Enhancing multi-site autism research through the development of a collaborative data platform.

Data repositories, particularly those storing data on vulnerable populations, increasingly need to carefully consider not only what data is being collected, but how it will be used. As such, the Autism Intervention Research Network on Physical Health (AIR-P) has created the Infrastructure for Collaborative Research (ICR) to establish standards on data collection practices in Autism repositories. The ICR will strive to encourage inter-site collaboration, amplify autistic voices, and widen accessibility to data. The ICR is staged as a three-tiered framework consisting of (1) a request for proposals system, (2) a REDCap-based data repository, and (3) public data dashboards to display aggregate de-identified data. Coupled with a review process including autistic and non-autistic researchers, this framework aims to propel the implementation of equitable autism research, enhance standardization within and between studies, and boost transparency and dissemination of findings. In addition, the inclusion of a contact registry that study participants can opt into creates the base for a robust participant pool. As such, researchers can leverage the platform to identify, reach, and distribute electronic materials to a greater proportion of potential participants who likely fall within their eligibility criteria. By incorporating practices that promote effective communication between researchers and participants, the ICR can facilitate research that is both considerate of and a benefit to autistic people.

Males at the Tails: How Socioeconomic Status Shapes the Gender Gap.

We document that the female advantage in childhood behavioural and academic outcomes is driven by gender gaps at the extremes of the outcome distribution. Using unconditional quantile regression, we show that family socioeconomic status particularly influences boys' relative to girls' outcomes at the lower tails of the outcome distribution, precisely where gender gaps are most pronounced. These relationships are not explained by school or neighbourhood factors, or parents' differential treatment of boys. The disproportionate effect of socioeconomic status on boys at the tails substantially contributes to the gender gap in high school dropout.

Updates to the Autism Intervention Research Network on Physical Health (AIR-P) Research Agenda.

INTRODUCTION: Autistic individuals, now representing one in 36 individuals in the U.S., experience disproportionate physical health challenges relative to non-autistic individuals. The Health Resources and Services Administration's (HRSA) Autism Intervention Research Network on Physical Health (AIR-P) is an interdisciplinary, multi-center Research Network that aims to increase the health, well-being, and quality of life of autistic individuals. The current paper builds on the initial AIR-P Research Agenda (proposed in Year 1) and provides an updated vision for the Network. METHODS: Updates to the Research Agenda were made via the administration of a Qualtrics survey, and disseminated widely to all AIR-P entities, including the Research Node Leaders, Steering Committee, Autistic Researcher Review Board, and collaborating academic and non-academic entities. Network members were tasked with evaluating the Year 1 Research Agenda and proposing additional priorities. RESULTS: Within each Research Node, all Year 1 priorities were endorsed as continued priorities for research on autism and physical health. Specific topics, including co-occurring conditions and self-determination, advocacy, and decision-making, were particularly endorsed. Opportunities for exploratory studies and intervention research were identified across Research Nodes. Qualitative responses providing feedback on additional research priorities were collected. CONCLUSION: The updated AIR-P Research Agenda represents an important step toward enacting large-scale health promotion efforts for autistic individuals across the lifespan. This updated agenda builds on efforts to catalyze autism research in historically underrepresented topic areas while adopting a neurodiversity-oriented approach to health promotion.

Telomere dynamics in female Columbian ground squirrels: recovery after emergence and loss after reproduction.

Telomeres are specialized non-coding DNA sequences located at the end of chromosomes and that protect genetic information. Telomere loss over lifespan is generally viewed as a phenomenon associated with aging in animals. Recently, telomere elongation after hibernation has been described in several mammals. Whether this pattern is an adaptation to repair DNA damage caused during rewarming from torpor or if it coevolved as a mechanism to promote somatic maintenance in preparation for the upcoming reproductive effort remains unclear. In a longitudinal study measuring telomere length using buccal swabs, we tested if telomere elongation was related to reproductive success in wild adult female Columbian ground squirrels (Urocitellus columbianus) that were monitored from emergence from hibernation to the end of the reproductive season. We found three key results. First, female telomere length increased at the start of the breeding season, both in breeding and non-breeding individuals. Second, post-emergence telomere lengthening was unrelated to female future reproductive output. Third, telomere length decreased in breeding females during lactation, but remained stable in non-breeding females over a similar period. Within breeders, telomeres shortened more in females producing larger and heavier litters. We concluded that telomere lengthening after hibernation did not constrain immediate female reproductive capacities. It was more likely to be part of the body recovery process that takes place after hibernation. Telomere erosion that occurs after birth may constitute a physiological cost of female reproduction.

Towards Replacing Titanium with Copper in the Bipolar Plates for Proton Exchange Membrane Water Electrolysis.

For proton exchange membrane water electrolysis (PEMWE) to become competitive, the cost of stack components, such as bipolar plates (BPP), needs to be reduced. This can be achieved by using coated low-cost materials, such as copper as alternative to titanium. Herein we report on highly corrosion-resistant copper BPP coated with niobium. All investigated samples showed excellent corrosion resistance properties, with corrosion currents lower than 0.1 µA cm-2 in a simulated PEM electrolyzer environment at two different pH values. The physico-chemical properties of the Nb coatings are thoroughly characterized by scanning electron microscopy (SEM), electrochemical impedance spectroscopy (EIS), X-ray photoelectron spectroscopy (XPS), and atomic force microscopy (AFM). A 30 µm thick Nb coating fully protects the Cu against corrosion due to the formation of a passive oxide layer on its surface, predominantly composed of Nb2O5. The thickness of the passive oxide layer determined by both EIS and XPS is in the range of 10 nm. The results reported here demonstrate the effectiveness of Nb for protecting Cu against corrosion, opening the possibility to use it for the manufacturing of BPP for PEMWE. The latter was confirmed by its successful implementation in a single cell PEMWE based on hydraulic compression technology.

Territorial scent-marking effects on vigilance behavior, space use, and stress in female Columbian ground squirrels.

Social environments can profoundly affect the behavior and stress physiology of group-living animals. In many territorial species, territory owners advertise territorial boundaries to conspecifics by scent marking. Several studies have investigated the information that scent marks convey about donors' characteristics (e.g., dominance, age, sex, reproductive status), but less is known about whether scents affect the behavior and stress of recipients. We experimentally tested the hypothesis that scent marking may be a potent source of social stress in territorial species. We tested this hypothesis for Columbian ground squirrels (Urocitellus columbianus) during lactation, when territorial females defend individual nest-burrows against conspecifics. We exposed lactating females, on their territory, to the scent of other lactating females. Scents were either from unfamiliar females, kin relatives (a mother, daughter, or sister), or their own scent (control condition). We expected females to react strongly to novel scents from other females on their territory, displaying increased vigilance, and higher cortisol levels, indicative of behavioral and physiological stress. We further expected females to be more sensitive to unfamiliar female scents than to kin scents, given the matrilineal social structure of this species and known fitness benefits of co-breeding in female kin groups. Females were highly sensitive to intruder (both unfamiliar and kin) scents, but not to their own scent. Surprisingly, females reacted more strongly to the scent of close kin than to the scent of unfamiliar females. Vigilance behavior increased sharply in the presence of scents; this increase was more marked for kin than unfamiliar female scents, and was mirrored by a marked 131% increase in free plasma cortisol levels in the presence of kin (but not unfamiliar female) scents. Among kin scents, lactating females were more vigilant to the scent of sisters of equal age, but showed a marked 318% increase in plasma free cortisol levels in response to the scent of older and more dominant mothers. These results suggest that scent marks convey detailed information on the identity of intruders, directly affecting the stress axis of territory holders.

Small-for-Gestational Age Birth Confers Similar Educational Performance through Middle School.

OBJECTIVE: To estimate the association between small for gestational age (SGA) at birth and educational performance on standardized testing and disability prevalence in elementary and middle school. STUDY DESIGN: Through linked birth certificates and school records, surviving infants born at 23-41 weeks of gestation who entered Florida's public schools 1998-2009 were identified. Twenty-three SGA definitions (3rd-25th percentile) were derived. Outcomes were scores on Florida Comprehensive Assessment Test (FCAT) and students' disability classification in grades 3 through 8. A "sibling cohort" subsample included families with at least 2 siblings from the same mother in the study period. Multivariable models estimated independent relationships between SGA and outcomes. RESULTS: Birth certificates for 80.2% of singleton infants were matched to Florida public school records (N = 1 254 390). Unadjusted mean FCAT scores were 0.236 SD lower among <10th percentile SGA infants compared with non-SGA infants; this difference declined to -0.086 SD after adjusting for maternal and infant characteristics. When siblings discordant in SGA status were compared within individual families, the association declined to -0.056 SD. For SGA <10th percentile infants, the observed prevalence of school-age disability was 15.0%, 7.7%, and 6.3% for unadjusted, demographics-adjusted, and sibling analyses, respectively. No inflection or discontinuity was detected across SGA definitions from 3rd to 25th percentile in either outcome, and the associations were qualitatively similar. CONCLUSIONS: The associations between SGA birth and students' standardized test scores and well-being were quantitatively small but persisted through elementary and middle school. The observed deficits were largely mitigated by demographic and familial factors.

Sylvatic plague management and prairie dogs - a meta-analysis.

Yersinia pestis, a bacterial pathogen that causes sylvatic plague, is present in the prairie dogs (Cynomys spp.) of North America. Epizootics of sylvatic plague through transmission in vectors (fleas) commonly completely extirpate colonies of prairie dogs. Wildlife managers employ a wide variety of insecticidal treatments to suppress plague and conserve prairie dog colonies. I compiled and statistically compared the available literature describing methods of plague control and their relative effectiveness in managing plague outbreaks by using meta-analyses. Natural log response ratios were used to calculate insecticide-induced vector mortality and vaccine-conferred survival increases in prairie dogs in 37 publications. Further, subgroupings were used to explore the most effective of the available vector suppression insecticides and plague suppression vaccines. After accounting for the type of treatment used and the method by which it was applied, I observed plague reduction through use of both insecticides and vaccines. Insecticides resulted in a significant reduction of the abundance of vectors by 91.34% compared to non-treated hosts (p<0.0001). Vaccines improved survival of prairie dog hosts by 4.00% (p<0.0001) compared to control populations. The use of insecticides such as deltamethrin and carbaryl is recommended to stop actively spreading epizootics, and dual antigen oral vaccines to initially suppress outbreaks.

Subtle short-term physiological costs of an experimental augmentation of fleas in wild Columbian ground squirrels.

Parasites affect many aspects of host physiology and behavior, and thus are generally thought to negatively impact host fitness. However, changes in form of short-term parasite effects on host physiological markers have generally been overlooked in favor of fitness measures. Here, we studied flea (Oropsylla idahoensis and Oropsylla opisocroistis tuberculata) parasitism on a natural population of Columbian ground squirrels (Urocitellus columbianus) in Sheep River Provincial Park, AB, Canada. Fleas were experimentally added to adult female U. columbianus at physiologically demanding times, including birth, lactation and weaning of their young. The body mass of adult females, as well as their oxidative stress and immunity were recorded multiple times over the active season under flea-augmented and control conditions. We also measured the prevalence of an internal parasite (Trypanosoma otospermophili). Doubly labeled water (DLW) was intra-peritoneally injected at peak lactation to examine energy expenditure. Effects of parasites on oxidative stress were only observed after offspring were weaned. There was no direct effect of experimentally heightened flea prevalence on energy use. A short-term 24 h mass loss (-17 g) was detected briefly after parasite addition, likely due to U. columbianus preferentially allocating time for grooming. Our parasite augmentation did not strongly affect hosts and suggested that short-term physiological effects were unlikely to culminate in long-term fitness consequences. Columbian ground squirrels appear to rapidly manage parasite costs, probably through grooming.

Socioeconomic status and genetic influences on cognitive development.

Accurate understanding of environmental moderation of genetic influences is vital to advancing the science of cognitive development as well as for designing interventions. One widely reported idea is increasing genetic influence on cognition for children raised in higher socioeconomic status (SES) families, including recent proposals that the pattern is a particularly US phenomenon. We used matched birth and school records from Florida siblings and twins born in 1994-2002 to provide the largest, most population-diverse consideration of this hypothesis to date. We found no evidence of SES moderation of genetic influence on test scores, suggesting that articulating gene-environment interactions for cognition is more complex and elusive than previously supposed.

Population pharmacokinetic analyses of the effect of carboplatin pretreatment on olaparib in recurrent or refractory women's cancers.

PURPOSE: Combining olaparib with carboplatin was recently shown to be active in both BRCA and non-BRCA mutant cancers in a recent phase I/Ib combination trial. The optimal drug sequence recommended was carboplatin 1-day before olaparib. However, carboplatin pre-treatment induced a ~50% faster olaparib clearance. METHODS: To further explore this drug interaction, a population pharmacokinetic (PK) model was designed that included a lag time parameter, a second absorption compartment from tablet formulation, a single distribution/elimination compartment, and covariance among the clearance and volume parameters. RESULTS: Clearance (6.8 L/h) and volume (33 L) estimates were comparable with literature. The only significant covariate was the presence of carboplatin on olaparib clearance, consistent with published noncompartmental PK and in vitro data. CONCLUSIONS: Simulations predicted lower steady-state peak/trough olaparib exposure through 24-36 h post carboplatin pre-treatment, but this effect was lost by day 2 and thus no dose adjustment is recommended.

Educational Performance of Children Born Prematurely.

Importance: Survivors of preterm birth often present with medical morbidities; however, variation in their long-term educational performance has not been well described. Objective: To estimate the association between gestational age and 4 outcomes in school-aged children: readiness to enter kindergarten, scores on standardized tests in elementary and middle school, gifted status, and low performance. Design, Setting, and Participants: In a retrospective cohort study, children born in Florida between 1992 and 2002 at 23 to 41 weeks' gestation who entered Florida's public schools between 1995 and 2012 were assessed for kindergarten readiness and tested in mathematics and reading in grades 3 through 8. Data analysis was performed from January 12, 2016, to March 1, 2017. Exposures: Gestational age at birth. Main Outcomes and Measures: Kindergarten readiness, scores on the Florida Comprehensive Achievement Test (FCAT), classified as gifted, and classified as low performance. Results: A total of 1 527 113 singleton infants with gestational ages of 23 to 41 weeks born between 1992 and 2002 were matched to Florida public school records. Of these, 1 301 497 children were included in the analysis; 641 479 (49.3%) were girls. A total of 301 (65.0%) Florida children born at 23 to 24 weeks' gestation were designated as ready to start kindergarten. When the FCAT test scores were adjusted for potentially confounding maternal and infant variables, children born at 23 to 24 weeks' gestation performed 0.66 SD (95% CI, -0.73 to -0.59) lower compared with those born at full term. A total of 123 554 (9.5%) of all Florida-born public school students were considered gifted, including 17 (1.8%) of those born at 23 to 24 weeks' gestation. In comparison, 75 458 (5.8%) of all Florida-born public school students were low performing; 310 (33.5%) of these children had been born at 23 to 24 weeks' gestation. Kindergarten readiness, FCAT scores, and gifted status were positively related to gestational age, whereas low performance was inversely related to gestational age. Conclusions and Relevance: Although gestational age has long been associated with poor educational performance, a sufficient proportion of children born near the limits of viability performed within expected school norms, warranting further investigation into how and why certain children are able to overcome the educational burdens that may follow preterm birth.

Combining adverse pregnancy and perinatal outcomes for women exposed to antiepileptic drugs during pregnancy, using a latent trait model.

BACKGROUND: Application of latent variable models in medical research are becoming increasingly popular. A latent trait model is developed to combine rare birth defect outcomes in an index of infant morbidity. METHODS: This study employed four statewide, retrospective 10-year data sources (1999 to 2009). The study cohort consisted of all female Florida Medicaid enrollees who delivered a live singleton infant during study period. Drug exposure was defined as any exposure to Antiepileptic drugs (AEDs) during pregnancy. Mothers with no AED exposure served as the AED unexposed group for comparison. Four adverse outcomes, birth defect (BD), abnormal condition of new born (ACNB), low birth weight (LBW), and pregnancy and obstetrical complication (PCOC), were examined and combined using a latent trait model to generate an overall severity index. Unidimentionality, local independence, internal homogeneity, and construct validity were evaluated for the combined outcome. RESULTS: The study cohort consisted of 3183 mother-infant pairs in total AED group, 226 in the valproate only subgroup, and 43,956 in the AED unexposed group. Compared to AED unexposed group, the rate of BD was higher in both the total AED group (12.8% vs. 10.5%, P < .0001), and the valproate only subgroup (19.6% vs. 10.5%, P < .0001). The combined outcome was significantly correlated with the length of hospital stay during delivery in both the total AED group (Rho = 0.24, P < .0001) and the valproate only subgroup (Rho = 0.16, P = .01). The mean score for the combined outcome in the total AED group was significantly higher (2.04 ± 0.02 vs. 1.88 ± 0.01, P < .0001) than AED unexposed group, whereas the valproate only subgroup was not. CONCLUSIONS: Latent trait modeling can be an effective tool for combining adverse pregnancy and perinatal outcomes to assess prenatal exposure to AED, but evaluation of the selected components is essential to ensure the validity of the combined outcome.

Long-term Cognitive and Health Outcomes of School-Aged Children Who Were Born Late-Term vs Full-Term.

IMPORTANCE: Late-term gestation (defined as the 41st week of pregnancy) is associated with increased risk of perinatal health complications. It is not known to what extent late-term gestation is associated with long-term cognitive and physical outcomes. Information about long-term outcomes may influence physician and patient decisions regarding optimal pregnancy length. OBJECTIVE: To compare the cognitive and physical outcomes of school-aged children who were born full term or late term. DESIGN, SETTING, AND PARTICIPANTS: We analyzed Florida birth certificates from 1994 to 2002 linked to Florida public school records from 1998 to 2013 and found 1 442 590 singleton births with 37 to 41 weeks' gestation in the Florida Bureau of Vital Statistics. Of these, 1 153 716 children (80.0%) were subsequently located in Florida public schools. Linear and logistic regression models were used to assess the association of gestational age with cognitive and physical outcomes at school age. Data analysis took place between April 2013 and January 2016. EXPOSURES: Late-term (born at 41 weeks) vs full-term (born at 39 or 40 weeks) gestation. MAIN OUTCOMES AND MEASURES: There were a number of measures used, including the average Florida Comprehensive Assessment Test mathematics and reading scores at ages 8 through 15 years; whether a child was classified as gifted, defined as a student with superior intellectual development and capable of high performance; poor cognitive outcome, defined as a child scoring in the fifth percentile of test takers or having a disability that exempted him or her from taking the Florida Comprehensive Assessment Test; and Exceptional Student Education placement owing to orthopedic, speech, or sensory impairment or being hospitalbound or homebound. RESULTS: Of 1 536 482 children born in Florida from singleton births from 1994 to 2002 with complete demographic information, 787 105 (51.2%) were male; 338 894 (22.1%) of mothers were black and 999 684 (65.1%) were married at time of birth, and the mean (SD) age for mothers at time of birth was 27.2 (6.2) years. Late-term infants had 0.7% of an SD (95% CI, 0.001-0.013; P = .02) higher average test scores in elementary and middle school, 2.8% (95% CI, 0.4-5.2; P = .02) higher probability of being gifted, and 3.1% (95% CI, 0.0-6.1; P = .05) reduced probability of poor cognitive outcomes compared with full-term infants. These cognitive benefits appeared strongest for children with disadvantaged family background characteristics. Late-term infants were also 2.1% (95% CI, -0.3 to 4.5; P = .08) more likely to be physically impaired. CONCLUSIONS AND RELEVANCE: There appears to be a tradeoff between cognitive and physical outcomes associated with late-term gestation. Children born late-term performed better on 3 measures of school-based cognitive functioning but worse on 1 measure of physical functioning relative to children born full term. Our findings provide longer-run information for expectant parents and physicians who are considering delivery at full term vs late term. These findings are most relevant to uncomplicated, low-risk pregnancies.

Potential selection bias associated with using geocoded birth records for epidemiologic research.

PURPOSE: There is an increasing use of geocoded birth registry data in environmental epidemiology research. Ungeocoded records are routinely excluded. METHODS: We used classification and regression tree analysis and logistic regression to investigate potential selection bias associated with this exclusion among all singleton Florida births in 2009 (n = 210,285). RESULTS: The rate of unsuccessful geocoding was 11.5% (n = 24,171). This ranged between 0% and 100% across zip codes. Living in a rural zip code was the strongest predictor of being ungeocoded. Other predictors for geocoding status varied with urbanity status. In urban areas, maternal race (adjusted odds ratio [aOR] ranging between 1.08 for Hispanic and 1.18 for black compared to white), maternal age [aOR: 1.16 (1.10-1.23) for ages 20-34 compared to <20], maternal nativity [aOR: 1.20 (1.15-1.25) for non-US versus US born], delivery at a birth center [aOR: 1.72 (1.49-2.00) compared to hospital delivery], multiparity [aOR: 0.91 (0.88-0.94)], maternal smoking [aOR: 0.82 (0.76-0.88)], and having nonprivate insurance [aOR: 1.25 (1.20-1.30) for Medicaid versus private insurance] were significantly associated with being ungeocoded. In rural areas, births delivered at birth center [aOR: 2.91 (1.80-4.73)] or home [aOR: 1.94 (1.28-2.95)] had increased odds compared to hospital births. The characteristics predictive of being ungeocoded were also significantly associated with adverse birth outcomes such as low birth weight and preterm delivery, and the association for maternal age was different when ungeocoded births were included and excluded. CONCLUSIONS: Geocoding status is not random. Women with certain exposure-outcome characteristics may be more likely to be ungeocoded and excluded, indicating potential selection bias.

Associations Between Residential Proximity to Power Plants and Adverse Birth Outcomes.

Few studies have assessed the associations between residential proximity to power plants and adverse birth outcomes including preterm delivery (PTD), very preterm delivery (VPTD), and term low birth weight (LBW). We geocoded 423,719 singleton Florida births born from 2004 to 2005 and all active power plants and determined residential proximity to the nearest power plant for each birth. Prenatal exposure to particulate matter less than 2.5 µm in diameter for women living near different types of power plants was also determined by using National Environmental Public Health Tracking Network data. Logistic regression models were used to test the hypothesized associations. Women who lived closer to coal and solid waste power plants were exposed to higher levels of particulate matter less than 2.5 µm in diameter compared with other types. We observed a 1.8% (95% confidence interval (CI): 1.3, 2.3) increased odds for PTD, 2.2% (95% CI: 1.0, 3.4) for VPTD, and 1.1% (95% CI: 0.2, 2.0) for term LBW for each 5 km closer to any power plant. When stratifying by different fuel type, we found that only solid waste had an association with term LBW, whereas oil, gas, and solid waste all had an association with PTD and VPTD. Results were consistent when exposure was categorized by number of power plants. Our study found evidence of increasing odds of adverse birth outcomes among infants born to pregnant women living closer to power plants. More research is warranted to better understand the causal relationship.

Association of Atmospheric Particulate Matter and Ozone with Gestational Diabetes Mellitus.

BACKGROUND: Ambient air pollution has been linked to the development of gestational diabetes mellitus (GDM). However, evidence of the association is very limited, and no study has estimated the effects of ozone. OBJECTIVE: Our aim was to determine the association of prenatal exposures to particulate matter ≤ 2.5 µm (PM2.5) and ozone (O3) with GDM. METHODS: We used Florida birth vital statistics records to investigate the association between the risk of GDM and two air pollutants (PM2.5 and O3) among 410,267 women who gave birth in Florida between 2004 and 2005. Individual air pollution exposure was assessed at the woman's home address at time of delivery using the hierarchical Bayesian space-time statistical model. We further estimated associations between air pollution exposures during different trimesters and GDM. RESULTS: After controlling for nine covariates, we observed increased odds of GDM with per 5-µg/m3 increase in PM2.5 (ORTrimester1 = 1.16; 95% CI: 1.11, 1.21; ORTrimester2 = 1.15; 95% CI: 1.10, 1.20; ORPregnancy = 1.20; 95% CI: 1.13, 1.26) and per 5-ppb increase in O3 (ORTrimester1 = 1.09; 95% CI: 1.07, 1.11; ORTrimester2 = 1.12; 95% CI: 1.10, 1.14; ORPregnancy = 1.18; 95% CI: 1.15, 1.21) during both the first trimester and second trimester as well as the full pregnancy in single-pollutant models. Compared with the single-pollutant model, the ORs for O3 were almost identical in the co-pollutant model. However, the ORs for PM2.5 during the first trimester and the full pregnancy were attenuated, and no association was observed for PM2.5 during the second trimester in the co-pollutant model (OR = 1.02; 95% CI: 0.98, 1.07). CONCLUSION: This population-based study suggests that exposure to air pollution during pregnancy is associated with increased risk of GDM in Florida, USA. CITATION: Hu H, Ha S, Henderson BH, Warner TD, Roth J, Kan H, Xu X. 2015. Association of atmospheric particulate matter and ozone with gestational diabetes mellitus. Environ Health Perspect 123:853-859; http://dx.doi.org/10.1289/ehp.1408456.

Quantitative determination of mithramycin in human plasma by a novel, sensitive ultra-HPLC-MS/MS method for clinical pharmacokinetic application.

Mithramycin is a neoplastic antibiotic synthesized by various Streptomyces bacteria. It is under investigation as a chemotherapeutic treatment for a wide variety of cancers. Ongoing and forthcoming clinical trials will require pharmacokinetic analysis of mithramycin in humans, both to see if target concentrations are achieved and to optimize dosing and correlate outcomes (response/toxicity) with pharmacokinetics. Two published methods for mithramycin quantitation exist, but both are immunoassays that lack current bioanalytical standards of selectivity and sensitivity. To provide an upgraded and more widely applicable assay, a UPLC-MS/MS method for quantitation of mithramycin in human plasma was developed. Solid-phase extraction allowed for excellent recoveries (>90%) necessary for high throughput analyses on sensitive instrumentation. However, a ∼55% reduction in analyte signal was observed as a result of plasma matrix effects. Mithramycin and the internal standard chromomycin were separated on a Waters Acquity BEH C18 column (2.1×50 mm, 1.7 µm) and detected using electrospray ionization operated in the negative mode at mass transitions m/z 1083.5→268.9 and 1181.5→269.0, respectively, on an AB Sciex QTrap 5500. The assay range was 0.5-500 ng/mL and proved to be linear (r(2)>0.996), accurate (≤10% deviation), and precise (CV<15%). Mithramycin was stable in plasma at room temperature for 24 h, as well as through three freeze-thaw cycles. This method was subsequently used to quantitate mithramycin plasma concentrations from patients enrolled on two clinical trials at the NCI.

Ambient Air Pollution and Hypertensive Disorders of Pregnancy: A Systematic Review and Meta-analysis.

Hypertensive disorders of pregnancy (HDP, including gestational hypertension, preeclampsia, and eclampsia) have a substantial public health impact. Maternal exposure to high levels of air pollution may trigger HDP, but this association remains unclear. The objective of our report is to assess and quantify the association between maternal exposures to criteria air pollutants (ozone, carbon monoxide, nitrogen dioxide, sulfur dioxide, and particulate matter ≤ 10, 2.5 µm) on HDP risk. PubMed, EMBASE, MEDLINE, Current Contents, Global Health, and Cochrane were searched (last search: September, 2013). After a detailed screening of 270 studies, 10 studies were extracted. We conducted meta-analyses if a pollutant in a specific exposure window was reported by at least four studies. Using fixed- and random-effects models, odds ratios (ORs) and 95% CIs were calculated for each pollutant with specific increment of concentration. Increases in risks of HDP (OR per 10 ppb = 1.16; 95% CI, 1.03-1.30) and preeclampsia (OR per 10 ppb = 1.10; 95% CI, 1.03-1.17) were observed to be associated with exposure to NO2 during the entire pregnancy, and significant associations between HDP and exposure to CO (OR per 1 ppm = 1.79; 95% CI, 1.31-2.45) and O3 (OR per 10 ppb = 1.09; 95% CI, 1.05-1.13) during the first trimester were also observed. Our review suggests an association between ambient air pollution and HDP risk. Although the ORs were relatively low, the population-attributable fractions were not negligible given the ubiquitous nature of air pollution.