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Combining pertinent data from multiple studies can increase the robustness of epidemiological investigations. Effective "pre-statistical" data harmonization is paramount to the streamlined conduct of collective, multi-study analysis. Harmonizing data and documenting decisions about the transformations of variables to a common set of categorical values and measurement scales are time consuming and can be error prone, particularly for numerous studies with large quantities of variables. The psHarmonize R package facilitates harmonization by combining multiple datasets, applying data transformation functions, and creating long and wide harmonized datasets. The user provides transformation instructions in a "harmonization sheet" that includes dataset names, variable names, and coding instructions and centrally tracks all decisions. The package performs harmonization, generates error logs as necessary, and creates summary reports of harmonized data. psHarmonize is poised to serve as a central feature of data preparation for the joint analysis of multiple studies.

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OBJECTIVE: This study aimed to identify whether cord blood DNA methylation at specific loci is associated with neonatal adiposity, a key risk factor for childhood obesity. METHODS: An epigenome-wide association study was conducted using the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study as a discovery sample. Linear regression models adjusted for maternal and offspring covariates and cell counts were used to analyze associations between neonatal adiposity as measured by sum of three skinfold thicknesses and cord blood DNA methylation. Assays were performed with Illumina EPIC arrays (791,359 CpG sites after quality control). Replication was performed in an independent cohort, Genetics of Glucose regulation in Gestation and Growth (Gen3G). RESULTS: In 2740 HAPO samples, significant associations were identified at 89 CpG sites after accounting for multiple testing (Bonferroni-adjusted p < 0.05). Replication analyses conducted in 139 Gen3G participants confirmed associations for seven CpG sites. These included IGF1R, which encodes a transmembrane receptor involved in cell growth and survival that binds insulin-like growth factor I and insulin, and KLF7, which encodes a regulator of cell proliferation and inhibitor of adipogenesis; both are key regulators of growth during fetal life. CONCLUSIONS: These findings support epigenetic mechanisms in the developmental origins of neonatal adiposity and as potential biomarkers of metabolic disease risk.

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AIMS/HYPOTHESIS: Pregnancy is accompanied by maternal metabolic adaptations to ensure fetal growth and development, including insulin resistance, which occurs primarily during the second and third trimesters of pregnancy, and a decrease in fasting blood sugar levels over the course of pregnancy. Glucose-related traits are regulated by genetic and environmental factors and modulated by physiological variations throughout the life course. We addressed the hypothesis that there are both overlaps and differences between genetic variants associated with glycaemia-related traits during and outside of pregnancy. METHODS: Genome-wide SNP data were used to identify genetic variations associated with glycaemia-related traits measured during an OGTT performed at ~28 weeks' gestation in 8067 participants in the Hyperglycaemia and Adverse Pregnancy Outcome (HAPO) Study. Associations outside of pregnancy were determined in 3977 individuals who also participated in the HAPO Follow-Up Study at 11-14 years postpartum. A Bayesian classification algorithm was used to determine whether SNPs associated with fasting and 2 h glucose and fasting C-peptide during pregnancy had a pregnancy-predominant effect vs a similar effect during pregnancy and postpartum. RESULTS: SNPs in six loci (GCKR, G6PC2, GCK, PPP1R3B, PCSK1 and MTNR1B) were significantly associated with fasting glucose during pregnancy, while SNPs in CDKAL1 and MTNR1B were associated with 1 h glucose and SNPs in MTNR1B and HKDC1 were associated with 2 h glucose. Variants in CDKAL1 and MTNR1B were associated with insulin secretion during pregnancy. Variants in multiple loci were associated with fasting C-peptide during pregnancy, including GCKR, IQSEC1, PPP1R3B, IGF1 and BACE2. GCKR and BACE2 were associated with 1 h C-peptide and GCKR, IQSEC1 and BACE2 with insulin sensitivity during pregnancy. The associations of MTNR1B with 2 h glucose, BACE2 with fasting and 1 h C-peptide and insulin sensitivity, and IQSEC1 with fasting C-peptide and insulin sensitivity that we identified during pregnancy have not been previously reported in non-pregnancy cohorts. The Bayesian classification algorithm demonstrated that the magnitude of effect of the lead SNP was greater during pregnancy compared with 11-14 years postpartum in PCSK1 and PPP1R3B with fasting glucose, in three loci, including MTNR1B, with 2 h glucose, and in six loci, including IGF1, with fasting C-peptide. CONCLUSIONS/INTERPRETATION: Our findings support the hypothesis that there are both overlaps and differences between the genetic architecture of glycaemia-related traits during and outside of pregnancy. Genetic variants at several loci, including PCSK1, PPP1R3B, MTNR1B and IGF1, appear to influence glycaemic regulation in a unique fashion during pregnancy. Future studies in larger cohorts will be needed to replicate the present findings, fully characterise the genetics of maternal glycaemia during pregnancy and determine similarities to and differences from the non-gravid state.

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OBJECTIVE: To examine the association between elevated blood pressure (BP) in the early third trimester and cardiometabolic health 10-14 years after delivery. METHODS: This is a secondary analysis from the prospective HAPO FUS (Hyperglycemia and Adverse Pregnancy Outcome Follow-Up Study). Blood pressure in the early third trimester was categorized per American College of Cardiology/American Heart Association thresholds for: normal BP below 120/80 mm Hg (reference), elevated BP 120-129/below 80 mm Hg, stage 1 hypertension 130-139/80-89 mm Hg, and stage 2 hypertension 140/90 mm Hg or higher. Cardiometabolic outcomes assessed 10-14 years after the index pregnancy were type 2 diabetes mellitus and measures of dyslipidemia, including low-density lipoprotein (LDL) cholesterol 130 mg/dL or higher, total cholesterol 200 mg/dL or higher, high-density lipoprotein (HDL) cholesterol 40 mg/dL or lower, and triglycerides 200 mg/dL or higher. Adjusted analysis was performed with the following covariates: study field center, follow-up duration, age, body mass index (BMI), height, family history of hypertension and diabetes, smoking and alcohol use, parity, and oral glucose tolerance test glucose z score. RESULTS: Among 4,692 pregnant individuals at a median gestational age of 27.9 weeks (interquartile range 26.6-28.9 weeks), 8.5% (n=399) had elevated BP, 14.9% (n=701) had stage 1 hypertension, and 6.4% (n=302) had stage 2 hypertension. At a median follow-up of 11.6 years, among individuals with elevated BP, there was a higher frequency of diabetes (elevated BP: adjusted relative risk [aRR] 1.88, 95% CI, 1.06-3.35; stage 1 hypertension: aRR 2.58, 95% CI, 1.62-4.10; stage 2 hypertension: aRR 2.83, 95% CI, 1.65-4.95) compared with those with normal BP. Among individuals with elevated BP, there was a higher frequency of elevated LDL cholesterol (elevated BP: aRR 1.27, 95% CI, 1.03-1.57; stage 1 hypertension: aRR 1.22, 95% CI, 1.02-1.45, and stage 2 hypertension: aRR 1.38, 95% CI, 1.10-1.74), elevated total cholesterol (elevated BP: aRR 1.27, 95% CI, 1.07-1.52; stage 1 hypertension: aRR 1.16, 95% CI, 1.00-1.35; stage 2 hypertension: aRR 1.41 95% CI, 1.16-1.71), and elevated triglycerides (elevated BP: aRR 2.24, 95% CI, 1.42-3.53; stage 1 hypertension: aRR 2.15, 95% CI, 1.46-3.17; stage 2 hypertension: aRR 3.24, 95% CI, 2.05-5.11) but not of low HDL cholesterol. CONCLUSION: The frequency of adverse cardiometabolic outcomes at 10-14 years after delivery was progressively higher among pregnant individuals with BP greater than 120/80 in the early third trimester.

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BACKGROUND: As part of the IMPACT Consortium of three effectiveness-implementation trials, the NU IMPACT trial was designed to evaluate implementation and effectiveness outcomes for an electronic health record (EHR)-embedded symptom monitoring and management program for outpatient cancer care. NU IMPACT uses a unique stepped-wedge cluster randomized design, involving six clusters of 26 clinics, for evaluation of implementation outcomes with an embedded patient-level randomized trial to evaluate effectiveness outcomes. Collaborative, consortium-wide efforts to ensure use of the most robust and recent analytic methodologies for stepped-wedge trials motivated updates to the statistical analysis plan for implementation outcomes in the NU IMPACT trial. METHODS: In the updated statistical analysis plan for NU IMPACT, the primary implementation outcome patient adoption, as measured by clinic-level monthly proportions of patient engagement with the EHR-based cancer symptom monitoring system, will be analyzed using generalized least squares linear regression with auto-regressive errors and adjustment for cluster and time effects (underlying secular trends). A similar strategy will be used for secondary patient and provider implementation outcomes. DISCUSSION: The analytic updates described here resulted from highly iterative, collaborative efforts among statisticians, implementation scientists, and trial leads in the IMPACT Consortium. This updated statistical analysis plan will serve as the a priori specified approach for analyzing implementation outcomes for the NU IMPACT trial.

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OBJECTIVE: Women with a history of gestational diabetes mellitus (GDM) are at increased risk of developing type 2 diabetes (T2D). It remains unclear whether genetic information improves prediction of incident T2D in these women. RESEARCH DESIGN AND METHODS: Using five independent cohorts representing four different ancestries (n = 1,895), we investigated whether a genome-wide T2D polygenic risk score (PRS) is associated with increased risk of incident T2D. We also calculated the area under the receiver operating characteristics curve (AUROC) and continuous net reclassification improvement (NRI) following the incorporation of T2D PRS into clinical risk models to assess the diagnostic utility. RESULTS: Among 1,895 women with previous history of GDM, 363 (19.2%) developed T2D in a range of 2 to 30 years. T2D PRS was higher in those who developed T2D (-0.08 vs. 0.31, P = 2.3 × 10-11) and was associated with an increased risk of incident T2D (odds ratio 1.52 per 1-SD increase, 95% CI 1.05-2.21, P = 0.03). In a model that includes age, family history of diabetes, systolic blood pressure, and BMI, the incorporation of PRS led to an increase in AUROC for T2D from 0.71 to 0.74 and an intermediate improvement of NRI (0.32, 95% CI 0.15-0.49, P = 3.0 × 10-4). Although there was variation, a similar trend was observed across study cohorts. CONCLUSIONS: In cohorts of GDM women with diverse ancestry, T2D PRS was significantly associated with future development of T2D. A significant but small improvement was observed in AUROC when T2D PRS was integrated into clinical risk models to predict incident T2D.

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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.

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BACKGROUND: Higher maternal pre-pregnancy body mass index (BMI) is associated with adverse pregnancy and perinatal outcomes. However, whether these associations are causal remains unclear. METHODS: We explored the relation of maternal pre-/early-pregnancy BMI with 20 pregnancy and perinatal outcomes by integrating evidence from three different approaches (i.e. multivariable regression, Mendelian randomisation, and paternal negative control analyses), including data from over 400,000 women. RESULTS: All three analytical approaches supported associations of higher maternal BMI with lower odds of maternal anaemia, delivering a small-for-gestational-age baby and initiating breastfeeding, but higher odds of hypertensive disorders of pregnancy, gestational hypertension, preeclampsia, gestational diabetes, pre-labour membrane rupture, induction of labour, caesarean section, large-for-gestational age, high birthweight, low Apgar score at 1 min, and neonatal intensive care unit admission. For example, higher maternal BMI was associated with higher risk of gestational hypertension in multivariable regression (OR = 1.67; 95% CI = 1.63, 1.70 per standard unit in BMI) and Mendelian randomisation (OR = 1.59; 95% CI = 1.38, 1.83), which was not seen for paternal BMI (OR = 1.01; 95% CI = 0.98, 1.04). Findings did not support a relation between maternal BMI and perinatal depression. For other outcomes, evidence was inconclusive due to inconsistencies across the applied approaches or substantial imprecision in effect estimates from Mendelian randomisation. CONCLUSIONS: Our findings support a causal role for maternal pre-/early-pregnancy BMI on 14 out of 20 adverse pregnancy and perinatal outcomes. Pre-conception interventions to support women maintaining a healthy BMI may reduce the burden of obstetric and neonatal complications. FUNDING: Medical Research Council, British Heart Foundation, European Research Council, National Institutes of Health, National Institute for Health Research, Research Council of Norway, Wellcome Trust.

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BACKGROUND: Cord blood (CB) leptin is positively associated with adiposity at birth, but the association with child adiposity is unclear. OBJECTIVES: We hypothesized that CB leptin is positively associated with adiposity in peripubertal children and with childhood leptin. METHODS: Leptin was measured in 986 CB and 931 childhood stored samples from a prospective birth cohort. Adiposity measures were collected at birth and mean age 11.5 years. Linear and logistic regression analyses were used to evaluate associations between log-transformed CB leptin and neonatal and childhood adiposity measures as continuous and categorical variables, respectively. RESULTS: CB leptin was positively associated with neonatal and childhood adiposity. Childhood associations were attenuated when adjusted for maternal body mass index (BMI) and glucose, but remained statistically significant for childhood body fat percentage (ß = 1.15%, confidence interval [CI] = 0.46-1.84), body fat mass (ß = 0.69 kg, 95% CI = 0.16-1.23), sum of skin-folds (ß = 1.77 mm, 95% CI = 0.31-3.24), log-transformed child serum leptin (ß = 0.13, 95% CI = 0.06-0.20), overweight/obesity (OR = 1.21, 95% CI = 1.03-1.42), obesity (OR = 1.31, 95% CI = 1.04-1.66) and body fat percentage >85th percentile (OR = 1.38, 95% CI = 1.12-1.73). Positive associations between newborn adiposity measures and CB leptin confirmed previous reports. CONCLUSION: CB leptin is positively associated with neonatal and childhood adiposity and child leptin levels, independent of maternal BMI and maternal hyperglycemia. CB leptin may be a biomarker of future adiposity risk.

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BACKGROUND: Perinatal outcomes vary for women with gestational diabetes mellitus (GDM). The precise factors beyond glycemic status that may refine GDM diagnosis remain unclear. We conducted a systematic review and meta-analysis of potential precision markers for GDM. METHODS: Systematic literature searches were performed in PubMed and EMBASE from inception to March 2022 for studies comparing perinatal outcomes among women with GDM. We searched for precision markers in the following categories: maternal anthropometrics, clinical/sociocultural factors, non-glycemic biochemical markers, genetics/genomics or other -omics, and fetal biometry. We conducted post-hoc meta-analyses of a subset of studies with data on the association of maternal body mass index (BMI, kg/m2) with offspring macrosomia or large-for-gestational age (LGA). RESULTS: A total of 5905 titles/abstracts were screened, 775 full-texts reviewed, and 137 studies synthesized. Maternal anthropometrics were the most frequent risk marker. Meta-analysis demonstrated that women with GDM and overweight/obesity vs. GDM with normal range BMI are at higher risk of offspring macrosomia (13 studies [n = 28,763]; odds ratio [OR] 2.65; 95% Confidence Interval [CI] 1.91, 3.68), and LGA (10 studies [n = 20,070]; OR 2.23; 95% CI 2.00, 2.49). Lipids and insulin resistance/secretion indices were the most studied non-glycemic biochemical markers, with increased triglycerides and insulin resistance generally associated with greater risk of offspring macrosomia or LGA. Studies evaluating other markers had inconsistent findings as to whether they could be used as precision markers. CONCLUSIONS: Maternal overweight/obesity is associated with greater risk of offspring macrosomia or LGA in women with GDM. Pregnancy insulin resistance or hypertriglyceridemia may be useful in GDM risk stratification. Future studies examining non-glycemic biochemical, genetic, other -omic, or sociocultural precision markers among women with GDM are warranted.

Gestational Diabetes (GDM) is high blood sugar that develops during pregnancy and may cause complications. GDM diagnosis is centered on blood sugar levels. Despite everyone receiving standard treatment, the clinical outcomes may vary from one individual to another. This indicates a need to identify factors that may help GDM diagnosis and result in improved classification of those at greatest risk for complications. Here, we systematically analyzed all published evidence for potential markers that could identify those with GDM who have greater risk of complications. We find that high maternal weight is a risk factor for offspring born larger for their gestational age. Other promising markers were identified, but further analysis is needed before they can be applied in the clinic.

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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.

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Maternal metabolites influence the size of newborns independently of maternal body mass index (BMI) and glycemia, highlighting the importance of maternal metabolism on offspring outcomes. This study examined associations of maternal metabolites during pregnancy with childhood adiposity, and cord blood metabolites with childhood adiposity using phenotype and metabolomic data from the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study and the HAPO Follow-Up Study. The maternal metabolites analyses included 2324 mother-offspring pairs, while the cord blood metabolites analyses included 937 offspring. Multiple logistic and linear regression were used to examine associations between primary predictors, maternal or cord blood metabolites, and childhood adiposity outcomes. Multiple maternal fasting and 1 hr metabolites were significantly associated with childhood adiposity outcomes in Model 1 but were no longer significant after adjusting for maternal BMI and/or maternal glycemia. In the fully adjusted model, fasting lactose levels were negatively associated with child BMI z-scores and waist circumference, while fasting urea levels were positively associated with waist circumference. One-hour methionine was positively associated with fat-free mass. There were no significant associations between cord blood metabolites and childhood adiposity outcomes. Few metabolites were associated with childhood adiposity outcomes after adjusting for maternal BMI and glucose, suggesting that maternal BMI accounts for the association between maternal metabolites and childhood adiposity.

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Genetic alterations help predict the clinical behavior of diffuse gliomas, but some variability remains uncorrelated. Here, we demonstrate that haploinsufficient deletions of chromatin-bound tumor suppressor NFKB inhibitor alpha (NFKBIA) display distinct patterns of occurrence in relation to other genetic markers and are disproportionately present at recurrence. NFKBIA haploinsufficiency is associated with unfavorable patient outcomes, independent of genetic and clinicopathologic predictors. NFKBIA deletions reshape the DNA and histone methylome antipodal to the IDH mutation and induce a transcriptome landscape partly reminiscent of H3K27M mutant pediatric gliomas. In IDH mutant gliomas, NFKBIA deletions are common in tumors with a clinical course similar to that of IDH wild-type tumors. An externally validated nomogram model for estimating individual patient survival in IDH mutant gliomas confirms that NFKBIA deletions predict comparatively brief survival. Thus, NFKBIA haploinsufficiency aligns with distinct epigenome changes, portends a poor prognosis, and should be incorporated into models predicting the disease fate of diffuse gliomas.

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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.

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Gaussian graphical models (GGMs) are a popular form of network model in which nodes represent features in multivariate normal data and edges reflect conditional dependencies between these features. GGM estimation is an active area of research. Currently available tools for GGM estimation require investigators to make several choices regarding algorithms, scoring criteria, and tuning parameters. An estimated GGM may be highly sensitive to these choices, and the accuracy of each method can vary based on structural characteristics of the network such as topology, degree distribution, and density. Because these characteristics are a priori unknown, it is not straightforward to establish universal guidelines for choosing a GGM estimation method. We address this problem by introducing SpiderLearner, an ensemble method that constructs a consensus network from multiple estimated GGMs. Given a set of candidate methods, SpiderLearner estimates the optimal convex combination of results from each method using a likelihood-based loss function. K $$ K $$ -fold cross-validation is applied in this process, reducing the risk of overfitting. In simulations, SpiderLearner performs better than or comparably to the best candidate methods according to a variety of metrics, including relative Frobenius norm and out-of-sample likelihood. We apply SpiderLearner to publicly available ovarian cancer gene expression data including 2013 participants from 13 diverse studies, demonstrating our tool's potential to identify biomarkers of complex disease. SpiderLearner is implemented as flexible, extensible, open-source code in the R package ensembleGGM at https://github.com/katehoffshutta/ensembleGGM.

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Venous thromboembolism (VTE) is a life-threating condition that is common in patients with adult-type diffuse gliomas, yet thromboprophylaxis is controversial because of possible intracerebral hemorrhage. Effective VTE prediction models exist for other cancers, but not glioma. Our objective was to develop a VTE prediction tool to improve glioma patient care, incorporating clinical, blood-based, histologic, and molecular markers. We analyzed preoperative arterial blood, tumor tissue, and clinical-pathologic data (including next-generation sequencing data) from 258 patients with newly diagnosed World Health Organization (WHO) grade 2 to 4 adult-type diffuse gliomas. Forty-six (17.8%) experienced VTE. Tumor expression of tissue factor (TF) and podoplanin (PDPN) each positively correlated with VTE, although only circulating TF and D-dimers, not circulating PDPN, correlated with VTE risk. Gliomas with mutations in isocitrate dehydrogenase 1 (IDH1) or IDH2 (IDHmut) caused fewer VTEs; multivariable analysis suggested that this is due to IDHmut suppression of TF, not PDPN. In a predictive time-to-event model, the following predicted increased VTE risk in newly diagnosed patients with glioma: (1) history of VTE; (2) hypertension; (3) asthma; (4) white blood cell count; (5) WHO tumor grade; (6) patient age; and (7) body mass index. Conversely, IDHmut, hypothyroidism, and MGMT promoter methylation predicted reduced VTE risk. These 10 variables were used to create a web-based VTE prediction tool that was validated in 2 separate cohorts of patients with adult-type diffuse glioma from other institutions. This study extends our understanding of the VTE landscape in these tumors and provides evidence-based guidance for clinicians to mitigate VTE risk in patients with glioma.

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BACKGROUND: Variations in dietary intake and environmental exposure patterns of essential and non-essential trace metals influence many aspects of human health throughout the life span. OBJECTIVE: To examine the relationship between urine profiles of essential and non-essential metals in mother-offspring pairs and their association with early dysglycemia. METHODS: Herein, we report findings from an ancillary study to the international Hyperglycemia and Adverse Pregnancy Outcome Follow-Up Study (HAPO-FUS) that examined urinary essential and non-essential metal profiles from mothers and offspring ages 10-14 years (1012 mothers, 1013 offspring, 968 matched pairs) from 10 international sites. RESULTS: Our analysis demonstrated a diverse exposure pattern across participating sites. In multiple regression modelling, a positive association between markers of early dysglycemia and urinary zinc was found in both mothers and offspring after adjustment for common risk factors for diabetes. The analysis showed weaker, positive, and negative associations of the 2-h glucose value with urinary selenium and arsenic respectively. A positive association between 2-h glucose values and cadmium was found only in mothers in the fully adjusted model when participants with established diabetes were excluded. There was a high degree of concordance between mother and offspring urinary metal profiles. Mother-to-offspring urinary metal ratios were unique for each metal, providing insights into changes in their homeostasis across the lifespan. SIGNIFICANCE: Urinary levels of essential and non-essential metals are closely correlated between mothers and their offspring in an international cohort. Urinary levels of zinc, selenium, arsenic, and cadmium showed varying degrees of association with early dysglycemia in a comparatively healthy cohort with a low rate of preexisting diabetes. IMPACT STATEMENT: Our data provides novel evidence for a strong correlation between mother and offspring urinary metal patterns with a unique mother-to-offspring ratio for each metal. The study also provides new evidence for a strong positive association between early dysglycemia and urinary zinc, both in mothers and offspring. Weaker positive associations with urinary selenium and cadmium and negative associations with arsenic were also found. The low rate of preexisting diabetes in this population provides the unique advantage of minimizing the confounding effect of preexisting, diabetes related renal changes that would alter the relationship between dysglycemia and renal metal excretion.

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Ventricular assist device (VAD) implantation requires patients and caregivers to attain self-care knowledge and skills before discharge from implant hospitalization. Inability to perform these skills can have devastating outcomes (i.e., death from pump malfunction, driveline site infections, and stroke). No standard-of-care guiding VAD self-care education exists. We sought to describe how select tertiary care VAD implant centers across the United States currently educate VAD patients and their caregivers. Using a multiple case studies design with a purposive sampling strategy, we conducted semistructured interviews of VAD coordinators responsible for VAD education at 18 centers. From audio recording of interviews, we used rapid qualitative analysis to organize and analyze the data. All centers spent significant time and effort educating patients and caregivers on VAD self-care. Although centers teach similar content, the rigor of assessments and follow-up education differed vastly. Only 3/18 (17%) centers performed competency-based assessments with a skills checklist and minimum passing standard assessing readiness to perform VAD self-care independently. Twelve of 18 (67%) centers provided formal follow-up education to address skills decay, yet wide variation existed in timing and content of education. Due to the diversity among centers regarding VAD self-care education, more prescriptive practice guidelines are needed.

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