Association between preeclampsia and attention-deficit hyperactivity disorder: a population-based and sibling-matched cohort study.

OBJECTIVE: To examine the association between preeclampsia and attention-deficit hyperactivity disorder (ADHD), using a large Swedish-based registry cohort. METHODS: This study comprised 2 047 619 children, with 114 934 (5.6%) cases of ADHD. Preeclampsia was based on two alternate definitions: (i) preeclampsia (using ICD-9/ICD-10) and (ii) preeclampsia and small for gestational age (SGA) combined. ADHD was determined in one of two ways: (i) if a diagnosis of ADHD was present in the National Patient Register or (ii) if an individual was in receipt of ADHD medication in the Prescribed Drug Register. Multivariate Cox proportional hazards regression analysis allowed adjustment for several perinatal/sociodemographic factors. Sibling-matched analysis further controlled for shared genetic and familial confounding. RESULTS: In the adjusted Cox model, preeclampsia was associated with an increase in likelihood of ADHD (HR: 1.15, 95% CI: 1.12, 1.19). The HR for preeclampsia and those born SGA was 1.43 (95% CI: 1.31, 1.55) in the adjusted model, compared to those unexposed to preeclampsia/SGA. The sibling-matched analysis did not materially change these associations (HR: 1.13, 95% CI: 1.05, 1.22) and 1.55 (95% CI: 1.28, 1.88). CONCLUSIONS: Exposure to preeclampsia or preeclampsia/SGA was associated with ADHD, independent of genetic/familial factors shared by siblings. However, it is important to note that sibling-matched analysis can only adjust for factors that are constant between pregnancies; therefore, residual confounding cannot be ruled out. Further research is needed to explore modifiable risk factors and identify those most-at-risk babies following delivery.

Comparison of three commercially available placental growth factor-based tests in women with suspected preterm pre-eclampsia: the COMPARE study.

OBJECTIVE: To compare the performance of three placental growth factor (PlGF)-based tests in predicting delivery within 14 days from testing in women with suspected preterm pre-eclampsia before 35 weeks' gestation. METHODS: This was a retrospective analysis of samples collected from three prospective pregnancy cohort studies. Participants were pregnant women with suspected preterm pre-eclampsia recruited in tertiary maternity units in the UK and Ireland. Samples were analyzed simultaneously according to the manufacturers' directions. The tests compared were the DELFIA Xpress PlGF 1-2-3 test, the Triage PlGF test and the Elecsys immunoassay soluble fms-like tyrosine kinase-1 (sFlt-1)/PlGF ratio. Areas under receiver-operating characteristics curves (AUCs) were compared. The main outcome measure was detection of a difference of 0.05 in AUC between tests for delivery within 14 days of testing. RESULTS: Plasma samples from 396 women and serum samples from 244 women were assayed. In predicting delivery within 14 days secondary to suspected pre-eclampsia prior to 35 weeks' gestation, no significant differences were observed in AUCs (P = 0.795), sensitivities (P = 0.249), positive predictive values (P = 0.765) or negative predictive values (P = 0.920) between the three tests. The specificity of the Elecsys sFlt-1/PlGF ratio test was higher than that of the other two tests (P < 0.001). CONCLUSIONS: The tests perform similarly in their prediction of need for delivery within 14 days in women with suspected pre-eclampsia. The high negative predictive values support the role of PlGF-based tests as 'rule-out' tests for pre-eclampsia. © 2018 Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Parental physical and lifestyle factors and their association with newborn body composition.

OBJECTIVE: To investigate the parental physical and lifestyle determinants of newborn body composition. DESIGN: Prospective cohort study. SETTING: Cork University Maternity Hospital, a tertiary referral hospital in Cork, Ireland. POPULATION: All babies were recruited as part of a prospective birth cohort, Babies After SCOPE: Evaluating the Longitudinal Impact Using Neurological and Nutritional Endpoints (BASELINE). These babies were recruited from women who had participated in the Screening of Pregnancy Endpoints (SCOPE) study Ireland, a prospective, multicentre cohort study METHODS: Multivariate linear regression was used to analyse the effect of a range of maternal and paternal physical and lifestyle features on neonatal body fat percentage (BF%). MAIN OUTCOME MEASURES: Neonatal BF%. Neonatal adiposity was assessed within 48 hours of birth using air displacement plethysmography (PEAPOD(®) ). RESULTS: In all, 1243 infants were enrolled in the study. Increasing maternal body mass index (adjusted mean difference 0.09; 0.04, 0.15) and waist height ratio (adjusted mean difference 6.59; 0.27, 12.92) were significantly associated with increased neonatal BF%. In contrast, maternal smoking was associated with reduced neonatal BF% compared with non smokers (adjusted mean difference -0.55; -1.07, -0.03). Infant sex significantly altered neonatal BF%, with female infants having higher neonatal BF% compared with male infants (adjusted mean difference 1.98; 1.54, 2.53). No association was observed between paternal body mass index (BMI), paternal age or paternal smoking and neonatal BF%. CONCLUSIONS: Maternal smoking, BMI, waist height ratio and infant sex were associated with altered BF%. TWEETABLE ABSTRACT: Maternal smoking, BMI, waist height ratio and infant sex are associated with altered neonatal body fat percentage.

The Practice of Vitamin D Deficiency Assessment in a Geriatric Day Hospital.

There has been no clear consensus on the assessment and treatment of vitamin D deficiency prior to the publication of the National Osteoporosis Society (NOS) Vitamin D Guideline in 2014. The aim of our study was to assess the practice in a medicine for the older person day hospital setting relative to this guideline. A 6-month retrospective analysis of all new patients who attended service from January to July 2013 was carried out. Seventy-six patients were included in the final analysis. Mean age was 83 years. 39 (51%) patients had sufficient levels while 37 (49%) patients had insufficient levels; 14 (19%) being inadequate and 23 (30%) deficient. Eighteen patients who had insufficient levels were subsequently prescribed supplements; 13 (72%) received vitamin D3 in combination with calcium while 5 (28%) received vitamin D3 alone. Based on the findings of this study, we have made some recommendations and adopted the guideline.

A systematic review of essential obstetric and newborn care capacity building in rural sub-Saharan Africa.

BACKGROUND: Progress in maternal survival in sub-Saharan Africa has been poor since the Millennium Declaration. OBJECTIVES: This systematic review aims to investigate the presence and rigour of evidence for effective capacity building for Essential Obstetric and Newborn Care (EONC) to reduce maternal mortality in rural, sub-Saharan Africa, where maternal mortality ratios are highest globally. SEARCH STRATEGY: MEDLINE (1990-January 2014), EMBASE (1990-January 2014), and the Cochrane Library were included in our search. Key developing world issues of The Lancet and the British Journal of Obstetrics and Gynaecology, African Ministry of Health websites, and the WHO reproductive health library were searched by hand. SELECTION CRITERIA: Studies investigating essential obstetric and newborn care packages in basic and comprehensive care facilities, at community and institutional level, in rural sub-Saharan Africa were included. Studies were included if they reported on healthcare worker performance, access to care, community behavioural change, and emergency obstetric and newborn care. DATA COLLECTION AND ANALYSIS: Data were extracted and all relevant studies independently appraised using structured abstraction and appraisal tools. MAIN RESULTS: There is moderate evidence to support the training of healthcare workers of differing cadres in the provision of emergency obstetric and newborn services to reduce institutional maternal mortality and case-fatality rates in rural sub-Saharan Africa. Community schemes that sensitise and enable access to maternal health services result in a modest rise in facility birth and skilled birth attendance in this rural setting. AUTHORS' CONCLUSION: Essential Obstetric and Newborn Care has merit as an intervention package to reduce maternal mortality in rural sub-Saharan Africa.

Previous pregnancy loss has an adverse impact on distress and behaviour in subsequent pregnancy.

OBJECTIVE: To investigate whether women with previous miscarriages or terminations have higher levels of anxiety, depression, stress, and altered behaviours in a subsequent pregnancy. DESIGN: A retrospective analysis of 5575 women recruited into the Screening for Pregnancy Endpoints (SCOPE) study, a prospective cohort study. SETTING: Auckland, New Zealand, Adelaide, Australia, Cork, Ireland, and Manchester, Leeds, and London, UK. POPULATION: Healthy nulliparous women with singleton pregnancies. METHODS: Outcomes were recorded at 15 and 20 weeks of gestation. MAIN OUTCOME MEASURES: Short-form State-Trait Anxiety Inventory (STAI) score, Perceived Stress Scale score, Edinburgh Postnatal Depression Scale score, and pregnancy-related behaviour measured using behavioural responses to pregnancy score. RESULTS: Of the 5465 women included in the final analysis, 559 (10%) had one and 94 (2%) had two previous miscarriages, and 415 (8%) had one and 66 (1%) had two previous terminations of pregnancy. Women with one previous miscarriage had increased anxiety (adjusted mean difference 1.85; 95% confidence interval, 95% CI 0.61-3.09), perceived stress (adjusted mean difference 0.76; 95% CI 0.48-1.03), depression (adjusted odds ratio, aOR 1.26; 95% CI 1.08-1.45), and limiting/resting behaviour in pregnancy (adjusted mean difference 0.80; 95% CI 0.62-0.97). In women with two miscarriages, depression was more common (aOR 1.65; 95% CI 1.01-2.70) and they had higher scores for limiting/resting behaviour in pregnancy (adjusted mean difference 1.70; 95% CI 0.90-2.53) at 15 weeks of gestation. Women with one previous termination displayed elevated perceived stress (adjusted mean difference 0.65; 95% CI 0.08-1.23) and depression (aOR 1.25; 95% 1.08-1.45) at 15 weeks of gestation. Women with two previous terminations displayed increased perceived stress (adjusted mean difference 1.43; 95% CI 0.00-2.87) and depression (aOR 1.67; 95% 1.28-2.18). CONCLUSIONS: This study highlights the psychological implications of miscarriage and termination of pregnancy.

Gene Ontology annotations and resources.

The Gene Ontology (GO) Consortium (GOC, http://www.geneontology.org) is a community-based bioinformatics resource that classifies gene product function through the use of structured, controlled vocabularies. Over the past year, the GOC has implemented several processes to increase the quantity, quality and specificity of GO annotations. First, the number of manual, literature-based annotations has grown at an increasing rate. Second, as a result of a new 'phylogenetic annotation' process, manually reviewed, homology-based annotations are becoming available for a broad range of species. Third, the quality of GO annotations has been improved through a streamlined process for, and automated quality checks of, GO annotations deposited by different annotation groups. Fourth, the consistency and correctness of the ontology itself has increased by using automated reasoning tools. Finally, the GO has been expanded not only to cover new areas of biology through focused interaction with experts, but also to capture greater specificity in all areas of the ontology using tools for adding new combinatorial terms. The GOC works closely with other ontology developers to support integrated use of terminologies. The GOC supports its user community through the use of e-mail lists, social media and web-based resources.

Focal amplification of the androgen receptor gene in hormone-naive human prostate cancer.

BACKGROUND: Androgen receptor (AR)-gene amplification, found in 20-30% of castration-resistant prostate cancer (CRPCa) is proposed to develop as a consequence of hormone-deprivation therapy and be a prime cause of treatment failure. Here we investigate AR-gene amplification in cancers before hormone deprivation therapy. METHODS: A tissue microarray (TMA) series of 596 hormone-naive prostate cancers (HNPCas) was screened for chromosome X and AR-gene locus-specific copy number alterations using four-colour fluorescence in situ hybridisation. RESULTS: Both high level gain in chromosome X (≥4 fold; n=4, 0.7%) and locus-specific amplification of the AR-gene (n=6, 1%) were detected at low frequencies in HNPCa TMAs. Fluorescence in situ hybridisation mapping whole sections taken from the original HNPCa specimen blocks demonstrated that AR-gene amplifications exist in small foci of cells (≤ 600 nm, ≤1% of tumour volume). Patients with AR gene-locus-specific copy number gains had poorer prostate cancer-specific survival. CONCLUSION: Small clonal foci of cancer containing high level gain of the androgen receptor (AR)-gene develop before hormone deprivation therapy. Their small size makes detection by TMA inefficient and suggests a higher prevalence than that reported herein. It is hypothesised that a large proportion of AR-amplified CRPCa could pre-date hormone deprivation therapy and that these patients would potentially benefit from early total androgen ablation.

Ellipticine derivative induces potent cytostatic effect in acute myeloid leukaemia cells.

A panel of novel ellipticine isomers were designed and synthesised with the aim of evaluating their anti-cancer effects on selected leukaemia cell lines. A preliminary NCI 60-cell screen demonstrated that these compounds display promising anti-tumour activity across a number of different cell types. We have consequently examined the effect of these derivatives in detail on the Acute Myeloid Leukaemia (AML) cell line, MV4-11. Cell cycle analyses revealed that the compounds had a range of distinctive cell cycle effects. 7-Hydroxyisoellipticine showed the most promise with respect to cytostatic activity. We demonstrated that this compound inhibited proliferation of leukaemia cells by preventing cells from progressing from G2 phase into mitosis over a period of 24 h at a concentration of 5 µM. Our research suggests that this is mediated by an induction of reactive oxygen species (ROS), which in turn activates the DNA damage response pathway. As a result of the activation of p53, cyclin B1 is inhibited. The induction of this pathway leads to apoptosis which is seen at 48 h using the same dose of 7-hydroxyisoellipticine. This study provides for the first time detailed cellular information on the potential use of isoellipticines as chemotherapeutic agents.

Predictors of depression in youth with Crohn disease.

OBJECTIVE: The aim of the study was to determine whether infliximab use and other potential predictors are associated with decreased prevalence and severity of depression in pediatric patients with Crohn disease (CD). METHODS: A total of 550 (n = 550) youth ages 9 to 17 years with biopsy-confirmed CD were consecutively recruited as part of a multicenter randomized controlled trial. Out of the 550, 499 patients met study criteria and were included in the analysis. At recruitment, each subject and a parent completed the Children's Depression Inventory (CDI). A child or parent CDI score ≥  12 was used to denote clinically significant depressive symptoms (CSDS). Child and parent CDI scores were summed to form total CDI (CDIT). Infliximab use, demographic information, steroid use, laboratory values, and Pediatric Crohn's Disease Activity Index (PCDAI) were collected as the potential predictors of depression. Univariate regression models were constructed to determine the relations among predictors, CSDS, and CDIT. Stepwise multivariate regression models were constructed to predict the relation between infliximab use and depression while controlling for other predictors of depression. RESULTS: Infliximab use was not associated with a decreased proportion of CSDS and CDIT after adjusting for multiple comparisons. CSDS and CDIT were positively associated with PCDAI, erythrocyte sedimentation rate, and steroid dose (P < 0.01) and negatively associated with socioeconomic status (SES) (P < 0.001). In multivariate models, PCDAI and SES were the strongest predictors of depression. CONCLUSIONS: Disease activity and SES are significant predictors of depression in youth with Crohn disease.

Characterization of relations among sleep, inflammation, and psychiatric dysfunction in depressed youth with Crohn disease.

OBJECTIVES: Recent reports demonstrate a link between inflammatory bowel disease (IBD) and sleep disturbance. Increased psychiatric dysfunction is consistently reported in patients with IBD. Our objective is to examine relations among sleep disturbance, inflammation, and psychiatric dysfunction in a pediatric population with Crohn disease (CD) and depression. METHODS: Pediatric patients with CD with depression (n = 96) and healthy controls (n = 19) completed measures of sleep (Pittsburgh Sleep Quality Index [PSQI]), depression, anxiety, and abdominal pain, and provided blood for inflammatory markers. CD activity was determined by the Pediatric Crohn's Disease Activity Index. Factor analysis was performed on subscales of the PSQI to derive measures of sleep disturbance. Univariate and multivariate regression analyses assessed relations between sleep disturbance, psychosocial, and biological measures of CD and psychiatric dysfunction. RESULTS: Sleep disturbance in depressed youth with CD was significantly greater than healthy controls, and was significantly related to measures of abdominal pain, depression, and anxiety, but not biomarkers of inflammation. Factor analysis of the PSQI demonstrated a 2-factor solution. The first factor, termed "Qualitative," included Subjective Sleep Quality, Daytime Dysfunction, Sleep Disturbance, and Sleep Latency, whereas the second factor, "Quantitative," consisted of Habitual Sleep Efficiency and Sleep Duration. This factor showed a significant relation to inflammatory markers. Multivariate modeling suggested that qualitative sleep disturbance was predicted by disease activity, pain, and anxiety, whereas quantitative sleep disturbance was predicted by disease activity. CONCLUSIONS: These results indicate that sleep disturbance in depressed youth with CD differs depending upon illness activity. Patients may require different interventions depending upon the sleep disturbance exhibited.

From data to function: functional modeling of poultry genomics data.

One of the challenges of functional genomics is to create a better understanding of the biological system being studied so that the data produced are leveraged to provide gains for agriculture, human health, and the environment. Functional modeling enables researchers to make sense of these data as it reframes a long list of genes or gene products (mRNA, ncRNA, and proteins) by grouping based upon function, be it individual molecular functions or interactions between these molecules or broader biological processes, including metabolic and signaling pathways. However, poultry researchers have been hampered by a lack of functional annotation data, tools, and training to use these data and tools. Moreover, this lack is becoming more critical as new sequencing technologies enable us to generate data not only for an increasingly diverse range of species but also individual genomes and populations of individuals. We discuss the impact of these new sequencing technologies on poultry research, with a specific focus on what functional modeling resources are available for poultry researchers. We also describe key strategies for researchers who wish to functionally model their own data, providing background information about functional modeling approaches, the data and tools to support these approaches, and the strengths and limitations of each. Specifically, we describe methods for functional analysis using Gene Ontology (GO) functional summaries, functional enrichment analysis, and pathways and network modeling. As annotation efforts begin to provide the fundamental data that underpin poultry functional modeling (such as improved gene identification, standardized gene nomenclature, temporal and spatial expression data and gene product function), tool developers are incorporating these data into new and existing tools that are used for functional modeling, and cyberinfrastructure is being developed to provide the necessary extendibility and scalability for storing and analyzing these data. This process will support the efforts of poultry researchers to make sense of their functional genomics data sets, and we provide here a starting point for researchers who wish to take advantage of these tools.

Perinatal palliative care: focus on comfort.

Providing comfort while a patient is living with a life-limiting condition or at end of life is the hallmark of palliative care regardless of the patient's age. In perinatal palliative care, the patient is unable to speak for themselves. In this manuscript we will present guidelines garnered from the 15-year experience of the Neonatal Comfort Care Program at Columbia University Irving Medical Center, and how they provide care for families along the perinatal journey. We will describe essential tools and strategies necessary to consider in assessing and providing comfort to infants facing a life-limiting diagnosis in utero, born at the cusp of viability or critically ill where the burden of care may outweigh the benefit.

Maternal Mid-Gestation Cytokine Dysregulation in Mothers of Children with Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a developmental disorder characterised by deficits in social interactions and communication, with stereotypical and repetitive behaviours. Recent evidence suggests that maternal immune dysregulation may predispose offspring to ASD. Independent samples t-tests revealed downregulation of IL-17A concentrations in cases, when compared to controls, at both 15 weeks (p = 0.02), and 20 weeks (p = 0.02), which persisted at 20 weeks following adjustment for confounding variables. This adds to the growing body of evidence that maternal immune regulation may play a role in foetal neurodevelopment.

Functional modelling of an equine bronchoalveolar lavage fluid proteome provides experimental confirmation and functional annotation of equine genome sequences.

The equine genome sequence enables the use of high-throughput genomic technologies in equine research, but accurate identification of expressed gene products and interpreting their biological relevance require additional structural and functional genome annotation. Here, we employ the equine genome sequence to identify predicted and known proteins using proteomics and model these proteins into biological pathways, identifying 582 proteins in normal cell-free equine bronchoalveolar lavage fluid (BALF). We improved structural and functional annotation by directly confirming the in vivo expression of 558 (96%) proteins, which were computationally predicted previously, and adding Gene Ontology (GO) annotations for 174 proteins, 108 of which lacked functional annotation. Bronchoalveolar lavage is commonly used to investigate equine respiratory disease, leading us to model the associated proteome and its biological functions. Modelling of protein functions using Ingenuity Pathway Analysis identified carbohydrate metabolism, cell-to-cell signalling, cellular function, inflammatory response, organ morphology, lipid metabolism and cellular movement as key biological processes in normal equine BALF. Comparative modelling of protein functions in normal cell-free bronchoalveolar lavage proteomes from horse, human, and mouse, performed by grouping GO terms sharing common ancestor terms, confirms conservation of functions across species. Ninety-one of 92 human GO categories and 105 of 109 mouse GO categories were conserved in the horse. Our approach confirms the utility of the equine genome sequence to characterize protein networks without antibodies or mRNA quantification, highlights the need for continued structural and functional annotation of the equine genome and provides a framework for equine researchers to aid in the annotation effort.

The impact of maternal celiac disease on birthweight and preterm birth: a Danish population-based cohort study.

BACKGROUND: Adverse pregnancy outcomes have been associated with maternal celiac disease (CD). In this study, we investigate the effect of treated and untreated maternal CD on infant birthweight and preterm birth. METHODS: A population-based cohort study consisted of all singleton live births in Denmark between 1 January 1979 and 31 December 2004 was used. A total of 1,504,342 babies were born to 836,241 mothers during the study period. Of those, 1105 babies were born to women with diagnosed CD and 346 were born to women with undiagnosed CD. Women with diagnosed CD were considered as treated with a gluten free diet while women with undiagnosed CD were considered as untreated. The outcome measures were: birthweight, small for gestational age (SGA: birthweight <10th centile), very small for gestational age (VSGA: birthweight <5th centile) and preterm birth. We compared these measures in treated and untreated women with those of a reference group (no history of CD). RESULTS: Women with untreated CD delivered smaller babies [difference = -98 g (95% CI: -130, -67)], with a higher risk of SGA infants [OR = 1.31 (95% CI: 1.06, 1.63)], VSGA infants [OR = 1.54 (95% CI: 1.17, 2.03)] and preterm birth [OR = 1.33 (95% CI: 1.02, 1.72)] compared with women without CD. Women with treated CD had no increased risk of reduced mean birthweight, risk of delivering SGA and VSGA infants or preterm birth compared with women without CD. CONCLUSION: Untreated maternal CD increases the risk of reduced birthweight, the risk of delivering SGA and VSGA infants and preterm birth. Diagnosis and presumed treatment of maternal CD with a gluten-free diet appeared to result in a birthweight and preterm birth rate similar to those in women without CD.

Tibial dyschondroplasia-associated proteomic changes in chicken growth plate cartilage.

Tibial dyschondroplasia (TD) is a poultry leg problem that affects the proximal growth plate of the tibia, preventing its transition to bone. To understand the disease-induced proteomic changes, we compared the protein extracts of cartilage from normal and TD-affected growth plates. TD was induced by feeding thiram to chickens 2 wk before tissue harvest. Proteins were extracted from whole tissues and from conditioned media (CM) prepared by incubating appropriate growth plate tissues in serum-free culture medium for 48 hr. The extracts were prefractionated to contain proteins ranging between 10 and 100 kD. Equal amounts of proteins were subjected to 2D gel electrophoresis with three individual samples per group. The gels were silver stained, and digital images were compared and analyzed with Melanie software to determine differentially expressed protein spots. On comparison of two sets of gels, 47 matching spots were detected in tissue extracts and 27 in CM extracts. Among the matching spots, 12 were determined to be down-regulated in tissue extracts (P < or = 0.05) and two in CM extracts (P < or = 0.05) of TD-affected growth plates. Altogether, 32 protein spots could be identified in both tissue and CM extracts by in-gel trypsin digestion, followed by peptide mass fingerprinting and mass spectrometry (MS)/MS fragmentation. The down-regulated proteins included alpha-enolase, G protein, origin recognition complex, peptidyl prolyl isomerase, calumenin, type II collagen precursor, and the expressed sequence tag pgm2n.pk014.f20, a protein with homology to human reticulocalbin-3 (RCN3). Most of the downregulated proteins are associated with signal transduction, energy metabolism, and secretory functions that are integral to cell viability. Consistent with our earlier findings that the TD chondrocytes are nonviable, the current results suggest that thiram very likely interferes with basic metabolic functions of chondrocytes, leading to their death and, consequently, to the pathogenesis of TD.