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Dark (hidden) photons are widely recognised as well motivated candidates for physics beyond the standard model, and have been invoked for the solution of several outstanding problems, including to account for the dark matter in the universe. In this paper, we consider a simple model for dark photons, which is coupled to ordinary matter only through kinetic mixing with ordinary photons. Within this framework, we calculate the flux of solar dark photons on Earth and revise the potential to detect it with the next generation of axion helioscopes, particularly with the International AXion Observatory (IAXO). This paper extends on previous theoretical analyses in two main ways. Firstly, it includes a more complete analysis of the possible sources of dark photons from the sun, including the contribution of the solar magnetic field and of nuclear processes, and secondly it includes predictions on the parameter space accessible in the gas-filled phase of IAXO., Comment: 23 pages, 7 figures, 1 table

As the master regulator in utero, the placenta is core to the Developmental Origins of Health and Disease (DOHaD) hypothesis but is historically understudied. To identify placental gene-trait associations (GTAs) across the life course, we perform distal mediator-enriched transcriptome-wide association studies (TWAS) for 40 traits, integrating placental multi-omics from the Extremely Low Gestational Age Newborn Study. At [Formula: see text], we detect 248 GTAs, mostly for neonatal and metabolic traits, across 176 genes, enriched for cell growth and immunological pathways. In aggregate, genetic effects mediated by placental expression significantly explain 4 early-life traits but no later-in-life traits. 89 GTAs show significant mediation through distal genetic variants, identifying hypotheses for distal regulation of GTAs. Investigation of one hypothesis in human placenta-derived choriocarcinoma cells reveal that knockdown of mediator gene EPS15 upregulates predicted targets SPATA13 and FAM214A, both associated with waist-hip ratio in TWAS, and multiple genes involved in metabolic pathways. These results suggest profound health impacts of placental genomic regulation in developmental programming across the life course.

RationaleAsthma and obesity often co-occur. It has been hypothesized that asthma may contribute to childhood obesity onset.ObjectivesTo determine if childhood asthma is associated with incident obesity and examine the role of asthma medication in this association.MethodsWe studied 8,716 children between ages 6 and 18.5 years who were nonobese at study entry participating in 18 US cohorts of the Environmental influences on Child Health Outcomes program (among 7,299 children with complete covariate data mean [SD] study entry age = 7.2 [1.6] years and follow up = 5.3 [3.1] years).Measurements and main resultsWe defined asthma based on caregiver report of provider diagnosis. Incident obesity was defined as the first documented body mass index ≥95th percentile for age and sex following asthma status ascertainment. Over the study period, 26% of children had an asthma diagnosis and 11% developed obesity. Cox proportional hazards models with sex-specific baseline hazards were fitted to assess the association of asthma diagnosis with obesity incidence. Children with asthma had a 23% (95% confidence intervals [CI] = 4, 44) higher risk for subsequently developing obesity compared with those without asthma. A novel mediation analysis was also conducted to decompose the total asthma effect on obesity into pathways mediated and not mediated by asthma medication use. Use of asthma medication attenuated the total estimated effect of asthma on obesity by 64% (excess hazard ratios = 0.64; 95% CI = -1.05, -0.23).ConclusionsThis nationwide study supports the hypothesis that childhood asthma is associated with later risk of obesity. Asthma medication may reduce this association and merits further investigation as a potential strategy for obesity prevention among children with asthma.

Given inconsistent evidence on preconception or prenatal tobacco use and offspring autism spectrum disorder (ASD), this study assessed associations of maternal smoking with ASD and ASD-related traits. Among 72 cohorts in the Environmental Influences on Child Health Outcomes consortium, 11 had ASD diagnosis and prenatal tobaccosmoking (n = 8648). and 7 had Social Responsiveness Scale (SRS) scores of ASD traits (n = 2399). Cohorts had diagnoses alone (6), traits alone (2), or both (5). Diagnoses drew from parent/caregiver report, review of records, or standardized instruments. Regression models estimated smoking-related odds ratios (ORs) for diagnoses and standardized mean differences for SRS scores. Cohort-specific ORs were meta-analyzed. Overall, maternal smoking was unassociated with child ASD (adjusted OR, 1.08; 95% confidence interval [CI], 0.72-1.61). However, heterogeneity across studies was strong: preterm cohorts showed reduced ASD risk for exposed children. After excluding preterm cohorts (biased by restrictions on causal intermediate and exposure opportunity) and small cohorts (very few ASD cases in either smoking category), the adjusted OR for ASD from maternal smoking was 1.44 (95% CI, 1.02-2.03). Children of smoking (versus non-smoking) mothers had more ASD traits (SRS T-score + 2.37 points, 95% CI, 0.73-4.01 points), with results homogeneous across cohorts. Maternal preconception/prenatal smoking was consistently associated with quantitative ASD traits and modestly associated with ASD diagnosis among sufficiently powered United States cohorts of non-preterm children. Limitations resulting from self-reported smoking and unmeasured confounders preclude definitive conclusions. Nevertheless, counseling on potential and known risks to the child from maternal smoking is warranted for pregnant women and pregnancy planners. LAY SUMMARY: Evidence on the association between maternal prenatal smoking and the child's risk for autism spectrum dis

BackgroundAlthough survival rates for infants born extremely preterm (gestation < 28 weeks) have improved significantly in recent decades, neurodevelopmental impairment remains a major concern. Children born extremely preterm remain at high risk for cognitive impairment from early childhood to adulthood. However, there is limited evidence on genetic factors associated with cognitive impairment in this population.MethodsFirst, we used a latent profile analysis (LPA) approach to characterize neurocognitive function at age 10 for children born extremely preterm. Children were classified into two groups: (1) no or low cognitive impairment, and (2) moderate-to-severe cognitive impairment. Second, we performed TOPMed-based genotype imputation on samples with genotype array data (n = 528). Third, we then conducted a genome-wide association study (GWAS) for LPA-inferred cognitive impairment. Finally, computational analysis was conducted to explore potential mechanisms underlying the variant x LPA association.ResultsWe identified two loci reaching genome-wide significance (p value < 5e-8): TEA domain transcription factor 4 (TEAD4 at rs11829294, p value = 2.40e-8) and syntaxin 18 (STX18 at rs79453226, p value = 1.91e-8). Integrative analysis with brain expression quantitative trait loci (eQTL), chromatin conformation, and epigenomic annotations suggests tetraspanin 9 (TSPAN9) and protein arginine methyltransferase 8 (PRMT8) as potential functional genes underlying the GWAS signal at the TEAD4 locus.ConclusionsWe conducted a novel computational analysis by utilizing an LPA-inferred phenotype with genetics data for the first time. This study suggests that rs11829294 and its LD buddies have potential regulatory roles on genes that could impact neurocognitive impairment for extreme preterm born children.

The family environment, with all its complexity and diverse components, plays a critical role in shaping neurodevelopmental outcomes in children. Herein we review several domains of the family environment (family socioeconomic status, family composition and home environment, parenting behaviors and interaction styles, parental mental health and functioning, and parental substance use) and discuss how these domains influence neurodevelopment, with particular emphasis on mental health outcomes. We also highlight a new initiative launched by the National Institutes of Health, the Environmental influences on Child Health Outcomes (ECHO) program. We discuss the role that ECHO will play in advancing our understanding of the impact of the family environment on children's risk for psychiatric outcomes. Lastly, we conclude with important unanswered questions and controversies in this area of research, highlighting how ECHO will contribute to resolving these gaps in our understanding, clarifying relationships between the family environment and children's mental health.

BackgroundChildren born extremely preterm are at heightened risk for intellectual and social impairment, including Autism Spectrum Disorder (ASD). There is increasing evidence for a key role of the placenta in prenatal developmental programming, suggesting that the placenta may, in part, contribute to origins of neurodevelopmental outcomes.MethodsWe examined associations between placental transcriptomic and epigenomic profiles and assessed their ability to predict intellectual and social impairment at age 10 years in 379 children from the Extremely Low Gestational Age Newborn (ELGAN) cohort. Assessment of intellectual ability (IQ) and social function was completed with the Differential Ability Scales-II and Social Responsiveness Scale (SRS), respectively. Examining IQ and SRS allows for studying ASD risk beyond the diagnostic criteria, as IQ and SRS are continuous measures strongly correlated with ASD. Genome-wide mRNA, CpG methylation and miRNA were assayeds with the Illumina Hiseq 2500, HTG EdgeSeq miRNA Whole Transcriptome Assay, and Illumina EPIC/850 K array, respectively. We conducted genome-wide differential analyses of placental mRNA, miRNA, and CpG methylation data. These molecular features were then integrated for a predictive analysis of IQ and SRS outcomes using kernel aggregation regression. We lastly examined associations between ASD and the multi-omic-predicted component of IQ and SRS.ResultsGenes with important roles in neurodevelopment and placental tissue organization were associated with intellectual and social impairment. Kernel aggregations of placental multi-omics strongly predicted intellectual and social function, explaining approximately 8% and 12% of variance in SRS and IQ scores via cross-validation, respectively. Predicted in-sample SRS and IQ showed significant positive and negative associations with ASD case-control status.LimitationsThe ELGAN cohort comprises children born pre-term, and generalization may be affected by unmeas

BACKGROUND: Maternal pre-pregnancy obesity, in term-born children, is associated with an increased risk of attention problems, however this relationship has not been explored among children born extremely preterm.AIM: To estimate the risk of attention problems at age 10years in children born very preterm to overweight (i.e., body mass index (BMI) 25-29kg/m2) and obese (i.e., BMI≥30kg/m2) women relative to the risk among children born to women who were neither overweight nor obese (i.e. BMI<25kg/m2).STUDY DESIGN: Multi-center prospective cohort study.METHODS: A total of 764 children born before the 28th week of gestation and whose mother's pre-pregnancy height and pre-pregnancy weight were obtained at birth had an IQ≥70 at age 10years when parents and teachers completed Child Symptom Inventory-4 questionnaires that included items about the presence of ADHD.RESULTS: Compared to children whose mother's pre-pregnancy weight was in the normal range (BMI<25kg/m2), children were at increased risk of parent-identified ADHD behaviors if their mother was overweight (odds ratio (OR)=1.9; 95% confidence interval (CI): 1.1, 3.3), or obese (OR=2.3; 95% CI: 1.4, 3.9). They were not at increased risk of teacher-identified ADHD characteristics if their mother was overweight before her pregnancy (OR=1.0; 95% CI: 0.6, 1.8), or obese (OR=1.0; 95% CI: 0.6, 1.6).CONCLUSION: Maternal overweight and obesity are associated with increased risk of parent-identified ADHD characteristics at 10years of age in children born extremely preterm.

ObjectivesThe diagnosis of surgical site infection following endoprosthetic reconstruction for bone tumours is frequently a subjective diagnosis. Large clinical trials use blinded Central Adjudication Committees (CACs) to minimise the variability and bias associated with assessing a clinical outcome. The aim of this study was to determine the level of inter-rater and intra-rater agreement in the diagnosis of surgical site infection in the context of a clinical trial.Materials and methodsThe Prophylactic Antibiotic Regimens in Tumour Surgery (PARITY) trial CAC adjudicated 29 non-PARITY cases of lower extremity endoprosthetic reconstruction. The CAC members classified each case according to the Centers for Disease Control (CDC) criteria for surgical site infection (superficial, deep, or organ space). Combinatorial analysis was used to calculate the smallest CAC panel size required to maximise agreement. A final meeting was held to establish a consensus.ResultsFull or near consensus was reached in 20 of the 29 cases. The Fleiss kappa value was calculated as 0.44 (95% confidence interval (CI) 0.35 to 0.53), or moderate agreement. The greatest statistical agreement was observed in the outcome of no infection, 0.61 (95% CI 0.49 to 0.72, substantial agreement). Panelists reached a full consensus in 12 of 29 cases and near consensus in five of 29 cases when CDC criteria were used (superficial, deep or organ space). A stable maximum Fleiss kappa of 0.46 (95% CI 0.50 to 0.35) at CAC sizes greater than three members was obtained.ConclusionsThere is substantial agreement among the members of the PARITY CAC regarding the presence or absence of surgical site infection. Agreement on the level of infection, however, is more challenging. Additional clinical information routinely collected by the prospective PARITY trial may improve the discriminatory capacity of the CAC in the parent study for the diagnosis of infection.Cite this article: J. Nuttall, N. Evaniew, P. Thornley, A. Grif

ObjectiveTo assess whether late surfactant treatment in extremely low gestational age (GA) newborn infants requiring ventilation at 7-14 days, who often have surfactant deficiency and dysfunction, safely improves survival without bronchopulmonary dysplasia (BPD).Study designExtremely low GA newborn infants (GA ≤28 0/7 weeks) who required mechanical ventilation at 7-14 days were enrolled in a randomized, masked controlled trial at 25 US centers. All infants received inhaled nitric oxide and either surfactant (calfactant/Infasurf) or sham instillation every 1-3 days to a maximum of 5 doses while intubated. The primary outcome was survival at 36 weeks postmenstrual age (PMA) without BPD, as evaluated by physiological oxygen/flow reduction.ResultsA total of 511 infants were enrolled between January 2010 and September 2013. There were no differences between the treated and control groups in mean birth weight (701 ± 164 g), GA (25.2 ± 1.2 weeks), percentage born at GA <26 weeks (70.6%), race, sex, severity of lung disease at enrollment, or comorbidities of prematurity. Survival without BPD did not differ between the treated and control groups at 36 weeks PMA (31.3% vs 31.7%; relative benefit, 0.98; 95% CI, 0.75-1.28; P = .89) or 40 weeks PMA (58.7% vs 54.1%; relative benefit, 1.08; 95% CI, 0.92-1.27; P = .33). There were no between-group differences in serious adverse events, comorbidities of prematurity, or severity of lung disease to 36 weeks.ConclusionLate treatment with up to 5 doses of surfactant in ventilated premature infants receiving inhaled nitric oxide was well tolerated, but did not improve survival without BPD at 36 or 40 weeks. Pulmonary and neurodevelopmental assessments are ongoing.Trial registrationClinicalTrials.gov: NCT01022580.

ObjectiveClinical studies of patients with bone sarcomas have been challenged by insufficient numbers at individual centres to draw valid conclusions. Our objective was to assess the feasibility of conducting a definitive multi-centre randomised controlled trial (RCT) to determine whether a five-day regimen of post-operative antibiotics, in comparison to a 24-hour regimen, decreases surgical site infections in patients undergoing endoprosthetic reconstruction for lower extremity primary bone tumours.MethodsWe performed a pilot international multi-centre RCT. We used central randomisation to conceal treatment allocation and sham antibiotics to blind participants, surgeons, and data collectors. We determined feasibility by measuring patient enrolment, completeness of follow-up, and protocol deviations for the antibiotic regimens.ResultsWe screened 96 patients and enrolled 60 participants (44 men and 16 women) across 21 sites from four countries over 24 months (mean 2.13 participants per site per year, standard deviation 2.14). One participant was lost to follow-up and one withdrew consent. Complete data were obtained for 98% of eligible patients at two weeks, 83% at six months, and 73% at one year (the remainder with partial data or pending queries). In total, 18 participants missed at least one dose of antibiotics or placebo post-operatively, but 93% of all postoperative doses were administered per protocol.ConclusionsIt is feasible to conduct a definitive multi-centre RCT of post-operative antibiotic regimens in patients with bone sarcomas, but further expansion of our collaborative network will be critical. We have demonstrated an ability to coordinate in multiple countries, enrol participants, maintain protocol adherence, and minimise losses to follow-up.

The role of bone morphogenetic proteins (BMPs) in the regulation of ovarian function has been extensively investigated but themechanism of regulation is not well understood. The aim of this study was to investigate the effect of mutation in the BMP receptorin Booroola sheep on the number of primordial follicles and rate of follicle recruitment in comparison with that in normal merino sheepin vivo. Whole sheep ovaries at Q1 the time of birth, 1.5 and 5 years old were collected and processed for the follicle quantification, usingcomputerised stereological methods and statistical analyses. At birth, the total number of primordial follicles in Booroola sheep wassignificantly lower than in merino sheep. At 1.5 and 5 years, a reversed pattern in favour of Booroola ewes was seen with significantlymore primordial follicles than merino. In parallel, the rate of primordial follicle recruitment to developing cohort was substantially lowerin Booroola ewes with only 51 and 66% of primordial follicle consumption at 1.5 and 5 years respectively compared to 92 and 97% inmerino ewes. On other hand, the mean numbers of developing primary follicles were smaller in Booroola sheep at the time of birth, yet,Booroola ewes possess more primary follicles than merino at 1.5 years. These findings suggest that attenuation of the intraovariansignalling pathway of BMPs may in fact be a successful means of rationalising follicle consumption, preventing unnecessary loss offollicles from the initial primordial follicle pool, hence increasing reproductive longevity and fertility.

Bats are ecologically and economically important mammals, but their populations are vulnerable to declines. Many species of bats in the United States and territories are endangered or threatened, have been candidates for such categories, or are species of concern. The importance and vulnerability of bat populations makes monitoring trends in their populations a goal for their management. However, scientifically rigorous monitoring of bat populations requires well-planned, statistically defensible efforts. This volume reports findings of an expert workshop held to examine this topic. Part I includes overviews of efforts at monitoring populations of bats in the U.S. and territories. These papers consider techniques and problems, and summarize what is known about the status and trends in selected groups of bats. Part I also includes a description of the bat monitoring program in the United Kingdom, a critique of monitoring programs in wildlife with recommendations for survey and sampling strategies, and an analysis of existing data on trends in bats in the U.S. and territories. In Part II, workshop participants critically analyze problems and make recommendations for improving methods, defining objectives and priorities, gaining mandates, and enhancing information exchange to facilitate future efforts for monitoring trends in U.S. bat populations.

Bats are ecologically and economically important mammals. The life histories of bats (particularly their low reproductive rates and the need for some species to gather in large aggregations at limited numbers of roosting sites) make their populations vulnerable to declines. Many of the species of bats in the United States (U.S.) and territories are categorized as endangered or threatened, have been candidates for such categories, or are considered species of concern. The importance and vulnerability of bat populations makes monitoring trends in their populations a goal for their future management. However, scientifically rigorous monitoring of bat populations requires well-planned, statistically defensible efforts. This volume reports findings of an expert workshop held to examine the topic of monitoring populations of bats. The workshop participants included leading experts in sampling and analysis of wildlife populations, as well as experts in the biology and conservation of bats. Findings are reported in this volume under two sections. Part I of the report presents contributed papers that provide overviews of past and current efforts at monitoring trends in populations of bats in the U.S. and territories. These papers consider current techniques and problems, and summarize what is known about the status and trends in populations of selected groups of bats. The contributed papers in Part I also include a description of the monitoring program developed for bat populations in the United Kingdom, a critique of monitoring programs in wildlife in general with recommendations for survey and sampling strategies, and a compilation and analysis of existing data on trends in bats of the U.S. and territories. Efforts directed at monitoring bat populations are piecemeal and have shortcomings. In Part II of the report, the workshop participants provide critical analyses of these problems and develop recommendations for improving methods, defining objectives and priorities, gai

This paper will describe the development of a prototype SAW resonator controlled 740 MHz precision local oscillator for satellite applications. The oscillator is housed in a 2.4 cubic inch package. It uses discreet components and a miniature component oven for temperature compensation and enhancement of short term stability. Considerations in the design and fabrication of resonators for this application will be discussed as well as those of the oscillator., This article is from the Proceedings of the Annual Symposium on Frequency Control (37th), 1-3 Jun 83, Marriott Hotel, Philadelphia, Pennsylvania, AD-A136 673, p394-404.