Prenatal exposure to air pollutant mixtures and birthweight in the upstate KIDS cohort.

BACKGROUND: Single-pollutant models have linked prenatal PM2.5 exposure to lower birthweight. However, analyzing air pollutant mixtures better captures pollutant interactions and total effects. Unfortunately, strong correlations between pollutants restrict traditional methods. OBJECTIVES: We explored the association between exposure to a mixture of air pollutants during different gestational age windows of pregnancy and birthweight. METHODS: We included 4,635 mother-infant dyads from a New York State birth cohort born 2008-2010. Air pollution data were sourced from the EPA's Community Multiscale Air Quality model and matched to the census tract centroid of each maternal home address. Birthweight and gestational age were extracted from vital records. We applied linear regression to study the association between prenatal exposure to PM2.5, PM10, NOX, SO2, and CO and birthweight during six sensitive windows. We then utilized Bayesian kernel machine regression to examine the non-linear effects and interactions within this five-pollutant mixture. Final models adjusted for maternal socio-demographics, infant characteristics, and seasonality. RESULTS: Single-pollutant linear regression models indicated that most pollutants were associated with a decrement in birthweight, specifically during the two-week window before birth. An interquartile range increase in PM2.5 exposure (IQR: 3.3 µg/m3) from the median during this window correlated with a 34 g decrement in birthweight (95 % CI: -54, -14), followed by SO2 (IQR: 2.0 ppb; ß: -31), PM10 (IQR: 4.6 µg/m3; ß: -29), CO (IQR: 60.8 ppb; ß: -27), and NOX (IQR: 7.9 ppb; ß: -26). Multi-pollutant BKMR models revealed that PM2.5, NOX, and CO exposure were negatively and non-linearly linked with birthweight. As the five-pollutant mixture increased, birthweight decreased until the median level of exposure. DISCUSSION: Prenatal exposure to air pollutants, notably PM2.5, during the final two weeks of pregnancy may negatively impact birthweight. The non-linear relationships between air pollution and birthweight highlight the importance of studying pollutant mixtures and their interactions.

Place-Based Child Opportunity at Birth and Child Development from Infancy to Age 4.

OBJECTIVE: The objective of this study was to evaluate whether the children's neighborhood quality, as a measure of place-based social determinants of health, is associated with the odds of developmental delay and developmental performance up to the age of 4 years. STUDY DESIGN: Mothers of 5702 children from the Upstate KIDS Study, a longitudinal population-based cohort of children born from 2008 through 2010, provided questionnaire data and a subset of 573 children participated in a clinic visit. The Child Opportunity Index 2.0 was linked to home census tract at birth. Probable developmental delays were assessed by the Ages and Stages Questionnaire up to 7 times between 4 and 36 months, and developmental performance was assessed via the Battelle Developmental Inventory at the age of 4 years. RESULTS: In unadjusted models, higher neighborhood opportunity was protective against developmental delays and was associated with slightly higher development scores at age 4. After adjusting for family-level confounding variables, 10-point higher Child Opportunity Index (on a 100-point scale) remained associated with a lower odds of any developmental delay (OR = .966, 95% CI = .940-.992), and specifically delays in the personal-social domain (OR = .921, 95% CI = .886-.958), as well as better development performance in motor (B = 0.79, 95% CI = 0.11-1.48), personal-social (B = 0.64, 95% CI = 0.003-1.28), and adaptive (B = 0.69, 95% CI = 0.04-1.34) domains at age 4. CONCLUSIONS: Community-level opportunities are associated with some aspects of child development prior to school entry. Pediatric providers may find it helpful to use neighborhood quality as an indicator to inform targeted developmental screening.

Examination of newborn DNA methylation among women with polycystic ovary syndrome/hirsutism.

Research suggests that polycystic ovary syndrome (PCOS) traits (e.g., hyperandrogenism) may create a suboptimal intrauterine environment and induce epigenetic modifications. Therefore, we assessed the associations of PCOS traits with neonatal DNA methylation (DNAm) using two independent cohorts. DNAm was measured in both cohorts using the Infinium MethylationEPIC array. Multivariable robust linear regression was used to determine associations of maternal PCOS exposure or preconception testosterone with methylation ß-values at each CpG probe and corrected for multiple testing by false-discovery rate (FDR). In the birth cohort, 12% (102/849) had a PCOS diagnosis (8.1% PCOS without hirsutism; 3.9% PCOS with hirsutism). Infants exposed to maternal PCOS with hirsutism compared to no PCOS had differential DNAm at cg02372539 [ß(SE): -0.080 (0.010); FDR p = 0.009], cg08471713 [ß(SE):0.077 (0.014); FDR p = 0.016] and cg17897916 [ß(SE):0.050 (0.009); FDR p = 0.009] with adjustment for maternal characteristics including pre-pregnancy BMI. PCOS with hirsutism was also associated with 8 differentially methylated regions (DMRs). PCOS without hirsutism was not associated with individual CpGs. In an independent preconception cohort, total testosterone concentrations were associated with 3 DMRs but not with individual CpGs, though the top quartile of testosterone compared to the lowest was marginally associated with increased DNAm at cg21472377 near an uncharacterized locus (FDR p = 0.09). Examination of these probes and DMRs indicate they may be under foetal genetic control. Overall, we found several associations among newborns exposed to PCOS, specifically when hirsutism was reported, and among newborns of women with relatively higher testosterone around conception.

Longitudinal Child Growth Patterns in Twins and Singletons in the Upstate KIDS Cohort.

OBJECTIVES: To investigate childhood growth patterns in twins and to determine whether they show the same signs of excess growth as singletons born small-for-gestational age (SGA), which may confer future cardiometabolic risk. STUDY DESIGN: In the Upstate KIDS cohort of infants delivered from 2008 through 2010, we compared height, weight, and body mass index (BMI) z-scores at 0-3 and 7-9 years of age, as well as risk of rapid weight gain (RWG) in infancy and overweight/obesity beginning at 2 years, among appropriate-for-gestational age (AGA) twins (n = 1121), AGA singletons (n = 2684), and two groups of SGA twins: uncertain SGA twins (<10th percentile for birthweight by a singleton reference but >10th% by a population-based twin birthweight reference; n = 319) and true SGA twins (<10th% by a population-based twin reference; n = 144). RESULTS: Compared with AGA twins, both SGA twin groups had lower weight and BMI z-scores at both time points. By 7-9 years, both groups caught up in height with AGA twins. Compared with AGA singletons, z-score differences decreased between 0-3 and 7-9 years for uncertain SGA and true SGA twins, though true SGA twins had the lowest z-scores for all measures. During infancy, twins were more likely to display RWG compared with AGA singletons (RR = 2.06 to 2.67), which may reflect normal catch-up growth, as no twin group had higher prevalence of overweight/obesity at either time point. CONCLUSIONS: Though twins had lower height, weight, and BMI z-scores at birth and into toddlerhood, differences were reduced by 7-9 years, with no evidence of pathological growth and no group of twins showing elevated risk of overweight/obesity.

Indoor air pollution exposure and early childhood development in the Upstate KIDS Study.

BACKGROUND: Limited human studies have investigated the impact of indoor air pollution on early childhood neurodevelopment among the US population. We aimed to examine the associations between prenatal and postnatal indoor air pollution exposure and early childhood development in a population-based birth cohort. METHODS: This analysis included 4735 mother-child pairs enrolled between 2008 and 2010 in the Upstate KIDS Study. Indoor air pollution exposure from cooking fuels, heating fuels, and passive smoke during pregnancy, and at 12 and 36 months after birth were assessed by questionnaires. Five domains of child development were assessed by the Ages and Stages Questionnaire at 4, 8, 12, 18, 24, 30, and 36 months. Generalized estimating equations were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for potential confounders. RESULTS: Exposure to unclean cooking fuels (natural gas, propane, or wood) throughout the study period was associated with increased odds of failing any development domain (OR = 1.28, 95% CI 1.07, 1.53), the gross motor domain (OR = 1.52, 95% CI: 1.09, 2.13), and the personal-social domain (OR = 1.36, 95% CI: 1.00, 1.85), respectively. Passive smoke exposure throughout the study period increased the odds of failing the problem-solving domain by 71% (OR = 1.71, 95% CI 1.01, 2.91) among children of non-smoking mothers. No association was found between heating fuel use and failing any or specific domains. CONCLUSION: Unclean cooking fuel use and passive smoke exposure during pregnancy and early life were associated with developmental delays in this large prospective birth cohort.

Determinants of maternal and neonatal PFAS concentrations: a review.

Per- and polyfluoroalkyl substances (PFAS) are used for their properties such as stain and water resistance. The substances have been associated with adverse health outcomes in both pregnant mothers and infants, including pre-eclampsia and low birthweight. A growing body of research suggests that PFAS are transferred from mother to fetus through the placenta, leading to in utero exposure. A systematic review was performed using the PubMed database to search for studies evaluating determinants of PFAS concentrations in blood matrices of pregnant mothers and neonates shortly after birth. Studies were included in this review if an observational study design was utilized, exposure to at least one PFAS analyte was measured, PFAS were measured in maternal or neonatal matrices, at least one determinant of PFAS concentrations was assessed, and results such as beta estimates were provided. We identified 35 studies for inclusion in the review and evaluated the PFAS and determinant relationships among the factors collected in these studies. Parity, breastfeeding history, maternal race and country of origin, and household income had the strongest and most consistent evidence to support their roles as determinants of certain PFAS concentrations in pregnant mothers. Reported study findings on smoking status, alcohol consumption, and pre-pregnancy body mass index (BMI) suggest that these factors are not important determinants of PFAS concentrations in pregnant mothers or neonates. Further study into informative factors such as consumer product use, detailed dietary information, and consumed water sources as potential determinants of maternal or neonatal PFAS concentrations is needed. Research on determinants of maternal or neonatal PFAS concentrations is critical to estimate past PFAS exposure, build improved exposure models, and further our understanding on dose-response relationships, which can influence epidemiological studies and risk assessment evaluations. Given the potential for adverse outcomes in pregnant mothers and neonates exposed to PFAS, it is important to identify and understand determinants of maternal and neonatal PFAS concentrations to better implement public health interventions in these populations.

Examining attention-deficit/hyperactivity disorder and related behavioral disorders by fertility treatment exposure in a prospective cohort.

PURPOSE: To evaluate whether underlying infertility and mode of conception are associated with childhood behavioral disorders. METHODS: Oversampling on fertility treatment exposure using vital records, the Upstate KIDS Study followed 2057 children (of 1754 mothers) from birth to 11 years. Type of fertility treatment and time to pregnancy (TTP) were self-reported. Mothers completed annual questionnaires reporting symptomology, diagnoses, and medications at 7-11 years of age. The information identified children with probable attention-deficit/hyperactivity disorder, anxiety or depression, and conduct or oppositional defiant disorders. We estimated adjusted relative risks (aRR) for disorders by underlying infertility (TTP > 12 months) or treatment exposure groups compared to children born to parents with TTP ≤ 12 months. RESULTS: Children conceived with fertility treatment (34%) did not have an increased risk of attention-deficit/hyperactivity disorder (aRR): 1.21; 95% CI: 0.88, 1.65), or conduct or oppositional defiant disorders (aRR: 1.31; 0.91, 1.86), but did have an increased risk of anxiety or depression (aRR: 1.63; 1.18, 2.24), which remained elevated even after adjusting for parental mood disorders (aRR: 1.40; 0.99, 1.96). Underlying infertility without the use of treatment was also associated with a risk of anxiety or depression (aRR: 1.82; 95% CI: 0.96, 3.43). CONCLUSIONS: Underlying infertility or its treatment was not associated with risk of attention-deficit/hyperactivity disorder. Observations of increased anxiety or depression require replication.

Effects on neonatal immunoglobulin concentrations by infant mode of delivery in the upstate KIDS study (2008-2010).

PROBLEM: Previous studies document an association between mode of delivery (MOD) and allergic conditions in children. Immunoglobulin (Ig) concentrations at birth may play a role. The goal of this study is to assess the impact of MOD on Ig concentrations at delivery from newborn dried blood spots (DBS). METHOD OF STUDY: The Upstate KIDS Study (2008-2010) is a prospective cohort of mother-child pairs recruited from New York State, excluding New York City. Ig subtypes IgA, IgE, IgG1 , IgG2 , IgG3 , IgG4 , and IgM were measured in residual NDBS from the Newborn Screening Program (N = 3274 infants). MOD was categorized as vaginal delivery (VD), emergency cesarean delivery (ECD) or planned cesarean delivery (PCD). Associations between MOD and Ig levels were assessed using ANOVA and multiple regression, with models adjusted for gestational age, birth weight, maternal race, plurality, and smoking status. RESULTS: IgA, and the IgG subtypes IgG3 and IgG4 were found to be significantly lower in PCD neonates relative to VD neonates in adjusted regression models: 3.57 mg/ml, (95% CI: 3.51, 3.63) compared to 3.64 mg/ml (95% CI: 3.59, 3.69); 8.95 ng/ml (95% CI: 8.88,9.03) compared to 9.03 ng/ml (95% CI: 8.98, 9.08) and 8.05 ng/ml (95% CI: 7.91, 8.20) compared to 8.22 ng/ml (95% CI: 7.91,8.20), respectively. CONCLUSIONS: MOD may thus be related to neonatal immune profile. Results were found to be robust to sensitivity testing based on maternal complications and indication for CD. Clinical implications are unclear given the small levels of association found in newborns, but the result suggests greater susceptibility to infection, and further study is warranted.

Maternal antenatal depression's effects on child developmental delays: Gestational age, postnatal depressive symptoms, and breastfeeding as mediators.

BACKGROUND: Maternal antenatal depression experienced around conception or during pregnancy may adversely affect child development. This study explores three potential mechanisms of the effects of antenatal depression on children's developmental delays at 2-3 years: gestational age of the child, continued depressive symptoms postnatally, and interrupted breastfeeding practices. METHODS: Mothers (N = 2888) of 3450 children, including 2303 singletons and 1147 multiples from the Upstate KIDS cohort provided data. Linked hospital discharge data was combined with mothers' reports to identify women with moderate to severe antenatal depression. Gestational age was extracted from birth certificates. Mothers completed a depression screener at 4 months postpartum, reported about their breastfeeding practices from 4 to 12 months postpartum, and completed a developmental delay screener when children were 24, 30, and 36 months. RESULTS: In unadjusted path analysis models, mothers with antenatal depression had more postnatal depressive symptoms and breastfed fewer months, which translated into children being more likely to have developmental delays. Gestational age was not a mediator. Effects were similar across girls and boys and singletons and twins, and largely held when adjusting for covariates. LIMITATIONS: Main limitations were the relatively advantaged sample and reliance on maternal report. CONCLUSIONS: Maternal antenatal depression may impact child development through continued depressive symptoms in the postpartum period and through reduced breastfeeding duration suggesting additional targets for intervention.

Displacement of peer play by screen time: associations with toddler development.

BACKGROUND: Young children's digital media use may adversely affect child development, but the mechanisms of this association are unclear. We evaluated whether screen time displaces reading and peer play time, which are subsequently associated with child development. METHODS: When children were 12, 18, 24, 30, and 36 months, mothers (n = 3894) reported the time their children spent on screens, being read to by an adult, and playing with other children. At 36 months, mothers completed the Ages and Stages Questionnaire©, an assessment of their child's developmental status. RESULTS: In unadjusted models, screen time from 12 to 36 months was not associated with reading but was associated with less time engaging in play with peers. In adjusted models accounting for developmental delay at 12 months, family and child characteristics, screen time was not directly associated with developmental delay. More peer play time was associated with a lower likelihood of developmental delay, and having higher screen time increased the likelihood of developmental delay indirectly through reduced peer play time. Results were similar for developmental delays in fine and gross motor, communication, and personal-social domains. CONCLUSIONS: Screen time in early childhood did not displace reported time spent reading, but did displace reported peer play time. IMPACT: Among children 1-3 years of age, more screen time was associated with less time engaged in peer play but not less reading with an adult. Having higher screen time from 1 to 3 years increased the odds of developmental delay indirectly through reduced peer play time. Ensuring that children engage in adequate time playing with peers may offset the negative associations between screen time and child development.

Interaction of maternal medication use with ambient heat exposure on congenital heart defects in the National Birth Defects Prevention Study.

BACKGROUND: Maternal exposure to weather-related extreme heat events (EHEs) has been associated with congenital heart defects (CHDs) in offspring. Certain medications may affect an individual's physiologic responses to EHEs. We evaluated whether thermoregulation-related medications modified associations between maternal EHE exposure and CHDs. METHODS: We linked geocoded residence data from the U.S. National Birth Defects Prevention Study, a population-based case-control study, to summertime EHE exposures. An EHE was defined using the 90th percentile of daily maximum temperature (EHE90) for each of six climate regions during postconceptional weeks 3-8. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for associations between EHE90 and the risk of CHDs were estimated by strata of maternal thermoregulation-related medication use and climate region. Interaction effects were evaluated on multiplicative and additive scales. RESULTS: Over 45% of participants reported thermoregulation-related medication use during the critical period of cardiogenesis. Overall, these medications did not significantly modify the association between EHEs and CHDs. Still, medications that alter central thermoregulation increased aORs (95% CI) of EHE90 from 0.73 (0.41, 1.30) among non-users to 5.09 (1.20, 21.67) among users in the Southwest region, U.S. This effect modification was statistically significant on the multiplicative (P = 0.03) and additive scales, with an interaction contrast ratio (95% CI) of 1.64 (0.26, 3.02). CONCLUSION: No significant interaction was found for the maternal use of thermoregulation-related medications with EHEs on CHDs in general, while medications altering central thermoregulation significantly modified the association between EHEs and CHDs in Southwest U.S. This finding deserves further research.

Exposure to perfluoroalkyl substances and neonatal immunoglobulin profiles in the upstate KIDS study (2008-2010).

Infant exposure to per/polyfluoroalkyl compounds is associated with immune disruption. We examined associations between neonatal concentrations of perflurooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) and immunoglobulin (Ig) isotype profiles in a prospective cohort of infants. We measured Ig isotypes, including IgA, IgE, IgM and the IgG subclasses IgG1, IgG2, IgG3, and IgG4, and PFOA and PFOS in newborn dried bloodspots from N = 3175 infants in the Upstate KIDS Study (2008-2010). We examined the association between newborn Ig isotype levels and individual PFOS and PFOA concentrations using mixed effects regression models with a random intercept to account for twins among study participants. We assessed the joint effect PFOA and PFOS with quantile-based g-computation on all singletons and one randomly selected twin (N = 2901), with Ig categorized as above or below median value. Models were adjusted for infant sex, and maternal pre-pregnancy body mass index, race, parity, age and infertility treatment. In adjusted models, PFOA was inversely associated with IgE (coefficient = -0.12 per unit increase in PFOA, 95% CI: -0.065, -0.17), whereas IgG2, IgM, and IgA were positively associated with PFOA (coefficient for IgG2 = 0.22, 95% CI: 0.15, 0.27; coefficient for IgM = 0.11, 95% CI: 0.08, 0.15; and coefficient for IgA = 0.15, 95% CI: 0.07, 0.18). There was no relation between PFOS and Ig isotypes. Analysis of the joint effect of PFOA and PFOS showed an OR of 1.2 (95% CI: 1.04, 1.36) for IgA and OR of 1.12 (95% CI: 1.00, 1.24) for IgG2 levels above the median for every quartile increase. PFOA levels were significantly associated with elevated IgA, IgM, IgG2, and reduced levels of IgE in single-pollutant models. A small but significant joint effect of PFOA and PFOS was observed. Our results suggest that early exposure to PFOA and PFOS may disrupt neonatal immunoglobulin levels.

Conception by fertility treatment and cardiometabolic risk in middle childhood.

OBJECTIVE: To evaluate whether children conceived using assisted reproductive technology (ART) or ovulation induction (OI) have greater cardiometabolic risk than children conceived without treatment. DESIGN: Clinical assessments in 2018-2019 in the Upstate KIDS cohort. SETTING: Clinical sites in New York. PATIENT(S): Three hundred thirty-three singletons and 226 twins from 448 families. INTERVENTION(S): Mothers reported their use of fertility treatment and its specific type at baseline and approximately 4 months after delivery. High validity of the self-reported use of ART was previously confirmed. The children were followed up from infancy through 8-10 years of age. A subgroup was invited to participate in clinic visits. MAIN OUTCOME MEASURE(S): The measurements of blood pressure (BP), arterial stiffness using pulse wave velocity, anthropometric measures, and body fat using bioelectrical impedance analysis were performed (n = 559). The levels of plasma lipids, C-reactive protein, and hemoglobin A1c were measured using blood samples obtained from 263 children. RESULT(S): The average age of the children was 9.4 years at the time of the clinic visits Approximately 39% were conceived using fertility treatment (18% using ART and 21% using OI). Singletons conceived using fertility treatment (any type or using ART or OI specifically) did not statistically differ in systolic or diastolic BP, heart rate, or pulse wave velocity. Singletons conceived using OI were smaller than singletons conceived without treatment, but the average body mass index of the latter was higher (z-score: 0.41 [SD, 1.24]) than the national norms. Twins conceived using either treatment had lower BP than twins conceived without treatment. However, twins conceived using OI had significantly higher arterial stiffness (0.59; 95% CI, 0.03-1.15 m/s), which was attenuated after accounting for maternal BP (0.29; 95% CI, -0.03 to 0.46 m/s). Twins did not significantly differ in size or fat measures across the groups. The mode of conception was not associated with the levels of lipids, C-reactive protein, or glycosylated hemoglobin. CONCLUSION(S): Clinical measures at the age of 9 years did not indicate greater cardiometabolic risk in children conceived using ART or OI compared with that in children conceived without treatment. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov #NCT03106493.

Modeling Collective Invasion and Single-Cell Mesenchymal Invasion in Three-Dimensional Matrigel-Collagen I Cultures.

Understanding the modes and mechanisms of tumor cell invasion is key to developing targeted therapies against metastatic disease. In vitro assays modeling tumor progression have primarily been optimized for studying classical single-cell migration through an epithelial-mesenchymal transition (EMT). Although experimental and clinical histopathological evidence has revealed that tumor invasion is plastic and that epithelial carcinomas can invade by a range of modes that vary from single, mesenchyme-like cells, all the way to cohesive, collective units, few in vitro assays have been designed to assess these modes specifically. Thus, we have developed a Matrigel-Collagen I overlay assay that is suitable for identifying and quantifying both collective and mesenchymal invasion. This three-dimensional (3D) culture assay utilizes the features of Matrigel and Collagen I to mimic the laminin-rich basement membrane and the stiff, fibrillar Collagen I tumor microenvironment allowing for spheroid invasion to be assessed at the interface between these two matrix components.

Maternal obesity, gestational weight gain, and offspring asthma and atopy.

BACKGROUND: Maternal obesity may affect offspring asthma and atopic disease risk by altering fetal immune system development. However, few studies evaluate gestational weight gain (GWG). OBJECTIVE: To evaluate relationships between maternal body mass index (BMI), GWG, and persistent wheeze, eczema, allergy, and asthma risk in offspring through middle childhood. METHODS: A total of 5939 children from Upstate KIDS, a population-based longitudinal cohort of children born in upstate New York (2008-2019) were included in the analysis. Persistent wheeze or asthma, eczema, and allergy were maternally reported at multiple study time points throughout early and middle childhood. Poisson regression models with robust SEs were used to estimate adjusted risk ratios (aRRs) and 95% confidence intervals (CIs) for offspring atopic outcomes by maternal prepregnancy BMI and GWG. RESULTS: Prepregnancy BMI was associated with increased risk of persistent wheeze by 3 years of age even after adjustments for maternal atopy (class I obesity: aRR, 1.58; 95% CI, 1.13-2.20; class II or III obesity: aRR, 1.69; 95% CI, 1.22-2.35). Associations with reported asthma in middle childhood did not reach statistical significance. Furthermore, no associations were found between prepregnancy BMI and atopic outcomes in either early or middle childhood. GWG was not associated with higher risk of early childhood persistent wheeze or middle childhood asthma. CONCLUSION: Maternal prepregnancy BMI was associated with increased risk of offspring wheeze, whereas excessive GWG was generally not associated with childhood asthma or atopy.

Targeting a Tumor-Specific Epitope on Podocalyxin Increases Survival in Human Tumor Preclinical Models.

Podocalyxin (Podxl) is a CD34-related cell surface sialomucin that is normally highly expressed by adult vascular endothelia and kidney podocytes where it plays a key role in blocking adhesion. Importantly, it is also frequently upregulated on a wide array of human tumors and its expression often correlates with poor prognosis. We previously showed that, in xenograft studies, Podxl plays a key role in metastatic disease by making tumor initiating cells more mobile and invasive. Recently, we developed a novel antibody, PODO447, which shows exquisite specificity for a tumor-restricted glycoform of Podxl but does not react with Podxl expressed by normal adult tissue. Here we utilized an array of glycosylation defective cell lines to further define the PODO447 reactive epitope and reveal it as an O-linked core 1 glycan presented in the context of the Podxl peptide backbone. Further, we show that when coupled to monomethyl auristatin E (MMAE) toxic payload, PODO447 functions as a highly specific and effective antibody drug conjugate (ADC) in killing ovarian, pancreatic, glioblastoma and leukemia cell lines in vitro. Finally, we demonstrate PODO447-ADCs are highly effective in targeting human pancreatic and ovarian tumors in xenografted NSG and Nude mouse models. These data reveal PODO447-ADCs as exquisitely tumor-specific and highly efficacious immunotherapeutic reagents for the targeting of human tumors. Thus, PODO447 exhibits the appropriate characteristics for further development as a targeted clinical immunotherapy.

Infertility treatment associated with childhood asthma and atopy.

STUDY QUESTION: Are children who were conceived with infertility treatment at an increased risk of developing asthma and atopic conditions? SUMMARY ANSWER: Infertility treatment is associated with an elevated risk of asthma and atopic conditions in early and middle childhood, even after adjustment for parental asthma and atopy. WHAT IS KNOWN ALREADY: Asthma and atopic conditions are prevalent in childhood. The development of these conditions may be linked to early life exposures, including the use of infertility treatments. STUDY DESIGN, SIZE, DURATION: Upstate KIDS is a prospective cohort study of singletons and multiples born between 2008 and 2010. A total of 5034 mothers and 6171 children were enrolled and followed up until 2019, and 2056 children participated in the middle childhood follow-up. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women reported the fertility agents used to become pregnant on a baseline questionnaire. Treatment was categorized as ART (∼22%) use, ovulation induction via oral/injectable medications with or without IUI (OI/IUI, ∼20%), or no treatment (∼58%). Outcomes were assessed by maternal report on questionnaires in early (up to age 3 years, prevalence 9-28%) and middle (7-9 years, prevalence 10-16%) childhood. Weighted Poisson regression models with robust standard errors were used to analyze the risk of atopic outcomes in relation to infertility treatment exposure. MAIN RESULTS AND THE ROLE OF CHANCE: Compared to children conceived without treatment, children conceived with any infertility treatment were at an increased risk of persistent wheeze by age 3 years (relative risk (RR): 1.66; 95% CI: 1.17, 2.33) with adjustments for parental atopy among other risk factors. Around 7-9 years, children conceived with treatment were more likely to have current asthma (RR: 1.30; 95% CI: 0.98, 1.71), eczema (RR: 1.77; 95% CI: 1.25, 2.49) or be prescribed allergy-related medications (RR: 1.45; 95% CI: 1.06, 1.99). Similar effect sizes were found when examining associations by treatment type (i.e. ART versus OI/IUI). LIMITATIONS, REASONS FOR CAUTION: Childhood outcomes were based on maternal report and are subject to potential misclassification. There was attrition in this study, which limits the precision of our measures of association. WIDER IMPLICATIONS OF THE FINDINGS: Though future research is needed to clarify the mechanisms involved, our findings support that both ART and OI/IUI influences the development of asthma and atopic conditions in the offspring from an early age. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Institutes of Health's Intramural Research Program at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD; contracts #HHSN275201200005C, #HHSN267200700019C, #HHSN275201400013C, #HHSN275201300026I/27500004, #HHSN275201300023I/27500017). The authors have no relevant conflicts of interest to disclose. TRIAL REGISTRATION NUMBER: N/A.

Age of Juice Introduction and Child Anthropometry at 2-3 and 7-9 Years.

OBJECTIVES: To assess the association between age of juice introduction and child anthropometry after the American Academy of Pediatrics changed their guidelines in 2017 to recommend delaying juice introduction until at least 12 months of age (previously 6 months), citing concerns of weight gain. STUDY DESIGN: Upstate KIDS is a prospective birth cohort with follow-up through 9 years of age. Juice introduction was assessed on parental questionnaires at 4-18 months and categorized as <6, 6-<12, and ≥12 months. Child height and weight were recorded at 2-3 and 7-9 years of age. Weight-, height-, and body mass index (BMI)-for-age and sex z scores were calculated using the Centers for Disease Control and Prevention reference. Overweight/obese and obese status were categorized as BMI-for-age z score ≥85th and ≥95th percentiles. Controlling for sociodemographic characteristics and parental BMI, we assessed the associations of age of juice introduction with child anthropometry. RESULTS: Prevalence of childhood obesity was 16.4% at 2-3 (n = 1713) and 22.8% at 7-9 years of age (n = 1283). Juice introduction at <6 vs ≥12 months was associated with higher weight-for-age z score at 2-3 years of age (mean difference = 0.21; 95% CI 0.04-0.37). At 7-9 years of age, juice introduction at <6 vs ≥12 months was related to higher BMI-for-age (0.38; 0.12-0.64) and weight-for-age z scores (0.27; 0.06-0.49). Risk of developing overweight/obesity and obesity was 1.54 (0.99-2.38) and 2.17 (1.11-4.23) times higher among children with juice introduced at <6 months. No associations were found with juice introduced at 6-<12 vs ≥12 months. CONCLUSIONS: Risk of developing overweight/obesity or obesity is higher among children introduced to juice before 6 months of age compared with ≥12 months.

Associations of toddler mechanical/distress feeding problems with psychopathology symptoms five years later.

BACKGROUND: Feeding problems are common in early childhood, and some evidence suggests that feeding problems may be associated with psychopathology. Few prospective studies have explored whether toddler feeding problems predict later psychopathology. METHODS: Mothers of 1,136 children from the Upstate KIDS cohort study provided data when children were 2.5 and 8 years of age. Food refusal (picky eating) and mechanical/distress feeding problems and developmental delays were assessed at 2.5 years. Child eating behaviors (enjoyment of food, food fussiness, and emotional under and overeating) and child psychopathology (attention-deficit/hyperactivity (ADHD), oppositional-defiant (OD), conduct disorder (CD), and anxiety/depression) symptoms were assessed at 8 years. RESULTS: Mechanical/distress feeding problems at age 2.5, but not food refusal problems, were associated with ADHD, problematic behavior (OD/CD), and anxiety/depression symptoms at 8 years in models adjusting for eating behaviors at 8 years and child and family covariates. Associations with mechanical/distress feeding problems were larger for ADHD and problematic behavior than anxiety/depression symptoms, though all were modest. Model estimates were similar for boys and girls. CONCLUSIONS: Much of the research on feeding problems focuses on picky eating. This study suggests that early mechanical and mealtime distress problems may serve as better predictors of later psychopathology than food refusal. Parents and pediatricians could monitor children with mechanical/distress feeding problems for signs of developing psychopathology.

Charting the course from abstract to published article.

OBJECTIVE: Abstracts act as short, efficient sources of new information. This intentional brevity potentially diminishes scientific reliability of described findings. The authors' objective was to 1) determine the proportion of abstracts submitted to the American Association of Neurological Surgeons (AANS) annual meeting that subsequently are published in peer-reviewed journals, 2) assess AANS abstract publications for publication bias, and 3) assess AANS abstract publications for differing results. METHODS: The authors screened all abstracts from the annual 2012 AANS meeting and identified their corresponding full-text publication, if applicable, by searching PubMed/MEDLINE. The abstract and subsequent publication were analyzed for result type (positive or negative) and differences in results. RESULTS: Overall, 49.3% of abstracts were published as papers. Many (18.1%) of these published papers differed in message from their original abstract. Publication bias exists, with positive abstracts being 40% more likely to be published than negative abstracts. The top journals in which the full-text articles were published were Journal of Neurosurgery (13.1%), Neurosurgery (7.3%), and World Neurosurgery (5.4%). CONCLUSIONS: Here, the authors demonstrate that alone, abstracts are not reliable sources of information. Many abstracts ultimately remain unpublished; therefore, they do not attain a level of scientific scrutiny that merits alteration of clinical care. Furthermore, many that are published have differing results or conclusions. In addition, positive publication bias exists, as positive abstracts are more likely to be published than negative abstracts.