultats de l'épreuve.

Meta-analysis of epigenome-wide association studies in newborns and children show widespread sex differences in blood DNA methylation.

BACKGROUND: Among children, sex-specific differences in disease prevalence, age of onset, and susceptibility have been observed in health conditions including asthma, immune response, metabolic health, some pediatric and adult cancers, and psychiatric disorders. Epigenetic modifications such as DNA methylation may play a role in the sexual differences observed in diseases and other physiological traits. METHODS: We performed a meta-analysis of the association of sex and cord blood DNA methylation at over 450,000 CpG sites in 8438 newborns from 17 cohorts participating in the Pregnancy And Childhood Epigenetics (PACE) Consortium. We also examined associations of child sex with DNA methylation in older children ages 5.5-10 years from 8 cohorts (n = 4268). RESULTS: In newborn blood, sex was associated at Bonferroni level significance with differences in DNA methylation at 46,979 autosomal CpG sites (p < 1.3 × 10-7) after adjusting for white blood cell proportions and batch. Most of those sites had lower methylation levels in males than in females. Of the differentially methylated CpG sites identified in newborn blood, 68% (31,727) met look-up level significance (p < 1.1 × 10-6) in older children and had methylation differences in the same direction. CONCLUSIONS: This is a large-scale meta-analysis examining sex differences in DNA methylation in newborns and older children. Expanding upon previous studies, we replicated previous findings and identified additional autosomal sites with sex-specific differences in DNA methylation. Differentially methylated sites were enriched in genes involved in cancer, psychiatric disorders, and cardiovascular phenotypes.

Multi-ancestry genome-wide association study of gestational diabetes mellitus highlights genetic links with type 2 diabetes.

Gestational diabetes mellitus (GDM) is associated with increased risk of pregnancy complications and adverse perinatal outcomes. GDM often reoccurs and is associated with increased risk of subsequent diagnosis of type 2 diabetes (T2D). To improve our understanding of the aetiological factors and molecular processes driving the occurrence of GDM, including the extent to which these overlap with T2D pathophysiology, the GENetics of Diabetes In Pregnancy Consortium assembled genome-wide association studies of diverse ancestry in a total of 5485 women with GDM and 347 856 without GDM. Through multi-ancestry meta-analysis, we identified five loci with genome-wide significant association (P < 5 × 10-8) with GDM, mapping to/near MTNR1B (P = 4.3 × 10-54), TCF7L2 (P = 4.0 × 10-16), CDKAL1 (P = 1.6 × 10-14), CDKN2A-CDKN2B (P = 4.1 × 10-9) and HKDC1 (P = 2.9 × 10-8). Multiple lines of evidence pointed to the shared pathophysiology of GDM and T2D: (i) four of the five GDM loci (not HKDC1) have been previously reported at genome-wide significance for T2D; (ii) significant enrichment for associations with GDM at previously reported T2D loci; (iii) strong genetic correlation between GDM and T2D and (iv) enrichment of GDM associations mapping to genomic annotations in diabetes-relevant tissues and transcription factor binding sites. Mendelian randomization analyses demonstrated significant causal association (5% false discovery rate) of higher body mass index on increased GDM risk. Our results provide support for the hypothesis that GDM and T2D are part of the same underlying pathology but that, as exemplified by the HKDC1 locus, there are genetic determinants of GDM that are specific to glucose regulation in pregnancy.

DNA methylation mediates the association between breastfeeding and early-life growth trajectories.

BACKGROUND: The role of breastfeeding in modulating epigenetic factors has been suggested as a possible mechanism conferring its benefits on child development but it lacks evidence. Using extensive DNA methylation data from the ALSPAC child cohort, we characterized the genome-wide landscape of DNA methylation variations associated with the duration of exclusive breastfeeding and assessed whether these variations mediate the association between exclusive breastfeeding and BMI over different epochs of child growth. RESULTS: Exclusive breastfeeding elicits more substantial DNA methylation variations during infancy than at other periods of child growth. At the genome-wide level, 13 CpG sites in girls (miR-21, SNAPC3, ATP6V0A1, DHX15/PPARGC1A, LINC00398/ALOX5AP, FAM238C, NATP/NAT2, CUX1, TRAPPC9, OSBPL1A, ZNF185, FAM84A, PDPK1) and 2 CpG sites in boys (IL16 and NREP), mediate the association between exclusive breastfeeding and longitudinal BMI. We found enrichment of CpG sites located within miRNAs and key pathways (AMPK signaling pathway, insulin signaling pathway, endocytosis). Overall DNA methylation variation corresponding to 3 to 5 months of exclusive breastfeeding was associated with slower BMI growth the first 6 years of life compared to no breastfeeding and in a dose-response manner with exclusive breastfeeding duration. CONCLUSIONS: Our study confirmed the early postnatal period as a critical developmental period associated with substantial DNA methylation variations, which in turn could mitigate the development of overweight and obesity from infancy to early childhood. Since an accelerated growth during these developmental periods has been linked to the development of sustained obesity later in life, exclusive breastfeeding could have a major role in preventing the risks of overweight/obesity and children and adults through DNA methylation mechanisms occurring early in life.

Changing Patterns of Disease Severity in Blastomyces dermatitidis Infection, Quebec, Canada.

This retrospective multicenter cohort study assessed temporal changes in the severity and mortality rate of blastomycosis in Quebec, Canada, and identified risk factors for death in patients with blastomycosis in 1988-2016. The primary outcome was 90-day all-cause deaths. Among 185 patients, 122 (66%) needed hospitalization and 30 (16%) died. We noted increases in the proportion of severe cases, in age at diagnosis and in the proportion of diabetic and immunocompromised patients over time. Independent risk factors for death were age (adjusted odds ratio [aOR] 1.04, 95% CI 1.00-1.07), immunosuppression (aOR 4.2, 95% CI 1.5-11.6), and involvement of >2 lung lobes (aOR 5.3, 95% CI 1.9-14.3). There was no association between the Blastomyces genotype group and all-cause mortality. The proportion of severe cases of blastomycosis has increased in Quebec over the past 30 years, partially explained by the higher number of immunosuppressed patients.

Study protocol for the Sino-Canadian Healthy Life Trajectories Initiative (SCHeLTI): a multicentre, cluster-randomised, parallel-group, superiority trial of a multifaceted community-family-mother-child intervention to prevent childhood overweight and obesity.

INTRODUCTION: Childhood overweight and obesity (OWO) is a primary global health challenge. Childhood OWO prevention is now a public health priority in China. The Sino-Canadian Healthy Life Trajectories Initiative (SCHeLTI), one of four trials being undertaken by the international HeLTI consortium, aims to evaluate the effectiveness of a multifaceted, community-family-mother-child intervention on childhood OWO and non-communicable diseases risk. METHODS AND ANALYSIS: This is a multicentre, cluster-randomised, controlled trial conducted in Shanghai, China. The unit of randomisation is the service area of Maternal Child Health Units (N=36). We will recruit 4500 women/partners/families in maternity and district level hospitals. Participants in the intervention group will receive a multifaceted, integrated package of health promotion interventions beginning in preconception or in the first trimester of pregnancy, continuing into infancy and early childhood. The intervention, which is centred on a modified motivational interviewing approach, will target early-life maternal and child risk factors for adiposity. Through the development of a biological specimen bank, we will study potential mechanisms underlying the effects of the intervention. The primary outcome for the trial is childhood OWO (body mass index for age ≥85th percentile) at 5 years of age, based on WHO sex-specific standards. The study has a power of 0.8 (α=0.05) to detect a 30% risk reduction in the proportion of children with OWO at 5 years of age, from 24.4% in the control group to 17% in the intervention group. Recruitment was launched on 30 August 2018 for the pilot study and 10 January 2019 for the formal study. ETHICS AND DISSEMINATION: The study has been approved by the Medical Research Ethics Committee of the International Peace Maternity and Child Health Hospital in Shanghai, China, and the Research Ethics Board of the Centre Intégré Universitaire de Santé et Services Sociaux de l'Estrie-CHUS in Sherbrooke, Canada. Data sharing policies are consistent with the governance policy of the HeLTI consortium and government legislation. TRIAL REGISTRATION NUMBER: ChiCTR1800017773. PROTOCOL VERSION: November 11, 2020 (Version #5).

Maternal glucose in pregnancy is associated with child's adiposity and leptin at 5 years of age.

BACKGROUND: Exposure to maternal hyperglycaemia in pregnancy has been associated with childhood obesity. Leptin regulation might be involved in this 'adiposity programming' and may depend on timing of exposure. OBJECTIVES: To investigate associations of maternal glycaemia at different periods in pregnancy with childhood adiposity and leptin levels at 5 years of age. METHODS: In a prospective pre-birth cohort, we measured maternal glucose levels after a 50 g oral glucose challenge test at first trimester (9.8 ± 2.3 weeks) and during a 75 g oral glucose tolerance test at second trimester (26.5 ± 0.9 weeks). We followed up children at 5 years; we measured anthropometry and body composition using dual-energy X-ray absorptiometry (DXA). We measured fasting leptin levels using immunoassays (Luminex) in 328 children. We conducted linear regression analyses, adjusting for potential confounders. RESULTS: Maternal glycaemia at first trimester was associated with childhood leptin levels at 5 years, independently of maternal pre-pregnancy BMI and other confounders (ß = .09 ± .04; P = .03). Higher post-load glucose levels at second trimester were associated with greater total body fat percentage measured by DXA (1 hour-glucose: ß = .010 ± .004; P = .03 and 2 hours-glucose: ß = .016 ± .005; P = .002), but not with leptin levels. CONCLUSIONS: Our results suggest that programming of leptin regulation may be sensitive to maternal hyperglycaemia specifically in early pregnancy.

Genetic Loci and Physiologic Pathways Involved in Gestational Diabetes Mellitus Implicated Through Clustering.

Hundreds of common genetic variants acting through distinguishable physiologic pathways influence the risk of type 2 diabetes (T2D). It is unknown to what extent the physiology underlying gestational diabetes mellitus (GDM) is distinct from that underlying T2D. In this study of >5,000 pregnant women from three cohorts, we aimed to identify physiologically related groups of maternal variants associated with GDM using two complementary approaches that were based on Bayesian nonnegative matrix factorization (bNMF) clustering. First, we tested five bNMF clusters of maternal T2D-associated variants grouped on the basis of physiology outside of pregnancy for association with GDM. We found that cluster polygenic scores representing genetic determinants of reduced ß-cell function and abnormal hepatic lipid metabolism were associated with GDM; these clusters were not associated with infant birth weight. Second, we derived bNMF clusters of maternal variants on the basis of pregnancy physiology and tested these clusters for association with GDM. We identified a cluster that was strongly associated with GDM as well as associated with higher infant birth weight. The effect size for this cluster's association with GDM appeared greater than that for T2D. Our findings imply that the genetic and physiologic pathways that lead to GDM differ, at least in part, from those that lead to T2D.

Epigenome-wide meta-analysis of blood DNA methylation in newborns and children identifies numerous loci related to gestational age.

BACKGROUND: Preterm birth and shorter duration of pregnancy are associated with increased morbidity in neonatal and later life. As the epigenome is known to have an important role during fetal development, we investigated associations between gestational age and blood DNA methylation in children. METHODS: We performed meta-analysis of Illumina's HumanMethylation450-array associations between gestational age and cord blood DNA methylation in 3648 newborns from 17 cohorts without common pregnancy complications, induced delivery or caesarean section. We also explored associations of gestational age with DNA methylation measured at 4-18 years in additional pediatric cohorts. Follow-up analyses of DNA methylation and gene expression correlations were performed in cord blood. DNA methylation profiles were also explored in tissues relevant for gestational age health effects: fetal brain and lung. RESULTS: We identified 8899 CpGs in cord blood that were associated with gestational age (range 27-42 weeks), at Bonferroni significance, P < 1.06 × 10- 7, of which 3343 were novel. These were annotated to 4966 genes. After restricting findings to at least three significant adjacent CpGs, we identified 1276 CpGs annotated to 325 genes. Results were generally consistent when analyses were restricted to term births. Cord blood findings tended not to persist into childhood and adolescence. Pathway analyses identified enrichment for biological processes critical to embryonic development. Follow-up of identified genes showed correlations between gestational age and DNA methylation levels in fetal brain and lung tissue, as well as correlation with expression levels. CONCLUSIONS: We identified numerous CpGs differentially methylated in relation to gestational age at birth that appear to reflect fetal developmental processes across tissues. These findings may contribute to understanding mechanisms linking gestational age to health effects.

Optimizing Practices, Use, Care and Services-Antipsychotics (OPUS-AP) in Long-term Care Centers in Québec, Canada: A Strategy for Best Practices.

OBJECTIVES: Antipsychotic medications are often used for the first-line management of behavioral and psychological symptoms of dementia (BPSD) contrary to guideline recommendations. The Optimizing Practices, Use, Care and Services-Antipsychotics (OPUS-AP) strategy aims to improve the well-being of long-term care (LTC) residents with major neurocognitive disorder (MNCD) by implementing a resident-centered approach, nonpharmacologic interventions, and antipsychotic deprescribing in inappropriate indications. DESIGN: Prospective, closed cohort supplemented by a developmental evaluation. SETTING AND PARTICIPANTS: Residents of designated wards in 24 LTC centers in Québec, Canada. METHODS: Provincial guidelines were disseminated, followed by the implementation of an integrated knowledge translation and mobilization strategy, including training, coaching, clinical tools, evaluation of clinical practices, and a change management strategy. Antipsychotic, benzodiazepine, and antidepressant prescriptions; BPSD; and falls were evaluated every 3 months, for 9 months, from January to October 2018. Semistructured interviews (n = 20) were conducted with LTC teams to evaluate the implementation of OPUS-AP. RESULTS: Of 1054 residents, 78.3% had an MNCD diagnosis and 51.7% an antipsychotic prescription. The cohort included 464 residents with both MNCD and antipsychotic prescription. Antipsychotic deprescribing (cessation or dose decrease) was attempted in 220 of the 344 residents still admitted at 9 months. Complete cessation was observed in 116 of these residents (52.7%) and dose reduction in 72 (32.7%), for a total of 188 residents (85.5%; 95% confidence interval: 80.1%, 89.8%). A decrease in benzodiazepine prescriptions and improvements in Cohen-Mansfield Agitation Inventory scores were observed among residents who had their antipsychotics deprescribed. Caregivers and clinicians expressed satisfaction as a result of observing an improved quality of life among residents. CONCLUSIONS AND IMPLICATIONS: Antipsychotic deprescribing was successful in a vast majority of LTC residents with MNCD without worsening of BPSD. Based on this success, phase 2 of OPUS-AP is now under way in 129 LTC centers in Québec.

Associations of sleep duration, sedentary behaviours and energy expenditure with maternal glycemia in pregnancy.

BACKGROUND: Women with high levels of physical activity (PA) are less likely to develop gestational diabetes mellitus (GDM), but the relations with sleep and sedentary behaviours (SB) are more controversial. We aimed to investigate all three components (sleep, PA, and SB) and their association with maternal glucose in pregnancy. METHODS: We included 766 pregnant women recruited at first trimester and that we followed at second trimester. We collected blood samples, anthropometry and standardized questionnaires about lifestyle including PA, SB, and sleep duration at both visits. Women completed a 50 g glucose challenge test at first trimester and 75-g oral glucose tolerance test (OGTT) at second trimester. We conducted regression analyses to test cross-sectional associations between sleep, PA, and SB with maternal glucose levels while taking into account potential confounders (maternal age, pre-pregnancy body mass index (BMI), gravidity, and smoking). We considered linear and quadratic relationships. RESULTS: At first trimester, we observed a linear relationship between shorter sleep duration and higher glucose levels, which was attenuated after adjustments for confounders. At second trimester, we found a quadratic relationship between sleep and glucose showing lowest levels at fasting and 1 h-post OGTT for women who slept 6-10 h/night. This association remained significant after adjusting for confounders and taking into account PA and/or SB. Greater amount of SB was associated with higher 1 h-glucose after adjustment for confounders (ß = 0.132; SE = 0.047; P = 0.005). CONCLUSIONS: Sleep duration is associated with glucose regulation in pregnancy, independently of PA and SB, and this association varies according to the period of gestation.