Metabolomic and genetic architecture of gestational diabetes subtypes.

AIMS/HYPOTHESIS: Physiological gestational diabetes mellitus (GDM) subtypes that may confer different risks for adverse pregnancy outcomes have been defined. The aim of this study was to characterise the metabolome and genetic architecture of GDM subtypes to address the hypothesis that they differ between GDM subtypes. METHODS: This was a cross-sectional study of participants in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study who underwent an OGTT at approximately 28 weeks' gestation. GDM was defined retrospectively using International Association of Diabetes and Pregnancy Study Groups/WHO criteria, and classified as insulin-deficient GDM (insulin secretion <25th percentile with preserved insulin sensitivity) or insulin-resistant GDM (insulin sensitivity <25th percentile with preserved insulin secretion). Metabolomic analyses were performed on fasting and 1 h serum samples in 3463 individuals (576 with GDM). Genome-wide genotype data were obtained for 8067 individuals (1323 with GDM). RESULTS: Regression analyses demonstrated striking differences between the metabolomes for insulin-deficient or insulin-resistant GDM compared to those with normal glucose tolerance. After adjustment for covariates, 33 fasting metabolites, including 22 medium- and long-chain acylcarnitines, were uniquely associated with insulin-deficient GDM; 23 metabolites, including the branched-chain amino acids and their metabolites, were uniquely associated with insulin-resistant GDM; two metabolites (glycerol and 2-hydroxybutyrate) were associated with the same direction of association with both subtypes. Subtype differences were also observed 1 h after a glucose load. In genome-wide association studies, variants within MTNR1B (rs10830963, p=3.43×10-18, OR 1.55) and GCKR (rs1260326, p=5.17×10-13, OR 1.43) were associated with GDM. Variants in GCKR (rs1260326, p=1.36×10-13, OR 1.60) and MTNR1B (rs10830963, p=1.22×10-9, OR 1.49) demonstrated genome-wide significant association with insulin-resistant GDM; there were no significant associations with insulin-deficient GDM. The lead SNP in GCKR, rs1260326, was associated with the levels of eight of the 25 fasting metabolites that were associated with insulin-resistant GDM and ten of 41 1 h metabolites that were associated with insulin-resistant GDM. CONCLUSIONS/INTERPRETATION: This study demonstrates that physiological GDM subtypes differ in their metabolome and genetic architecture. These findings require replication in additional cohorts, but suggest that these differences may contribute to subtype-related adverse pregnancy outcomes.

Use of fasting plasma glucose to determine the approach for diagnosing gestational diabetes mellitus.

AIMS: Estimate the impact of OGTTs only on women with a screening FPG of 4.5-5.0 mmol/L using data from HAPO. METHODS: HAPO participants had 75-g OGTTs (24-32 weeks' gestation). At follow-up, children had adiposity assessed (overweight/obesity, obesity) and mothers and children had OGTTs. GDM was defined retrospectively using IADPSG criteria. Odds for neonatal (birthweight, percent neonatal fat, sum of skinfolds, cord C-peptide > 90th percentiles) and follow-up outcomes were assessed in those with HAPO FPG ≤ 4.4 or > 4.4 mmol/L and GDM or no GDM focusing on women with FPG > 4.4 and no GDM (Group 3) vs women with GDM and FPG ≤ 4.4 (Group 2). RESULTS: This strategy would miss a diagnosis of GDM in 14.7%. Odds for neonatal outcomes in Groups 2 and 3 were not different (ORs: 1.14 to 1.29). Odds at follow-up for type 2 diabetes and disorders of glucose metabolism in mothers were higher in Group 2 (ORs: 3.51, 2.57). Odds for childhood impaired glucose tolerance or adiposity outcomes were not different for Groups 2 and 3. CONCLUSIONS: HAPO mothers whose GDM diagnosis would be missed were not at greater risk for adverse neonatal and childhood outcomes than mothers with FPG of 4.5-5.0 without GDM.

Association of Maternal Metabolites and Metabolite Networks with Newborn Outcomes in a Multi-Ancestry Cohort.

The in utero environment is important for newborn size at birth, which is associated with childhood adiposity. We examined associations between maternal metabolite levels and newborn birthweight, sum of skinfolds (SSF), and cord C-peptide in a multinational and multi-ancestry cohort of 2337 mother-newborn dyads. Targeted and untargeted metabolomic assays were performed on fasting and 1 h maternal serum samples collected during an oral glucose tolerance test performed at 24-32 week gestation in women participating in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study. Anthropometric measurements were obtained on newborns at birth. Following adjustment for maternal BMI and glucose, per-metabolite analyses demonstrated significant associations between maternal metabolite levels and birthweight, SSF, and cord C-peptide. In the fasting state, triglycerides were positively associated and several long-chain acylcarnitines were inversely associated with birthweight and SSF. At 1 h, additional metabolites including branched-chain amino acids, proline, and alanine were positively associated with newborn outcomes. Network analyses demonstrated distinct clusters of inter-connected metabolites significantly associated with newborn phenotypes. In conclusion, numerous maternal metabolites during pregnancy are significantly associated with newborn birthweight, SSF, and cord C-peptide independent of maternal BMI and glucose, suggesting that metabolites in addition to glucose contribute to newborn size at birth and adiposity.

NIH Toolbox® Episodic Memory Measure Differentiates Older Adults with Exceptional Memory Capacity from those with Average-for-Age Cognition.

OBJECTIVE: Older adults with exceptional memory function, designated "SuperAgers," include individuals over age 80, with episodic memory at least as good as individuals ages 50s-60s. The Northwestern University SuperAging cohort is defined by performance on an established test of verbal memory. The purpose of this study was to determine if superior verbal memory extends to nonverbal memory in SuperAgers by examining differences in the National Institutes of Health Toolbox® (NIHTB) between older adults with exceptional memory and those with average-for-age cognition. METHOD: SuperAgers (n = 46) and cognitively average-for-age older adults (n = 31) completed a comprehensive neuropsychological battery and the NIHTB Cognition module. Multiple linear regressions were used to examine differences on subtests between groups. RESULTS: There was a significant effect of group on the Picture Sequence Memory score, (p = .007), such that SuperAgers had higher scores than cognitively average-for-age older adults. There were no other group effects across other non-episodic memory NIHTB Cognition measures. CONCLUSIONS: Findings from this study demonstrated stronger performance on the memory measure of the NIHTB in SuperAgers compared to cognitively average-for-age older adults demonstrating superior memory in not only verbal but also nonverbal episodic memory in this group. Additionally, this study adds to the literature validating the NIHTB in older adults, particularly in a novel population of adults over age 80 with exceptional memory.

Network Approaches to Integrate Analyses of Genetics and Metabolomics Data with Applications to Fetal Programming Studies.

The integration of genetics and metabolomics data demands careful accounting of complex dependencies, particularly when modelling familial omics data, e.g., to study fetal programming of related maternal-offspring phenotypes. Efforts to identify genetically determined metabotypes using classic genome wide association approaches have proven useful for characterizing complex disease, but conclusions are often limited to a series of variant-metabolite associations. We adapt Bayesian network models to integrate metabotypes with maternal-offspring genetic dependencies and metabolic profile correlations in order to investigate mechanisms underlying maternal-offspring phenotypic associations. Using data from the multiethnic Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study, we demonstrate that the strategic specification of ordered dependencies, pre-filtering of candidate metabotypes, incorporation of metabolite dependencies, and penalized network estimation methods clarify potential mechanisms for fetal programming of newborn adiposity and metabolic outcomes. The exploration of Bayesian network growth over a range of penalty parameters, coupled with interactive plotting, facilitate the interpretation of network edges. These methods are broadly applicable to integration of diverse omics data for related individuals.

Associations of glycemia and lipid levels in pregnancy with dyslipidemia 10-14 years later: The HAPO follow-up study.

AIMS: To examine associations of pregnancy glycemia with future dyslipidemia. METHODS: We analyzed data from Hyperglycemia and Adverse Pregnancy Outcome Follow-Up Study participants. We examined associations of gestational diabetes (GDM), sum of fasting, 1-hour, and 2-hour glucose z-scores after 75-g load, insulin sensitivity, and lipid levels at 24-32 weeks' gestation with dyslipidemia 10-14 years postpartum. RESULTS: Among 4,693 women, 14.3% had GDM. At follow-up, mean (SD) age was 41.7 (5.7) years, 32.3% had total cholesterol (TC) ≥ 5.17, 27.2% had HDL cholesterol < 1.29, 22.4% had LDL cholesterol (LDL-C) ≥ 3.36, 10.9% had triglycerides ≥ 1.69 mmol/L, and 2.9% had type 2 diabetes. After covariate adjustment, pregnancy glycemic measures were associated with all follow-up dyslipidemias. After additional adjustment for pregnancy lipids, GDM remained associated with TC ≥ 5.17 mmol/L (odds ratio [95% CI], 1.63 [1.22-2.18]) and LDL-C ≥ 3.36 mmol/L (1.63 [1.20-2.22]), even in the absence of type 2 diabetes development (1.55 [1.15-2.10] and 1.56 [1.13-2.16], respectively). Continuous glycemic measures in pregnancy were significantly associated with all follow-up dyslipidemias, independent of pregnancy lipids and type 2 diabetes. CONCLUSIONS: Pregnancy glycemia was associated with dyslipidemia 10-14 years later, independent of pregnancy lipid levels and in the absence of type 2 diabetes development. Lipid screening after GDM deserves special consideration.

Development of a Model for the Pediatric Survival After Veno-Arterial Extracorporeal Membrane Oxygenation Score: The Pedi-SAVE Score.

Pediatric cardiac extracorporeal membrane oxygenation (ECMO) patients have high mortality rates. The purpose of our study was to develop and validate the Pediatric Survival After Veno-arterial ECMO (Pedi-SAVE) score for predicting survival at hospital discharge after pediatric cardiac veno-arterial (VA) ECMO. We used data for pediatric cardiac VA-ECMO patients from the Extracorporeal Life Support Organization registry (1/1/2001-12/31/2015). Development and validation cohorts were created using 2:1 random sampling. Predictors of survival to develop pre- and postcannulation models were selected using multivariable logistic regression and random forest models. ß-coefficients were standardized to create the Pedi-SAVE score. Of 10,091 pediatric cardiac VA-ECMO patients, 4,996 (50%) survived to hospital discharge. Pre- and postcannulation Pedi-SAVE scores predicted that the lowest risk patients have a 65% and 74% chance of survival at hospital discharge, respectively, compared to 33% and 22% in the highest risk patients. In the validation cohort, pre- and postcannulation Pedi-SAVE scores had c-statistics of 0.64 and 0.71, respectively. Precannulation factors associated with survival included: nonsingle ventricle congenital heart disease, older age, white race, lower STAT mortality category, higher pH, not requiring acid-buffer administration, <2 cardiac procedures, and indication for VA-ECMO other than failure to wean from cardiopulmonary bypass. Postcannulation, additional factors associated with survival included: lower ECMO pump flows at 24 hours and lack of complications. The Pedi-SAVE score is a novel validated tool to predict survival at hospital discharge for pediatric cardiac VA-ECMO patients, and is an important advancement in risk adjustment and benchmarking for this population.

Neuropsychological Profiles of Older Adults with Superior versus Average Episodic Memory: The Northwestern "SuperAger" Cohort.

OBJECTIVE: SuperAgers are adults over the age of 80 with superior episodic memory performance and at least average-for-age performance in non-episodic memory domains. This study further characterized the neuropsychological profile of SuperAgers compared to average-for-age episodic memory peers to determine potential cognitive mechanisms contributing to their superior episodic memory performance. METHOD: Retrospective analysis of neuropsychological test data from 56 SuperAgers and 23 similar-age peers with average episodic memory was conducted. Independent sample t-tests evaluated between-group differences in neuropsychological scores. Multiple linear regression determined the influence of non-episodic memory function on episodic memory scores across participants. RESULTS: As a group, SuperAgers had better scores than their average memory peers on measures of attention, working memory, naming, and speeded set shifting. Scores on tests of processing speed, visuospatial function, verbal fluency, response inhibition, and abstract reasoning did not differ. On an individual level, there was variability among SuperAgers with regard to non-episodic memory performance, with some performing above average-for-age across cognitive domains while others performed in the average-for-age range on non-memory tests. Across all participants, attention and executive function scores explained 20.4% of the variance in episodic memory scores. CONCLUSIONS: As a group, SuperAgers outperformed their average memory peers in multiple cognitive domains, however, there was considerable intragroup variability suggesting that SuperAgers' episodic memory strength is not simply related to globally superior cognitive functioning. Attention and executive function performance explained approximately one-fifth of the variance in episodic memory and maybe areas to target with cognitive interventions.

Fetal alleles predisposing to metabolically favorable adiposity are associated with higher birth weight.

BACKGROUND: Higher birthweight is associated with higher adult body mass index (BMI). Alleles that predispose to greater adult adiposity might act in fetal life to increase fetal growth and birthweight. Whether there are fetal effects of recently identified adult metabolically favorable adiposity alleles on birthweight is unknown. AIM: We aimed to test the effect on birthweight of fetal genetic predisposition to higher metabolically favorable adult adiposity and compare that with the effect of fetal genetic predisposition to higher adult BMI. METHODS: We used published genome wide association study data (n = upto 406 063) to estimate fetal effects on birthweight (adjusting for maternal genotype) of alleles known to raise metabolically favorable adult adiposity or BMI. We combined summary data across single nucleotide polymorphisms (SNPs) with random effects meta-analyses. We performed weighted linear regression of SNP-birthweight effects against SNP-adult adiposity effects to test for a dose-dependent association. RESULTS: Fetal genetic predisposition to higher metabolically favorable adult adiposity and higher adult BMI were both associated with higher birthweight (3 g per effect allele (95% CI: 1-5) averaged over 14 SNPs; P = 0.002; 0.5 g per effect allele (95% CI: 0-1) averaged over 76 SNPs; P = 0.042, respectively). SNPs with greater effects on metabolically favorable adiposity tended to have greater effects on birthweight (R2 = 0.2912, P = 0.027). There was no dose-dependent association for BMI (R2 = -0.0019, P = 0.602). CONCLUSIONS: Fetal genetic predisposition to both higher adult metabolically favorable adiposity and BMI is associated with birthweight. Fetal effects of metabolically favorable adiposity-raising alleles on birthweight are modestly proportional to their effects on future adiposity, but those of BMI-raising alleles are not.

Higher maternal adiposity reduces offspring birthweight if associated with a metabolically favourable profile.

AIMS/HYPOTHESIS: Higher maternal BMI during pregnancy is associated with higher offspring birthweight, but it is not known whether this is solely the result of adverse metabolic consequences of higher maternal adiposity, such as maternal insulin resistance and fetal exposure to higher glucose levels, or whether there is any effect of raised adiposity through non-metabolic (e.g. mechanical) factors. We aimed to use genetic variants known to predispose to higher adiposity, coupled with a favourable metabolic profile, in a Mendelian randomisation (MR) study comparing the effect of maternal 'metabolically favourable adiposity' on offspring birthweight with the effect of maternal general adiposity (as indexed by BMI). METHODS: To test the causal effects of maternal metabolically favourable adiposity or general adiposity on offspring birthweight, we performed two-sample MR. We used variants identified in large, published genetic-association studies as being associated with either higher adiposity and a favourable metabolic profile, or higher BMI (n = 442,278 and n = 322,154 for metabolically favourable adiposity and BMI, respectively). We then extracted data on the metabolically favourable adiposity and BMI variants from a large, published genetic-association study of maternal genotype and offspring birthweight controlling for fetal genetic effects (n = 406,063 with maternal and/or fetal genotype effect estimates). We used several sensitivity analyses to test the reliability of the results. As secondary analyses, we used data from four cohorts (total n = 9323 mother-child pairs) to test the effects of maternal metabolically favourable adiposity or BMI on maternal gestational glucose, anthropometric components of birthweight and cord-blood biomarkers. RESULTS: Higher maternal adiposity with a favourable metabolic profile was associated with lower offspring birthweight (-94 [95% CI -150, -38] g per 1 SD [6.5%] higher maternal metabolically favourable adiposity, p = 0.001). By contrast, higher maternal BMI was associated with higher offspring birthweight (35 [95% CI 16, 53] g per 1 SD [4 kg/m2] higher maternal BMI, p = 0.0002). Sensitivity analyses were broadly consistent with the main results. There was evidence of outlier SNPs for both exposures; their removal slightly strengthened the metabolically favourable adiposity estimate and made no difference to the BMI estimate. Our secondary analyses found evidence to suggest that a higher maternal metabolically favourable adiposity decreases pregnancy fasting glucose levels while a higher maternal BMI increases them. The effects on neonatal anthropometric traits were consistent with the overall effect on birthweight but the smaller sample sizes for these analyses meant that the effects were imprecisely estimated. We also found evidence to suggest that higher maternal metabolically favourable adiposity decreases cord-blood leptin while higher maternal BMI increases it. CONCLUSIONS/INTERPRETATION: Our results show that higher adiposity in mothers does not necessarily lead to higher offspring birthweight. Higher maternal adiposity can lead to lower offspring birthweight if accompanied by a favourable metabolic profile. DATA AVAILABILITY: The data for the genome-wide association studies (GWAS) of BMI are available at https://portals.broadinstitute.org/collaboration/giant/index.php/GIANT_consortium_data_files . The data for the GWAS of body fat percentage are available at https://walker05.u.hpc.mssm.edu .

Maternal Metabolites Associated With Gestational Diabetes Mellitus and a Postpartum Disorder of Glucose Metabolism.

CONTEXT: Gestational diabetes is associated with a long-term risk of developing a disorder of glucose metabolism. However, neither the metabolic changes characteristic of gestational diabetes in a large, multi-ancestry cohort nor the ability of metabolic changes during pregnancy, beyond glucose levels, to identify women at high risk for progression to a disorder of glucose metabolism has been examined. OBJECTIVE: This work aims to identify circulating metabolites present at approximately 28 weeks' gestation associated with gestational diabetes mellitus (GDM) and development of a disorder of glucose metabolism 10 to 14 years later. METHODS: Conventional clinical and targeted metabolomics analyses were performed on fasting and 1-hour serum samples following a 75-g glucose load at approximately 28 weeks' gestation from 2290 women who participated in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study. Postpartum metabolic traits included fasting and 2-hour plasma glucose following a 75-g glucose load, insulin resistance estimated by the homeostasis model assessment of insulin resistance, and disorders of glucose metabolism (prediabetes and type 2 diabetes) during the HAPO Follow-Up Study. RESULTS: Per-metabolite analyses identified numerous metabolites, ranging from amino acids and carbohydrates to fatty acids and lipids, before and 1-hour after a glucose load that were associated with GDM as well as development of a disorder of glucose metabolism and metabolic traits 10 to 14 years post partum. A core group of fasting and 1-hour metabolites mediated, in part, the relationship between GDM and postpartum disorders of glucose metabolism, with the fasting and 1-hour metabolites accounting for 15.7% (7.1%-30.8%) and 35.4% (14.3%-101.0%) of the total effect size, respectively. For prediction of a postpartum disorder of glucose metabolism, the addition of circulating fasting or 1-hour metabolites at approximately 28 weeks' gestation showed little improvement in prediction performance compared to clinical factors alone. CONCLUSION: The results demonstrate an association of multiple metabolites with GDM and postpartum metabolic traits and begin to define the underlying pathophysiology of the transition from GDM to a postpartum disorder of glucose metabolism.

Modularity and granularity across the language network-A primary progressive aphasia perspective.

Tests of grammar, repetition and semantics were administered to 62 prospectively enrolled right-handed participants with primary progressive aphasia (PPA). Structural brain images were obtained at the time of testing. Regression analyses uncovered 3 clearly delineated non-overlapping left hemisphere clusters where cortical thinning (atrophy) was significantly correlated with impaired performance. A morphosyntactic cluster associated with the grammaticality of sentence construction was located predominantly within the middle and inferior frontal gyri; a phonolexical cluster associated with language repetition was located in the temporoparietal junction; a lexicosemantic cluster associated with object naming and single word comprehension was located within the middle and anterior parts of the temporal lobe and extended into insular, orbitofrontal, and mediotemporal cortices. Commonality analyses were undertaken to explore whether these three clusters were as modular as indicated by the regression analyses or whether some underlying functional granularity could be uncovered. Modularity was defined as the exclusive association of an anatomical cluster with a single type of language task whereas granularity was defined as the association of a single anatomical cluster with more than one type of language task. The commonality analyses revealed a predominantly modular organization with quantitatively minor instances of inter-cluster granularity. The results also reconfirmed previous work on PPA which had shown that Wernicke's area is not essential for word comprehension, that naming impairments can be based either on deficits of lexical retrieval or word comprehension, and that the essential substrates of word comprehension encompass much wider areas of the temporal lobe than the temporal pole. The anatomy of the language network has traditionally been explored through patients with focal cerebrovascular accidents and experiments based on functional activation. Investigations on PPA are showing that focal neurodegenerations can add new perspectives to existing models of the language network.

Functional decline in the aphasic variant of Alzheimer's disease.

INTRODUCTION: Primary progressive aphasia (PPA) is a clinical dementia syndrome associated with frontotemporal lobar degeneration (FTLD) or Alzheimer's disease (AD). Impairment in activities of daily living is essential for dementia diagnosis, yet less is known about the neuropathologic impact on functional decline in PPA, especially over time. METHODS: Activities of Daily Living Questionnaire (ADLQ) ratings were compared by suspected underlying pathology between 17 PPAAß+ and 11 PPAAß- participants at 6-month intervals for 2 years using a linear mixed-effects model. A general linear model examined associations between functional decline and cortical thickness at baseline. RESULTS: Groups did not differ in demographics or aphasia severity at baseline, yet overall and subdomain scores of the ADLQ were significantly worse for PPAAß+ compared to PPAAß- (P = .015) at each interval across 18 months. DISCUSSION: Functional decline appears more pronounced and disrupts more aspects of life activities for individuals with non-semantic PPA with suspected AD versus non-AD neuropathology.

Newborn Adiposity and Cord Blood C-Peptide as Mediators of the Maternal Metabolic Environment and Childhood Adiposity.

OBJECTIVE: Excessive childhood adiposity is a risk factor for adverse metabolic health. The objective was to investigate associations of newborn body composition and cord C-peptide with childhood anthropometrics and explore whether these newborn measures mediate associations of maternal midpregnancy glucose and BMI with childhood adiposity. RESEARCH DESIGN AND METHODS: Data on mother/offspring pairs (N = 4,832) from the epidemiological Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study and HAPO Follow-up Study (HAPO FUS) were analyzed. Linear regression was used to study associations between newborn and childhood anthropometrics. Structural equation modeling was used to explore newborn anthropometric measures as potential mediators of the associations of maternal BMI and glucose during pregnancy with childhood anthropometric outcomes. RESULTS: In models including maternal glucose and BMI adjustments, newborn adiposity as measured by the sum of skinfolds was associated with child outcomes (adjusted mean difference, 95% CI, P value) BMI (0.26, 0.12-0.39, <0.001), BMI z-score (0.072, 0.033-0.11, <0.001), fat mass (kg) (0.51, 0.26-0.76, <0.001), percentage of body fat (0.61, 0.27-0.95, <0.001), and sum of skinfolds (mm) (1.14, 0.43-1.86, 0.0017). Structural equation models demonstrated significant mediation by newborn sum of skinfolds and cord C-peptide of maternal BMI effects on childhood BMI (proportion of total effect 2.5% and 1%, respectively), fat mass (3.1%, 1.2%), percentage of body fat (3.6%, 1.8%), and sum of skinfolds (2.9%, 1.8%), and significant mediation by newborn sum of skinfolds and cord C-peptide of maternal glucose effects on child fat mass (proportion of total association 22.0% and 21.0%, respectively), percentage of body fat (15.0%, 18.0%), and sum of skinfolds (15.0%, 20.0%). CONCLUSIONS: Newborn adiposity is independently associated with childhood adiposity and, along with fetal hyperinsulinemia, mediates, in part, associations of maternal glucose and BMI with childhood adiposity.

Associations of Maternal Cardiovascular Health in Pregnancy With Offspring Cardiovascular Health in Early Adolescence.

Importance: Pregnancy may be a key window to optimize cardiovascular health (CVH) for the mother and influence lifelong CVH for her child. Objective: To examine associations between maternal gestational CVH and offspring CVH. Design, Setting, and Participants: This cohort study used data from the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study (examinations: July 2000-April 2006) and HAPO Follow-Up Study (examinations: February 2013-December 2016). The analyses included 2302 mother-child dyads, comprising 48% of HAPO Follow-Up Study participants, in an ancillary CVH study. Participants were from 9 field centers across the United States, Barbados, United Kingdom, China, Thailand, and Canada. Exposures: Maternal gestational CVH at a target of 28 weeks' gestation, based on 5 metrics: body mass index, blood pressure, total cholesterol level, glucose level, and smoking. Each metric was categorized as ideal, intermediate, or poor using pregnancy guidelines. Total CVH was categorized as follows: all ideal metrics, 1 or more intermediate (but 0 poor) metrics, 1 poor metric, or 2 or more poor metrics. Main Outcomes and Measures: Offspring CVH at ages 10 to 14 years, based on 4 metrics: body mass index, blood pressure, total cholesterol level, and glucose level. Total CVH was categorized as for mothers. Results: Among 2302 dyads, the mean (SD) ages were 29.6 (2.7) years for pregnant mothers and 11.3 (1.1) years for children. During pregnancy, the mean (SD) maternal CVH score was 8.6 (1.4) out of 10. Among pregnant mothers, the prevalence of all ideal metrics was 32.8% (95% CI, 30.6%-35.1%), 31.7% (95% CI, 29.4%-34.0%) for 1 or more intermediate metrics, 29.5% (95% CI, 27.2%-31.7%) for 1 poor metric, and 6.0% (95% CI, 3.8%-8.3%) for 2 or more poor metrics. Among children of mothers with all ideal metrics, the prevalence of all ideal metrics was 42.2% (95% CI, 38.4%-46.2%), 36.7% (95% CI, 32.9%-40.7%) for 1 or more intermediate metrics, 18.4% (95% CI, 14.6%-22.4%) for 1 poor metric, and 2.6% (95% CI, 0%-6.6%) for 2 or more poor metrics. Among children of mothers with 2 or more poor metrics, the prevalence of all ideal metrics was 30.7% (95% CI, 22.0%-40.4%), 28.3% (95% CI, 19.7%-38.1%) for 1 or more intermediate metrics, 30.7% (95% CI, 22.0%-40.4%) for 1 poor metric, and 10.2% (95% CI, 1.6%-20.0%) for 2 or more poor metrics. The adjusted relative risks associated with 1 or more intermediate, 1 poor, and 2 or more poor (vs all ideal) metrics, respectively, in mothers during pregnancy were 1.17 (95% CI, 0.96-1.42), 1.66 (95% CI, 1.39-1.99), and 2.02 (95% CI, 1.55-2.64) for offspring to have 1 poor (vs all ideal) metrics, and the relative risks were 2.15 (95% CI, 1.23-3.75), 3.32 (95% CI,1.96-5.62), and 7.82 (95% CI, 4.12-14.85) for offspring to have 2 or more poor (vs all ideal) metrics. Additional adjustment for categorical birth factors (eg, preeclampsia) did not fully explain these significant associations (eg, relative risk for association between 2 or more poor metrics among mothers during pregnancy and 2 or more poor metrics among offspring after adjustment for an extended set of birth factors, 6.23 [95% CI, 3.03-12.82]). Conclusions and Relevance: In this multinational cohort, better maternal CVH at 28 weeks' gestation was significantly associated with better offspring CVH at ages 10 to 14 years.

Memory Resilience in Alzheimer Disease With Primary Progressive Aphasia.

OBJECTIVE: To determine whether memory is preserved longitudinally in primary progressive aphasia (PPA) associated with Alzheimer disease (AD) and to identify potential factors that maintain memory despite underlying neurofibrillary degeneration of mediotemporal memory areas. METHODS: Longitudinal memory assessment was done in 17 patients with PPA with autopsy or biomarker evidence of AD (PPA-AD) and 14 patients with amnestic dementia of the Alzheimer type with AD at autopsy (DAT-AD). RESULTS: In PPA-AD, episodic memory, tested with nonverbal items, was preserved at the initial testing and showed no decline at retesting 2.35 ± 0.78 years later, at which time symptoms had been present for 6.26 ± 2.21 years. In contrast, language functions declined significantly during the same period. In DAT-AD, both verbal memory and language declined with equal severity. Although imaging showed asymmetric left-sided mediotemporal atrophy in PPA-AD, autopsy revealed bilateral hippocampo-entorhinal neurofibrillary degeneration at Braak stages V and VI. Compared to DAT-AD, however, the PPA-AD group had lower incidence of APOE ε4 and of mediotemporal TAR DNA-binding protein 43 (TDP-43) pathology. CONCLUSIONS: Memory preservation in PPA is not just an incidental finding at onset but a core feature that persists for years despite the hippocampo-entorhinal AD neuropathology that is as severe as that of DAT-AD. Asymmetry of mediotemporal atrophy and a lesser impact of APOE ε4 and of TDP-43 on the integrity of memory circuitry may constitute some of the factors underlying this resilience. Our results also suggest that current controversies on memory in PPA-AD reflect inconsistencies in the diagnosis of logopenic PPA, the clinical variant most frequently associated with AD. CLINICALTRIALSGOV IDENTIFIER: NCT00537004 and NCT03371706.

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.

Does Value Vary by Center Surgical Volume for Neonates With Truncus Arteriosus? A Multicenter Study.

BACKGROUND: Truncus arteriosus is a congenital heart defect with high resource use, cost, and mortality. Value assessment (outcome relative to cost) can improve quality of care and decrease cost. This study hypothesized that truncus arteriosus repair at a high-volume center would result in better outcomes at lower cost (higher value) compared with a low-volume center. METHODS: This study retrospectively analyzed a multicenter cohort of neonates undergoing truncus arteriosus repair (2004 to 2015) by using the Pediatric Health Information Systems database. Multivariate quantile, logistic, and negative binomial regression models were used to evaluate total hospital cost, in-hospital mortality, ventilation days, intensive care unit length of stay (LOS), hospital LOS, and days of inotropic agent use by center volume (high-volume >3/year) and age at repair while adjusting for sex, ethnicity, race, genetic abnormality, prematurity, low birth weight, concurrent interrupted arch repair, and truncal valve repair. RESULTS: Of 1024 neonates with truncus arteriosus, 495 (48%) were treated at high-volume centers. Costs at the 75th percentile were lower at high-volume vs low-volume centers by $28,456 (P = .02) at all ages at repair. Patients at high-volume centers had lower median postoperative ventilation days (5 days vs 6 days; P < .001), intensive care unit LOS (13 days vs 19 days; P < .001), hospital LOS (23 days vs 28 days; P = .02), and inotropic agent use (3 days vs 4 days; P = .004). In-hospital mortality did not differ by center volume. CONCLUSIONS: In neonates undergoing truncus arteriosus repair, costs are lower and outcomes are better at high-volume centers, thus resulting in higher value at all ages of repair. Value-based interventions should be considered to improve outcomes and decrease cost in truncus arteriosus care.

Associations of gestational cardiovascular health with pregnancy outcomes: the Hyperglycemia and Adverse Pregnancy Outcome study.

BACKGROUND: The American Heart Association's formal characterization of cardiovascular health combines several metrics in a health-oriented, rather than disease-oriented, framework. Although cardiovascular health assessment during pregnancy has been recommended, its significance for pregnancy outcomes is unknown. OBJECTIVE: The purpose of this study was to examine the association of gestational cardiovascular health-formally characterized by a combination of 5 metrics-with adverse maternal and newborn outcomes. STUDY DESIGN: We analyzed data from the Hyperglycemia and Adverse Pregnancy Outcome study, including 2304 mother-newborn dyads from 6 countries. Maternal cardiovascular health was defined by the combination of the following 5 metrics measured at a mean of 28 (24-32) weeks' gestation: body mass index, blood pressure, lipids, glucose, and smoking. Levels of each metric were categorized using pregnancy guidelines, and the total cardiovascular health was scored (0-10 points, where 10 was the most favorable). Cord blood was collected at delivery, newborn anthropometrics were measured within 72 hours, and medical records were abstracted for obstetrical outcomes. Modified Poisson and multinomial logistic regression were used to test the associations of gestational cardiovascular health with pregnancy outcomes, adjusted for center and maternal and newborn characteristics. RESULTS: The average age of women at study exam was 29.6 years old, and they delivered at a mean gestational age of 39.8 weeks. The mean total gestational cardiovascular health score was 8.6 (of 10); 36.3% had all ideal metrics and 7.5% had 2+ poor metrics. In fully adjusted models, each 1 point higher (more favorable) cardiovascular health score was associated with lower risks for preeclampsia (relative risk, 0.67 [95% confidence interval, 0.61-0.73]), unplanned primary cesarean delivery (0.88 [0.82-0.95]), newborn birthweight >90th percentile (0.81 [0.75-0.87]), sum of skinfolds >90th percentile (0.84 [0.77-0.92]), and insulin sensitivity <10th percentile (0.83 [0.77-0.90]). Cardiovascular health categories demonstrated graded associations with outcomes; for example, relative risks (95% confidence intervals) for preeclampsia were 3.13 (1.39-7.06), 5.34 (2.44-11.70), and 9.30 (3.95-21.86) for women with ≥1 intermediate, 1 poor, or ≥2 poor (vs all ideal) metrics, respectively. CONCLUSION: More favorable cardiovascular health at 24 to 32 weeks' gestation was associated with lower risks for several adverse pregnancy outcomes in a multinational cohort.