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Sample records for adverse neurodevelopmental outcome

  1. Influence of Clinical Status on the Association Between Plasma Total and Unbound Bilirubin and Death or Adverse Neurodevelopmental Outcomes in Extremely Low Birth Weight Infants

    PubMed Central

    Oh, William; Stevenson, David K.; Tyson, Jon E.; Morris, Brenda H.; Ahlfors, Charles E.; Bender, G. Jesse; Wong, Ronald J.; Perritt, Rebecca; Vohr, Betty R.; Van Meurs, Krista P.; Vreman, Hendrik J.; Das, Abhik; Phelps, Dale L.; O’Shea, T. Michael; Higgins, Rosemary D.

    2010-01-01

    Objectives To assess the influence of clinical status on the association between total plasma bilirubin and unbound bilirubin on death or adverse neurodevelopmental outcomes at 18–22 months corrected age in extremely low birth weight infants. Method Total plasma biirubin and unbound biirubin were measured in 1,101 extremely low birth weight infants at 5±1 day of age. Clinical criteria were used to classify infants as clinically stable or unstable. Survivors were examined at 18–22 months corrected age by certified examiners. Outcome variables were death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss, and death prior to follow-up. For all outcomes, the interaction between bilirubin variables and clinical status was assessed in logistic regression analyses adjusted for multiple risk factors. Results Regardless of clinical status, an increasing level of unbound bilirubin was associated with higher rates of death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss and death before follow-up. Total plasma bilirubin values were directly associated with death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss, and death before follow-up in unstable infants, but not in stable infants. An inverse association between total plasma bilirubin and death or cerebral palsy was found in stable infants. Conclusions In extremely low birth weight infants, clinical status at 5 days of age affects the association between total plasma and unbound bilirubin and death or adverse neurodevelopmental outcomes at 18–22 months of corrected age. An increasing level of UB is associated a higher risk of death or adverse neurodevelopmental outcomes regardless of clinical status. Increasing levels of total plasma bilirubin are directly associated with increasing risk of death or adverse neurodevelopmental outcomes in unstable, but not in stable infants. PMID:20105142

  2. Early neurodevelopmental outcomes of extremely preterm infants.

    PubMed

    Rogers, Elizabeth E; Hintz, Susan R

    2016-12-01

    Infants born at extreme preterm gestation are at risk for both death and disability. Although rates of survival have improved for this population, and some evidence suggests a trend toward decreased neuromotor impairment over the past decades, a significant improvement in overall early neurodevelopmental outcome has not yet been realized. This review will examine the rates and types of neurodevelopmental impairment seen after extremely preterm birth, including neurosensory, motor, cognitive, and behavioral outcomes. We focus on early outcomes in the first 18-36 months of life, as the majority of large neonatal studies examining neurodevelopmental outcomes stop at this age. However, this early age is clearly just a first glimpse into lifetime outcomes; the neurodevelopmental effects of extreme prematurity may last through school age, adolescence, and beyond. Importantly, prematurity appears to be an independent risk factor for adverse development, but this population demonstrates considerable variability in the types and severity of impairments. Understanding both the nature and prevalence of neurodevelopmental impairment among extremely preterm infants is important because it can lead to targeted interventions that in turn may lead to improved outcomes.

  3. Survival and Neurodevelopmental Outcomes among Periviable Infants.

    PubMed

    Younge, Noelle; Goldstein, Ricki F; Bann, Carla M; Hintz, Susan R; Patel, Ravi M; Smith, P Brian; Bell, Edward F; Rysavy, Matthew A; Duncan, Andrea F; Vohr, Betty R; Das, Abhik; Goldberg, Ronald N; Higgins, Rosemary D; Cotten, C Michael

    2017-02-16

    Background Data reported during the past 5 years indicate that rates of survival have increased among infants born at the borderline of viability, but less is known about how increased rates of survival among these infants relate to early childhood neurodevelopmental outcomes. Methods We compared survival and neurodevelopmental outcomes among infants born at 22 to 24 weeks of gestation, as assessed at 18 to 22 months of corrected age, across three consecutive birth-year epochs (2000-2003 [epoch 1], 2004-2007 [epoch 2], and 2008-2011 [epoch 3]). The infants were born at 11 centers that participated in the National Institute of Child Health and Human Development Neonatal Research Network. The primary outcome measure was a three-level outcome - survival without neurodevelopmental impairment, survival with neurodevelopmental impairment, or death. After accounting for differences in infant characteristics, including birth center, we used multinomial generalized logit models to compare the relative risk of survival without neurodevelopmental impairment, survival with neurodevelopmental impairment, and death. Results Data on the primary outcome were available for 4274 of 4458 infants (96%) born at the 11 centers. The percentage of infants who survived increased from 30% (424 of 1391 infants) in epoch 1 to 36% (487 of 1348 infants) in epoch 3 (P<0.001). The percentage of infants who survived without neurodevelopmental impairment increased from 16% (217 of 1391) in epoch 1 to 20% (276 of 1348) in epoch 3 (P=0.001), whereas the percentage of infants who survived with neurodevelopmental impairment did not change significantly (15% [207 of 1391] in epoch 1 and 16% [211 of 1348] in epoch 3, P=0.29). After adjustment for changes in the baseline characteristics of the infants over time, both the rate of survival with neurodevelopmental impairment (as compared with death) and the rate of survival without neurodevelopmental impairment (as compared with death) increased over time

  4. The Epigenetic Link between Prenatal Adverse Environments and Neurodevelopmental Disorders

    PubMed Central

    Kundakovic, Marija; Jaric, Ivana

    2017-01-01

    Prenatal adverse environments, such as maternal stress, toxicological exposures, and viral infections, can disrupt normal brain development and contribute to neurodevelopmental disorders, including schizophrenia, depression, and autism. Increasing evidence shows that these short- and long-term effects of prenatal exposures on brain structure and function are mediated by epigenetic mechanisms. Animal studies demonstrate that prenatal exposure to stress, toxins, viral mimetics, and drugs induces lasting epigenetic changes in the brain, including genes encoding glucocorticoid receptor (Nr3c1) and brain-derived neurotrophic factor (Bdnf). These epigenetic changes have been linked to changes in brain gene expression, stress reactivity, and behavior, and often times, these effects are shown to be dependent on the gestational window of exposure, sex, and exposure level. Although evidence from human studies is more limited, gestational exposure to environmental risks in humans is associated with epigenetic changes in peripheral tissues, and future studies are required to understand whether we can use peripheral biomarkers to predict neurobehavioral outcomes. An extensive research effort combining well-designed human and animal studies, with comprehensive epigenomic analyses of peripheral and brain tissues over time, will be necessary to improve our understanding of the epigenetic basis of neurodevelopmental disorders. PMID:28335457

  5. Neurodevelopmental Outcome in Preterm Infants

    ERIC Educational Resources Information Center

    Bos, Arend F.; Roze, Elise

    2011-01-01

    Aim: To determine the distribution of cognitive and motor scores in preterm children, and to establish the influence of brain lesions and decreasing gestational age thereon. Method: One hundred and six very preterm children (63 males, 43 females; gestational age 24.0-31.6wk; birthweight 480-2275g) were assessed for cognition and motor outcome at 6…

  6. Neurodevelopmental Outcomes in Children With Hemifacial Microsomia

    PubMed Central

    Collett, Brent R.; Speltz, Matthew L.; Cloonan, Yona Keich; Leroux, Brian G.; Kelly, Judith P.; Werler, Martha M.

    2011-01-01

    Objective To determine whether preadolescent children with hemifacial microsomia (HFM) have higher risk of neurodevelopmental delays than unaffected control individuals. Design Case-control follow-up study of neurodevelopment in children with and without HFM. Setting Case individuals were originally recruited from 26 craniofacial centers across the United States and Canada, and controls were recruited through community pediatricians. Participants One hundred thirty-six children with HFM (cases) and 568 unaffected children (controls). Main Exposure History of HFM. Main Outcome Measures The Peabody Picture Vocabulary Test–Third Edition, the Beery-Buktenica Developmental Test of Visual Motor Integration–Fifth Edition, and the Academic Competence scales from the Child Behavior Checklist and the Teacher Report Form. Results Children with HFM scored lower than controls on all measures (effect size = −0.27 to −0.45; P < .001 to P = .008). Compared with controls, cases were 2 to 3 times as likely to score in the at-risk range. Relative to controls, outcomes were worse for male cases and those whose mothers were 25 years or younger at the time of their birth. Cases with HFM plus other malformations had poorer outcomes, as did cases with hearing, vision, or speech impairments. Conclusions This is the first study, to our knowledge, to show that children with HFM have poorer neurodevelopmental outcomes than unaffected children, but further study using more detailed assessments is indicated. Clinically, the findings suggest that early neurodevelopmental screening is warranted for all children with HFM. PMID:21300653

  7. Neurodevelopmental outcomes of infants born prematurely.

    PubMed

    Aylward, Glen P

    2014-01-01

    Long-term follow-up of infants born prematurely is necessary to determine neurodevelopmental outcomes, particularly with the expansion of interest from major disabilities to high prevalence/low severity dysfunctions. Models of pathogenesis include changes due to developmental disruptions and to injury, the magnitude and type of change influenced by the infant's age, and central nervous system recovery and reorganization. Alterations in neurogenesis, migration, myelination, cell death, and synaptogenesis occur even in the absence of insult. Despite increased knowledge regarding these processes, the functional significance of brain abnormalities is unclear. Because of methodologic problems in follow-up studies, it is difficult to characterize outcome definitively. Nonetheless, an acceptable degree of agreement across studies is found with regard to specific neurodevelopmental outcomes: motor/neurologic function, visuomotor integrative skills, IQ, academic achievement, language, executive function, and attention-deficit hyperactivity disorder/behavioral issues. In general, children born prematurely have more problems in these areas than do their normal birth weight counterparts. Suggestions for improved analyses and clarification of outcomes include use of cluster analysis, structural equation modeling, growth curve analysis, developmental epidemiologic approaches, and better control of background variables using risk indexes and factor scores. Better assessment techniques measuring functions documented to be at higher risk of problems are discussed.

  8. Neurodevelopmental outcome of fetuses referred for ventriculomegaly

    PubMed Central

    Beeghly, M.; Ware, J.; Soul, J.; Plessis, A. Du; Khwaja, O.; Senapati, G. M.; Robson, C. D.; Robertson, R. L.; Poussaint, T. Y.; Barnewolt, C. E.; Feldman, H. A.; Estroff, J. A.; Levine, D.

    2010-01-01

    Objective To characterize the delivery and postnatal neurodevelopmental outcomes of fetuses referred for ventriculomegaly (VM). Methods Under an internal review board-approved protocol, pregnant women were referred for magnetic resonance imaging (MRI) after sonographic diagnosis of VM and classified into one of four diagnostic groups: Group 1, normal central nervous system (CNS); Group 2, isolated mild VM (10–12 mm); Group 3, isolated VM > 12 mm; and Group 4, other CNS findings. Pregnancy outcome was obtained. Follow-up visits were offered with assessment of neurodevelopmental, adaptive and neurological functioning at 6 months and 1 year and/or 2 years of age. Atrial diameter and VM group differences in developmental outcomes were evaluated using repeated measures logistic regression and Fishers exact test, respectively. Results Of 314 fetuses, 253 (81%) were liveborn and survived the neonatal period. Fetuses in Groups 4 and 3 were less likely to progress to live delivery and to survive the neonatal period (60% and 84%, respectively) than were those in Groups 2 or 1 (93% and 100%, respectively, P < 0.001). Of the 143 fetuses followed postnatally, between 41% and 61% had a Bayley Scales of Infant Development (BSID-II) psychomotor developmental index score in the delayed range (< 85) at the follow-up visits, whereas the BSID-II mental developmental index and Vineland Adaptive Behavior composite scores were generally in line with normative expectations. Among those that were liveborn, neither VM group nor prenatal atrial diameter was related to postnatal developmental outcome. Conclusions Diagnostic category and degree of fetal VM based on ultrasound and MRI measurements are associated with the incidence of live births and thus abnormal outcome. Among those undergoing formal postnatal testing, VM grade is not associated with postnatal developmental outcome, but motor functioning is more delayed than is cognitive or adaptive functioning. PMID:20069560

  9. Neuroimaging and Neurodevelopmental Outcome in Extremely Preterm Infants

    PubMed Central

    Barnes, Patrick D.; Bulas, Dorothy; Slovis, Thomas L.; Finer, Neil N.; Wrage, Lisa A.; Das, Abhik; Tyson, Jon E.; Stevenson, David K.; Carlo, Waldemar A.; Walsh, Michele C.; Laptook, Abbot R.; Yoder, Bradley A.; Van Meurs, Krisa P.; Faix, Roger G.; Rich, Wade; Newman, Nancy S.; Cheng, Helen; Heyne, Roy J.; Vohr, Betty R.; Acarregui, Michael J.; Vaucher, Yvonne E.; Pappas, Athina; Peralta-Carcelen, Myriam; Wilson-Costello, Deanne E.; Evans, Patricia W.; Goldstein, Ricki F.; Myers, Gary J.; Poindexter, Brenda B.; McGowan, Elisabeth C.; Adams-Chapman, Ira; Fuller, Janell; Higgins, Rosemary D.

    2015-01-01

    BACKGROUND: Extremely preterm infants are at risk for neurodevelopmental impairment (NDI). Early cranial ultrasound (CUS) is usual practice, but near-term brain MRI has been reported to better predict outcomes. We prospectively evaluated MRI white matter abnormality (WMA) and cerebellar lesions, and serial CUS adverse findings as predictors of outcomes at 18 to 22 months’ corrected age. METHODS: Early and late CUS, and brain MRI were read by masked central readers, in a large cohort (n = 480) of infants <28 weeks’ gestation surviving to near term in the Neonatal Research Network. Outcomes included NDI or death after neuroimaging, and significant gross motor impairment or death, with NDI defined as cognitive composite score <70, significant gross motor impairment, and severe hearing or visual impairment. Multivariable models evaluated the relative predictive value of neuroimaging while controlling for other factors. RESULTS: Of 480 infants, 15 died and 20 were lost. Increasing severity of WMA and significant cerebellar lesions on MRI were associated with adverse outcomes. Cerebellar lesions were rarely identified by CUS. In full multivariable models, both late CUS and MRI, but not early CUS, remained independently associated with NDI or death (MRI cerebellar lesions: odds ratio, 3.0 [95% confidence interval: 1.3–6.8]; late CUS: odds ratio, 9.8 [95% confidence interval: 2.8–35]), and significant gross motor impairment or death. In models that did not include late CUS, MRI moderate-severe WMA was independently associated with adverse outcomes. CONCLUSIONS: Both late CUS and near-term MRI abnormalities were associated with outcomes, independent of early CUS and other factors, underscoring the relative prognostic value of near-term neuroimaging. PMID:25554820

  10. Exposure to Mixtures of Metals and Neurodevelopmental Outcomes: A Review

    PubMed Central

    von Stackelberg, Katherine; Guzy, Elizabeth; Chu, Tian; Henn, Birgit Claus

    2016-01-01

    Current risk assessment guidance calls for an individual chemical-by-chemical approach that fails to capture potential interactive effects of exposure to environmental mixtures in the context of genomic influences. As an exploratory analysis, we develop a systematic review of prenatal and perinatal exposure to mixtures of lead (Pb), arsenic (As), cadmium (Cd), and manganese (Mn) and nonspecific developmental outcomes in children, including reduced IQ and decreased performance on developmental tests, using an adverse outcome pathway (AOP) framework to integrate lines of evidence based on evolving guidance developed by the Organization for Economic Cooperation and Development (OECD). Toxicological evidence suggests a greater than additive effect of combined exposures to As-Pb-Cd and Mn in the presence of one or more metals. Several epidemiologic studies also suggest synergistic effects from binary combinations of Pb-As and Pb-Cd. However, monitoring data from the National Health and Nutrition Examination Survey (NHANES) reveals the majority of the U.S. population has biomarker levels below those corresponding to exposure concentrations from the epidemiologic studies. This systematic review integrates relevant and diverse data sources using an AOP framework and provides an initial application of the OECD guidance in the context of potential neurodevelopmental toxicity of several metals, recognizing the evolving nature of regulatory interpretation and acceptance. PMID:26096925

  11. Adverse neurodevelopmental effects and hearing loss in children associated with manganese in well water, North Carolina, USA

    PubMed Central

    Langley, Ricky L; Kao, Yimin; Mort, Sandra A.; Bateman, Allen; Simpson, Barbara D.; Reich, Brian J

    2017-01-01

    Aim Heavy metals such as manganese, arsenic and lead can act as neurotoxins. There have been few human studies of neurobehavioral/neurodevelopmental effects of arsenic and manganese on children in the United States. Since 1998, North Carolina has tested all new private wells for manganese, arsenic and lead. This study was conducted to evaluate adverse neurodevelopmental effects (delayed milestones, speech/language disorders and hearing loss) in children and metal concentrations in well water. Methods A quasi-regression model of the number of children (0–35 months of age) with adverse neurodevelopmental effects as outcome measures and aggregate mean metal concentration (arsenic, lead, and manganese) in private well water in each county as exposures. Results Over 70,000 private well water samples from 1998 to 2011 were analyzed for metal content. From 2008 to 2011, an average of 17,000 children was enrolled in the Infant Toddler Program. On average, 1.7% of children in this age range in each county had a speech/language disorder, 0.24% had a diagnosis of delayed milestones, and 0.026% had a diagnosis of hearing loss. The county mean manganese concentration was significantly and positively associated with the prevalence of delayed milestones and hearing loss in the children. No association was found for metal concentrations and speech/language disorders. Conclusion This ecological study indicates that further investigation of manganese in well water and associated neurodevelopmental health outcomes in children is needed. PMID:28344850

  12. Two-Year Neurodevelopmental Outcomes of Ventilated Preterm Infants Treated with Inhaled Nitric Oxide

    PubMed Central

    Walsh, Michele C.; Hibbs, Anna Maria; Martin, Camilia R.; Cnaan, Avital; Keller, Roberta L.; Vittinghoff, Eric; Martin, Richard J.; Truog, William E.; Ballard, Philip L.; Zadell, Arlene; Wadlinger, Sandra R.; Coburn, Christine E.; Ballard, Roberta A.

    2009-01-01

    Objective In a randomized multi-center trial, we demonstrated that inhaled nitric oxide begun between 7 and 21 days and treated for 24 days significantly increased survival without bronchopulmonary dysplasia (BPD) in ventilated premature infants weighing < 1250 g. Since some preventative BPD treatments are associated with neurodevelopmental impairment, we designed a follow-up study to assess the safety of nitric oxide. Study design Our hypothesis was that inhaled nitric oxide will not increase neurodevelopmental impairment compared with placebo. We prospectively evaluated neurodevelopmental and growth outcomes at 24 months PMA in 477 (89%) of 535 surviving infants enrolled in the trial. Results In the treated group, 109 of 243 children (45%) had neurodevelopmental impairment (moderate or severe cerebral palsy, bilateral blindness, bilateral hearing loss or score of less than 70 on the Bayley Scales II), compared with 114 of 234 (49%) in the placebo group (Relative Risk 0.92; 95% confidence interval, 0.75 to 1.12; p = 0.39). No differences on any subcomponent of neurodevelopmental impairment or growth variables were found between inhaled nitric oxide or placebo. Conclusions Inhaled nitric oxide improved survival free of bronchopulmonary dysplasia with no adverse neurodevelopmental effects at 2 years of age. PMID:20138299

  13. Surgery and Neurodevelopmental Outcome of Very Low Birth Weight Infants

    PubMed Central

    Morriss, Frank H.; Saha, Shampa; Bell, Edward F.; Colaizy, Tarah T.; Stoll, Barbara J.; Hintz, Susan R.; Shankaran, Seetha; Vohr, Betty R.; Hamrick, Shannon E. G.; Pappas, Athina; Jones, Patrick M.; Carlo, Waldemar A.; Laptook, Abbot R.; Van Meurs, Krisa P.; Sánchez, Pablo J.; Hale, Ellen C.; Newman, Nancy S.; Das, Abhik; Higgins, Rosemary D.

    2014-01-01

    IMPORTANCE Reduced death and neurodevelopmental impairment among infants is a goal of perinatal medicine. OBJECTIVE To assess the association between surgery during the initial hospitalization and death or neurodevelopmental impairment of very low birth weight infants. DESIGN Retrospective cohort analysis of patients enrolled in the National Institute of Child Health and Human Development Neonatal Research Network Generic Database from 1998–2009 and evaluated at 18–22 months’ corrected age. SETTING 22 academic neonatal intensive care units. PARTICIPANTS Inclusion criteria were: birth weight 401–1500 g; survival to 12 hours; available for follow-up. Some conditions were excluded. 12 111 infants were included in analyses, 87% of those eligible. EXPOSURES Surgical procedures; surgery also classified by expected anesthesia type as major (general anesthesia) or minor surgery (non-general anesthesia). MAIN OUTCOME MEASURES Multivariable logistic regression analyses planned a priori were performed for the primary outcome of death or neurodevelopmental impairment and for the secondary outcome of neurodevelopmental impairment among survivors. Multivariable linear regression analyses were performed as planned for the adjusted means of Bayley Scales of Infant Development, Second Edition, Mental Developmental Index and Psychomotor Developmental Index for patients born before 2006. RESULTS There were 2186 major, 784 minor and 9141 no surgery patients. The risk-adjusted odds ratio of death or neurodevelopmental impairment for all surgery patients compared with those who had no surgery was 1.29 (95% confidence interval 1.08–1.55). For patients who had major surgery compared with those who had no surgery the risk-adjusted odds ratio of death or neurodevelopmental impairment was 1.52 (95% confidence interval 1.24–1.87). Patients classified as having minor surgery had no increased adjusted risk. Among survivors who had major surgery compared with those who had no surgery

  14. Neurodevelopmental outcomes in children with Down syndrome and infantile spasms

    PubMed Central

    Tapp, Sarah; Anderson, Tovi; Visootsak, Jeannie

    2015-01-01

    Down syndrome (DS) is the most common genetic cause of intellectual disability in the United States. The prevalence of seizure in individuals with DS is 1–13%, and infantile spasm (IS) occurs in 6–32% of those with seizures. Since IS is relatively common in children with DS, it is important to understand the impact IS has on the neurodevelopmental outcomes in order to provide appropriate anticipatory guidance to help maximize the potential of these children. Our study is the first to compare the neurodevelopmental outcomes of children with DS and IS (DS + IS) to children with DS and no history of seizures (DS − IS). Using the Bayley Scales of Infant and Toddler Development III, we assessed the neurodevelopment of 29 subjects (eight DS + IS and 21 DS − IS). Neurodevelopmental outcome was poor in the DS + IS cohort, but the delay in treatment does not appear to contribute to any differences in their developmental scores. However, when compared to children with DS − IS, the DS + IS cohort scored approximately 20 points less in all domains including cognitive, motor, and language (P < 0.05). Our results indicate that IS may impact the neurodevelopmental outcomes of children with DS + IS; thus, it is important to provide ongoing developmental and educational assessments and potentially additional therapies for children with DS + IS. PMID:26523121

  15. Reverse Engineering Adverse Outcome Pathways

    SciTech Connect

    Perkins, Edward; Chipman, J.K.; Edwards, Stephen; Habib, Tanwir; Falciani, Francesco; Taylor, Ronald C.; Van Aggelen, Graham; Vulpe, Chris; Antczak, Philipp; Loguinov, Alexandre

    2011-01-30

    The toxicological effects of many stressors are mediated through unknown, or poorly characterized, mechanisms of action. We describe the application of reverse engineering complex interaction networks from high dimensional omics data (gene, protein, metabolic, signaling) to characterize adverse outcome pathways (AOPs) for chemicals that disrupt the hypothalamus-pituitary-gonadal endocrine axis in fathead minnows. Gene expression changes in fathead minnow ovaries in response to 7 different chemicals, over different times, doses, and in vivo versus in vitro conditions were captured in a large data set of 868 arrays. We examined potential AOPs of the antiandrogen flutamide using two mutual information theory methods, ARACNE and CLR to infer gene regulatory networks and potential adverse outcome pathways. Representative networks from these studies were used to predict a network path from stressor to adverse outcome as a candidate AOP. The relationship of individual chemicals to an adverse outcome can be determined by following perturbations through the network in response to chemical treatment leading to the nodes associated with the adverse outcome. Identification of candidate pathways allows for formation of testable hypotheses about key biologic processes, biomarkers or alternative endpoints, which could be used to monitor an adverse outcome pathway. Finally, we identify the unique challenges facing the application of this approach in ecotoxicology, and attempt to provide a road map for the utilization of these tools. Key Words: mechanism of action, toxicology, microarray, network inference

  16. Pesticide Exposure and Neurodevelopmental Outcomes: Review of the Epidemiologic and Animal Studies

    PubMed Central

    Burns, Carol J.; McIntosh, Laura J.; Mink, Pamela J.; Jurek, Anne M.; Li, Abby A.

    2013-01-01

    Assessment of whether pesticide exposure is associated with neurodevelopmental outcomes in children can best be addressed with a systematic review of both the human and animal peer-reviewed literature. This review analyzed epidemiologic studies testing the hypothesis that exposure to pesticides during pregnancy and/or early childhood is associated with neurodevelopmental outcomes in children. Studies that directly queried pesticide exposure (e.g., via questionnaire or interview) or measured pesticide or metabolite levels in biological specimens from study participants (e.g., blood, urine, etc.) or their immediate environment (e.g., personal air monitoring, home dust samples, etc.) were eligible for inclusion. Consistency, strength of association, and dose response were key elements of the framework utilized for evaluating epidemiologic studies. As a whole, the epidemiologic studies did not strongly implicate any particular pesticide as being causally related to adverse neurodevelopmental outcomes in infants and children. A few associations were unique for a health outcome and specific pesticide, and alternative hypotheses could not be ruled out. Our survey of the in vivo peer-reviewed published mammalian literature focused on effects of the specific active ingredient of pesticides on functional neurodevelopmental endpoints (i.e., behavior, neuropharmacology and neuropathology). In most cases, effects were noted at dose levels within the same order of magnitude or higher compared to the point of departure used for chronic risk assessments in the United States. Thus, although the published animal studies may have characterized potential neurodevelopmental outcomes using endpoints not required by guideline studies, the effects were generally observed at or above effect levels measured in repeated-dose toxicology studies submitted to the U.S. Environmental Protection Agency (EPA). Suggestions for improved exposure assessment in epidemiology studies and more effective

  17. Pesticide exposure and neurodevelopmental outcomes: review of the epidemiologic and animal studies.

    PubMed

    Burns, Carol J; McIntosh, Laura J; Mink, Pamela J; Jurek, Anne M; Li, Abby A

    2013-01-01

    Assessment of whether pesticide exposure is associated with neurodevelopmental outcomes in children can best be addressed with a systematic review of both the human and animal peer-reviewed literature. This review analyzed epidemiologic studies testing the hypothesis that exposure to pesticides during pregnancy and/or early childhood is associated with neurodevelopmental outcomes in children. Studies that directly queried pesticide exposure (e.g., via questionnaire or interview) or measured pesticide or metabolite levels in biological specimens from study participants (e.g., blood, urine, etc.) or their immediate environment (e.g., personal air monitoring, home dust samples, etc.) were eligible for inclusion. Consistency, strength of association, and dose response were key elements of the framework utilized for evaluating epidemiologic studies. As a whole, the epidemiologic studies did not strongly implicate any particular pesticide as being causally related to adverse neurodevelopmental outcomes in infants and children. A few associations were unique for a health outcome and specific pesticide, and alternative hypotheses could not be ruled out. Our survey of the in vivo peer-reviewed published mammalian literature focused on effects of the specific active ingredient of pesticides on functional neurodevelopmental endpoints (i.e., behavior, neuropharmacology and neuropathology). In most cases, effects were noted at dose levels within the same order of magnitude or higher compared to the point of departure used for chronic risk assessments in the United States. Thus, although the published animal studies may have characterized potential neurodevelopmental outcomes using endpoints not required by guideline studies, the effects were generally observed at or above effect levels measured in repeated-dose toxicology studies submitted to the U.S. Environmental Protection Agency (EPA). Suggestions for improved exposure assessment in epidemiology studies and more effective

  18. Reverse engineering adverse outcome pathways.

    PubMed

    Perkins, Edward J; Chipman, J Kevin; Edwards, Stephen; Habib, Tanwir; Falciani, Francesco; Taylor, Ronald; Van Aggelen, Graham; Vulpe, Chris; Antczak, Philipp; Loguinov, Alexandre

    2011-01-01

    The toxicological effects of many stressors are mediated through unknown, or incompletely characterized, mechanisms of action. The application of reverse engineering complex interaction networks from high dimensional omics data (gene, protein, metabolic, signaling) can be used to overcome these limitations. This approach was used to characterize adverse outcome pathways (AOPs) for chemicals that disrupt the hypothalamus-pituitary-gonadal endocrine axis in fathead minnows (FHM, Pimephales promelas). Gene expression changes in FHM ovaries in response to seven different chemicals, over different times, doses, and in vivo versus in vitro conditions, were captured in a large data set of 868 arrays. Potential AOPs of the antiandrogen flutamide were examined using two mutual information-based methods to infer gene regulatory networks and potential AOPs. Representative networks from these studies were used to predict network paths from stressor to adverse outcome as candidate AOPs. The relationship of individual chemicals to an adverse outcome can be determined by following perturbations through the network in response to chemical treatment, thus leading to the nodes associated with the adverse outcome. Identification of candidate pathways allows for formation of testable hypotheses about key biological processes, biomarkers, or alternative endpoints that can be used to monitor an AOP. Finally, the unique challenges facing the application of this approach in ecotoxicology were identified and a road map for the utilization of these tools presented.

  19. Cytokines and Neurodevelopmental Outcomes in Extremely Low Birth Weight Infants

    PubMed Central

    Carlo, Waldemar A.; McDonald, Scott A.; Tyson, Jon E.; Stoll, Barbara J.; Ehrenkranz, Richard A.; Shankaran, Seetha; Goldberg, Ronald N.; Das, Abhik; Schendel, Diana; Thorsen, Poul; Skogstrand, Kristin; Hougaard, David M.; Oh, William; Laptook, Abbot R.; Duara, Shahnaz; Fanaroff, Avroy A.; Donovan, Edward F.; Korones, Sheldon B.; Stevenson, David K.; Papile, Lu-Ann; Finer, Neil N.; O’Shea, T. Michael; Poindexter, Brenda B.; Wright, Linda L.; Ambalavanan, Namasivayam; Higgins, Rosemary D.

    2011-01-01

    Objective To determine if selected pro-inflammatory and anti-inflammatory cytokines/mediators of inflammation reported to be related to development of cerebral palsy predict neurodevelopmental outcome in extremely low birth weight infants. Study design Infants with birth weights ≤ 1000 g (n=1067) had blood samples collected at birth and on days 3±1, 7±1, 14±3, and 21±3 to examine the association between cytokines and neurodevelopmental outcomes. The analyses were focused on five cytokines (IL-1β, IL-8, TNF-α, RANTES, and IL-2) reported to be most predictive of CP in term and late preterm infants. Results IL-8 was higher on days 0–4 and subsequently in infants who developed CP compared with infants who did not develop CP in both unadjusted and adjusted analyses. Other cytokines (IL-12, IL-17, TNF-β, SIL-rα, MIP-1β) were found to be altered on days 0–4 in infants who developed CP. Conclusions CP in former preterm infants may, in part, have a late perinatal and/or early neonatal inflammatory origin. PMID:21798559

  20. Adverse Outcomes in Group Psychotherapy

    PubMed Central

    Roback, Howard B.

    2000-01-01

    Group forms of therapy have been growing at a rapid rate, in part because of their documented effectiveness and economic considerations such as managed care. It is therefore becoming increasingly important to assess the psychological risks of these interventions. The author provides an overview of the published literature and conference presentations on negative effects in adult outpatient groups. Although much of the literature on adverse outcomes in group therapy focuses on single risk factors (e.g., negative leader, group process, or patient characteristics), the author argues that an interactional model should be encouraged. Means of reducing casualties are also discussed, as well as methodological issues and research directions. PMID:10896735

  1. Early-Childhood Neurodevelopmental Outcomes Are Not Improving for Infants Born at <25 Weeks' Gestational Age

    PubMed Central

    Kendrick, Douglas E.; Wilson-Costello, Deanne E.; Das, Abhik; Bell, Edward F.; Vohr, Betty R.; Higgins, Rosemary D.

    2011-01-01

    OBJECTIVE: We compared neurodevelopmental outcomes at 18 to 22 months' corrected age of infants born with extremely low birth weight at an estimated gestational age of <25 weeks during 2 periods: 1999–2001 (epoch 1) and 2002–2004 (epoch 2). PATIENTS AND METHODS: We conducted a multicenter, retrospective analysis of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Perinatal and neonatal variables and outcomes were compared between epochs. Neurodevelopmental outcomes at 18 to 22 months' corrected age were evaluated with neurologic exams and Bayley Scales of Infant Development II. Logistic regression analyses determined the independent risk of epoch for adverse outcomes. RESULTS: Infant survival was similar between epochs (epoch 1, 35.4%, vs epoch 2, 32.3%; P = .09). A total of 411 of 452 surviving infants in epoch 1 and 405 of 438 surviving infants in epoch 2 were evaluated at 18 to 22 months' corrected age. Cesarean delivery (P = .03), surgery for patent ductus arteriosus (P = .004), and late sepsis (P = .01) were more common in epoch 2, but postnatal steroid use was dramatically reduced (63.5% vs 32.8%; P < .0001). Adverse outcomes at 18 to 22 months' corrected age were common in both epochs. Moderate-to-severe cerebral palsy was diagnosed in 11.1% of surviving infants in epoch 1 and 14.9% in epoch 2 (adjusted odds ratio [OR]: 1.52 [95% confidence interval (CI): 0.86–2.71]; P = .15), the Mental Developmental Index was <70 in 44.9% in epoch 1 and 51% in epoch 2 (OR: 1.30 [95% CI: 0.91–1.87]; P = .15), and neurodevelopmental impairment was diagnosed in 50.1% of surviving infants in epoch 1 and 58.7% in epoch 2 (OR: 1.4 [95% CI: 0.98–2.04]; P = .07). CONCLUSIONS: Early-childhood outcomes for infants born at <25 weeks' estimated gestational age were unchanged between the 2 periods. PMID:21187312

  2. Cord Blood DNA Methylation Biomarkers for Predicting Neurodevelopmental Outcomes

    PubMed Central

    Hodyl, Nicolette A.; Roberts, Claire T.; Bianco-Miotto, Tina

    2016-01-01

    Adverse environmental exposures in pregnancy can significantly alter the development of the fetus resulting in impaired child neurodevelopment. Such exposures can lead to epigenetic alterations like DNA methylation, which may be a marker of poor cognitive, motor and behavioral outcomes in the infant. Here we review studies that have assessed DNA methylation in cord blood following maternal exposures that may impact neurodevelopment of the child. We also highlight some key studies to illustrate the potential for DNA methylation to successfully identify infants at risk for poor outcomes. While the current evidence is limited, in that observations to date are largely correlational, in time and with larger cohorts analyzed and longer term follow-up completed, we may be able to develop epigenetic biomarkers that not only indicate adverse early life exposures but can also be used to identify individuals likely to be at an increased risk of impaired neurodevelopment even in the absence of detailed information regarding prenatal environment. PMID:27918480

  3. Strategic approaches to adverse outcome pathway development

    EPA Science Inventory

    Adverse outcome pathways (AOPs) are conceptual frameworks for organizing biological and toxicological knowledge in a manner that supports extrapolation of data pertaining to the initiation or early progression of toxicity to an apical adverse outcome that occurs at a level of org...

  4. DoMINO: Donor milk for improved neurodevelopmental outcomes

    PubMed Central

    2014-01-01

    Background Provision of mother’s own milk is the optimal way to feed infants, including very low birth weight infants (VLBW, <1500 g). Importantly for VLBW infants, who are at elevated risk of neurologic sequelae, mother’s own milk has been shown to enhance neurocognitive development. Unfortunately, the majority of mothers of VLBW infants are unable to provide an adequate supply of milk and thus supplementation with formula or donor milk is necessary. Given the association between mother’s own milk and neurodevelopment, it is important to ascertain whether provision of human donor milk as a supplement may yield superior neurodevelopmental outcomes compared to formula. Our primary hypothesis is that VLBW infants fed pasteurized donor milk compared to preterm formula as a supplement to mother’s own milk for 90 days or until hospital discharge, whichever comes first, will have an improved cognitive outcome as measured at 18 months corrected age on the Bayley Scales of Infant Development, 3rd ed. Secondary hypotheses are that the use of pasteurized donor milk will: (1) reduce a composite of death and serious morbidity; (2) support growth; and (3) improve language and motor development. Exploratory research questions include: Will use of pasteurized donor milk: (1) influence feeding tolerance and nutrient intake (2) have an acceptable cost effectiveness from a comprehensive societal perspective? Methods/Design DoMINO is a multi-centre, intent-to-treat, double blinded, randomized control trial. VLBW infants (n = 363) were randomized within four days of birth to either (1) pasteurized donor milk or (2) preterm formula whenever mother’s own milk was unavailable. Study recruitment began in October 2010 and was completed in December 2012. The 90 day feeding intervention is complete and long-term follow-up is underway. Discussion Preterm birth and its complications are a leading cause long-term morbidity among Canadian children. Strategies to mitigate this

  5. Severe bronchiolitis in infants born very preterm and neurodevelopmental outcome at 2 years.

    PubMed

    Gouin, Marion; Nguyen, Sylvie; Savagner, Christophe; Troussier, Francoise; Gascouin, Géraldine; Rozé, Jean-Christophe; Flamant, Cyril

    2013-05-01

    Preterm infants are at greater risk of bronchopulmonary dysplasia, which is associated with neurodevelopmental impairment. These infants are also more likely to develop severe bronchiolitis, which can contribute to neurodevelopmental impairment. The aim of this study was to determine whether severe bronchiolitis in very preterm infants (born before 33 weeks of gestation) was associated with an increased risk of neurodevelopmental impairment at 2 years of age. We analyzed a population-based cohort of infants (the Loire Infant Follow-up Team cohort) born between 1 January 2003 and 31 December 2009. Severe bronchiolitis was defined as hospitalization due to bronchiolitis during the first year of life. Neurodevelopmental outcome was assessed at 2 years of corrected age. A total of 2,405 infants were included in this analysis and categorized based on neonatal respiratory status: 1,308 (54.4 %) received no respiratory assistance, 864(35.9 %) received oxygen for <28 days, and 167 (6.9 %) had mild and 66 (2.7) moderate or severe bronchopulmonary dysplasia. At 2 years, 502 children displayed non-optimal neurodevelopmental outcome (20.9 %). Moderate or severe bronchopulmonary dysplasia was significantly associated with non-optimal neurodevelopmental outcome at 2 years (adjusted odds ratios (OR) = 2.3 [95 % confidence interval (CI): 1.3-3.9], p = 0.003). In the first year, 318 infants acquired severe bronchiolitis (13.2 %), which was not associated with non-optimal neurodevelopmental outcome (adjusted OR = 1.0 [95 % CI: 0.8-1.4]; p = 0.88). In conclusion, respiratory status in the neonatal period was significantly associated with non-optimal neurodevelopmental outcome at 2 years, while severe bronchiolitis was not.

  6. Neurodevelopmental outcome at two years of age after general and awake-regional anaesthesia in infancy: a randomised controlled trial

    PubMed Central

    Davidson, Andrew J.; Disma, Nicola; de Graaff, Jurgen C.; Withington, Davinia E.; Dorris, Liam; Bell, Graham; Stargatt, Robyn; Bellinger, David C.; Schuster, Tibor; Arnup, Sarah J.; Hardy, Pollyanna; Hunt, Rodney W.; Takagi, Michael J.; Giribaldi, Gaia; Hartmann, Penelope L.; Salvo, Ida; Morton, Neil S.; von Ungern Sternberg, Britta S; Locatelli, Bruno Guido; Wilton, Niall; Lynn, Anne; Thomas, Joss J.; Polaner, David; Bagshaw, Oliver; Szmuk, Peter; Absalom, Anthony R.; Frawley, Geoff; Berde, Charles; Ormond, Gillian D; Marmor, Jacki; Ellen, Mary

    2016-01-01

    Summary Background There is pre-clinical evidence that general anaesthetics affect brain development. There is mixed evidence from cohort studies that young children exposed to anaesthesia may have an increased risk of poorer neurodevelopmental outcome. This trial aims to determine if GA in infancy has any impact on neurodevelopmental outcome. The primary outcome for the trial is neurodevelopmental outcome at 5 years of age. The secondary outcome is neurodevelopmental outcome at two years of age and is reported here. Methods We performed an international assessor-masked randomised controlled equivalence trial in infants less than 60 weeks post-menstrual age, born at greater than 26 weeks gestational age having inguinal herniorrhaphy. Infants were excluded if they had existing risk factors for neurologic injury. Infants were randomly assigned to awake-regional (RA) or sevoflurane-based general anaesthesia (GA). Web-based randomisation was performed in blocks of two or four and stratified by site and gestational age at birth. The outcome for analysis was the composite cognitive score of the Bayley Scales of Infant and Toddler Development, Third Edition. The analysis was as-per-protocol adjusted for gestational age at birth. A difference in means of five points (1/3 SD) was predefined as the clinical equivalence margin. The trial was registered at ANZCTR, ACTRN12606000441516 and ClinicalTrials.gov, NCT00756600. Findings Between February 2007, and January 2013, 363 infants were randomised to RA and 359 to GA. Outcome data were available for 238 in the RA and 294 in the GA arms. The median duration of anaesthesia in the GA arm was 54 minutes. For the cognitive composite score there was equivalence in means between arms (RA-GA: +0·169, 95% CI −2·30 to +2·64). Interpretation For this secondary outcome we found no evidence that just under an hour of sevoflurane anaesthesia in infancy increases the risk of adverse neurodevelopmental outcome at two years of age compared

  7. Construction and Characterization of a Population-Based Cohort to Study the Association of Anesthesia Exposure with Neurodevelopmental Outcomes

    PubMed Central

    Hu, Danqing; Flick, Randall P.; Gleich, Stephen J.; Scanlon, Maura M.; Zaccariello, Michael J.; Colligan, Robert C.; Katusic, Slavica K.; Schroeder, Darrell R.; Hanson, Andrew C.; Buenvenida, Shonie L.; Wilder, Robert T.; Sprung, Juraj; Warner, David O.

    2016-01-01

    Exposure to general anesthesia at an early age has been associated with adverse neurodevelopmental outcomes in both animal and human studies, but some of these studies employed anesthetic agents that are no longer in clinical use. In this manuscript, we describe the methods used to construct a new population-based study cohort to study the association between early anesthetic exposure and subsequent neurodevelopmental outcomes. A birth cohort of all children born in Olmsted County, MN from January 1, 1996 to December 31, 2000 was identified. For each, school enrollment status in the Independent School District (ISD) 535 at age 5 or 6 and all episodes of anesthetic exposure before age 3 were identified. A study cohort was created by matching children enrolled in ISD 535 based on the propensity of receiving general anesthesia. Three analyses were performed to characterize the study cohort by comparing the birth and parental information, comorbidities, and socioeconomic status. The first analysis compared the characteristics of birth cohort children who were and were not enrolled in ISD 535. The second analysis evaluated the success of the propensity matching schemes in creating groups of children that were similar in measured characteristics except for anesthesia exposure. The third analysis compared the characteristics of children with anesthesia exposures who were and were not included in the final cohort based on propensity matching. Results of these analyses demonstrate only slight differences among the comparison groups, and therefore these are unlikely to compromise our future analysis of anesthetic exposure and neurodevelopmental outcomes. PMID:27167371

  8. Neurodevelopmental outcome and risk factors for impaired development of African American infants in an underserved urban population: a population-based study.

    PubMed

    Perenyi, Agnes; Katz, Joanne S; Sklar, Tzipporah; Flom, Peter

    2011-08-01

    We aimed 1) to define risk factors for adverse outcome in urban African American patients, 2) to determine whether clinical variables as risk factors are congruent with previously published data, and 3) to identify the proportion of infants with different outcomes. The study included African American infants who were born and participated in neurodevelopmental follow-up. Infants with gestational age range of 23 to 41 weeks, and birth weight (BW) range of 495 to 3,965 g were classified by developmental outcome. Among the smallest infants, BW, gestational age, gender and respiratory distress syndrome were significantly (p<.05) associated with adverse outcome. No significant risk factors were identified for adverse outcome in the two other birth weight categories. Adverse outcomes were seen more frequently in infants with BW ≤1,500 g than in larger infants. The number of infants with severe outcome was found higher than previously reported and may be related to different racial/generational origin.

  9. RACIAL RESIDENTIAL SEGREGATION AND ADVERSE BIRTH OUTCOMES

    EPA Science Inventory

    INTRODUCTION. The disparity between black and white women's adverse birth outcomes has been subject to much investigation, yet the factors underlying its persistence remain elusive, which has encouraged research on neighborhood-level influences, including racial residential segr...

  10. Adverse Outcome Pathways: From Definition to Application

    EPA Science Inventory

    A challenge for both human health and ecological toxicologists is the transparent application of mechanistic (e.g., molecular, biochemical, histological) data to risk assessments. The adverse outcome pathway (AOP) is a conceptual framework designed to meet this need. Specifical...

  11. Neurodevelopmental Outcomes of Extremely Low Birth Weight Infants with Spontaneous Intestinal Perforation or Surgical Necrotizing Enterocolitis

    PubMed Central

    Wadhawan, Rajan; Oh, William; Hintz, Susan R; Blakely, Martin L; Das, Abhik; Bell, Edward F.; Saha, Shampa; Laptook, Abbot R.; Shankaran, Seetha; Stoll, Barbara J.; Walsh, Michele C.; Higgins, Rosemary D.

    2013-01-01

    Objective To determine if extremely low birth weight infants with surgical necrotizing enterocolitis have a higher risk of death or neurodevelopmental impairment and neurodevelopmental impairment among survivors (secondary outcome) at 18–22 months corrected age compared to infants with spontaneous intestinal perforation and infants without necrotizing enterocolitis or spontaneous intestinal perforation. Study Design Retrospective analysis of the Neonatal Research Network very low birth weight registry, evaluating extremely low birth weight infants born between 2000–2005. The study infants were designated into 3 groups: 1) Spontaneous intestinal perforation without necrotizing enterocolitis; 2) Surgical necrotizing enterocolitis (Bell's stage III); and 3) Neither spontaneous intestinal perforation nor necrotizing enterocolitis. Multivariate logistic regression analysis was performed to evaluate the association between the clinical group and death or neurodevelopmental impairment, controlling for multiple confounding factors including center. Results Infants with surgical necrotizing enterocolitis had the highest rate of death prior to hospital discharge (53.5%) and death or neurodevelopmental impairment (82.3%) compared to infants in the spontaneous intestinal perforation group (39.1% and 79.3%) and no necrotizing enterocolitis/no spontaneous intestinal perforation group (22.1% and 53.3%; p<0.001). Similar results were observed for neurodevelopmental impairment among survivors. On logistic regression analysis, both spontaneous intestinal perforation and surgical necrotizing enterocolitis were associated with increased risk of death or neurodevelopmental impairment (adjusted OR 2.21, 95% CI: 1.5, 3.2 and adjusted OR 2.11, 95% CI: 1.5, 2.9 respectively) and neurodevelopmental impairment among survivors (adjusted OR 2.17, 95% CI: 1.4, 3.2 and adjusted OR 1.70, 95% CI: 1.2, 2.4 respectively). Conclusions Spontaneous intestinal perforation and surgical necrotizing

  12. Neurodevelopmental Outcomes in Postnatal Growth-Restricted Preterm Infants with Postnatal Head-Sparing

    PubMed Central

    Meyers, Jeffrey M.; Bann, Carla M.; Stoll, Barbara J.; D’Angio, Carl T.; Bell, Edward F.; Duncan, Andrea F.; Guillet, Ronnie

    2016-01-01

    Objective To compare neurodevelopmental outcomes in postnatal growth-restricted infants born < 29 weeks with and without postnatal head-sparing. Study Design We analyzed developmental outcomes at 2 years of age among postnatally growth-restricted infants with and without head-sparing. The primary outcome was Bayley III cognitive composite score; secondary outcomes included Bayley III motor composite score, moderate/severe cerebral palsy, GMFCS level ≥2, and presence or absence of neurodevelopmental impairment (NDI). Results Of 1098 infants evaluated at 18–22 months, 658 were postnatally growth-restricted, of whom 301 had head-sparing. In the multivariate model including independent risk factors for poor growth and poor developmental outcome, infants with head-sparing had higher adjusted motor composite scores (mean difference 4.65, p<0.01), but no differences in other neurodevelopmental outcomes. Conclusion Postnatal head-sparing is associated with improved neurodevelopmental outcome in extremely preterm infants, specifically Bayley III motor scores, but whether beneficial effects of PHS persist later in life is unknown. PMID:27629374

  13. Putative adverse outcome pathways relevant to neurotoxicity

    PubMed Central

    Bal-Price, Anna; Crofton, Kevin M.; Sachana, Magdalini; Shafer, Timothy J.; Behl, Mamta; Forsby, Anna; Hargreaves, Alan; Landesmann, Brigitte; Lein, Pamela J.; Louisse, Jochem; Monnet-Tschudi, Florianne; Paini, Alicia; Rolaki, Alexandra; Schrattenholz, André; Suñol, Cristina; van Thriel, Christoph; Whelan, Maurice; Fritsche, Ellen

    2016-01-01

    The Adverse Outcome Pathway (AOP) framework provides a template that facilitates understanding of complex biological systems and the pathways of toxicity that result in adverse outcomes (AOs). The AOP starts with an molecular initiating event (MIE) in which a chemical interacts with a biological target(s), followed by a sequential series of KEs, which are cellular, anatomical, and/or functional changes in biological processes, that ultimately result in an AO manifest in individual organisms and populations. It has been developed as a tool for a knowledge-based safety assessment that relies on understanding mechanisms of toxicity, rather than simply observing its adverse outcome. A large number of cellular and molecular processes are known to be crucial to proper development and function of the central (CNS) and peripheral nervous systems (PNS). However, there are relatively few examples of well-documented pathways that include causally linked MIEs and KEs that result in adverse outcomes in the CNS or PNS. As a first step in applying the AOP framework to adverse health outcomes associated with exposure to exogenous neurotoxic substances, the EU Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM) organized a workshop (March 2013, Ispra, Italy) to identify potential AOPs relevant to neurotoxic and developmental neurotoxic outcomes. Although the AOPs outlined during the workshop are not fully described, they could serve as a basis for further, more detailed AOP development and evaluation that could be useful to support human health risk assessment in a variety of ways. PMID:25605028

  14. The Complement System and Adverse Pregnancy Outcomes

    PubMed Central

    Regal, Jean F.; Gilbert, Jeffrey S.; Burwick, Richard M.

    2015-01-01

    Adverse pregnancy outcomes significantly contribute to morbidity and mortality for mother and child, with lifelong health consequences for both. The innate and adaptive immune system must be regulated to insure survival of the feta allograft, and the complement system is no exception. An intact complement system optimizes placental development and function and is essential to maintain host defense and fetal survival. Complement regulation is apparent at the placental interface from early pregnancy with some degree of complement activation occurring normally throughout gestation. However, a number of pregnancy complications including early pregnancy loss, fetal growth restriction, hypertensive disorders of pregnancy and preterm birth are associated with excessive or misdirected complement activation, and are more frequent in women with inherited or acquired complement system disorders or complement gene mutations. Clinical studies employing complement biomarkers in plasma and urine implicate dysregulated complement activation in components of each of the adverse pregnancy outcomes. In addition, mechanistic studies in rat and mouse models of adverse pregnancy outcomes address the complement pathways or activation products of importance and allow critical analysis of the pathophysiology. Targeted complement therapeutics are already in use to control adverse pregnancy outcomes in select situations. A clearer understanding of the role of the complement system in both normal pregnancy and complicated or failed pregnancy will allow a rational approach to future therapeutic strategies for manipulating complement with the goal of mitigating adverse pregnancy outcomes, preserving host defense, and improving long term outcomes for both mother and child. PMID:25802092

  15. Neurodevelopmental outcome in patients with terminal deletion of the short arm of chromosome 20

    SciTech Connect

    Frazer, C.H.; Hobbs, N.; Rappaport, L.

    1994-09-01

    Clinical geneticists and genetic counselors are often expected to provide information concerning anticipated neurodevelopmental outcome in children with chromosome abnormalities. Accurate prediction, however, may be impossible, and is at the least hampered by insufficient data and by natural variation in expression. Our experience with a now 27-month-old boy with terminal 20p- underscores this issue. A newborn male with multiple congenital anomalies, including pulmonary artery stenosis, vertebral anomalies, posterior ocular embryotoxon and multiple dysmorphic features was found to have 46,XY,del(20)(p11.23ter) de novo, including the location for Alagille Syndrome (AS). Early clinical course was also notable for obstructive apnea and cardiorespiratory arrests. Available literature suggested a poor neurodevelopmental prognosis. At age 27 months, he exhibits hypotonia and gross motor skills assessed at 12-15 months. However, cognitive and language skills were at the 20 months level. No structural neurological lesions have been identified. We attempted to obtain updated outcome information on previous cases for comparison. 11 previously published reports with similar extent of deletion of 20p demonstrated varied, but often more severe neurodevelopmental impairment. The majority described early global delays, with significant motor delay. However, little longitudinal or functional information was available. In contrast, our patient demonstrates good neurodevelopmental and functional progress. Caution should be exercised in counseling regarding neurodevelopmental outcome in cases of chromosomal anomaly, due to lack of information and natural variability. Standardized assessment and reporting of longitudinal neurodevelopmental follow-up are necessary for more appropriate counseling concerning outcome in chromosomal anomalies.

  16. Neurodevelopmental outcome in Angelman syndrome: genotype-phenotype correlations.

    PubMed

    Mertz, Line Granild Bie; Thaulov, Per; Trillingsgaard, Anegen; Christensen, Rikke; Vogel, Ida; Hertz, Jens Michael; Ostergaard, John R

    2014-07-01

    Angelman syndrome (AS) is a neurogenetic disorder characterized by intellectual disability, developmental delay, lack of speech, and epileptic seizures. Previous studies have indicated that children with AS due to 15q11.2-q13 deletions have a more severe developmental delay and present more often autistic features than those with AS caused by other genetic etiologies. The present study investigated the neurodevelopmental profiles of the different genetic etiologies of AS, and examined the evolution of mental development and autistic features over a 12-year period in children with a 15q11.2-q13 deletion. This study included 42 children with AS. Twelve had a Class I deletion, 18 had Class II deletions, three showed atypical large deletions, five had paternal uniparental disomy (pUPD) and four had UBE3A mutations. Children with a deletion (Class I and Class II) showed significantly reduced developmental age in terms of visual perception, receptive language, and expressive language when compared to those with a UBE3A mutation and pUPD. Within all subgroups, expressive language performance was significantly reduced when compared to the receptive performance. A follow-up study of seven AS cases with 15q11.2-q13 deletions revealed that over 12 years, the level of autistic features did not change, but both receptive and expressive language skills improved.

  17. The adverse outcome pathway knowledge base

    EPA Science Inventory

    The rapid advancement of the Adverse Outcome Pathway (AOP) framework has been paralleled by the development of tools to store, analyse, and explore AOPs. The AOP Knowledge Base (AOP-KB) project has brought three independently developed platforms (Effectopedia, AOP-Wiki, and AOP-X...

  18. Adverse outcome pathway (AOP) development and evaluation

    EPA Science Inventory

    The Adverse Outcome Pathway provides a construct for assembling mechanistic information at different levels of biological organization in a form designed to support regulatory decision making. In particular, it frames the link between molecular and cellular events that can be mea...

  19. Major malformation risk, pregnancy outcomes, and neurodevelopmental outcomes associated with metformin use during pregnancy.

    PubMed

    Andrade, Chittaranjan

    2016-04-01

    There are several reasons why metformin treatment may be considered for women in neuropsychiatric practice. These include prevention or attenuation of antipsychotic-associated weight gain, prevention or treatment of gestational diabetes mellitus (GDM), treatment of type 2 diabetes mellitus, and improvement of conception chances and pregnancy outcomes in the presence of polycystic ovarian disease (PCOD). This article examines the benefits and risks associated with metformin use during pregnancy. The available data suggest that metformin exposure during the first trimester is not associated with major congenital malformations; that metformin reduces the risk of early pregnancy loss, preeclampsia, preterm delivery, and GDM in women with PCOD; that metformin is associated with at least comparable benefits relative to insulin treatment in women with mild GDM; and that neurodevelopmental outcomes at age 1.5-2.5 years are comparable after gestational exposure to metformin and insulin. Whereas study designs were not always ideal and sample sizes were mostly small to modest, the study findings are more encouraging than discouraging and can guide shared decision-making in women who are receiving or may need metformin during pregnancy.

  20. Adverse Outcome Pathway (AOP) Network Development for ...

    EPA Pesticide Factsheets

    Adverse outcome pathways (AOPs) are descriptive biological sequences that start from a molecular initiating event (MIE) and end with an adverse health outcome. AOPs provide biological context for high throughput chemical testing and further prioritize environmental health risk research. According to the Organization for Economic Co-operation and Development guidelines, AOPs are pathways with one MIE anchored to an adverse outcome (AO) by key events (KEs) and key event relationships (KERs). However, this approach does not always capture the cumulative impacts of multiple MIEs on the AO. For example, hepatic lipid flux due to chemical-induced toxicity initiates from multiple ligand-activated receptors and signaling pathways that cascade across biology to converge upon a common fatty liver (FL, also known as steatosis) outcome. To capture this complexity, a top-down strategy was used to develop a FL AOP network (AOPnet). Literature was queried based on the terms steatosis, fatty liver, cirrhosis, and hepatocellular carcinoma. Search results were analyzed for physiological and pathophysiological organ level, cellular and molecular processes, as well as pathway intermediates, to identify potential KEs and MIEs that are key for hepatic lipid metabolism, maintenance, and dysregulation. The analysis identified four apical KE nodes (hepatic fatty acid uptake, de novo fatty acid and lipid synthesis, fatty acid oxidation, and lipid efflux) juxtaposed to the FL AO. The apic

  1. Impact of congenital heart disease on brain development and neurodevelopmental outcome.

    PubMed

    Donofrio, Mary T; Massaro, An N

    2010-01-01

    Advances in cardiac surgical techniques and perioperative intensive care have led to improved survival in babies with congenital heart disease (CHD). While it is true that the majority of children with CHD today will survive, many will have impaired neurodevelopmental outcome across a wide spectrum of domains. While continuing to improve short-term morbidity and mortality is an important goal, recent and ongoing research has focused on defining the impact of CHD on brain development, minimizing postnatal brain injury, and improving long-term outcomes. This paper will review the impact that CHD has on the developing brain of the fetus and infant. Neurologic abnormalities detectable prior to surgery will be described. Potential etiologies of these findings will be discussed, including altered fetal intrauterine growth, cerebral blood flow and brain development, associated congenital brain abnormalities, and risk for postnatal brain injury. Finally, reported neurodevelopmental outcomes after surgical repair of CHD will be reviewed.

  2. Impact of Congenital Heart Disease on Brain Development and Neurodevelopmental Outcome

    PubMed Central

    Donofrio, Mary T.; Massaro, An N.

    2010-01-01

    Advances in cardiac surgical techniques and perioperative intensive care have led to improved survival in babies with congenital heart disease (CHD). While it is true that the majority of children with CHD today will survive, many will have impaired neurodevelopmental outcome across a wide spectrum of domains. While continuing to improve short-term morbidity and mortality is an important goal, recent and ongoing research has focused on defining the impact of CHD on brain development, minimizing postnatal brain injury, and improving long-term outcomes. This paper will review the impact that CHD has on the developing brain of the fetus and infant. Neurologic abnormalities detectable prior to surgery will be described. Potential etiologies of these findings will be discussed, including altered fetal intrauterine growth, cerebral blood flow and brain development, associated congenital brain abnormalities, and risk for postnatal brain injury. Finally, reported neurodevelopmental outcomes after surgical repair of CHD will be reviewed. PMID:20862365

  3. Neurodevelopmental Outcomes Following Two Different Treatment Approaches (Early Ligation versus Selective Ligation) for Patent Ductus Arteriosus

    PubMed Central

    Wickremasinghe, Andrea C.; Rogers, Elizabeth E.; Piecuch, Robert E.; Johnson, Bridget C.; Golden, Suzanne; Moon-Grady, Anita J.; Clyman, Ronald I.

    2012-01-01

    Objective To examine whether a change in the approach to management of persistent patent ductus arteriosus (PDA), from “early ligation” to “selective ligation,” is associated with an increased risk of abnormal neurodevelopmental outcome. Study design In 2005, we changed our PDA treatment protocol (in infants ≤27 6/7 weeks gestation) from an “early ligation” approach, with PDA ligation quickly if they failed to close after indomethacin (Period 1: 1/99–12/04), to a “selective ligation” approach, with PDA ligation only if specific criteria were met (Period 2: 1/05–5/09). All infants in both periods received prophylactic indomethacin. Multivariate analysis was used to compare the odds of a composite Abnormal Neurodevelopmental Outcome (Bayley MDI or Cognitive score <70, cerebral palsy, blindness, and/or deafness) associated with each treatment approach at 18–36 months (n=224). Results During Period 1, 23% of the infants in follow-up failed indomethacin treatment, and all were ligated; during Period 2, 30% of infants failed indomethacin, and 66% were ligated after meeting pre-specified criteria. Infants treated with the “selective ligation” strategy had fewer Abnormal Outcomes than infants treated with the “early ligation” approach (OR=0.07, p=0.046). Infants ligated before 10 days of age had an increased incidence of Abnormal Neurodevelopmental Outcome. The significant difference in outcomes between the two PDA treatment strategies could be accounted for, in part, by the earlier age of ligation during Period 1. Conclusions A “selective ligation” approach for PDAs that fail to close with indomethacin does not worsen neurodevelopmental outcome at 18–36 months. PMID:22795222

  4. Clinical outcomes and neurodevelopmental outcome of prenatally diagnosed agenesis of corpus callosum in single center of Korea

    PubMed Central

    Kim, Sung Eun; Jang, Hye-In; Chang, Kylie Hae-jin; Sung, Ji-Hee; Lee, Jiwon; Lee, Jeehun; Choi, Suk-Joo; Roh, Cheong-Rae; Kim, Jong-Hwa

    2017-01-01

    Objective With recent advances and frequent use of prenatal ultrasound, the antenatal diagnosis of agenesis of the corpus callosum (ACC) is not rare in obstetrics practices. However, information regarding the long-term neurological outcome remains uncertain. The aim of this study was to investigate clinical outcomes of prenatally diagnosed ACC and to analyze postnatal neurodevelopmental outcomes of ACC neonates born in our single center. Methods We retrospectively reviewed 56 cases of prenatally suspected ACC referred to our center. Results Fifty-six fetuses were diagnosed with ACC, and 12 of those were followed-up in our center until delivery. Of the remaining 44, 7 were delivered after being referred back to the original hospital, 23 were lost to follow-up, and 14 had unknown outcomes. Among all 56, 29 were considered to have isolated ACC and 27 were considered to have non-isolated ACC. Of the 10 live fetuses delivered in our center, four had isolated ACC, three had non-isolated ACC, and the rest had outcomes unrelated to ACC. Neurodevelopmental outcome was followed-up until approximately age 3 years. Of the four with isolated ACC, three (75%) had normal neurodevelopmental outcomes. Conclusion Similar to other studies, the results of our single-center study included positive neurodevelopmental outcomes for those with isolated ACC. However, despite our endeavor to counsel patients with prenatally diagnosed ACC, the delivery rate in our center was quite low. Therefore, larger, multicenter, retrospective studies including long-term neurological development outcomes are crucial and urgently needed to provide better counseling. PMID:28217666

  5. Neurodevelopmental Outcomes of Children with Low-Grade Gliomas

    ERIC Educational Resources Information Center

    Ris, M. Douglas; Beebe, Dean W.

    2008-01-01

    As a group, children with low-grade gliomas (LGGs) enjoy a high rate of long-term survival and do not require the intensity of neurotoxic treatments used with higher risk pediatric brain tumors. Because they are generally considered to have favorable neurobehavioral outcomes, they have not been studied as thoroughly as higher-grade brain tumors by…

  6. Recurrent adverse pregnancy outcome and antiphospholipid antibodies.

    PubMed

    Reece, E A; Gabrielli, S; Cullen, M T; Zheng, X Z; Hobbins, J C; Harris, E N

    1990-07-01

    Antiphospholipid antibodies, which include lupus-like anticoagulant and anticardiolipin antibody, have been linked to a number of adverse pregnancy outcomes, although their exact pathogenic mechanisms remain poorly defined. The relative risk of complications such as intrauterine growth retardation, spontaneous abortions, and stillbirth in patients with antiphospholipid antibodies also remains undetermined. Heightened attention has been focused on the association, leading to investigations into the pathogenesis. Uncontrolled studies have also explored therapeutic regimens such as aspirin, steroids, and heparin, and clinical trials have used various treatment protocols. Although knowledge into the association of antiphospholipid antibodies and recurrent adverse pregnancy outcome is limited and continues to evolve, this association provides new insights into the disease and offers promise for pharmacologic prophylaxis. In this article, current concepts on pathogenesis, diagnosis, and therapy are reviewed and recommendations are made for clinical care of these patients.

  7. Neurodevelopmental outcomes in infants exposed in utero to antipsychotics: a systematic review of published data.

    PubMed

    Gentile, Salvatore; Fusco, Maria Luigia

    2016-11-21

    The proportion of pregnancies exposed to either second-generation antipsychotics (SGAs) or first-generation antipsychotics (FGAs) varies between 0.3%-2% of all pregnancies, but, until now, little is known about the potential neurobehavioral teratogenicity of antipsychotics. Assessing this safety facet is the aim of this article. PubMed, Scopus, and Google Scholar were searched for eligible articles. PubMed (1954 to May 2016) was searched using several medical subject headings, variously combined. PubMed search results were also limited using the search filter for human studies published in English. Scopus and Google Scholar searches were filtered for article title (antipsychotics/neuroleptics, pregnancy). After excluding duplicates, 9,250 articles were identified and 29 met the following inclusion criteria: only articles that provided original/primary data on neurodevelopmental outcome in human offspring older than 4 months of age, independently of the study design, were selected for review. Indeed, some relevant neurodevelopmental milestones are achieved at this time. Length of study and neurodevelopmental assessment methodology did not influence the study selection. Unfortunately, published data on neurodevelopmental teratogenicity of SGAs mainly derive from case reports and small case-series studies. Even findings emerging from case-control and prospective/retrospective studies are of limited clinical relevance because of their small sample sizes. Limited data are also available on FGAs. Hence, we have to conclude that the long-term neurodevelopmental outcomes for children exposed in utero remain unclear. Low to very low quality evidence of retrieved data makes impossible to confirm or exclude potential long-lasting untoward effects on infant neurocognitive development associate with antenatal exposure to either SGAs or FGAs.

  8. [Cerebral brain injury in preterm infants and the role of neuroimaging in predicting neurodevelopmental outcomes].

    PubMed

    Schneider, J; Vasung, L; Truttmann, A C; Huppi, P S

    2014-02-19

    Due to advances in neonatal intensive care over the last decades, the pattern of brain injury seen in very preterm infants has evolved in more subtle lesions that are still essential to diagnose in regard to neurodevelopmental outcome. While cranial ultrasound is still used at the bedside, magnetic resonance imaging (MRI) is becoming increasingly used in this population for the assessment of brain maturation and white and grey matter lesions. Therefore, MRI provides a better prognostic value for the neurodevelopmental outcome of these preterms. Furthermore, the development of new MRI techniques, such as diffusion tensor imaging, resting state functional connectivity and magnetic resonance spectroscopy, may further increase the prognostic value, helping to counsel parents and allocate early intervention services.

  9. Correlation of serum KL-6 and CC16 levels with neurodevelopmental outcome in premature infants at 12 months corrected age

    PubMed Central

    Zhang, Zhiqun; Lu, Hui; Zhu, Yunxia; Xiang, Junhua; Huang, Xianmei

    2015-01-01

    The aim of this study was to evaluate KL-6 and CC16 levels and their correlation with neurodevelopmental outcome among very low birth weight pre-term infants at 12 months corrected age. This prospective cohort study was performed from 2011 to 2013 by enrolling pre-term neonates of gestational age ≤ 32 weeks and birth weight ≤ 1500 g. Serum KL-6 and CC16 levels were determined 7 days after birth and their correlation with neurodevelopment was evaluated using Gesell Mental Developmental Scales. Of the 86 eligible pre-term infants, 63 completed follow-up, of which 15 had bronchopulmonary dysplasia. At 12 months corrected age, 49 infants had favorable outcomes and 14 infants had poor neurodevelopmental outcome. KL-6 levels were higher and CC16 levels were lower in infants with poor neurodevelopmental outcome compared with those infants who had favourable neurodevelopmental outcome. Serum KL-6 levels less than 90.0 ng/ml and CC16 levels greater than 320.0 pg/ml at 7 days of life were found to be predictive of a favourable outcome at 12 months corrected age. These biological markers could predict neurodevelopmental outcome at 12 months corrected age in very low birth weight premature infants, and help the clinician plan early therapeutic interventions to minimize or avoid poor neurodevelopmental outcome. PMID:25631862

  10. Impact of pulmonary hypertension on neurodevelopmental outcome in preterm infants with bronchopulmonary dysplasia: a cohort study

    PubMed Central

    Nakanishi, H; Uchiyama, A; Kusuda, S

    2016-01-01

    Objectives: To evaluate the impact of pulmonary hypertension (PH) on long-term growth and neurodevelopmental outcomes of extremely preterm infants with bronchopulmonary dysplasia (BPD). Study Design: A single-center retrospective cohort of preterm infants born at <28 weeks gestational age from 2000 to 2011 was evaluated at 3 years of age. Growth and neurodevelopmental outcomes were compared among 3 groups: non-BPD, BPD without PH and BPD with PH. BPD was defined according to oxygen demand at 36 weeks postmenstrual age. PH was diagnosed by echocardiography during the neonatal intensive care unit stay. Results: Sixty-two infants without BPD, 60 with BPD without PH and 20 with BPD with PH were analyzed. Regardless of PH status, somatic growth was smaller in both BPD groups of infants than in non-BPD infants, with further reduction in the group having BPD with PH. Furthermore, a developmental quotient of <70 was more prevalent in the BPD infants with PH than in the BPD infants without PH (odds ratio (OR): 4.37; 95% confidence interval, CI: 1.16 to 16.5). Multivariate analysis demonstrated that BPD with PH was one of the independent perinatal risk factors for developmental quotient <70 at 3 years of age (OR: 4.94, 95% confidence interval: 1.06 to 24.1). Conclusion: PH had an additional negative effect on long-term growth and neurodevelopmental outcomes of extremely preterm infants with BPD. PMID:27442157

  11. Accelerating Adverse Outcome Pathway (AOP) development ...

    EPA Pesticide Factsheets

    The Adverse Outcome Pathway (AOP) framework is increasingly being adopted as a tool for organizing and summarizing the mechanistic information connecting molecular perturbations by environmental stressors with adverse outcomes relevant for ecological and human health outcomes. However, the conventional process for assembly of these AOPs is time and resource intensive, and has been a rate limiting step for AOP use and development. Therefore computational approaches to accelerate the process need to be developed. We previously developed a method for generating computationally predicted AOPs (cpAOPs) by association mining and integration of data from publicly available databases. In this work, a cpAOP network of ~21,000 associations was established between 105 phenotypes from TG-GATEs rat liver data from different time points (including microarray, pathological effects and clinical chemistry data), 994 REACTOME pathways, 688 High-throughput assays from ToxCast and 194 chemicals. A second network of 128,536 associations was generated by connecting 255 biological target genes from ToxCast to 4,980 diseases from CTD using either HT screening activity from ToxCast for 286 chemicals or CTD gene expression changes in response to 2,330 chemicals. Both networks were separately evaluated through manual extraction of disease-specific cpAOPs and comparison with expert curation of the relevant literature. By employing data integration strategies that involve the weighting of n

  12. Correlation between visual function, neurodevelopmental outcome, and magnetic resonance imaging findings in infants with periventricular leucomalacia

    PubMed Central

    Cioni, G.; Bertuccelli, B.; Boldrini, A.; Canapicchi, R.; Fazzi, B.; Guzzetta, A.; Mercuri, E.

    2000-01-01

    AIM—To evaluate the correlation between visual function and neurodevelopmental outcome in children with periventricular leucomalacia at 1 and 3years.
METHOD—Visual acuity, visual field, ocular motility, and optokinetic nystagmus were tested in 29 infants with periventricular leucomalacia by brain magnetic resonance imaging. All infants also had a structured neurological examination and a Griffiths developmental assessment.
RESULTS—21 of the infants showed at least one abnormality of visual function. The degree of visual impairment—that is, the number of visual tests showing abnormal results—correlated well with the results on developmental assessment at both ages.
CONCLUSION—Multivariate analysis showed that visual impairment was the most important variable in determining the neurodevelopmental scores of these infants, more than their motor disability and the extent of their lesions on magnetic resonance imaging.

 PMID:10685987

  13. Adverse Outcome Pathways – Tailoring Development to Support Use

    EPA Science Inventory

    Adverse Outcome Pathways (AOPs) represent an ideal framework for connecting high-throughput screening (HTS) data and other toxicity testing results to adverse outcomes of regulatory importance. The AOP Knowledgebase (AOP-KB) captures AOP information to facilitate the development,...

  14. Adverse outcome pathway (AOP) development I: Strategies and principles

    EPA Science Inventory

    An adverse outcome pathway (AOP) is a conceptual framework that organizes existing knowledge concerning biologically plausible, and empirically-supported, links between molecular-level perturbation of a biological system and an adverse outcome at a level of biological organizatio...

  15. Adverse Outcome Pathway (AOP) Network Development for Fatty Liver

    EPA Science Inventory

    Adverse outcome pathways (AOPs) are descriptive biological sequences that start from a molecular initiating event (MIE) and end with an adverse health outcome. AOPs provide biological context for high throughput chemical testing and further prioritize environmental health risk re...

  16. Adverse outcome pathway development II: best practices.

    PubMed

    Villeneuve, Daniel L; Crump, Doug; Garcia-Reyero, Natàlia; Hecker, Markus; Hutchinson, Thomas H; LaLone, Carlie A; Landesmann, Brigitte; Lettieri, Teresa; Munn, Sharon; Nepelska, Malgorzata; Ottinger, Mary Ann; Vergauwen, Lucia; Whelan, Maurice

    2014-12-01

    Organization of existing and emerging toxicological knowledge into adverse outcome pathway (AOP) descriptions can facilitate greater application of mechanistic data, including those derived through high-throughput in vitro, high content omics and imaging, and biomarker approaches, in risk-based decision making. The previously ad hoc process of AOP development is being formalized through development of internationally harmonized guidance and principles. The goal of this article was to outline the information content desired for formal AOP description and some rules of thumb and best practices intended to facilitate reuse and connectivity of elements of an AOP description in a knowledgebase and network context. For example, key events (KEs) are measurements of change in biological state that are indicative of progression of a perturbation toward a specified adverse outcome. Best practices for KE description suggest that each KE should be defined as an independent measurement made at a particular level of biological organization. The concept of "functional equivalence" can help guide both decisions about how many KEs to include in an AOP and the specificity with which they are defined. Likewise, in describing both KEs and evidence that supports a causal linkage or statistical association between them (ie, a key event relationship; KER), best practice is to build from and contribute to existing KE or KER descriptions in the AOP knowledgebase rather than creating redundant descriptions. The best practices proposed address many of the challenges and uncertainties related to AOP development and help promote a consistent and reliable, yet flexible approach.

  17. Adverse outcome pathway (AOP) development and evaluation ...

    EPA Pesticide Factsheets

    The Adverse Outcome Pathway provides a construct for assembling mechanistic information at different levels of biological organization in a form designed to support regulatory decision making. In particular, it frames the link between molecular and cellular events that can be measured in high throughput toxicity testing and the organism or population-level events that are commonly relevant in defining risk. Recognizing the importance of this emerging framework, the Organisation for Economic Co-operation and Development (OECD) launched a program to support the development, documentation and consideration of AOPs by the international community in 2012 (http://www.oecd.org/chemicalsafety/testing/adverse-outcome-pathways-molecular-screening-and-toxicogenomics.htm). In 2014, a handbook (https://aopkb.org/common/AOP_Handbook.pdf) was developed to guide users in the documentation and evaluation of AOPs and their entry into an official knowledgebase. The handbook draws on longstanding experience in consideration of mechanistic data (e.g., mode of action analysis) to inform risk assessment. To further assist users, a training program was developed by members of the OECD Extended Advisory Group to teach users the basic principles of AOP development and the best practices as outlined in the OECD AOP handbook. Training sessions began in early 2015, and this course will provide training for interested SOT scientists. Following this course, all participants will be familiar w

  18. PUTATIVE ADVERSE OUTCOME PATHWAY FOR INHIBITON ...

    EPA Pesticide Factsheets

    The adverse outcome pathway (AOP) provides a framework for organizing knowledge to define links between a molecular initiating event (MIE) and an adverse outcome (AO) occurring at a higher level of biological organization, such as the individual or population. The AOP framework proceeds from a general (e.g., not chemical specific) molecular mode of action, designated as a MIE, through stepwise changes in biological status, defined as key events (KEs), to a final AO that can be used in risk assessment. Because aromatase-inhibiting pharmaceuticals are widely used to treat breast cancer patients, we explored the unintended consequences that might occur in fish exposed to these chemicals through wastewater discharge into the aquatic environment. Unlike mammals, fish have two isoforms of aromatase, one that predominates in the ovary (cyp19a1a) and a second (cyp19a1b) that prevails in the brain. Aromatase activity in fish brain can be 100 to 1000 times that in mammals and is associated with reproduction. We have developed a putative AOP for inhibition of brain aromatase in fish leading to reproductive dysfunction based on review of relevant literature and reproductive experiments with the marine fish cunner (Tautogolabrus adspersus) exposed to aromatase-inhibiting pharmaceuticals in the laboratory. The first KE in this AOP is a decrease in brain aromatase activity due to exposure to an aromatase inhibitor. KEs then progress through subsequent steps including decreas

  19. Neonatal and neurodevelopmental outcome of children aged 3-10 years born following assisted oocyte activation.

    PubMed

    Vanden Meerschaut, Frauke; D'Haeseleer, Evelien; Gysels, Hannelore; Thienpont, Ylenia; Dewitte, Griet; Heindryckx, Björn; Oostra, An; Roeyers, Herbert; Van Lierde, Kristiane; De Sutter, Petra

    2014-01-01

    Assisted oocyte activation (AOA) using a calcium ionophore has been used for more than a decade following intracytoplasmic sperm injection (ICSI) fertilization failure. However, since AOA does not mimic precisely the physiological fertilization process, concerns exist about its use in human assisted reproduction. This study assessed the neonatal and neurodevelopmental outcome of children aged ≥ 3 years who had been born following AOA in our centre. Twenty-one children participated in the study (81% response rate; mean age 63.6 ± 21.07 months). Neonatal data were collected via questionnaires. Neurodevelopmental outcome was tested using the Reynell Developmental Language Scales or Clinical Evaluation of Language Fundamentals, Wechsler Preschool and Primary Scale of Intelligence or Wechsler Intelligence Scale for Children, and the Movement Assessment Battery for Children III. Behaviour was scored by the Social Communication Questionnaire, the Child Behaviour Checklist and the Teachers Report Form. For all tests and questionnaires, the mean outcomes lay within the expected ranges. These are first data on the developmental outcome of AOA children. The high response rate and the robustness of the tests support the data, which are reassuring although still considered preliminary. Therefore, AOA should still be performed only in selected couples.

  20. Predicting neurodevelopmental outcomes at preschool age for children with very low birth weight.

    PubMed

    Howe, Tsu-Hsin; Sheu, Ching-Fan; Hsu, Yung-Wen; Wang, Tien-Ni; Wang, Lan-Wan

    2016-01-01

    The purpose of this study was to examine predictors of neurodevelopmental outcome in very low birth weight children without major impairment at 5 years of age, as well as to identify the contribution of early neurodevelopmental assessment to preterm children's later developmental outcomes. The participants in this study included 126 children who were prematurely born with very low birth weight. Outcomes of the childrens' later development were measured in tests that factored cognitive function, motor performance, and adaptive behavior. The results indicated that more than 50% of full-scale intelligence and 30% of both motor performance and adaptive behavior at the age of 5 can be explained by four predictors. The four predictors include preterm children's medical complications at birth, maternal education, early motor assessments, and cognitive assessments. Adding each test score obtained in early ages provides additional information to predict children's cognitive, motor, and adaptive behavior at 5 years of age. Manifold assessments conducted in multiple time periods strengthen the predictive values of later developmental outcomes. In addition, the findings of this study indicate that very low birth weight children tend to have lower adaptive behavior at 5 years old. With regard to our findings, we believe that having adaptive function is a reflection of a child's overall integrated abilities. Further study is warranted to increase understanding of this topic, as well as to be able to predict adaptive strengths and weakness and pinpoint limiting factors that may be useful for targeting behaviors in intervention.

  1. D-Dimer elevation and adverse outcomes.

    PubMed

    Halaby, Rim; Popma, Christopher J; Cohen, Ander; Chi, Gerald; Zacarkim, Marcelo Rodrigues; Romero, Gonzalo; Goldhaber, Samuel Z; Hull, Russell; Hernandez, Adrian; Mentz, Robert; Harrington, Robert; Lip, Gregory; Peacock, Frank; Welker, James; Martin-Loeches, Ignacio; Daaboul, Yazan; Korjian, Serge; Gibson, C Michael

    2015-01-01

    D-Dimer is a biomarker of fibrin formation and degradation. While a D-dimer within normal limits is used to rule out the diagnosis of deep venous thrombosis and pulmonary embolism among patients with a low clinical probability of venous thromboembolism (VTE), the prognostic association of an elevated D-dimer with adverse outcomes has received far less emphasis. An elevated D-dimer is independently associated with an increased risk for incident VTE, recurrent VTE, and mortality. An elevated D-dimer is an independent correlate of increased mortality and subsequent VTE across a broad variety of disease states. Therefore, medically ill subjects in whom the D-dimer is elevated constitute a high risk subgroup in which the prospective evaluation of the efficacy and safety of antithrombotic therapy is warranted.

  2. Influence of Congenital Heart Defect on Psychosocial and Neurodevelopmental Outcomes in Children with Down Syndrome

    PubMed Central

    Visootsak, Jeannie; Huddleston, Lillie; Buterbaugh, Allison; Perkins, Adrienne; Sherman, Stephanie; Hunter, Jessica

    2015-01-01

    Objective To evaluate the family psychosocial outcomes of children with Down syndrome and atrioventricular septal defect, and examine the impact of these variables on the child’s neurodevelopmental outcome. Methods This was a cross-sectional study that consisted of 57 children with Down syndrome (20 cases and 37 controls), approximately 12–14 months of age. In both groups, we assessed the development of the child, the quality of the child’s home environment, and parenting stress. Results Compared with the Down syndrome without congenital heart defect group, the atrioventricular septal defect group revealed lower scores in all developmental domains, less optimal home environments, and higher parental stress. Significant differences in development were seen in the areas of cognition (p=0.04), expressive language (p=0.05), and gross motor (p<0.01). The Home Observation for Measurement of the Environment revealed significant differences in emotional and verbal responsiveness of the mother between the two groups. The Parenting Stress Index revealed the Down syndrome with atrioventricular septal defect group had a significantly higher child demandingness subdomain scores compared to the Down syndrome without congenital heart defect group. Conclusions The diagnosis of a congenital heart defect in addition to the diagnosis of Down syndrome may provide additional stress to the child and parents, elevating parental concern and disrupting family dynamics, resulting in further neurodevelopmental deficits. Finding that parental stress and home environment may play a role in the neurodevelopmental outcomes may prompt new family-directed interventions and anticipatory guidance for the families of children with Down syndrome who have a congenital heart defect. PMID:25683160

  3. The role of neuroimaging in predicting neurodevelopmental outcomes of preterm neonates.

    PubMed

    Kwon, Soo Hyun; Vasung, Lana; Ment, Laura R; Huppi, Petra S

    2014-03-01

    Magnetic resonance imaging (MRI) is a safe and high-resolution neuroimaging modality that is increasingly used in the neonatal population to assess brain injury and its consequences on brain development. It is superior to cranial ultrasound for the definition of patterns of both white and gray matter maturation and injury and therefore has the potential to provide prognostic information on the neurodevelopmental outcomes of the preterm population. Furthermore, the development of sophisticated MRI strategies, including diffusion tensor imaging, resting state functional connectivity, and magnetic resonance spectroscopy, may increase the prognostic value, helping to guide parental counseling and allocate early intervention services.

  4. Usefulness of an early neurofunctional assessment in predicting neurodevelopmental outcome in very low birthweight infants

    PubMed Central

    Picciolini, O; Giannì, M L; Vegni, C; Fumagalli, M; Mosca, F

    2006-01-01

    Objective To evaluate whether early neurofunctional assessment may be useful in predicting neurodevelopmental outcome in children of very low birth weight (VLBW). Design Observational longitudinal study. Settings Northern Italy. Patients A total of 250 VLBW children (129 boys, 121 girls) born consecutively 1996–1999. Main outcome measures Neurodevelopment at 36 months of chronological age, classified in accordance with the classification of Tardieu and the International classification of functioning. Results Of the infants exhibiting normal neurodevelopment (n  =  183) or major dysfunction (n  =  17) at 3 months of corrected age, 72% and 94% respectively did not change their score during the study. Minor dysfunctions at 3 months of corrected age were transient in 17 (34%) children. After adjustment for neonatal variables, neurodevelopment at 3 months of corrected age remained predictive of dysfunction at 36 months (odds ratio  =  4.33, 95% confidence interval 2.05 to 9.12). If the results for the normal and minor dysfunction groups were pooled, the predictive qualities of the 3 month neurofunctional assessment were: sensitivity 0.5, specificity 0.99, positive predictive value 0.94, negative predictive value 0.93. Conclusion Early neurofunctional evaluation may be useful in predicting later neurodevelopmental outcome in VLBW children. PMID:16492947

  5. Neurodevelopmental outcome for offspring of women treated for antenatal depression: a systematic review.

    PubMed

    Previti, Giovanni; Pawlby, Susan; Chowdhury, Sahmina; Aguglia, Eugenio; Pariante, Carmine M

    2014-12-01

    The aim of this systematic review is to appraise existing literature on the effects of treatments for antenatal depression on the neurodevelopment outcomes of the offspring. We conducted a systematic review of the literature to identify studies on different kinds of treatments for antenatal depression (antidepressants and alternative therapies) and their effects on infants' neurodevelopment. After reading the title, abstract, or full text and applying exclusion criteria, a total of 22 papers were selected. Nineteen papers studied the effects of antidepressant drugs, one on docosahexanoic acid (DHA) (fish oil capsules) and two on massage therapy; however, no studies used a randomized controlled design, and in most studies, the control group comprise healthy women not exposed to depression. Comparisons between newborns exposed to antidepressants in utero with those not exposed showed significant differences in a wide range of neurobehavioral outcomes, although in many cases, these symptoms were transient. Two studies found a slight delay in psychomotor development, and one study found a delay in mental development. Alternative therapies may have some benefits on neurodevelopmental outcomes. Our review suggests that antidepressant treatment may be associated with some neurodevelopmental changes, but we cannot exclude that some of these effects may be due to depression per se.

  6. Assessing quality of nursing care as a confounding variable in an outcome study on neurodevelopmental treatment.

    PubMed

    Hafsteinsdóttir, Thóra B; Kruitwagen, Cas; Strijker, Karin; van der Weide, Lies; Grypdonck, Maria H F

    2007-01-01

    When planning a study measuring the effects of a neurodevelopmental treatment (NDT), we were confronted with the methodological problem that while measuring the effects of NDT, a rival hypothesis is that the decision to implement the NDT might be related to the quality of nursing care. Therefore, we measured the quality of nursing care as a possible confounding variable in relation to this outcome study. The quality of nursing care was measured on 12 wards participating in the experimental and control groups of the outcome study. Data were collected from 125 patients and 71 nurses and patients' records. The findings showed no significant differences in the quality of nursing care between the 2 groups of wards (P = .49). This method may be useful to other researchers conducting outcome research and who are confronted with a similar methodological problem.

  7. The effect of kangaroo care on neurodevelopmental outcomes in preterm infants.

    PubMed

    Head, Lauren M

    2014-01-01

    Preterm birth is associated with long-term deficits in executive functioning and cognitive performance. As advances in neonatal care enable more preterm infants to survive, development of strategies to address high rates of neurodevelopmental disabilities and poor academic achievement in preterm infants are crucial. Evidence suggests that infants' brains are plastic in nature and, therefore, can be shaped by the environment. Kangaroo care has become popularized as a means of modifying the stress of the NICU environment. However, few studies have examined whether kangaroo care affects neurodevelopmental outcomes in preterm infants. This review examined available literature that investigated the effect of kangaroo care on cognition in preterm infants. Current evidence suggests that short-term benefits of kangaroo care are associated with improved neurodevelopment. However, few studies have examined the long-term impact of kangaroo care on cognitive outcomes in preterm infants. To address neurological disparities in children born preterm, research using kangaroo care as a strategy to improve neurodevelopment in preterm infants is warranted.

  8. Peripartum cocaine use and adverse pregnancy outcome.

    PubMed

    Little, Bertis B.; Snell, Laura M.; Trimmer, Kenneth J.; Ramin, Susan M.; Ghali, Fred; Blakely, Craig A.; Garret, Andrea

    1999-09-01

    The objective of the study was to analyze possible adverse effects of peripartum cocaine use on maternal and fetal outcomes. Informed consent was given by 720 (97%) of 740 women who delivered consecutively at a large urban public hospital to test an umbilical cord blood sample for the presence of non-medically administered drugs of abuse and alcohol and to be interviewed for the study. Samples were tested for the presence of a cocaine metabolite (benzoylecgonine-BZE) by radioimmunoassay. The presence of other substances of abuse (alcohol, methamphetamine, opiates) resulted in exclusion from the sample of 143 subjects. Thus, in this cohort analysis, drug-free controls (N = 469) were compared to those positive for cocaine only (N = 108). Peripartum exposure to cocaine only, and no other substances of abuse, was associated with an increased frequency of abruptio placentae (1.9% vs 0% for control, P < 0.004), thick meconium stained amniotic fluid (3.9% vs 0.7% for controls, P < 0.006), premature rupture of membranes (P < 0.02), genitourinary anomalies (OR = 3.6, P < 0.05), abdominal wall defects (OR = 4.4, P < 0.01) and increased frequency of low birth weight (OR = 2.0, P < 0.02). These are important findings because previous studies have been complicated by the confounding effects of other substances of abuse. Am. J. Hum. Biol. 11:598-602, 1999. Copyright 1999 Wiley-Liss, Inc.

  9. Constructing Adverse Outcome Pathways: a Demonstration of ...

    EPA Pesticide Factsheets

    Adverse outcome pathway (AOP) provides a conceptual framework to evaluate and integrate chemical toxicity and its effects across the levels of biological organization. As such, it is essential to develop a resource-efficient and effective approach to extend molecular initiating events (MIEs) of chemicals to their downstream phenotypes of a greater regulatory relevance. A number of ongoing public phenomics (high throughput phenotyping) efforts have been generating abundant phenotypic data annotated with ontology terms. These phenotypes can be analyzed semantically and linked to MIEs of interest, all in the context of a knowledge base integrated from a variety of ontologies for various species and knowledge domains. In such analyses, two phenotypic profiles (PPs; anchored by genes or diseases) each characterized by multiple ontology terms are compared for their semantic similarities within a common ontology graph, but across boundaries of species and knowledge domains. Taking advantage of publicly available ontologies and software tool kits, we have implemented an OS-Mapping (Ontology-based Semantics Mapping) approach as a Java application, and constructed a network of 19383 PPs as nodes with edges weighed by their pairwise semantic similarity scores. Individual PPs were assembled from public phenomics data. Out of possible 1.87×108 pairwise connections among these nodes, about 71% of them have similarity scores between 0.2 and the maximum possible of 1.0.

  10. Adapting biomarker technologies to adverse outcome ...

    EPA Pesticide Factsheets

    Adverse outcome pathways (AOP) research is a relatively new concept in human systems biology for assessing the molecular level linkage from an initiating (chemical) event that could lead to a disease state. Although most implementations of AOPs are based on liquids analyses, there are now new technologies being considered derived from the broad field of breath research, especially in applications of gas-phase analysis and instrumentation. The ultimate goal is to discover disease progressions in human or animal systems, identify them at the molecular or cellular level, and then choose analytes that can distinctly define the presence of a particular path (Ankley et al. 2010, Villeneuve et al. 2014). Once such in vivo pathways are identified, then in vitro assays can be developed for streamlined testing of chemical effects without additional human or animal based studies (Pleil et al. 2012). Recent work has focused on discovery analysis in breath, or other biological media, wherein as many as possible compounds are cataloged and then linked to their biochemical source as exogenous (external), endogenous (internal) or from the microbiome (Pleil et al. 2013a, de Lacy Costello 2014, Pleil et al. 2013b, Trefz et al. 2013, Pleil et al. 2014). Such research lays the groundwork for identifying compounds from systems biology that might be relevant for developing AOPs for in vitro research. The National Exposure Research Laboratory’s (NERL’s) Human Exposure and Atm

  11. Analyzing risks of adverse pregnancy outcomes.

    PubMed

    Kramer, Michael S; Zhang, Xun; Platt, Robert W

    2014-02-01

    Approaches for analyzing the risks of adverse pregnancy outcomes have been the source of much debate and many publications. Much of the problem, in our view, is the conflation of time at risk with gestational age at birth (or birth weight, a proxy for gestational age). We consider the causal questions underlying such analyses with the help of a generic directed acyclic graph. We discuss competing risks and populations at risk in the context of appropriate numerators and denominators, respectively. We summarize 3 different approaches to quantifying risks with respect to gestational age, each of which addresses a distinct etiological or prognostic question (i.e., cumulative risk, prospective risk, or instantaneous risk (hazard)) and suggest the appropriate denominators for each. We show how the gestational age-specific risk of perinatal death (PND) can be decomposed as the product of the gestational age-specific risk of birth and the risk of PND conditional on birth at a given gestational age. Finally, we demonstrate how failure to consider the first of these 2 risks leads to selection bias. This selection bias creates the well-known crossover paradox, thus obviating the need to posit common causes of early birth and PND other than the study exposure.

  12. Neurodevelopmental Outcomes in Children Born to Climate Refugee Mothers in Bangladesh: Experiences from Cyclone Aila.

    PubMed

    Khan, N Z; Muslima, H; Shilpi, A B; Majumder, S K; Khan, A E

    2016-10-01

    Cyclone Aila hit the South-West coast of Bangladesh in May 2009, when in Dacope Upazilla over 50,000 people were left homeless as climate refugees (CRs) for over two years. We determined neurodevelopmental status of children born as CRs compared to their non-Climate Refugee (NCR) counterparts. Pregnant mothers were enrolled from May 2009 to April 2010 in entire Dacope in a study which profiled their health conditions. From among these mothers, 12 months post-Aila 267 CR mother-child dyads, and 552 NCR mother-child dyads were enrolled to assess their children's neurodevelopmental outcomes. There were significantly more landless families among CRs compared to NCRs (p value = 0.0001; OR = 1.86, 95% CI: 1.37 - 2.51). The mean±SD age at assessment of CR children was 8.52±4.57 months compared to a mean age 9.09±4.13 months of the NCR children (p=0.610). Neurodevelopmental Impairments (NDIs) were three times higher in the former (21.3%), compared to the latter (7.4%) group (p=0.0001; OR 3.83, 95% CI: 2.16 - 5.21). Specifically, expressive language (p value 0.002; OR 2.86, 95% CI: 1.46 - 5.57) and gross motor functions (p=0.007; OR 2.27, 95% CI 1.22 - 4.20) were the most significantly affected areas of impairment. Children born to CR mothers had a three times higher proportion of NDIs. The findings are of concern as in Bangladesh large populations are forced to leave their homes and become CRs annually. Optimum antenatal care of pregnant women as well as their offsprings within refugee situations needs to be ensured to prevent NDIs and poor quality of survival.

  13. The impact of cerebral embolization during infant cardiac surgery on neurodevelopmental outcomes at intermediate follow-up.

    PubMed

    Naik, R J; Wagner, J B; Chowdhury, D; Barnes, M l; Wagner, D S; Burson, K C; Eslinger, P J; Clark, J B

    2014-09-01

    Cerebral embolization during pediatric cardiac surgery may be an underappreciated source of subsequent neurodevelopmental impairment. Transcranial Doppler ultrasound is a neuromonitoring tool that can provide intraoperative surveillance for cerebral embolization. We hypothesized that increased cerebral embolic signals detected during infant cardiac surgery would be associated with worse neurodevelopmental outcomes at follow-up. A study group of 24 children who underwent infant cardiac surgery with transcranial Doppler detection of cerebral embolic signals returned at intermediate follow-up for standardized neurodevelopmental assessment. The children were evaluated using two neurocognitive tests and the parents completed two questionnaires regarding observed behavior. Statistical analysis assessed for correlation between the number of cerebral embolic signals at surgery and the results of the neurodevelopmental assessment. Of the 67 test parameters analyzed, five showed a significant association with the number of embolic signals, yet, all in the contrary direction of the clinical hypothesis, likely representing a Type I error. Thus, in this small cohort of patients, the number of cerebral embolic signals detected during infant cardiac surgery was not shown to be associated with worse neurodevelopmental outcomes at intermediate follow-up. A larger study is probably necessary to ascertain the potential influence of cerebral embolic signals on eventual neurologic outcomes in children. The clinical relevance of cerebral embolic signals during pediatric cardiac surgery remains undetermined and deserves further investigation.

  14. Clinical Data Predict Neurodevelopmental Outcome Better than Head Ultrasound in Extremely Low Birth Weight Infants

    PubMed Central

    Broitman, Eduardo; Ambalavanan, Namasivayam; Higgins, Rosemary D.; Vohr, Betty R.; Das, Abhik; Bhaskar, Brinda; Murray, Kennan; Hintz, Susan R.; Carlo, Waldemar A.

    2007-01-01

    Objective To determine the relative contribution of clinical data versus head ultrasound (HUS) in predicting neurodevelopmental impairment (NDI) in extremely low birth weight (ELBW) infants. Study design 2103 ELBW infants (<1000g) admitted to a National Institute of Child Health and Human Development Neonatal Research Network center who had a HUS within the first 28 days, a repeat one around 36 weeks’ post-menstrual age, and neurodevelopmental assessment at 18–22 months corrected age were selected. Multivariate logistic regression models were developed using clinical and/or HUS variables. The primary outcome was the predictive abilities of the HUS done before 28 days after birth and closer to 36 weeks post-menstrual age, either alone or in combination with “Early” and “Late” clinical variables. Results Models using clinical variables alone predicted NDI better than models with only HUS variables at both 28 days and 36 weeks (both p < 0.001), and addition of the HUS data did not improve prediction. NDI was absent in 30% and 28% of the infants with grade IV intracranial hemorrhage or periventricular leukomalacia, respectively, but was present in 39% of the infants with a normal head ultrasound. Conclusions Clinical models were better than head ultrasound models in predicting neurodevelopment. PMID:17961693

  15. Metabolic alterations and neurodevelopmental outcome of infants with transposition of the great arteries.

    PubMed

    Park, I Sook; Yoon, S Young; Min, J Yeon; Kim, Y Hwue; Ko, J Kok; Kim, K Soo; Seo, D Man; Lee, J Hee

    2006-01-01

    Abnormal neurodevelopment has been reported for infants who were born with transposition of the great arteries (TGA) and underwent arterial switch operation (ASO). This study evaluates the cerebral metabolism of TGA infants at birth and before ASO and neurodevelopment 1 year after ASO. Proton magnetic resonance spectroscopy (1H-MRS) was performed on 16 full-term TGA brains before ASO within 3-6 days after birth. The brain metabolite ratios of [NAA/Cr], [Cho/Cr], and [mI/Cr] evaluated measured. Ten infants were evaluated at 1 year using the Bayley Scales of Infants Development II (BSED II). Cerebral metabolism of infants with TGA was altered in parietal white matter (PWM) and occipital gray matter (OGM) at birth before ASO. One year after ASO, [Cho/Cr] in PWM remained altered, but all metabolic ratios in OGM were normal. The results of BSID II at 1 year showed delayed mental and psychomotor development. This delayed neurodevelopmental outcome may reflect consequences of the altered cerebral metabolism in PWM measured by 1H-MRS. It is speculated that the abnormal hemodynamics due to TGA in utero may be responsible for the impaired cerebral metabolism and the subsequent neurodevelopmental deficit.

  16. Neonatal Factors Associated with a Good Neurodevelopmental Outcome in Very Preterm Infants.

    PubMed

    Asztalos, Elizabeth V; Church, Paige T; Riley, Patricia; Fajardo, Carlos; Shah, Prakesh S

    2017-03-01

    Objective This study aims to examine the association between the absence of neonatal comorbidities, as well as the presence of indicators of clinical progress with good neurodevelopmental (ND) outcomes, at 18 months corrected age in a national cohort of preterm infants of < 29 weeks' gestation. Design Study subjects included preterm infants (< 29 weeks' gestation) born in 2010 and 2011. Univariate analyses were conducted and regression estimates were calculated for variables where odds of a good ND outcome, composite scores ≥ 100 in three domains (cognitive, language, and motor) in the Bayley Scales of Infant and Toddler Development, 3rd ed. (Bayley-III), were estimated. Results In total, 2,069 infants were included in the analyses. For all three domains evaluated on the Bayley-III, cognition, language, motor, respectively, the absence of three major morbidities was associated with a score ≥ 100: bronchopulmonary dysplasia, necrotizing enterocolitis, and severe neurological injury. Less time spent on positive pressure support and on total parenteral nutrition administration were associated with a positive motor outcome and showed a positive trend for both cognition and language scores. Conclusion The absence of neonatal comorbidities was associated with good ND outcome. Less time spent on positive pressure support and parenteral nutrition may also contribute to a good ND outcome.

  17. Informatics approaches in the Biological Characterization of Adverse Outcome Pathways

    EPA Science Inventory

    Adverse Outcome Pathways (AOPs) are a conceptual framework to characterize toxicity pathways by a series of mechanistic steps from a molecular initiating event to population outcomes. This framework helps to direct risk assessment research, for example by aiding in computational ...

  18. Effect of Long-Chain Polyunsaturated Fatty Acid Supplementation on Neurodevelopmental Outcome in Full-Term Infants

    PubMed Central

    Hadders-Algra, Mijna

    2010-01-01

    It takes more than 20 years before the human brain obtains its complex, adult configuration. Most dramatic developmental changes occur prenatally and early postnatally. During development, long-chain polyunsaturated fatty acids (LCPUFA) such as doxosahexaenoic acid (DHA) and arachidonic acid (AA) are accreted in the brain. Since breastfeeding is associated with a better developmental outcome than formula feeding, and human milk in contrast to traditional standard formula contains LCPUFA, the question arose whether LCPUFA supplementation of infant formula may promote the neurodevelopmental outcome. The current paper reviews the evidence available in full-term infants. It concludes that postnatal supplementation of formula with LCPUFA is associated with a beneficial effect on short-term neurodevelopmental outcome. However, no evidence is available that LCPUFA supplementation enhances neurodevelopmental outcome in full-term infants beyond the age of four months. Nevertheless, it should be realized that very limited information is available on the effect of LCPUFA supplementation on neurodevelopmental outcome at school age or later. It is conceivable that effects of LCPUFA supplementation first emerge or re-emerge at school age when more complex neural functions are expressed. PMID:22254056

  19. Neurodevelopmental outcome in babies with a low Apgar score from Zimbabwe.

    PubMed

    Wolf, M J; Wolf, B; Bijleveld, C; Beunen, G; Casaer, P

    1997-12-01

    The early identification of neurological dysfunction in the neonatal period, the predictive value of single items of the neonatal neurological examination (NNE) adapted from Prechtl and the developmental outcome at 1 year of age in infants with a low Apgar score in Zimbabwe were studied. One hundred and sixty-five infants were examined with the NNE and 142 with the Bayley Scale of Infant Development (BSID) at 1 year of age. Twenty-three infants had cerebral palsy, ten had a motor delay or developmental delay, and four were mentally retarded. The NNE proved to be a sensitive instrument for detecting neurodevelopmental abnormality. Logistic regression analysis was used to investigate the relationship between the BSID and nine selected predictors from the NNE. This resulted in a correct classification of 94%. However, the number of false negatives was high. By using only the variability of movements and fixation as predictors the number of false negatives was reduced to one.

  20. Etiological Subgroups of Small-for-Gestational-Age: Differential Neurodevelopmental Outcomes

    PubMed Central

    Li, Xiuhong; Eiden, Rina D.; Epstein, Leonard H.; Shenassa, Edmond D.; Xie, Chuanbo; Wen, Xiaozhong

    2016-01-01

    Objectives It remains unclear why substantial variations in neurodevelopmental outcomes exist within small-for-gestational-age (SGA) children. We prospectively compared 5-y neurodevelopmental outcomes across SGA etiological subgroups. Methods Children born SGA (N = 1050) from U.S. Early Childhood Longitudinal Study-Birth Cohort (2001–2007) was divided into etiological subgroups by each of 7 well-established prenatal risk factors. We fit linear regression models to compare 5-y reading, math, gross motor and fine motor scores across SGA subgroups, adjusting for socio-demographic confounders. Results Compared to singleton SGA subgroup, multiple-birth SGA subgroup had lower mean reading (adjusted mean difference, -4.08 [95% confidence interval, -6.10, -2.06]) and math (-2.22 [-3.61, -0.84]) scores. These disadvantages in reading and math existed only among multiple-birth SGA subgroup without ovulation stimulation (reading, -4.50 [-6.64, -2.36]; math, -2.91 [-4.37, -1.44]), but not among those with ovulation stimulation (reading, -2.33 [-6.24, 1.57]; math 0.63 [-1.86, 3.12]). Compared to singleton SGA subgroup without maternal smoking and inadequate gestational weight gain, singleton SGA subgroup with co-occurrence of maternal smoking and inadequate gestational weight gain (GWG) had lower mean reading (-4.81 [-8.50, -1.12]) and math (-2.95 [-5.51, -0.38]) scores. These differences were not mediated by Apgar score. Conclusions Multiple-birth SGA subgroups (vs. singleton SGA) or singleton SGA subgroup with co-occurrence of smoking and inadequate GWG (vs. singleton SGA subgroup without maternal smoking and inadequate gestational weight gain) have poorer cognitive development up to 5 y. PMID:27501456

  1. Adverse Outcome Pathways: From Research to Regulation - Scientific Workshop Report

    EPA Science Inventory

    An adverse outcome pathway (AOP) organizes existing knowledge on chemical mode of action, starting with a molecular initiating event such as receptor binding, continuing through key events, and ending with an adverse outcome such as reproductive impairment. AOPs can help identify...

  2. Intimate Partner Violence, PTSD, and Adverse Health Outcomes

    ERIC Educational Resources Information Center

    Dutton, Mary Ann; Green, Bonnie L.; Kaltman, Stacey I.; Roesch, Darren M.; Zeffiro, Thomas A.; Krause, Elizabeth D.

    2006-01-01

    The high prevalence of adverse health outcomes related to intimate partner violence (IPV) is well documented. Yet we know little about the pathways that lead to adverse health outcomes. Research concerning the psychological, biological, neurological, behavioral, and physiological alterations following exposure to IPV--many of which are associated…

  3. Impact of Hospital-Based Environmental Exposures on Neurodevelopmental Outcomes of Preterm Infants

    PubMed Central

    Santos, Janelle; Pearce, Sarah E.; Stroustrup, Annemarie

    2015-01-01

    Purpose of review Over 300,000 infants are hospitalized in a neonatal intensive care unit (NICU) in the United States annually during a developmental period critical to later neurobehavioral function. Environmental exposures during the fetal period and infancy have been shown to impact long-term neurobehavioral outcomes. This review summarizes evidence linking NICU-based environmental exposures to neurodevelopmental outcomes of children born preterm, Recent findings Preterm infants experience multiple exposures important to neurodevelopment during the NICU hospitalization. The physical layout of the NICU, management of light and sound, social interactions with parents and NICU staff, and chemical exposures via medical equipment are important to long-term neurobehavioral outcomes in this highly vulnerable population. Summary Existing research documents NICU-based exposure to 1) neurotoxic chemicals, 2) aberrant light, 3) excess sound, and 4) restricted social interaction. In total, this creates an environment of co-existing excesses (chemicals, light, sound) and deprivation (touch, speech). The full impact of these co-exposures on the long-term neurodevelopment of preterm infants has not been adequately elucidated. Research into the importance of the NICU from an environmental health perspective is in its infancy, but could provide understanding about critical modifiable factors impacting the neurobehavioral health of hundreds of thousands of children each year. PMID:25635585

  4. Neurodevelopmental outcome at early school age of children born to mothers with gestational diabetes

    PubMed Central

    Ornoy, A; Wolf, A; Ratzon, N; Greenbaum, C; Dulitzky, M

    1999-01-01

    AIMS—To study the metabolic derangements in the second half of pregnancy caused by gestational diabetes, on the long term development of children.
METHODS—The neuropsychological function of 32 school age children born to 32 mothers with well controlled gestational diabetes and 57 control children matched by age, birth order, and parental socioeconomic status was studied.
RESULTS—There were no differences in head circumference and height, but the children born to diabetic mothers were heavier. The verbal IQ scores of index children below the age of 9 years were lower than those of control children. No differences were found between the groups in various sensory and motor functions and in the Touwen and Prechtl neurological test. The young index group children performed less well than controls in fine and gross motor functions, as observed on the Bruininks-Oseretzky test of motor proficiency. The scores of young children born to mothers with gestational diabetes were also lower than controls on the Pollack tapper test, and there were more index group children who scored abnormally on the parents' Conners questionnaire. No correlation was found between the performance of the index group children on various neurodevelopmental tests and the severity of perinatal complications. The differences tended to disappear with age.
CONCLUSIONS—Gestational diabetes, as a result of the metabolic abnormalities in the second half of pregnancy, induces long term minor neurological deficits which are more pronounced in younger children. There does not seem to be any direct relation between the appearance of congenital anomalies and neurodevelopmental outcome.

 PMID:10375355

  5. Neurodevelopmental outcomes for children with hypoplastic left heart syndrome at the age of 5 years.

    PubMed

    Brosig, Cheryl; Mussatto, Kathleen; Hoffman, George; Hoffmann, Raymond G; Dasgupta, Mahua; Tweddell, James; Ghanayem, Nancy

    2013-10-01

    This study aimed to determine the neurodevelopmental (ND) outcome for children with hypoplastic left heart syndrome (HLHS) at early school age. English-speaking patients who underwent the Norwood procedure between 2000 and 2005 were eligible at 4-6 years of age for ND testing. Of the 72 eligible patients, 44 (61 %) agreed to participate, and 37 completed ND testing before the close of the study. Three subjects were excluded from analyses due to late stroke. The ND testing included intelligence, visual motor integration, memory and motor and language skills. Parents and teachers completed measures of behavior and attention problems. Subjects' scores and parent/teacher ratings were converted to z-scores and compared with test norms. Higher scores on child measures represent better outcomes, whereas higher scores on parent and teacher rating scales indicate more problems. The average ND performance of the tested cohort fell within one standard deviation of the test norms for all measures. However, the subjects performed significantly lower than the test norms on measures of visual-motor integration, fine motor skills, memory, and word structure (z = -0.42 to -0.54; p < 0.005). On the parent and teacher completed measures, the subjects scored higher than the test norms on attention problems (z = 0.40-0.62; p < 0.005). Although the overall ND performance of the cohort was normal, the subjects showed relative weakness in visual motor and attention skills. Ongoing developmental monitoring of these children is recommended to guide interventions that may improve individual outcomes and to assess the impact of changes in clinical management strategies on functional outcomes.

  6. Neurodevelopmental Outcomes for Children With Hypoplastic Left Heart Syndrome at the Age of 5 Years

    PubMed Central

    Mussatto, Kathleen; Hoffman, George; Hoffmann, Raymond G.; Dasgupta, Mahua; Tweddell, James; Ghanayem, Nancy

    2014-01-01

    This study aimed to determine the neurodevelopmental (ND) outcome for children with hypoplastic left heart syndrome (HLHS) at early school age. English-speaking patients who underwent the Norwood procedure between 2000 and 2005 were eligible at 4–6 years of age for ND testing. Of the 72 eligible patients, 44 (61 %) agreed to participate, and 37 completed ND testing before the close of the study. Three subjects were excluded from analyses due to late stroke. The ND testing included intelligence, visual motor integration, memory and motor and language skills. Parents and teachers completed measures of behavior and attention problems. Subjects’ scores and parent/teacher ratings were converted to z-scores and compared with test norms. Higher scores on child measures represent better outcomes, whereas higher scores on parent and teacher rating scales indicate more problems. The average ND performance of the tested cohort fell within one standard deviation of the test norms for all measures. However, the subjects performed significantly lower than the test norms on measures of visual-motor integration, fine motor skills, memory, and word structure (z = −0.42 to −0.54; p < 0.005). On the parent and teacher completed measures, the subjects scored higher than the test norms on attention problems (z = 0.40–0.62; p < 0.005). Although the overall ND performance of the cohort was normal, the subjects showed relative weakness in visual motor and attention skills. Ongoing developmental monitoring of these children is recommended to guide interventions that may improve individual outcomes and to assess the impact of changes in clinical management strategies on functional outcomes. PMID:23503929

  7. Accelerating Adverse Outcome Pathway Development via Systems Approaches

    EPA Science Inventory

    The Adverse Outcome Pathway has emerged as an internationally harmonized mechanism for organizing biological information in a chemical agnostic manner. This construct is valuable for interpreting the results from high-throughput toxicity (HTT) assessment by providing a mechanisti...

  8. Adverse outcome pathway (AOP) development: Guiding principles and best practices

    EPA Science Inventory

    Adverse outcome pathways (AOPs) represent a conceptual framework that can support greater application of mechanistic data in regulatory decision-making. However, in order for the scientific community to collectively address the daunting challenge of describing relevant toxicologi...

  9. Adverse outcome pathway (AOP) development II: Best practices

    EPA Science Inventory

    Organization of existing and emerging toxicological knowledge into adverse outcome pathway (AOP) descriptions can facilitate greater application of mechanistic data, including high throughput in vitro, high content omics and imaging, and biomarkers, in risk-based decision-making....

  10. Neurodevelopmental outcomes and neural mechanisms associated with non-right handedness in children born very preterm

    PubMed Central

    Pascoe, L; Scratch, SE; Burnett, AC; Thompson, DK; Lee, KJ; Doyle, LW; Cheong, JLY; Inder, TE; Anderson, PJ

    2016-01-01

    Objective Non-right handedness (NRH) is reportedly more common in very preterm (VPT; <32 weeks’ gestation) children compared with term-born peers, but it is unclear whether neonatal brain injury or altered brain morphology and microstructure underpins NRH in this population. Given that NRH has been inconsistently reported to be associated with cognitive and motor difficulties, this study aimed to examine associations between handedness and neurodevelopmental outcomes in VPT 7 year-olds. Further, the relationship between neonatal brain injury and integrity of motor tracts (corpus callosum and corticospinal tract) with handedness at age 7 years in VPT children was explored. Method One hundred and seventy-five VPT and 69 term-born children completed neuropsychological and motor assessments and a measure of handedness at 7 years’ corrected age. At term-equivalent age, brain injury on MRI was assessed and diffusion tensor measures were obtained for the corpus callosum and posterior limb of the internal capsule. Results There was little evidence of stronger NRH in the VPT group compared with term controls (regression coefficient [b] −1.95, 95% confidence interval [CI] −5.67 to 1.77). Poorer academic and working memory outcomes were associated with stronger NRH in the VPT group. While there was little evidence that neonatal unilateral brain injury was associated with stronger NRH, increased area and fractional anisotropy of the corpus callosum splenium were predictive of stronger NRH in the VPT group. Conclusions VPT birth may alter the relationship between handedness and academic outcomes, and neonatal corpus callosum integrity predicts hand preference in VPT children at school age. PMID:26328609

  11. Relationship between Proton Magnetic Resonance Spectroscopy of Frontoinsular Gray Matter and Neurodevelopmental Outcomes in Very Low Birth Weight Children at the Age of 4.

    PubMed

    Durlak, Wojciech; Herman-Sucharska, Izabela; Urbanik, Andrzej; Klimek, Małgorzata; Karcz, Paulina; Dutkowska, Grażyna; Nitecka, Magdalena; Kwinta, Przemko

    2016-01-01

    Very low birth weight is associated with long term neurodevelopmental complications. Macroscopic brain abnormalities in prematurity survivors have been investigated in several studies. However, there is limited data regarding local cerebral metabolic status and neurodevelopmental outcomes. The purpose of this study was to characterize the relationship between proton magnetic resonance spectra in basal ganglia, frontal white matter and frontoinsular gray matter, neurodevelopmental outcomes assessed with the Leiter scale and the Developmental Test of Visual Perception and selected socioeconomic variables in a cohort of very low birth weight children at the age of four. Children were divided in three groups based on the severity of neurodevelopmental impairment. There were no differences in spectroscopy in basal ganglia and frontal white matter between the groups. Lower concentrations of N-acetylaspartate (NAA), choline (Cho) and myoinositol (mI) were observed in the frontoinsular cortex of the left hemisphere in children with neurodevelopmental impairment compared to children with normal neurodevelopmental outcomes. Higher parental education, daycare attendance and breastfeeding after birth were associated with more favorable neurodevelopmental prognosis, whereas rural residence was more prevalent in children with moderate and severe impairment. Our study demonstrates the role of long term neurometabolic disruption in the left frontoinsular cortex and selected socioeconomic variables in determination of neurodevelopmental prognosis in prematurity survivors.

  12. Deep grey matter growth predicts neurodevelopmental outcomes in very preterm children.

    PubMed

    Young, Julia M; Powell, Tamara L; Morgan, Benjamin R; Card, Dallas; Lee, Wayne; Smith, Mary Lou; Sled, John G; Taylor, Margot J

    2015-05-01

    We evaluated whether the volume and growth rate of critical brain structures measured by MRI in the first weeks of life following very preterm (<32/40 weeks) birth could predict subsequent neurodevelopmental outcomes at 4 years of age. A significant proportion of children born very prematurely have cognitive deficits, but these problems are often only detected at early school age. Structural T2-weighted magnetic resonance images were acquired in 96 very preterm neonates scanned within 2 weeks of birth and 70 of these at term-equivalent age. An automated 3D image analysis procedure was used to measure the volume of selected brain structures across all scans and time points. At 4 years of age, 53 children returned for neuropsychological assessments evaluating IQ, language and visual motor integration. Associations with maternal education and perinatal measures were also explored. Multiple regression analyses revealed that growth of the caudate and globus pallidus between preterm birth and term-equivalent age predicted visual motor integration scores after controlling for sex and gestational age. Further associations were found between caudate and putamen growth with IQ and language scores. Analyses at either preterm or term-equivalent age only found associations between normalized deep grey matter growth and visual motor integration scores at term-equivalent age. Maternal education levels were associated with measures of IQ and language, but not visual motor integration. Thalamic growth was additionally linked with perinatal measures and presence of white matter lesions. These results highlight deep grey matter growth rates as promising biomarkers of long-term outcomes following very preterm birth, and contribute to our understanding of the brain-behaviour relations in these children.

  13. Accelerating Adverse Outcome Pathway Development Using Publicly Available Data Sources

    EPA Science Inventory

    The adverse outcome pathway (AOP) concept links molecular perturbations with organism and population-level outcomes to support high-throughput toxicity testing. International efforts are underway to define AOPs and store the information supporting these AOPs in a central knowledg...

  14. Neurodevelopmental outcomes at 5 years in children exposed prenatally to maternal dental amalgam: the Seychelles Child Development Nutrition Study.

    PubMed

    Watson, Gene E; van Wijngaarden, Edwin; Love, Tanzy M T; McSorley, Emeir M; Bonham, Maxine P; Mulhern, Maria S; Yeates, Alison J; Davidson, Philip W; Shamlaye, Conrad F; Strain, J J; Thurston, Sally W; Harrington, Donald; Zareba, Grazyna; Wallace, Julie M W; Myers, Gary J

    2013-01-01

    Limited human data are available to assess the association between prenatal mercury vapor (Hg⁰)) exposure from maternal dental amalgam restorations and neurodevelopment of children. We evaluated the association between maternal dental amalgam status during gestation and children's neurodevelopmental outcomes at 5 years in the Seychelles Child Development Nutrition Study (SCDNS). Maternal amalgam status was determined prospectively in a longitudinal cohort study examining the associations of prenatal exposure to nutrients and methylmercury (MeHg) with neurodevelopment. A total of 236 mother-child pairs initially enrolled in the SCDNS in 2001 were eligible to participate. Maternal amalgam status was measured as number of amalgam surfaces (the primary metric) and number of occlusal points. The neurodevelopmental assessment battery was comprised of age-appropriate tests of cognitive, language, and perceptual functions, and scholastic achievement. Linear regression analysis controlled for MeHg exposure, maternal fatty acid status, and other covariates relevant to child development. Maternal amalgam status evaluation yielded an average of 7.0 surfaces (range 0-28) and 11.0 occlusal points (range 0-40) during pregnancy. Neither the number of maternal amalgam surfaces nor occlusal points were associated with any outcome. Our findings do not provide evidence to support a relationship between prenatal exposure to Hg⁰ from maternal dental amalgam and neurodevelopmental outcomes in children at 5 years of age.

  15. Risk of Adverse Pregnancy Outcomes in Women with CKD.

    PubMed

    Piccoli, Giorgina Barbara; Cabiddu, Gianfranca; Attini, Rossella; Vigotti, Federica Neve; Maxia, Stefania; Lepori, Nicola; Tuveri, Milena; Massidda, Marco; Marchi, Cecilia; Mura, Silvia; Coscia, Alessandra; Biolcati, Marilisa; Gaglioti, Pietro; Nichelatti, Michele; Pibiri, Luciana; Chessa, Giuseppe; Pani, Antonello; Todros, Tullia

    2015-08-01

    CKD is increasingly prevalent in pregnancy. In the Torino-Cagliari Observational Study (TOCOS), we assessed whether the risk for adverse pregnancy outcomes is associated with CKD by comparing pregnancy outcomes of 504 pregnancies in women with CKD to outcomes of 836 low-risk pregnancies in women without CKD. The presence of hypertension, proteinuria (>1 g/d), systemic disease, and CKD stage (at referral) were assessed at baseline. The following outcomes were studied: cesarean section, preterm delivery, and early preterm delivery; small for gestational age (SGA); need for neonatal intensive care unit (NICU); new onset of hypertension; new onset/doubling of proteinuria; CKD stage shift; "general" combined outcome (preterm delivery, NICU, SGA); and "severe" combined outcome (early preterm delivery, NICU, SGA). The risk for adverse outcomes increased across stages (for stage 1 versus stages 4-5: "general" combined outcome, 34.1% versus 90.0%; "severe" combined outcome, 21.4% versus 80.0%; P<0.001). In women with stage 1 CKD, preterm delivery was associated with baseline hypertension (odds ratio [OR], 3.42; 95% confidence interval [95% CI], 1.87 to 6.21), systemic disease (OR, 3.13; 95% CI, 1.51 to 6.50), and proteinuria (OR, 3.69; 95% CI, 1.63 to 8.36). However, stage 1 CKD remained associated with adverse pregnancy outcomes (general combined outcome) in women without baseline hypertension, proteinuria, or systemic disease (OR, 1.88; 95% CI, 1.27 to 2.79). The risk of intrauterine death did not differ between patients and controls. Findings from this prospective study suggest a "baseline risk" for adverse pregnancy-related outcomes linked to CKD.

  16. Adverse birth outcomes in a malarious area.

    PubMed

    Kalanda, B F; Verhoeff, F H; Chimsuku, L; Harper, G; Brabin, B J

    2006-06-01

    To determine factors associated with fetal growth, preterm delivery and stillbirth in an area of high malaria transmission in Southern Malawi, a cross-sectional study of pregnant women attending and delivering at two study hospitals was undertaken. A total of 243 (17.3%) babies were preterm and 54 (3.7%) stillborn. Intra-uterine growth retardation (IUGR) occurred in 285 (20.3%), of whom 109 (38.2%) were low birthweight and 26 (9.1%) preterm. Factors associated with IUGR were maternal short stature [adjusted odds ratio (AOR) 1.6, 95% confidence interval (CI) 1.0-2.5]; primigravidae (AOR 1.9, 95% CI 1.4-2.7); placental or peripheral malaria at delivery (AOR 1.4, 95% CI 1.0-1.9) and maternal anaemia at recruitment (Hb<8 g/dl) (AOR 1.9, 95% CI 1.3-2.7). Increasing parasite density in the placenta was associated with both IUGR (P=0.008) and prematurity (P=0.02). Factors associated with disproportionate fetal growth were maternal malnutrition [mid-upper arm circumference (MUAC)<23 cm, AOR 1.9, 95% CI 1.0-3.7] and primigravidae (AOR 1.8, 95% CI 1.0-3.1). Preterm delivery and stillbirth were associated with <5 antenatal care visits (AOR 2.2, 95% CI 1.3-3.7 and AOR 3.1, 95% CI 1.4-7.0 respectively) and stillbirth with a positive Venereal Disease Research Laboratory (VDRL) test (AOR 4.7, 95% CI 1.5-14.8). Interventions to reduce poor pregnancy outcomes must reduce the burden of malaria in pregnancy, improve antenatal care and maternal malnutrition.

  17. MORTALITY AS AN ADVERSE OUTCOME OF SARCOPENIA

    PubMed Central

    ARANGO-LOPERA, V.E.; ARROYO, P.; GUTIERREZ-ROBLEDO, L.M.; PEREZ-ZEPEDA, M.U.; CESARI, M.

    2016-01-01

    Sarcopenia has an important impact in elderly. Recently the European Working Group on Sarcopenia in Older People (EWGSOP) defined sarcopenia as the loss of muscle mass plus low muscle strength or low physical performance. Lack of clinical sounding outcomes (ie external validity), is one of the flaws of this algorithm. The aim of our study was to determine the association of sarcopenia and mortality in a group of Mexican elderly. A total of 345 elderly were recruited in Mexico City, and followed up for three years. The EWGSOP algorithm was integrated by: gait speed, grip strength and calf circumference. Other covariates were assessed in order to test the independent association of sarcopenia with mortality. Of the 345 subjects, 53.3% were women; with a mean age of 78.5 (SD 7) years. During the three year follow-up a total of 43 (12.4%) subjects died. Age, cognition, ADL, IADL, health self-perception, ischemic heart disease and sarcopenia were associated in the bivariate analysis with survival. Negative predictive value for sarcopenia regarding mortality was of 90%. Kaplan-Meier curves along with their respective log-rank test were significant for sarcopenia. The components of the final Cox-regression multivariate model were age, ischemic heart disease, ADL and sarcopenia. Adjusted HR for age was 3.24 (CI 95% 1.55-6.78 p 0.002), IHD 5.07 (CI 95% 1.89-13.59 p 0.001), health self-perception 5.07 (CI 95% 1.9-13.6 p 0.001), ADL 0.75 (CI 95% 0.56-0.99 p 0.048) and sarcopenia 2.39 (CI 95% 1.05-5.43 p 0.037). PMID:23459979

  18. A Quantative Adverse Outcome Pathway Linking Aromatase Inhibition in Fathead Minnows with Population Dynamics

    EPA Science Inventory

    A Quantitative Adverse Outcome Pathway Linking Aromatase Inhibition in Fathead Minnows with Population DynamicsAn adverse outcome pathway (AOP) is a qualitative description linking a molecular initiating event (MIE) with measureable key events leading to an adverse outcome (AO). ...

  19. Neurodevelopmental outcome of hypoglycaemia in healthy, large for gestational age, term newborns

    PubMed Central

    Brand, P; Molenaar, N; Kaaijk, C; Wierenga, W

    2005-01-01

    Aims: To evaluate the effects of transient hypoglycaemia on the first day of life in 75 healthy term large for gestational age (LGA) infants, born to non-diabetic mothers, on their neurodevelopmental outcome at the age of 4 years. Methods: Screening for hypoglycaemia was performed 1, 3, and 5 hours after birth, and continued if blood glucose levels were low. Treatment with intravenous glucose for hypoglycaemia was started if hypoglycaemia was severe or symptomatic. Patients' development and behaviour was examined at the age of 4 years by the Denver Developmental Scale, a non-verbal intelligence test, and the Child Behaviour Check List. Results: There were no significant differences between children with neonatal normoglycaemia (n = 15) and hypoglycaemia (plasma glucose <2.2 mmol/l 1 hour after birth, or <2.5 mmol/l subsequently; n = 60) in Denver developmental scale scores and child behaviour checklist scores. Although total IQ did not differ between hypoglycaemic and normoglycaemic children, one subscale (reasoning) did (mean difference 9.3, 95% CI 1.3 to 17.2). The correlation between reasoning IQ and neonatal blood glucose levels was weak and not statistically significant. When other definitions for hypoglycaemia were applied, the difference in reasoning IQ was not found. There were no differences in any of the test scores between hypoglycaemic children who had and who had not been treated with intravenous glucose. Conclusion: Transient mild hypoglycaemia in healthy, term LGA newborns does not appear to be harmful to psychomotor development at the age of 4 years. PMID:15613521

  20. Long-term neurodevelopmental outcomes after intrauterine and neonatal insults: a systematic review

    PubMed Central

    Mwaniki, Michael K; Atieno, Maurine; Lawn, Joy E; Newton, Charles RJC

    2012-01-01

    Summary Background Neonatal interventions are largely focused on reduction of mortality and progression towards Millennium Development Goal 4 (child survival). However, little is known about the global burden of long-term consequences of intrauterine and neonatal insults. We did a systematic review to estimate risks of long-term neurocognitive and other sequelae after intrauterine and neonatal insults, especially in low-income and middle-income countries. Methods We searched Medline, Cumulative Index to Nursing and Allied Health Literature, the Cochrane Library, and Embase for studies published between Jan 1, 1966, and June 30, 2011, that reported neurodevelopmental sequelae after preterm or neonatal insult. For unpublished studies and grey literature, we searched Dissertation Abstracts International and the WHO library. We reviewed publications that had data for long-term outcome after defined neonatal insults. We summarised the results with medians and IQRs, and calculated the risk of at least one sequela after insult. Findings Of 28 212 studies identified by our search, 153 studies were suitable for inclusion, documenting 22 161 survivors of intrauterine or neonatal insults. The overall median risk of at least one sequela in any domain was 39·4% (IQR 20·0–54·8), with a risk of at least one severe impairment in any insult domain of 18·5% (7·7–33·3), of at least one moderate impairment of 5·0% (0·0–13·3%), and of at least one mild impairment of 10·0% (1·4–17·9%). The pooled risk estimate of at least one sequela (weighted mean) associated with one or more of the insults studied (excluding HIV) was 37·0% (95% CI 27·0–48·0%) and this risk was not significantly affected by region, duration of the follow-up, study design, or period of data collection. The most common sequelae were learning difficulties, cognition, or developmental delay (n=4032; 59%); cerebral palsy (n=1472; 21%); hearing impairment (n=1340; 20%); and visual impairment (n

  1. Frailty as a predictor of short-term adverse outcomes

    PubMed Central

    Coelho, Tiago; Paúl, Constança; Gobbens, Robbert J.J.

    2015-01-01

    The objectives of this study were to compare how different frailty measures (Frailty Phenotype/FP, Groningen Frailty Indicator/GFI and Tilburg Frailty Indicator/TFI) predict short-term adverse outcomes. Secondarily, adopting a multidimensional approach to frailty (integral conceptual model–TFI), this study aims to compare how physical, psychological and social frailty predict the outcomes. A longitudinal study was carried out with 95 community-dwelling elderly. Participants were assessed at baseline for frailty, determinants of frailty, and adverse outcomes (healthcare utilization, quality of life, disability in basic and instrumental activities of daily living/ADL and IADL). Ten months later the outcomes were assessed again. Frailty was associated with specific healthcare utilization indicators: the FP with a greater utilization of informal care; GFI with an increased contact with healthcare professionals; and TFI with a higher amount of contacts with a general practitioner. After controlling for the effect of life-course determinants, comorbidity and adverse outcome at baseline, GFI predicted IADL disability and TFI predicted quality of life. The effect of the FP on the outcomes was not significant, when compared with the other measures. However, when comparing TFI’s domains, the physical domain was the most significant predictor of the outcomes, even explaining part of the variance of ADL disability. Frailty at baseline was associated with adverse outcomes at follow-up. However, the relationship of each frailty measure (FP, GFI and TFI) with the outcomes was different. In spite of the role of psychological frailty, TFI’s physical domain was the determinant factor for predicting disability and most of the quality of life. PMID:26246968

  2. Gastroschisis: Antenatal Sonographic Predictors of Adverse Neonatal Outcome

    PubMed Central

    Ferraro, Zachary Michael; Moretti, Felipe; Fung Kee Fung, Karen

    2014-01-01

    Objectives. The aim of this review was to identify clinically significant ultrasound predictors of adverse neonatal outcome in fetal gastroschisis. Methods. A quasi-systematic review was conducted in PubMed and Ovid using the key terms “gastroschisis,” “predictors,” “outcome,” and “ultrasound.” Results. A total of 18 papers were included. The most common sonographic predictors were intra-abdominal bowel dilatation (IABD), intrauterine growth restriction (IUGR), and bowel dilatation not otherwise specified (NOS). Three ultrasound markers were consistently found to be statistically insignificant with respect to predicting adverse outcome including abdominal circumference, stomach herniation and dilatation, and extra-abdominal bowel dilatation (EABD). Conclusions. Gastroschisis is associated with several comorbidities, yet there is much discrepancy in the literature regarding which specific ultrasound markers best predict adverse neonatal outcomes. Future research should include prospective trials with larger sample sizes and use well-defined and consistent definitions of the adverse outcomes investigated with consideration given to IABD. PMID:25587450

  3. Association of Neurodevelopmental Outcomes and Neonatal Morbidities of Extremely Premature Infants With Differential Exposure to Antenatal Steroids

    PubMed Central

    Chawla, Sanjay; Natarajan, Girija; Shankaran, Seetha; Pappas, Athina; Stoll, Barbara J.; Carlo, Waldemar A.; Saha, Shampa; Das, Abhik; Laptook, Abbot R.; Higgins, Rosemary D.

    2017-01-01

    IMPORTANCE Many premature infants are born without exposure to antenatal steroids (ANS) or with incomplete courses. This study evaluates the dose-dependent effect of ANS on rates of neonatal morbidities and early childhood neurodevelopmental outcomes of extremely premature infants. OBJECTIVE To compare rates of neonatal morbidities and 18- to 22-month neurodevelopmental outcomes of extremely premature infants exposed to no ANS or partial or complete courses of ANS. DESIGN, SETTING, AND PARTICIPANTS In this observational cohort study, participants were extremely premature infants (birth weight range, 401–1000 g; gestational age, 22–27 weeks) who were born at participating centers of the National Institute of Child Health and Human Development Neonatal Research Network between January 2006 and December 2011. Data were analyzed between October 2013 and May 2016. MAIN OUTCOMES AND MEASURES Rates of death or neurodevelopmental impairment at 18 to 22 months’ corrected age. Neurodevelopmental impairment was defined as the presence of any of the following: moderate to severe cerebral palsy, a cognitive score less than 85 on the Bayley Scales of Infant and Toddler Development III, blindness, or deafness. RESULTS There were 848 infants in the no ANS group, 1581 in the partial ANS group, and 3692 in the complete ANS group; the mean (SD) birth weights were 725 (169), 760 (173), and 753 (170) g, respectively, and the mean (SD) gestational ages were 24.5 (1.4), 24.9 (2), and 25.1 (1.1) weeks. Of 6121 eligible infants, 4284 (70.0%) survived to 18- to 22-month follow-up, and data were available for 3892 of 4284 infants (90.8%). Among the no, partial, and complete ANS groups, there were significant differences in the rates of mortality (43.1%, 29.6%, and 25.2%, respectively), severe intracranial hemorrhage among survivors (23.3%, 19.1%, and 11.7%), death or necrotizing enterocolitis (48.1%, 37.1%, and 32.5%), and death or bronchopulmonary dysplasia (74.9%, 68.9%, and 65

  4. The effect of maternal pravastatin therapy on adverse sensorimotor outcomes of the offspring in a murine model of preeclampsia.

    PubMed

    Carver, Alissa R; Tamayo, Esther; Perez-Polo, J Regino; Saade, George R; Hankins, Gary D V; Costantine, Maged M

    2014-04-01

    Animal and human studies show that in-utero exposure to preeclampsia alters fetal programming and results in long-term adverse cardiovascular outcomes in the offspring. Human epidemiologic data also suggest that offspring born to preeclamptic mothers are also at risk of adverse long term neurodevelopmental outcomes. Pravastatin, a hydrophilic lipid-lowering drug with pleiotropic properties, was found to prevent the altered cardiovascular phenotype of preeclampsia and restore fetal growth in animal models, providing biological plausibility for its use as a preventive agent for preeclampsia. In this study, we used a murine model of preeclampsia based on adenovirus over-expression of the anti-angiogenic factor soluble Fms-like tyrosine kinase 1, and demonstrated that adult offspring born to preeclamptic dams perform poorly on assays testing vestibular function, balance, and coordination, and that prenatal pravastatin treatment prevents impairment of fetal programming.

  5. Application of the adverse outcome pathway framework - advances and challenges

    EPA Science Inventory

    The adverse outcome pathway (AOP) framework, while not new in concept, has gained attention in recent years as a set of organizing principles and tools that can help facilitate greater use of mechanistic or pathway-based data in risk assessment and regulatory decision-making. Reg...

  6. Proteomics for Adverse Outcome Pathway Discovery using Human Kidney Cells?

    EPA Science Inventory

    An Adverse Outcome Pathway (AOP) is a conceptual framework that applies molecular-based data for use in risk assessment and regulatory decision support. AOP development is based on effects data of chemicals on biological processes (i.e., molecular initiating events, key intermedi...

  7. Ultrasound diagnosis and neurodevelopmental outcome of localised and extensive cystic periventricular leucomalacia

    PubMed Central

    Pierrat, V; Duquennoy, C; van Haastert, I C; Ernst, M; Guilley, N; de Vries, L S

    2001-01-01

    AIMS—To compare the ultrasound (US) evolution and neurodevelopmental outcome of infants with localised (grade II) and extensive (grade III) cystic periventricular leucomalacia (c-PVL).
METHODS—Over a nine year period, c-PVL was diagnosed in 96/3451 (2.8%) infants in two hospital cohorts. Eighteen were excluded from the study. Thirty nine infants with grade II PVL were compared with 39 infants with grade III PVL.
RESULTS—The two populations were comparable for gestational age and birth weight. In infants with grade II PVL, cysts were noted to develop more often after the first month of life (53%) in contrast with grade III PVL (22%) (odds ratio (OR) 3.81 (95% confidence interval (CI) 1.19 to 12.63)). Cysts were also more often unilateral in grade II (54%) than in grade III PVL (0%) (OR indefinite; RR 3.17 (95% CI 2.16 to 4.64)). At 40 weeks postmenstrual age (PMA), cysts were no longer seen on US in 13/38 infants with grade II PVL, with ventriculomegaly being the only visible sequel in nine cases. In grade III PVL, cysts were still present in 25 of the 27 surviving infants. Nine infants with grade II PVL were free of motor sequelae at follow up compared with one infant with grade III PVL (OR 8.07 (95% CI 0.92 to 181.66)). Twenty two out of 29children with grade II PVL who developed cerebral palsy achieved independent walking compared with 3/26 with grade III PVL (OR 75 (95% CI 11.4 to 662)).
CONCLUSIONS—In the cohort studied, 50% of the infants with c-PVL had a more localised form (grade II). In grade II PVL, the cysts developed beyond the first month of life in more than half of the cases and were often no longer visible, on US, at 40 weeks PMA. In order not to miss this diagnosis, sequential US should also be performed beyond the first month of life. Mild ventriculomegaly noted at term can sometimes be due to grade II c-PVL. Cerebral palsy was slightly less common and tended to be less severe in infants with grade II PVL than in those with grade III

  8. Residential Proximity to Environmental Hazards and Adverse Health Outcomes

    PubMed Central

    Maantay, Juliana A.; Chakraborty, Jayajit

    2011-01-01

    How living near environmental hazards contributes to poorer health and disproportionate health outcomes is an ongoing concern. We conducted a substantive review and critique of the literature regarding residential proximity to environmental hazards and adverse pregnancy outcomes, childhood cancer, cardiovascular and respiratory illnesses, end-stage renal disease, and diabetes. Several studies have found that living near hazardous wastes sites, industrial sites, cropland with pesticide applications, highly trafficked roads, nuclear power plants, and gas stations or repair shops is related to an increased risk of adverse health outcomes. Government agencies should consider these findings in establishing rules and permitting and enforcement procedures to reduce pollution from environmentally burdensome facilities and land uses. PMID:22028451

  9. Drinking water contaminants and adverse pregnancy outcomes: a review.

    PubMed Central

    Bove, Frank; Shim, Youn; Zeitz, Perri

    2002-01-01

    Concern for exposures to drinking water contaminants and their effects on adverse birth outcomes has prompted several studies evaluating chlorination disinfection by-products and chlorinated solvents. Some of these contaminants are found to be teratogenic in animal studies. This review evaluates 14 studies on chlorination disinfection by-products such as trihalomethanes (THMs) and five studies on chlorinated solvents such as trichloroethylene (TCE). The adverse birth outcomes discussed in this review include small for gestational age (SGA), low birth weight, preterm birth, birth defects, spontaneous abortions, and fetal deaths. Because of heterogeneities across the studies in the characterization of birth outcomes, the assessment and categorization of exposures, and the levels and mixtures of contaminants, a qualitative review was conducted. Generally, the chief bias in these studies was exposure misclassification that most likely underestimated the risk, as well as distorted exposure-response relationships. The general lack of confounding bias by risk factors resulted from these factors not being associated with drinking water exposures. The studies of THMs and adverse birth outcomes provide moderate evidence for associations with SGA, neural tube defects (NTDs), and spontaneous abortions. Because fewer studies have been conducted for the chlorinated solvents than for THMs, the evidence for associations is less clear. Nevertheless, the findings of excess NTDs, oral clefts, cardiac defects, and choanal atresia in studies that evaluated TCE-contaminated drinking water deserve follow-up. PMID:11834464

  10. Accelerating Adverse Outcome Pathway (AOP) development via computationally predicted AOP networks

    EPA Science Inventory

    The Adverse Outcome Pathway (AOP) framework is increasingly being adopted as a tool for organizing and summarizing the mechanistic information connecting molecular perturbations by environmental stressors with adverse outcomes relevant for ecological and human health outcomes. Ho...

  11. Racial Discrimination and Adverse Birth Outcomes: An Integrative Review

    PubMed Central

    Alhusen, Jeanne L.; Bower, Kelly; Epstein, Elizabeth; Sharps, Phyllis

    2016-01-01

    Introduction This article presents an integrative review of the literature examining the relationship between racial discrimination and adverse birth outcomes. Methods Searches for research studies published from 2009 to 2015 were conducted using PubMed, CINAHL, Scopus, PsycINFO, Web of Science, and Embase. Articles were assessed for potential inclusion using the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) 2009 framework. Results Fifteen studies met criteria for review. The majority of the studies found a significant relationship between racial discrimination and low birth weight, preterm birth, and small for gestational age. Each of the studies that examined more proximal variables related to birth outcomes such as entry into prenatal care, employment opportunities, neighborhood characteristics, or inflammatory markers found significant associations between the specific variables examined and racial discrimination. Participants in qualitative studies discussed experiences of institutional racism with regard to several components of prenatal care including access and quality of care. Discussion Racial discrimination is a significant risk factor for adverse birth outcomes. To best understand the mechanisms by which racial discrimination impacts birth outcomes, and to inform the development of effective interventions that eliminate its harmful effects on health, longitudinal research that incorporates comprehensive measures of racial discrimination is needed. Health care providers must fully acknowledge and address the psychosocial factors that impact health outcomes in minority racial/ethnic women. PMID:27737504

  12. Maternal language and adverse birth outcomes in a statewide analysis.

    PubMed

    Sentell, Tetine; Chang, Ann; Ahn, Hyeong Jun; Miyamura, Jill

    2016-01-01

    Limited English proficiency is associated with disparities across diverse health outcomes. However, evidence regarding adverse birth outcomes across languages is limited, particularly among U.S. Asian and Pacific Islander populations. The study goal was to consider the relationship of maternal language to birth outcomes using statewide hospitalization data. Detailed discharge data from Hawaii childbirth hospitalizations from 2012 (n = 11,419) were compared by maternal language (English language or not) for adverse outcomes using descriptive and multivariable log-binomial regression models, controlling for race/ethnicity, age group, and payer. Ten percent of mothers spoke a language other than English; 93% of these spoke an Asian or Pacific Islander language. In multivariable models, compared to English speakers, non-English speakers had significantly higher risk (adjusted relative risk [ARR]: 2.02; 95% confidence interval [CI]: 1.34-3.04) of obstetric trauma in vaginal deliveries without instrumentation. Some significant variation was seen by language for other birth outcomes, including an increased rate of primary Caesarean sections and vaginal births after Caesarean, among non-English speakers. Non-English speakers had approximately two times higher risk of having an obstetric trauma during a vaginal birth when other factors, including race/ethnicity, were controlled. Non-English speakers also had higher rates of potentially high-risk deliveries.

  13. Maternal Language and Adverse Birth Outcomes in a Statewide Analysis

    PubMed Central

    Sentell, Tetine; Chang, Ann; Jun Ahn, Hyeong; Miyamura, Jill

    2016-01-01

    Background Limited English proficiency is associated with disparities across diverse health outcomes. However, evidence regarding adverse birth outcomes across languages is limited, particularly among US Asian and Pacific Islander populations. The study goal was to consider the relationship of maternal language to birth outcomes using statewide hospitalization data. Methods Detailed discharge data from Hawai‘i childbirth hospitalizations from 2012 (n=11,419) were compared by maternal language (English language or not) for adverse outcomes using descriptive and multivariable log-binomial regression models, controlling for race/ethnicity, age group, and payer. Results Ten percent of mothers spoke a language other than English; 93% of these spoke an Asian or Pacific Islander language. In multivariable models, compared to English speakers non-English speakers had significantly higher risk (adjusted relative risk [ARR]: 2.02; 95% Confidence Interval [CI]: 1.34–3.04) of obstetric trauma in vaginal deliveries without instrumentation. Some significant variation was seen by language for other birth outcomes, including an increased rate of primary Caesarean sections and vaginal births after Caesarean among non-English speakers. Conclusions Non-English speakers had approximately two times higher risk of having an obstetric trauma during a vaginal birth when other factors, including race/ethnicity, were controlled. Non-English speakers also had higher rates of potentially high-risk deliveries. PMID:26361937

  14. Adverse outcome pathways: From research to regulation scientific workshop report.

    PubMed

    Kleinstreuer, Nicole C; Sullivan, Kristie; Allen, David; Edwards, Stephen; Mendrick, Donna L; Embry, Michelle; Matheson, Joanna; Rowlands, J Craig; Munn, Sharon; Maull, Elizabeth; Casey, Warren

    2016-04-01

    An adverse outcome pathway (AOP) helps to organize existing knowledge on chemical mode of action, starting with a molecular initiating event such as receptor binding, continuing through key events, and ending with an adverse outcome such as reproductive impairment. AOPs can help identify knowledge gaps where more research is needed to understand the underlying mechanisms, aid in chemical hazard characterization, and guide the development of new testing approaches that use fewer or no animals. A September 2014 workshop in Bethesda, Maryland considered how the AOP concept could improve regulatory assessments of chemical toxicity. Scientists from 21 countries, representing industry, academia, regulatory agencies, and special interest groups, attended the workshop, titled Adverse Outcome Pathways: From Research to Regulation. Workshop plenary presentations were followed by breakout sessions that considered regulatory acceptance of AOPs and AOP-based tools, criteria for building confidence in an AOP for regulatory use, and requirements to build quantitative AOPs and AOP networks. Discussions during the closing session emphasized a need to increase transparent and inclusive collaboration, especially with disciplines outside of toxicology. Additionally, to increase impact, working groups should be established to systematically prioritize and develop AOPs. Multiple collaborative projects and follow-up activities resulted from the workshop.

  15. Caregiving burden and parent-child quality of life outcomes in neurodevelopmental conditions: the mediating role of behavioral disengagement.

    PubMed

    Carona, Carlos; Silva, Neuza; Crespo, Carla; Canavarro, Maria Cristina

    2014-12-01

    The aim of this study was to analyze the direct and indirect effects, via parents' behavioral disengagement coping, of caregiving burden on the quality of life (QL) of parents and their children with neurodevelopmental conditions. Self-completion questionnaires on the target variables were administered to a sample of 156 parents who had a child with a neurodevelopmental condition, namely epilepsy (n = 65) and cerebral palsy (n = 91). Structural equation modeling was used to test a mediation model and ascertain direct and indirect effects among study variables. Significant direct effects of caregiving burden on parents' and their children's QL were found. Additionally, caregiving burden had a significant indirect effect on parents' QL, via behavioral disengagement, but not on their children's QL. Finally, this model was found to be invariant across conditions and patients' age groups. Caregiving burden may be elected as a strategic intervention target to improve parent-child QL outcomes in neuropediatric settings. Parents should be encouraged to avoid or reduce behavioral disengagement coping in relation to their caregiving stress, and alternatively adopt active coping strategies that may positively affect their children's QL and impede or attenuate the deleterious effects of caregiving burden on their own QL.

  16. Weight-of-evidence evaluation of an adverse outcome ...

    EPA Pesticide Factsheets

    Ongoing honey bee colony losses are of significant international concern because of the essential role these insects play in pollinating staple food crops. Chemical and non-chemical stressors both have been implicated as possible contributors to colony failure, however, the potential role of commonly-used neonicotinoid insecticides has emerged as particularly concerning. Neonicotinoids act on the nicotinic acetylcholine receptor (nAChR) to eliminate target pest insects, however, mounting evidence indicates that these chemicals may adversely affect beneficial pollinators, such as the honey bee, via impacts on learning and memory thereby affecting foraging success. However, the mechanisms linking activation of the nAChR to adverse effects on learning and memory are uncertain. Additionally, clear connections between observed impacts on individual bees and colony level effects are lacking. Therefore, the objective of this work was to develop adverse outcome pathways (AOPs) as a means to evaluate the biological plausibility and empirical evidence supporting (or refuting) the linkage between the nAChR and colony level impacts. Development of these AOPs has led to the identification of research gaps which, for example, may be of high priority in understanding how perturbation of pathways involved in neurotransmission can adversely affect honey bee health, causing colony instability and further failure. From this effort, an AOP network also was developed, laying the f

  17. Association of antenatal corticosteroids with mortality and neurodevelopmental outcomes among infants born at 22–25 weeks gestation

    PubMed Central

    Carlo, Waldemar A.; McDonald, Scott A.; Fanaroff, Avroy A.; Vohr, Betty R.; Stoll, Barbara J.; Ehrenkranz, Richard A.; Andrews, William W.; Wallace, Dennis; Das, Abhik; Bell, Edward F.; Walsh, Michele C.; Laptook, Abbot R.; Shankaran, Seetha; Poindexter, Brenda B.; Hale, Ellen C.; Newman, Nancy S.; Davis, Alexis S.; Schibler, Kurt; Kennedy, Kathleen A.; Sanchez, Pablo J.; Van Meurs, Krisa P.; Goldberg, Ronald N.; Watterberg, Kristi L.; Faix, Roger G.; Frantz, Ivan D.; Higgins, Rosemary D.

    2013-01-01

    Context Current guidelines, initially published in 1995, recommend antenatal corticosteroids for mothers with preterm labor from 24–34 weeks gestational age, but not before 24 weeks because of lack of data. However, many infants born before 24 weeks are provided intensive care now. Objective To determine if antenatal corticosteroids are associated with improvement in major outcomes in infants born at 22 and 23 weeks. Design, Setting, Participants Data for this cohort study were collected prospectively on 401–1000 gram inborn infants (N=10,541) of 22–25 weeks gestation born between 1993–2009 at 23 academic perinatal centers in the United States. Certified examiners unaware of exposure to antenatal corticosteroids performed follow-up examinations on 4,924 (86.5%) of the infants born in 1993–2008 who survived to 18–22 months. Logistic regression models generated adjusted odds ratios, controlling for maternal and neonatal variables. Main Outcome Measures Mortality and neurodevelopmental impairment at 18–22 months corrected age RESULTS Death or neurodevelopmental impairment at 18–22 months was lower for infants whose mothers received antenatal corticosteroids born at 23 weeks (antenatal corticosteroids, 83.4% vs no antenatal corticosteroids, 90.5%; adjusted odds ratio 0.58; 95% CI, 0.42–0.80), at 24 weeks (antenatal corticosteroids, 68.4% vs no antenatal corticosteroids, 80.3%; adjusted odds ratio 0.62; 95% CI, 0.49–0.78), and at 25 weeks (antenatal corticosteroids, 52.7% vs no antenatal corticosteroids, 67.9%; adjusted odds ratio 0.61; 95% CI, 0.50–0.74) but not at 22 weeks (antenatal corticosteroids, 90.2% vs no antenatal corticosteroids, 93.1%; adjusted odds ratio 0.80; 95% CI, 0.29–12.21). Death by 18–22 months, hospital death, death/intraventricular hemorrhage/periventricular leukomalacia, and death/necrotizing enterocolitis were significantly lower for infants born at 23, 24, and 25 weeks gestational age if the mothers had received

  18. Long-term neurodevelopmental and cardiovascular outcome after intrauterine transfusions for fetal anaemia: a review.

    PubMed

    Lindenburg, Irene T M; van Klink, Jeanine M; Smits-Wintjens, Vivianne E H J; van Kamp, Inge L; Oepkes, Dick; Lopriore, Enrico

    2013-09-01

    Perinatal survival rates after intrauterine transfusions (IUT) for red cell alloimmunisation now exceed 90%, which demonstrates the safety and efficacy of one of the most successful procedures in fetal therapy. However, improved perinatal survival could lead to an increased number of children with long-term disabilities. The importance of long-term follow-up studies in fetal therapy lies in both the necessity of evaluation of antenatal management as well as in evidence-based preconceptional and prenatal counselling. This review describes the possible long-term cardiovascular and neurodevelopmental sequelae after IUT treatment for different indications including red cell alloimmunisation, parvovirus B19 infection, fetomaternal haemorrhage and twin anaemia-polycythaemia sequence.

  19. The role of Mycoplasma and Ureaplasma in adverse pregnancy outcomes.

    PubMed

    Murtha, Amy P; Edwards, James M

    2014-12-01

    Genital mycoplasmas are frequently found in the vaginal flora across socioeconomic and ethnic groups and have been demonstrated to be involved in adverse perinatal outcomes. Both Mycoplasma and Ureaplasma spp cause inflammation potentially leading to spontaneous preterm birth and PPROM as well as postdelivery infectious complications and neonatal infections. Herein we have provided an overview of the existing literature and supportive evidence for genital mycoplasma's role in perinatal complications. Future research will need to focus on clearly delineating the species, allowing for discrimination of their effects.

  20. UMBILICAL CORD SERUM INTERLEUKIN-6, C-REACTIVE PROTEIN, AND MYELOPEROXIDASE CONCENTRATIONS AT BIRTH AND ASSOCIATION WITH NEONATAL MORBIDITIES AND LONG TERM NEURODEVELOPMENTAL OUTCOMES

    PubMed Central

    Sorokin, Yoram; Romero, Roberto; Mele, Lisa; Iams, Jay D.; Peaceman, Alan M.; Leveno, Kenneth J.; Harper, Margaret; Caritis, Steve N.; Mercer, Brian M.; Thorp, John M.; O’Sullivan, Mary Jo; Ramin, Susan M.; Carpenter, Marshall W.; Rouse, Dwight J.; Sibai, Baha

    2015-01-01

    OBJECTIVE To determine if umbilical cord serum concentrations of interleukin-6 (IL-6), C-reactive protein (CRP), and myeloperoxidase (MPO), in pregnancies at risk for preterm birth (PTB), are associated with neonatal morbidities and/or altered neurodevelopmental outcomes in the children. STUDY DESIGN Umbilical cord serum samples were collected at birth from 400 newborns delivered within a multicenter randomized controlled trial of repeated versus single course of antenatal corticosteroids (ACs), in women at increased risk for PTB. Newborns were followed through discharge and were evaluated between 36 and 42 months corrected age with neurological examination and Bayley Scales of Infant Development. Umbilical cord serum concentrations of IL-6, CRP, and MPO were determined using enzyme-linked immunoassays. Multivariate logistic regression analyses explored the relationship between umbilical cord serum IL-6, CRP and MPO levels, adverse newborn outcomes and PTB < 32 weeks of gestational age (GA). RESULTS Univariate analysis revealed that umbilical cord IL-6 above the 75th percentile was associated with increased respiratory distress syndrome (RDS) and chronic lung disease (CLD), but not with necrotizing enterocolitis (NEC), intraventricular hemorrhage (IVH), or neonatal sepsis; however, this association was not significant after adjusting for gestational age at delivery and treatment group. No significant associations between CRP or MPO, and RDS, CLD, NEC, sepsis or IVH were evident. Regression analysis revealed that CRP above the 75th percentile was associated with a decreased risk of CLD (O.R. 0.10, 95% C.I. 0.02–0.41). No associations between umbilical cord IL-6, CRP or MPO, and MDI < 70 or PDI < 70 were evident. Umbilical cord serum IL-6, CRP, and MPO, above the 75th percentile, were associated with more frequent PTB < 32 weeks GA. CONCLUSION Elevated umbilical cord serum concentration of CRP is associated with reduced risk for CLD even after adjusting for

  1. Pharmacogenetics of the Neurodevelopmental Impact of Anticancer Chemotherapy

    ERIC Educational Resources Information Center

    Robaey, Philippe; Krajinovic, Maja; Marcoux, Sophie; Moghrabi, Albert

    2008-01-01

    Pharmacogenetics holds the promise of minimizing adverse neurodevelopmental outcomes of cancer patients by identifying patients at risk, enabling the individualization of treatment and the planning of close follow-up and early remediation. This review focuses first on methotrexate, a drug often implicated in neurotoxicity, especially when used in…

  2. An “ADME Module” in the Adverse Outcome Pathway ...

    EPA Pesticide Factsheets

    The Adverse Outcome Pathway (AOP) framework has generated intense interest for its utility to organize knowledge on the toxicity mechanisms, starting from a molecular initiating event (MIE) to an adverse outcome across various levels of biological organization. While the AOP framework is designed to be chemical agnostic, it is widely recognized that considering chemicals’ absorption, distribution, metabolism, and excretion (ADME) behaviors is critical in applying the AOP framework in chemical-specific risk assessment. Currently, information being generated as part of the Organisation for Economic Co-operation and Development (OECD) AOP Development Programme is being consolidated into an AOP Knowledgebase (http://aopwiki.org). To enhance the use of this Knowledgebase in risk assessment, an ADME Module has been developed to contain the ADME information needed to connect MIEs and other key events in an AOP for specific chemicals. The conceptual structure of this module characterizes the potential of a chemical to reach the target MIE based on either its structure-based features or relative rates of ADME. The key features of this module include (1) a framework for connecting biology-based AOP to biochemical-based ADME and chemical/human activity-based exposure pathways; (2) links to qualitative tools (e.g., structure-based cheminformatic model) that screen for chemicals that could potentially reach the target MIE; (3) links to quantitative tools (e.g., dose-r

  3. Managing adverse birth outcomes: helping parents and families cope.

    PubMed

    Van Dinter, Maureen C; Graves, Lisa

    2012-05-01

    Unexpected adverse fetal and neonatal outcomes (e.g., stillbirth, birth trauma, congenital anomalies) present a crisis for the family and the medical care team. In cases of stillbirth, the family physician should be flexible in supporting the parents' choices, validate the loss, and work as a team with the nursing staff. Psychosocial support includes offering counseling services, assessing women for postpartum depression and anxiety, and considering the effect of the loss on the entire family. Although infants with birth asphyxia or major anomalies may require transfer to facilities with a neonatal intensive care unit, the physician will usually provide ongoing care for the mother in the postpartum period. A comprehensive assessment can determine the etiology of fetal demise in most cases, which may guide future preconception and maternity care. Women with a previous adverse pregnancy outcome may have increased psychological stress in a subsequent pregnancy. Knowledge of community resources will facilitate care for the mother and her partner or family. Physicians may need to seek peer support to cope with their own feelings of loss.

  4. Innate immunity, coagulation and placenta-related adverse pregnancy outcomes.

    PubMed

    Li, Min; Huang, S Joseph

    2009-12-01

    Maternal immunity undergoes subtle adjustment in order to tolerate the semi-allogeneic embryo and maintain the host defense against potential pathogens. Concomitantly, coagulation systems change from an anti-coagulant state to a pro-coagulant state to meet the hemostatic challenge of placentation and delivery. Innate immunity and blood coagulation systems are the first line of defense to protect a host against exogenous challenges, including alloantigens and mechanical insults, and preserve the integrity of an organism. The interactions between coagulation and immune systems have been extensively studied. Immune cells play a pivotal role in the initiation of the coagulation cascade, whereas coagulation proteases display substantial immuno-modulatory effects. Upon exogenous challenges, the immune and coagulation systems are capable of potentiating each other leading to a vicious cycle. Natural killer (NK) cells, macrophages (Mphis) and dendritic cells (DCs) are three major innate immune cells that have been demonstrated to play essential roles in early pregnancy. However, immune maladaptation and hemostatic imbalance have been suggested to be responsible for adverse pregnant outcomes, such as preeclampsia (PE), miscarriage, recurrent spontaneous abortion (RSA) and intrauterine growth restriction (IUGR). In this review, we will summarize the mutual regulation between blood coagulation and innate immune systems as well as their roles in the maintenance of normal pregnancy and in the pathogenesis of adverse pregnancy outcomes.

  5. Assessing the Influence of Researcher-Partner Involvement on the Process and Outcomes of Participatory Research in Autism Spectrum Disorder and Neurodevelopmental Disorders: A Scoping Review

    ERIC Educational Resources Information Center

    Jivraj, Jamil; Sacrey, Lori-Ann; Newton, Amanda; Nicholas, David; Zwaigenbaum, Lonnie

    2014-01-01

    Participatory research aims to increase the relevance and broaden the implementation of health research by involving those affected by the outcomes of health studies. Few studies within the field of neurodevelopmental disorders, particularly autism spectrum disorders, have involved autistic individuals as partners. This study sought to identify…

  6. Histone Modifications in a Mouse Model of Early Adversities and Panic Disorder: Role for Asic1 and Neurodevelopmental Genes

    PubMed Central

    Cittaro, Davide; Lampis, Valentina; Luchetti, Alessandra; Coccurello, Roberto; Guffanti, Alessandro; Felsani, Armando; Moles, Anna; Stupka, Elia; D’ Amato, Francesca R.; Battaglia, Marco

    2016-01-01

    Hyperventilation following transient, CO2-induced acidosis is ubiquitous in mammals and heritable. In humans, respiratory and emotional hypersensitivity to CO2 marks separation anxiety and panic disorders, and is enhanced by early-life adversities. Mice exposed to the repeated cross-fostering paradigm (RCF) of interference with maternal environment show heightened separation anxiety and hyperventilation to 6% CO2-enriched air. Gene-environment interactions affect CO2 hypersensitivity in both humans and mice. We therefore hypothesised that epigenetic modifications and increased expression of genes involved in pH-detection could explain these relationships. Medullae oblongata of RCF- and normally-reared female outbred mice were assessed by ChIP-seq for H3Ac, H3K4me3, H3K27me3 histone modifications, and by SAGE for differential gene expression. Integration of multiple experiments by network analysis revealed an active component of 148 genes pointing to the mTOR signalling pathway and nociception. Among these genes, Asic1 showed heightened mRNA expression, coherent with RCF-mice’s respiratory hypersensitivity to CO2 and altered nociception. Functional enrichment and mRNA transcript analyses yielded a consistent picture of enhancement for several genes affecting chemoception, neurodevelopment, and emotionality. Particularly, results with Asic1 support recent human findings with panic and CO2 responses, and provide new perspectives on how early adversities and genes interplay to affect key components of panic and related disorders. PMID:27121911

  7. Histone Modifications in a Mouse Model of Early Adversities and Panic Disorder: Role for Asic1 and Neurodevelopmental Genes.

    PubMed

    Cittaro, Davide; Lampis, Valentina; Luchetti, Alessandra; Coccurello, Roberto; Guffanti, Alessandro; Felsani, Armando; Moles, Anna; Stupka, Elia; D' Amato, Francesca R; Battaglia, Marco

    2016-04-28

    Hyperventilation following transient, CO2-induced acidosis is ubiquitous in mammals and heritable. In humans, respiratory and emotional hypersensitivity to CO2 marks separation anxiety and panic disorders, and is enhanced by early-life adversities. Mice exposed to the repeated cross-fostering paradigm (RCF) of interference with maternal environment show heightened separation anxiety and hyperventilation to 6% CO2-enriched air. Gene-environment interactions affect CO2 hypersensitivity in both humans and mice. We therefore hypothesised that epigenetic modifications and increased expression of genes involved in pH-detection could explain these relationships. Medullae oblongata of RCF- and normally-reared female outbred mice were assessed by ChIP-seq for H3Ac, H3K4me3, H3K27me3 histone modifications, and by SAGE for differential gene expression. Integration of multiple experiments by network analysis revealed an active component of 148 genes pointing to the mTOR signalling pathway and nociception. Among these genes, Asic1 showed heightened mRNA expression, coherent with RCF-mice's respiratory hypersensitivity to CO2 and altered nociception. Functional enrichment and mRNA transcript analyses yielded a consistent picture of enhancement for several genes affecting chemoception, neurodevelopment, and emotionality. Particularly, results with Asic1 support recent human findings with panic and CO2 responses, and provide new perspectives on how early adversities and genes interplay to affect key components of panic and related disorders.

  8. Constructing, Quantifying, and Validating an Adverse Outcome Pathway for Vascular Developmental Toxicity

    EPA Science Inventory

    Constructing, Quantifying, and Validating an Adverse Outcome Pathway for Vascular Developmental Toxicity The adverse outcome pathway (AOP) for embryonic vascular disruption1 leading to a range of adverse prenatal outcomes was recently entered into the AOP wiki and accepted as par...

  9. Adverse perinatal outcomes in borderline amniotic fluid index

    PubMed Central

    Jamal, Ashraf; Kazemi, Maryam; Marsoosi, Vajiheh; Eslamian, Laleh

    2016-01-01

    Background: Normal amniotic fluid predicts normal placental function, fetal growth and fetal well-being. Objective: To determine adverse pregnancy outcomes in borderline amniotic fluid index (AFI). Materials and Methods: Pregnant women (37-40 wks) with diagnosis of borderline AFI between December 2012 and August 2014 were identified. Antepartum, intrapartum and neonatal data were collected and compared with those of pregnant women with normal AFI. An AFI less than 8 and more than 5 cm was defined for borderline AFI. Pregnancy outcomes included Cesarean section for non-reassuring fetal heart rate, meconium stained amniotic fluid, 5-min Apgar score <7, low birth weight, umbilical cord blood pH at term and NICU admission. Results: Gestational age at delivery in pregnancies with borderline AFI was significantly lower than normal AFI. Cesarean section rate for non-reassuring fetal heart rate in women of borderline AFI was significantly higher and there was an increased incidence of birth weight less than 10th percentile for gestation age in borderline AFI group. Incidence of low Apgar score and low umbilical artery pH in pregnancies with borderline AFI was significantly higher than women with normal AFI. There were no significant difference in the rate of NICU admission and meconium staining in both groups. Conclusion: There are significant differences for adverse pregnancy outcomes , such as Cesarean section due to non-reassuring fetal heart rate, birth weight less than 10th percentile for gestation age, low 5 min Apgar score and low umbilical artery pH between pregnancies with borderline and normal AFI. PMID:27981256

  10. Adverse Experiences in Early Childhood and Kindergarten Outcomes

    PubMed Central

    Wade, Roy; Lin, Yong; Morrow, Lesley M.; Reichman, Nancy E.

    2016-01-01

    OBJECTIVE: To examine associations between adverse childhood experiences (ACEs) in early childhood and teacher-reported academic and behavioral problems in kindergarten. METHODS: We conducted a secondary analysis of data from the Fragile Families and Child Wellbeing Study, a national urban birth cohort. Subjects with primary caregiver-reported information on ACE exposures ascertained at 5 years and teacher-reported outcomes at the end of the child’s kindergarten year were included. Outcomes included teacher ratings of academic skills, emergent literacy skills, and behavior. We included 8 ACE exposures on the basis of the original Centers for Disease Control and Prevention Kaiser study and created an ACE score by summing individual adversities. We examined the associations between teacher-reported academic and behavioral outcomes and ACE scores by using logistic regression. RESULTS: In the study sample, 1007 children were included. Fifty-five percent had experienced 1 ACE and 12% had experienced ≥ 3. Adjusting for potential confounders, experiencing ≥ 3 ACEs was associated with below-average language and literacy skills (adjusted odds ratio [AORs]: 1.8; 95% confidence interval [CI]: 1.1–2.9) and math skills (AOR: 1.8, 95% CI: 1.1–2.9), poor emergent literacy skills, attention problems (AOR: 3.5, 95% CI: 1.8–6.5), social problems (AOR: 2.7, 95% CI: 1.4–5.0), and aggression (AOR: 2.3, 95% CI: 1.2–4.6). CONCLUSIONS: In this study of urban children, experiencing ACEs in early childhood was associated with below-average, teacher-reported academic and literacy skills and behavior problems in kindergarten. These findings underscore the importance of integrated approaches that promote optimal development among vulnerable children. PMID:26768347

  11. Inherited disorders as a risk factor and predictor of neurodevelopmental outcome in pediatric cancer.

    PubMed

    Ullrich, Nicole J

    2008-01-01

    Each year in the United States, an average of one to two children per 10,000 develop cancer. The etiology of most childhood cancer remains largely unknown but is likely attributable to random or induced genetic aberrations in somatic tissue. However, a subset of children develops cancer in the setting of an underlying inheritable condition involving a germline genetic mutation or chromosomal aberration. Despite overall improved survival rates for children with cancer over recent decades, many patients experience neurological and neurocognitive complications during the course of their illness and/or as late effects of treatment. Improvements in therapy, longer survival times, and improved imaging techniques have all increased both the time that patients are at risk and the ability to detect such complications. How an underlying inherited disorder influences the incidence, timing, etiology, and treatment of such sequelae has not been extensively documented, but evidence exists for an increased risk for secondary malignancies and in some cases life-threatening sensitivity/toxicity to conventionally dosed cancer treatments, thus emphasizing the need for the early recognition of such syndromes. This review outlines the major tumor- and treatment-related neurodevelopmental sequelae in pediatric cancer patients, with particular attention to children with an underlying inheritable disorder.

  12. Neurodevelopmental outcome of very low birth weight babies admitted to a Malaysian nursery.

    PubMed

    Ho, J J; Amar, H S; Mohan, A J; Hon, T H

    1999-04-01

    This paper examines the prevalence and pattern of neurodevelopmental handicap at 2 years of age in very-low-birth-weight (VLBW) infants admitted during 1993 to a level 3 nursery in Malaysia. The study included all VLBW babies born in the hospital or referred for neonatal care. Control infants were randomly selected during attendance at a primary health care clinic. A total of 82 (54.6%) out of the 150 VLBW infants admitted survived for 2 years, 77 (93.9%) of which were evaluated. The mean General Quotient (GQ) on the Griffiths Scales was 94 (15.7) for the study group and 104 (8.3) for the 60 controls. For GQ, 21 infants (27.3%) of the study population were 1 or more standard deviations (SD) below the mean, as compared with 1 infant (1.6%) of the control group who was 1-2 SD below the mean. Visual impairment occurred in 2 study infants and none of the controls. There was no hearing impairment in either group. In conclusion, mortality was higher than reported in developing countries but the rate of handicap was not different. Neonatal intensive care should continue to be upgraded in developing countries but at a rate compatible with the availability of resources.

  13. [Adverse Sensory Input of Childhood Maltreatment Modified by Early Experience Ascertaining the Neural Basis of Neurodevelopmental and Attachment Disorders].

    PubMed

    Tomoda, Akemi

    2015-01-01

    Childhood maltreatment, which markedly increases the risk of psychopathology such as depression, PTSD, and reduced cognitive abilities, is associated with structural and functional brain differences. Our earlier studies elucidated potential discernible effects on the brain morphology of childhood maltreatment on the gray matter volume or cortical thickness. Further, our preliminary studies revealed a significantly reduced gray matter volume (GMV) in the left primary visual cortex (Brodmann area 17) in the reactive attachment disorder (RAD) group compared to the typically developed group. These visual cortex GMV abnormalities may also be associated with such visual stimulus-induced emotion regulation impairments of RAD, leading to an increase in the risk of future psychopathology. Brain regions that process and convey the adverse sensory input of the abuse might be modified specifically by such experiences, particularly in subjects exposed to a single type of maltreatment. Thus, exposure to multiple types of maltreatment is more commonly associated with morphological alterations in corticolimbic regions.

  14. The Baby Moves prospective cohort study protocol: using a smartphone application with the General Movements Assessment to predict neurodevelopmental outcomes at age 2 years for extremely preterm or extremely low birthweight infants

    PubMed Central

    Olsen, J; Kwong, A; Doyle, LW; Marschik, PB; Einspieler, C; Cheong, JLY

    2016-01-01

    Introduction Infants born extremely preterm (EP; <28 weeks' gestation) and/or with extremely low birth weight (ELBW; <1000 g birth weight) are at increased risk for adverse neurodevelopmental outcomes. However, it is challenging to predict those EP/ELBW infants destined to have long-term neurodevelopmental impairments in order to target early intervention to those in most need. The General Movements Assessment (GMA) in early infancy has high predictive validity for neurodevelopmental outcomes in preterm infants. However, access to a GMA may be limited by geographical constraints and a lack of GMA-trained health professionals. Baby Moves is a smartphone application (app) developed for caregivers to video and upload their infant's general movements to be scored remotely by a certified GMA assessor. The aim of this study is to determine the predictive ability of using the GMA via the Baby Moves app for neurodevelopmental impairment in infants born EP/ELBW. Methods and analysis This prospective cohort study will recruit infants born EP/ELBW across the state of Victoria, Australia in 2016 and 2017. A control group of normal birth weight (>2500 g birth weight), term-born (≥37 weeks' gestation) infants will also be recruited as a local reference group. Parents will video their infant's general movements at two time points between 3 and 4 months' corrected age using the Baby Moves app. Videos will be scored by certified GMA assessors and classified as normal or abnormal. Parental satisfaction using the Baby Moves app will be assessed via survey. Neurodevelopmental outcome at 2 years' corrected age includes developmental delay according to the Bayley Scales of Infant and Toddler Development-III and cerebral palsy diagnosis. Ethics and dissemination This study was approved by the Human Research and Ethics Committees at the Royal Children's Hospital, The Royal Women's Hospital, Monash Health and Mercy Health in Melbourne, Australia. Study findings will be

  15. Excessive folic acid intake and relation to adverse health outcome.

    PubMed

    Selhub, Jacob; Rosenberg, Irwin H

    2016-07-01

    The recent increase in the intake of folic acid by the general public through fortified foods and supplements, has raised safety concern based on early reports of adverse health outcome in elderly with low B12 status who took high doses of folic acid. These safety concerns are contrary to the 2015 WHO statement that "high folic acid intake has not reliably been shown to be associated with negative healeffects". In the folic acid post-fortification era, we have shown that in elderly participants in NHANES 1999-2002, high plasma folate level is associated with exacerbation of both clinical (anemia and cognitive impairment) and biochemical (high MMA and high Hcy plasma levels) signs of vitamin B12 deficiency. Adverse clinical outcomes in association with high folate intake were also seen among elderly with low plasma B12 levels from the Framingham Original Cohort and in a study from Australia which combined three elderly cohorts. Relation between high folate and adverse biochemical outcomes were also seen in the Sacramento Area Latino Study on Aging (High Hcy, high MMA and lower TC2) and at an outpatient clinic at Yale University where high folate is associated with higher MMA in the elderly but not in the young. Potential detrimental effects of high folic acid intake may not be limited to the elderly nor to those with B12 deficiency. A study from India linked maternal high RBC folate to increased insulin resistance in offspring. Our study suggested that excessive folic acid intake is associated with lower natural killer cells activity in elderly women. In a recent study we found that the risk for unilateral retinoblastoma in offspring is 4 fold higher in women that are homozygotes for the 19 bp deletion in the DHFR gene and took folic acid supplement during pregnancy. In the elderly this polymorphism is associated with lower memory and executive scores, both being significantly worse in those with high plasma folate. These and other data strongly imply that

  16. Neuropsychological Outcomes of Preterm Birth in Children With No Major Neurodevelopmental Impairments in Early Life

    PubMed Central

    Joo, Ji Woon; Choi, Ja Young; Rha, Dong-wook; Kwak, Eun Hee

    2015-01-01

    Objectives To investigate cognition, social adaptive functioning, behavior, and emotional development in the preschool period and to determine the effects of the age of onset of walking on those developmental areas in children who were born preterm without major neurodevelopmental impairments (NDI) early in life. Methods Fifty-eight children who were born preterm without major NDI early in life participated in this study. The Korean versions of the Wechsler Preschool and Primary Scale of Intelligence or the Bayley Scales of Infant Development, the social maturity scale, the Korean version of the Child Behavior Checklist (CBCL), Conners' abbreviated parent/teacher rating scale, the Childhood Autism Rating Scale, and a speech developmental test were administered. The participants were divided into two groups: early walkers (group A) and late walkers (group B). Results The full-scale intelligence quotient (IQ) and performance IQ were significantly lower in group B than in group A, while the verbal IQ did not differ significantly between the groups. The children in group B had greater risks of cognitive deficits than did the children in group A, especially in performance skills. The social quotient (SQ) was significantly lower in group B than in group A (p<0.05). The rates of mild or significant deficits based on SQ and the CBCL did not differ significantly between the groups. Four children in group A and one child in group B had attention/hyperactivity problems. One child in group A had autistic behavior. Only one child in group B showed a significant speech developmental delay. Conclusions Problems in cognition, social adaptive functioning, and emotional and behavioral development can occur in children without major NDI early in life. Late walkers had significantly lower scores in cognition and social adaptive functioning than did early walkers. PMID:26605165

  17. Neurodevelopmental outcome in babies weighing less than 2001 g at birth.

    PubMed Central

    Marlow, N; D'Souza, S W; Chiswick, M L

    1987-01-01

    From 1976 to 1980, 1034 infants with birth weights of 500-2000 g were cared for in the neonatal medical unit; 724 were discharged. Twenty (2.8%) subsequently died and 654 (90.3%) were followed up at a median age of 3 years 3 months. Fifty five (7.6%) survivors had major neurodevelopmental handicaps not attributable to congenital anomalies. Increasing prevalence of major handicap was found with decreasing birth weight and gestation. Children with birth weights of less than 1251 g had a higher incidence of all major disabilities. Handicapped children with a birth weight less than 1251 g were more likely to have blindness, deafness, multiple disabilities, and more severe cerebral palsy. There were 146 (20.2%) children with minor disabilities: neurological impairments (n = 11), borderline results on psychometric testing (n = 18), visual impairments (n = 52), hearing impairments (n = 40), and speech impairments (n = 71). Children weighing less than 1251 g at birth had a higher incidence of minor visual and hearing impairments. In 389 children the mean Griffiths quotient was 101.6 (SD 17.2) (range 50-147), and 158 children had a mean Wechsler preschool and primary intelligence quotient of 101.8 (13.2) (range 56-127): these quotients did not vary with birth weight or gestation but did vary with socioeconomic group, schooling, and family structure. During the study period an improving prognosis in terms of both survival and handicap was observed in children weighing less than 1251 g at birth. PMID:2441792

  18. Poverty in childhood and adverse health outcomes in adulthood.

    PubMed

    Raphael, Dennis

    2011-05-01

    The experience of poverty during childhood is a potent predictor of a variety of adverse health outcomes during middle and late adulthood. Children who live in poverty are more likely as adults than their peers to develop and die earlier from a range of diseases. These effects are especially strong for cardiovascular disease and type II diabetes. Most disturbingly, these effects appear in large part to be biologically embedded such that later improved life circumstances have only a modest ameliorative effect. Considering these findings and the relatively high rates of child poverty in nations such as Canada, UK, and USA, those concerned with improving the health of citizens should focus their attention on advocating for public policy that will reduce the incidence of child poverty.

  19. Risk Prediction for Adverse Pregnancy Outcomes in a Medicaid Population

    PubMed Central

    Hall, Eric S.; Greenberg, James M.; Kelly, Elizabeth A.

    2015-01-01

    Abstract Background: Despite prior efforts to develop pregnancy risk prediction models, there remains a lack of evidence to guide implementation in clinical practice. The current aim was to develop and validate a risk tool grounded in social determinants theory for use among at-risk Medicaid patients. Methods: This was a retrospective cohort study of 409 women across 17 Cincinnati health centers between September 2013 and April 2014. The primary outcomes included preterm birth, low birth weight, intrauterine fetal demise, and neonatal death. After random allocation into derivation and validation samples, a multivariable model was developed, and a risk scoring system was assessed and validated using area under the receiver operating characteristic curve (AUROC) values. Results: The derived multivariable model (n=263) included: prior preterm birth, interpregnancy interval, late prenatal care, comorbid conditions, history of childhood abuse, substance use, tobacco use, body mass index, race, twin gestation, and short cervical length. Using a weighted risk score, each additional point was associated with an odds ratio of 1.57 for adverse outcomes, p<0.001, AUROC=0.79. In the validation sample (n=146), each additional point conferred an odds ratio of 1.20, p=0.03, AUROC=0.63. Using a cutoff of 20% probability for the outcome, sensitivity was 29%, with specificity 82%. Positive and negative predictive values were 22% and 85%, respectively. Conclusions: Risk scoring based on social determinants can discriminate pregnancy risk within a Medicaid population; however, performance is modest and consistent with prior prediction models. Future research is needed to evaluate whether implementation of risk scoring in Medicaid prenatal care programs improves clinical outcomes. PMID:26102375

  20. Adverse outcome pathway (AOP) development I: strategies and principles.

    PubMed

    Villeneuve, Daniel L; Crump, Doug; Garcia-Reyero, Natàlia; Hecker, Markus; Hutchinson, Thomas H; LaLone, Carlie A; Landesmann, Brigitte; Lettieri, Teresa; Munn, Sharon; Nepelska, Malgorzata; Ottinger, Mary Ann; Vergauwen, Lucia; Whelan, Maurice

    2014-12-01

    An adverse outcome pathway (AOP) is a conceptual framework that organizes existing knowledge concerning biologically plausible, and empirically supported, links between molecular-level perturbation of a biological system and an adverse outcome at a level of biological organization of regulatory relevance. Systematic organization of information into AOP frameworks has potential to improve regulatory decision-making through greater integration and more meaningful use of mechanistic data. However, for the scientific community to collectively develop a useful AOP knowledgebase that encompasses toxicological contexts of concern to human health and ecological risk assessment, it is critical that AOPs be developed in accordance with a consistent set of core principles. Based on the experiences and scientific discourse among a group of AOP practitioners, we propose a set of five fundamental principles that guide AOP development: (1) AOPs are not chemical specific; (2) AOPs are modular and composed of reusable components-notably key events (KEs) and key event relationships (KERs); (3) an individual AOP, composed of a single sequence of KEs and KERs, is a pragmatic unit of AOP development and evaluation; (4) networks composed of multiple AOPs that share common KEs and KERs are likely to be the functional unit of prediction for most real-world scenarios; and (5) AOPs are living documents that will evolve over time as new knowledge is generated. The goal of the present article was to introduce some strategies for AOP development and detail the rationale behind these 5 key principles. Consideration of these principles addresses many of the current uncertainties regarding the AOP framework and its application and is intended to foster greater consistency in AOP development.

  1. Adverse Outcome Pathway (AOP) Development I: Strategies and Principles

    PubMed Central

    Villeneuve, Daniel L.; Crump, Doug; Garcia-Reyero, Natàlia; Hecker, Markus; Hutchinson, Thomas H.; LaLone, Carlie A.; Landesmann, Brigitte; Lettieri, Teresa; Munn, Sharon; Nepelska, Malgorzata; Ottinger, Mary Ann; Vergauwen, Lucia; Whelan, Maurice

    2014-01-01

    An adverse outcome pathway (AOP) is a conceptual framework that organizes existing knowledge concerning biologically plausible, and empirically supported, links between molecular-level perturbation of a biological system and an adverse outcome at a level of biological organization of regulatory relevance. Systematic organization of information into AOP frameworks has potential to improve regulatory decision-making through greater integration and more meaningful use of mechanistic data. However, for the scientific community to collectively develop a useful AOP knowledgebase that encompasses toxicological contexts of concern to human health and ecological risk assessment, it is critical that AOPs be developed in accordance with a consistent set of core principles. Based on the experiences and scientific discourse among a group of AOP practitioners, we propose a set of five fundamental principles that guide AOP development: (1) AOPs are not chemical specific; (2) AOPs are modular and composed of reusable components—notably key events (KEs) and key event relationships (KERs); (3) an individual AOP, composed of a single sequence of KEs and KERs, is a pragmatic unit of AOP development and evaluation; (4) networks composed of multiple AOPs that share common KEs and KERs are likely to be the functional unit of prediction for most real-world scenarios; and (5) AOPs are living documents that will evolve over time as new knowledge is generated. The goal of the present article was to introduce some strategies for AOP development and detail the rationale behind these 5 key principles. Consideration of these principles addresses many of the current uncertainties regarding the AOP framework and its application and is intended to foster greater consistency in AOP development. PMID:25466378

  2. Apnea after awake-regional and general anesthesia in infants: The General Anesthesia compared to Spinal anesthesia (GAS) study: comparing apnea and neurodevelopmental outcomes, a randomized controlled trial

    PubMed Central

    Davidson, Andrew J.; Morton, Neil S.; Arnup, Sarah J.; de Graaff, Jurgen C.; Disma, Nicola; Withington, Davinia E.; Frawley, Geoff; Hunt, Rodney W.; Hardy, Pollyanna; Khotcholava, Magda; von Ungern Sternberg, Britta S.; Wilton, Niall; Tuo, Pietro; Salvo, Ida; Ormond, Gillian; Stargatt, Robyn; Locatelli, Bruno Guido; McCann, Mary Ellen

    2015-01-01

    Background Post-operative apnea is a complication in young infants. Awake-regional anesthesia (RA) may reduce the risk; however the evidence is weak. The General Anesthesia compared to Spinal anesthesia (GAS) study is a randomized, controlled, trial designed to assess the influence of general anesthesia (GA) on neurodevelopment. A secondary aim is to compare rates of apnea after anesthesia. Methods Infants ≤ 60 weeks postmenstrual age scheduled for inguinal herniorraphy were randomized to RA or GA. Exclusion criteria included risk factors for adverse neurodevelopmental outcome and infants born < 26 weeks’ gestation. The primary outcome of this analysis was any observed apnea up to 12 hours post-operatively. Apnea assessment was unblinded. Results 363 patients were assigned to RA and 359 to GA. Overall the incidence of apnea (0 to 12 hours) was similar between arms (3% in RA and 4% in GA arms, Odds Ratio (OR) 0.63, 95% Confidence Intervals (CI): 0.31 to 1.30, P=0.2133), however the incidence of early apnea (0 to 30 minutes) was lower in the RA arm (1% versus 3%, OR 0.20, 95%CI: 0.05 to 0.91, P=0.0367). The incidence of late apnea (30 minutes to 12 hours) was 2% in both RA and GA arms (OR 1.17, 95%CI: 0.41 to 3.33, P=0.7688). The strongest predictor of apnea was prematurity (OR 21.87, 95% CI 4.38 to 109.24) and 96% of infants with apnea were premature. Conclusions RA in infants undergoing inguinal herniorraphy reduces apnea in the early post-operative period. Cardio-respiratory monitoring should be used for all ex-premature infants. PMID:26001033

  3. Accelerating Adverse Outcome Pathway Development Using Publicly Available Data Sources.

    PubMed

    Oki, Noffisat O; Nelms, Mark D; Bell, Shannon M; Mortensen, Holly M; Edwards, Stephen W

    2016-03-01

    The adverse outcome pathway (AOP) concept links molecular perturbations with organism and population-level outcomes to support high-throughput toxicity (HTT) testing. International efforts are underway to define AOPs and store the information supporting these AOPs in a central knowledge base; however, this process is currently labor-intensive and time-consuming. Publicly available data sources provide a wealth of information that could be used to define computationally predicted AOPs (cpAOPs), which could serve as a basis for creating expert-derived AOPs in a much more efficient way. Computational tools for mining large datasets provide the means for extracting and organizing the information captured in these public data sources. Using cpAOPs as a starting point for expert-derived AOPs should accelerate AOP development. Coupling this with tools to coordinate and facilitate the expert development efforts will increase the number and quality of AOPs produced, which should play a key role in advancing the adoption of HTT testing, thereby reducing the use of animals in toxicity testing and greatly increasing the number of chemicals that can be tested.

  4. Assessing the influence of researcher-partner involvement on the process and outcomes of participatory research in autism spectrum disorder and neurodevelopmental disorders: a scoping review.

    PubMed

    Jivraj, Jamil; Sacrey, Lori-Ann; Newton, Amanda; Nicholas, David; Zwaigenbaum, Lonnie

    2014-10-01

    Participatory research aims to increase the relevance and broaden the implementation of health research by involving those affected by the outcomes of health studies. Few studies within the field of neurodevelopmental disorders, particularly autism spectrum disorders, have involved autistic individuals as partners. This study sought to identify and characterize published participatory research partnerships between researchers and individuals with autism spectrum disorder or other neurodevelopmental disorders and examine the influence of participatory research partnerships on the research process and reported study outcomes. A search of databases and review of gray literature identified seven studies that described participatory research partnerships between academic researchers and individuals with autism spectrum disorder or other neurodevelopmental disorders. A comparative analysis of the studies revealed two key themes: (1) variations in the participatory research design and (2) limitations during the reporting of the depth of the partner's involvement. Both themes potentially limit the application and generalizability of the findings. The results of the review are discussed in relation to the use of evaluative frameworks for such participatory research studies to determine the potential benefits of participatory research partnerships within the neurodevelopmental and autism spectrum disorder populations.

  5. Triple therapy with pyridoxine, arginine supplementation and dietary lysine restriction in pyridoxine-dependent epilepsy: Neurodevelopmental outcome.

    PubMed

    Coughlin, Curtis R; van Karnebeek, Clara D M; Al-Hertani, Walla; Shuen, Andrew Y; Jaggumantri, Sravan; Jack, Rhona M; Gaughan, Sommer; Burns, Casey; Mirsky, David M; Gallagher, Renata C; Van Hove, Johan L K

    2015-01-01

    Pyridoxine-dependent epilepsy (PDE) is an epileptic encephalopathy characterized by response to pharmacologic doses of pyridoxine. PDE is caused by deficiency of α-aminoadipic semialdehyde dehydrogenase resulting in impaired lysine degradation and subsequent accumulation of α-aminoadipic semialdehyde. Despite adequate seizure control with pyridoxine monotherapy, 75% of individuals with PDE have significant developmental delay and intellectual disability. We describe a new combined therapeutic approach to reduce putative toxic metabolites from impaired lysine metabolism. This approach utilizes pyridoxine, a lysine-restricted diet to limit the substrate that leads to neurotoxic metabolite accumulation and L-arginine to compete for brain lysine influx and liver mitochondrial import. We report the developmental and biochemical outcome of six subjects who were treated with this triple therapy. Triple therapy reduced CSF, plasma, and urine biomarkers associated with neurotoxicity in PDE. The addition of arginine supplementation to children already treated with dietary lysine restriction and pyridoxine further reduced toxic metabolites, and in some subjects appeared to improve neurodevelopmental outcome. Dietary lysine restriction was associated with improved seizure control in one subject, and the addition of arginine supplementation increased the objective motor outcome scale in two twin siblings, illustrating the contribution of each component of this treatment combination. Optimal results were noted in the individual treated with triple therapy early in the course of the disease. Residual disease symptoms could be related to early injury suggested by initial MR imaging prior to initiation of treatment or from severe epilepsy prior to diagnosis. This observational study reports the use of triple therapy, which combines three effective components in this rare condition, and suggests that early diagnosis and treatment with this new triple therapy may ameliorate the

  6. Antenatal psychosocial risk factors associated with adverse postpartum family outcomes.

    PubMed Central

    Wilson, L M; Reid, A J; Midmer, D K; Biringer, A; Carroll, J C; Stewart, D E

    1996-01-01

    OBJECTIVE: To determine the strength of the association between antenatal psychosocial risk factors and adverse postpartum outcomes in the family, such as assault of women by their partner, child abuse, postpartum depression, marital dysfunction and physical illness. DATA SOURCES: MEDLINE, Cinahl, Famli, Psych Abstracts and the Oxford Database of Perinatal Trials were searched from relevant articles published from Jan. 1, 1980, to Dec. 31, 1993, with the use of MeSH terms "depression, involutional," "child abuse," "child neglect," "domestic violence," "family," "marital adjustment," "family health," "newborn health," "child health," "physical illness," "social support," "psychosocial risk," "prediction," "risk factors," "obstetrics" and "prenatal care." Further articles were identified from bibliographies. STUDY SELECTION: Of the 370 articles identified through the search, 118 were included for review. Studies were included if they examined the association between psychosocial risk factors and the outcomes of interest. Articles were excluded if they were reviews of poor quality or they had one or more of the following features: insufficient description of the sample, a high attrition rate, a lack of standardized outcome measures, outcomes other than the ones of interest or results that had already been reported in a previous study. DATA EXTRACTION: The strength of evidence of each study was evaluated. On the basis of the evidence, each risk factor was assigned a rating of the strength of its association with each of the postpartum outcomes. The ratings were class A (good evidence of association), class B (fair evidence) and class C (no clear evidence). Of the 129 antenatal psychosocial risk factors studied, 15 were found to have a class A association with at least one of the postpartum outcomes. DATA SYNTHESIS: Child abuse and abuse of the mother by her partner were most strongly correlated (class A evidence) with a history of lack of social support, recent life

  7. Neonatal and childhood neurodevelopmental, health and educational outcomes of children exposed to antidepressants and maternal depression during pregnancy: protocol for a retrospective population-based cohort study using linked administrative data

    PubMed Central

    Singal, Deepa; Brownell, Marni; Chateau, Dan; Ruth, Chelsea; Katz, Laurence Y

    2016-01-01

    Introduction Antidepressants are commonly prescribed during pregnancy; however, there are inconsistent data on the safety of these medications during the prenatal period. To address this gap, this study will investigate short-term and long-term neurodevelopmental, physical and mental health, and educational outcomes of children who have been exposed to selective serotonin reuptake inhibitors (SSRIs) or selective serotonin norepinephrine reuptake inhibitors (SNRIs) and/or maternal depression during pregnancy. Methods and analysis Administrative data will be linked to generate 4 population-based exposed groups from all children born in Manitoba between 1996 and 2014 whose mother had at least 2 prescriptions for either an SSRI or SNRI: (1) throughout the prenatal period (beginning of pregnancy until birth); (2) in the first trimester (≤14 weeks gestation); (3) in the second trimester (15–26 weeks gestation); (4) in the third trimester (≥27 weeks gestation) and 1 population-based unexposed group consisting of children whose mothers had a diagnosis of mood or anxiety disorder during pregnancy but did not use antidepressants. Propensity scores and inverse probability treatment weights will be used to adjust for confounding. Multivariate regression modelling will determine whether, compared with untreated mood/anxiety disorder, prenatal exposure to antidepressant medications is associated with: (1) adverse birth and neonatal outcomes, including: preterm birth, low birth weight, low Apgar scores, respiratory distress, congenital malformations and persistent pulmonary hypertension; (2) adverse early childhood outcomes, including: early childhood education challenges, diagnosis of neurodevelopmental disorders and diagnosis of mental disorders. We will determine if exposure effects differ between SSRIs and SRNIs, and determine if exposure effects differ between gestation timing of exposure to antidepressants. Ethics and dissemination Ethical approval was obtained

  8. Adverse outcome pathway development from protein alkylation to liver fibrosis.

    PubMed

    Horvat, Tomislav; Landesmann, Brigitte; Lostia, Alfonso; Vinken, Mathieu; Munn, Sharon; Whelan, Maurice

    2017-04-01

    In modern toxicology, substantial efforts are undertaken to develop alternative solutions for in vivo toxicity testing. The adverse outcome pathway (AOP) concept could facilitate knowledge-based safety assessment of chemicals that does not rely exclusively on in vivo toxicity testing. The construction of an AOP is based on understanding toxicological processes at different levels of biological organisation. Here, we present the developed AOP for liver fibrosis and demonstrate a linkage between hepatic injury caused by chemical protein alkylation and the formation of liver fibrosis, supported by coherent and consistent scientific data. This long-term process, in which inflammation, tissue destruction, and repair occur simultaneously, results from the complex interplay between various hepatic cell types, receptors, and signalling pathways. Due to the complexity of the process, an adequate liver fibrosis cell model for in vitro evaluation of a chemical's fibrogenic potential is not yet available. Liver fibrosis poses an important human health issue that is also relevant for regulatory purposes. An AOP described with enough mechanistic detail might support chemical risk assessment by indicating early markers for downstream events and thus facilitating the development of an in vitro testing strategy. With this work, we demonstrate how the AOP framework can support the assembly and coherent display of distributed mechanistic information from the literature to support the use of alternative approaches for prediction of toxicity. This AOP was developed according to the guidance document on developing and assessing AOPs and its supplement, the users' handbook, issued by the Organisation for Economic Co-operation and Development.

  9. Adverse Outcome Pathway (AOP) for a Mutagenic Mode of ...

    EPA Pesticide Factsheets

    AOPs provide a framework to describe a sequence of measureable key events (KEs), beginning with a molecular initiating event (MIE), followed by a series of identified KEs linked to one another by KE Relationships (KERs), all anchored by a specific adverse outcome (AO). Each KE/KER is supported by data and evaluated against criteria to assess biological plausibility, weight/strength of evidence, specificity, and confidence. AOPs offer an approach to using toxicological data and predictive modeling to actualize use of mode-of-action (MOA) for such purposes as read-across, integrated approaches to testing & assessment, and risk assessment. Different applications will depend partly on the scientific confidence underpinning each KE/KER and the overall AOP. An OECD program encourages development of AOPs, with a wiki that allows for public review & comment to foster collaborations and broaden understanding & application of AOPs. Developing an AOP for a mutagenic MOA for cancer as a case study in the OECD program lays a path towards determination of such an MOA and its use in chemical assessment programs. Aflatoxin B1 (AFB1), with ubiquitous exposure and a rich database, was selected for this case study. AFB1 has been determined to induce HCC via a DNA-reactive MOA in many species, including humans. The sequential KEs identified for AFB1 are as follows: pre-MIE: Hepatic metabolic activation; MIE: Formation of a pro-mutagenic DNA adduct (N7-AFB1-guanine or AFB1-FAPy); KE

  10. Application of adverse outcome pathway-based tools to ...

    EPA Pesticide Factsheets

    Increasing numbers and diversity of chemical contaminants are being detected in ambient surface waters. States, regions, and communities across the US are faced with the issue of understanding which chemicals may warrant concern and at what concentrations. Integrating new scientific data streams and predictive approaches into the process of numeric water aquatic life criteria development offers the potential to develop more criteria, for more chemicals, more rapidly. For example, well established models of non-polar narcosis provide an effective estimate of “baseline” toxicity. Emerging data streams from high throughput, pathway-based, toxicity testing programs provide broad spectrum screening for more specific modes of action that may result in deviations from “baseline” toxicity predictions (i.e., excess toxicity). The adverse outcome pathway (AOP) framework provides a scientifically credible basis for linking specific pathway-perturbations to predicted hazard and facilitates systematic consideration of taxa and life stages likely to be sensitive. Application of this information can facilitate more targeted and hypothesis-driven approaches to the collection of data for use in numeric criteria development. It can also support interim application of appropriate AOP-based prediction models in cases where empirical data are lacking. While these approaches will be subject to error and uncertainty, they offer the ability to provide a scientifically-based pre

  11. Sexually transmitted infections, adverse pregnancy outcome and neonatal infection.

    PubMed

    Moodley, P; Sturm, A W

    2000-08-01

    Prevention and treatment of sexually transmitted infections (STIs) in the sexually active population are the main steps to prevent perinatal infection. However, the spread of STIs continues at an astronomical pace despite various attempts at controlling the epidemic. An important reason for this lack of STI control is that a large percentage of infected people go untreated because they have asymptomatic or unrecognized infections. The microbial differential diagnosis of STIs implicated in adverse pregnancy outcome is broad and includes viral, bacterial and protozoal infections. Infertility, ectopic pregnancy, pelvic inflammatory disease, chorioamnionitis, premature rupture of membranes, preterm birth and puerperal sepsis are some of complications seen in women as a result of infection with sexually transmitted pathogens. In addition, STIs may facilitate the acquisition and transmission of HIV. In the fetus or neonate, complications include abnormalities of the major organ systems. Infections in the form of pneumonia or conjunctivitis may also occur. Due to the lack of simple, inexpensive and sensitive point-of-care tests, screening for STIs in pregnancy is not performed routinely.

  12. Developing and applying adverse outcome pathways: What you need to know

    EPA Science Inventory

    Adverse outcome pathways (AOPs) are a conceptual framework for organizing existing information concerning the predictive linkages between the initiation or early progression of a biological perturbation in an organism and the adverse outcome(s) of regulatory relevance (e.g., impa...

  13. Choline status and neurodevelopmental outcomes at 5 years of age in the Seychelles Child Development Nutrition Study.

    PubMed

    Strain, J J; McSorley, Emeir M; van Wijngaarden, Edwin; Kobrosly, Roni W; Bonham, Maxine P; Mulhern, Maria S; McAfee, Alison J; Davidson, Philip W; Shamlaye, Conrad F; Henderson, Juliette; Watson, Gene E; Thurston, Sally W; Wallace, Julie M W; Ueland, Per M; Myers, Gary J

    2013-07-28

    Choline is an essential nutrient that is found in many food sources and plays a critical role in the development of the central nervous system. Animal studies have shown that choline status pre- and postnatally can have long-lasting effects on attention and memory; however, effects in human subjects have not been well studied. The aim of the present study was to examine the association between plasma concentrations of free choline and its related metabolites in children and their neurodevelopment in the Seychelles Child Development Nutrition Study, an ongoing longitudinal study assessing the development of children born to mothers with high fish consumption during pregnancy. Plasma concentrations of free choline, betaine, dimethylglycine (DMG), methionine and homocysteine and specific measures of neurodevelopment were measured in 210 children aged 5 years. The children's plasma free choline concentration (9·17 (sd 2·09) μmol/l) was moderately, but significantly, correlated with betaine (r 0·24; P= 0·0006), DMG (r 0·15; P= 0·03), methionine (r 0·24; P= 0·0005) and homocysteine (r 0·19; P= 0·006) concentrations. Adjusted multiple linear regression revealed that betaine concentrations were positively associated with Preschool Language Scale – total language scores (β = 0·066; P= 0·04), but no other associations were evident. We found no indication that free choline concentration or its metabolites, within the normal physiological range, are associated with neurodevelopmental outcomes in children at 5 years of age. As there is considerable animal evidence suggesting that choline status during development is associated with cognitive outcome, the issue deserves further study in other cohorts.

  14. Neurodevelopmental disorders in children born to mothers with systemic lupus erythematosus.

    PubMed

    Vinet, É; Pineau, C A; Clarke, A E; Fombonne, É; Platt, R W; Bernatsky, S

    2014-10-01

    Children born to women with systemic lupus erythematosus seem to have a potentially increased risk of neurodevelopmental disorders compared to children born to healthy women. Recent experimental data suggest in utero exposure to maternal antibodies and cytokines as important risk factors for neurodevelopmental disorders. Interestingly, women with systemic lupus erythematosus display high levels of autoantibodies and cytokines, which have been shown, in animal models, to alter fetal brain development and induce behavioral anomalies in offspring. Furthermore, subjects with systemic lupus erythematosus and neurodevelopmental disorders share a common genetic predisposition, which could impair the fetal immune response to in utero immunologic insults. Moreover, systemic lupus erythematosus pregnancies are at increased risk of adverse obstetrical outcomes and medication exposures, which have been implicated as potential risk factors for neurodevelopmental disorders. In this article, we review the current state of knowledge on neurodevelopmental disorders and their potential determinants in systemic lupus erythematosus offspring.

  15. Neurodevelopmental disorders.

    PubMed

    Thapar, Anita; Cooper, Miriam; Rutter, Michael

    2017-04-01

    Neurodevelopmental disorders such as attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder, although most commonly considered in childhood, can be lifelong conditions. In this Personal View that is shaped by clinical experience and research, we adopt a conceptual approach. First, we discuss what disorders are neurodevelopmental and why such a grouping is useful. We conclude that both distinction and grouping are helpful and that it is important to take into account the strong overlap across neurodevelopmental disorders. Then we highlight some challenges in bridging research and clinical practice. We discuss the complexity of clinical phenotypes and the importance of the social context. We also argue the importance of viewing neurodevelopmental disorders as traits but highlight that this is not the only approach to use. Finally, we consider developmental change across the life-span. Overall, we argue strongly for a flexible approach in clinical practice that takes into consideration the high level of heterogeneity and overlap in neurodevelopmental disorders and for research to link more closely to what is observed in real-life practice.

  16. Predictors of neurodevelopmental outcome for preterm infants with brain injury: MRI, medical and environmental factors

    PubMed Central

    Badr, Lina Kurdahi; Bookheimer, Susan; Purdy, Isabell; Deeb, Mary

    2009-01-01

    This multi-center correlational prospective study examined early neonatal predictors of neurodevelopment in 59 premature infants (mean birth weight=1713.8±1242.5 g; mean gestational age=31.2±3.6 weeks) suspected to have sustained brain injury at birth. The mental and motor development of the infants selected from five university-affiliated hospitals was assessed at baseline (59 infants), 12 (55 infants), and 18 months (46 infants) using Bayley II scales. Factors correlating with Bayley II scores at 12 and 18 months included head circumference, results of neurological and magnetic resonance imaging (MRI) examination at baseline, environmental factors such as mother–infant interactions and levels of parental stress, and infant medical factors such as Apgar scores at 5 min and length of hospital stay. Multiple regression analyses distinguished the most significant predictors of mental and motor development. The best predictors of mental and motor development at 18 months were head circumference, neurological examinations, and MRI results. These findings suggest that in infants suspected of brain injury at birth, neurological assessments and head circumference measurements are just as predictive of developmental outcome at 18 months as MRI, and this is especially relevant in developing countries or other locations where MRI is not possible. The presence of this information may offer the potential of early tailored interventions to improve the mental and motor development of children in developing countries or other facilities where MRI is unavailable. PMID:19141366

  17. Neurodevelopmental Outcomes in Children with Down Syndrome and Congenital Heart Defects

    PubMed Central

    Visootsak, Jeannie; Mahle, William T.; Kirshbom, Paul; Huddleston, Lillie; Caron-Besch, Marcia; Ransom, Amy; Sherman, Stephanie L

    2011-01-01

    Trisomy 21, the chromosomal condition responsible for Down syndrome (DS, OMIM #190685), is the most common identifiable genetic cause of intellectual disability. Approximately half of all children with DS are born with a significant congenital heart defect (CHD), the most common of which is an atrioventricular septal defect (AVSD). As children with comorbid DS and CHD increasingly survive cardiac surgery, characterization of their early developmental trajectories is critical for designing early interventions to maximize individual potential. Herein, the developmental domains (cognitive, language, and motor) of children with DS and AVSD (DS + AVSD, n=12) were compared to children with DS and a structurally normal heart (DS – CHD, n=17) using the Bayley Scales of Infant and Toddler Development III. The DS + AVSD cohort mean age was relatively the same as controls with DS – CHD, 14.5 ±7.3 months compared with 14.1 ± 8.4 months, respectively. Although the motor domain was the only domain that showed a statistically significant difference between groups (p < .05), both cognitive standard scores (p = 0.63) and language composite standard scores (p = 0.10) were lower in the DS + AVSD cases compared with the DS – CHD controls although it is not statistically significant. Since this is the first study to examine the early developmental outcomes of children with DS + AVSD, the findings may be useful for clinicians in providing anticipatory guidance. PMID:21932314

  18. Adverse perinatal outcome and later kidney biopsy in the mother.

    PubMed

    Vikse, Bjørn Egil; Irgens, Lorentz M; Bostad, Leif; Iversen, Bjarne M

    2006-03-01

    Strong associations of adverse perinatal outcomes have been identified with later cardiovascular disease in the mother. Few studies have addressed associations with kidney disease. This study investigated whether perinatal outcomes are associated with later clinical kidney disease as diagnosed by kidney biopsy. The Medical Birth Registry of Norway contains data on all childbirths in Norway since 1967. The Norwegian Kidney Biopsy Registry contains data on all kidney biopsies in Norway since 1988. All women with a first singleton delivery from 1967 to 1998 were included. Pregnancy-related predictors of later kidney biopsy were analyzed by Cox regression analyses. A total of 756,420 women were included, and after a mean period of 15.9+/-9.4 yr, 588 had a kidney biopsy. Compared with women without preeclampsia and with offspring with birth weight of >or=2.5 kg, women with no preeclampsia and with offspring with birth weight of 1.5 to 2.5 kg had a relative risk (RR) for a later kidney biopsy of 1.7, women with no preeclampsia and with offspring with birth weight of <1.5 kg had an RR of 2.9, women with preeclampsia and with offspring with a birth weight of >or=2.5 kg had an RR of 2.5, women with preeclampsia and with offspring with a birth weight of 1.5 to 2.5 kg had an RR of 4.5, and women with preeclampsia and with offspring with a birth weight of <1.5 kg had an RR of 17. Similar results were found in adjusted analyses and after exclusion of women with diabetes, kidney disease, or rheumatic disease before pregnancy. The same risk patterns applied to any of the specific categories of kidney disease as well as specific kidney diseases investigated. Women who have preeclampsia and give birth to offspring with low birth weight and short gestation have a substantially increased risk for having a later kidney biopsy.

  19. Early neurological stability predicts adverse outcome after acute ischemic stroke.

    PubMed

    Irvine, Hannah J; Battey, Thomas Wk; Ostwaldt, Ann-Christin; Campbell, Bruce Cv; Davis, Stephen M; Donnan, Geoffrey A; Sheth, Kevin N; Kimberly, W Taylor

    2016-10-01

    Background Deterioration in the National Institutes of Health Stroke Scale (NIHSS) in the early days after stroke is associated with progressive infarction, brain edema, and/or hemorrhage, leading to worse outcome. Aims We sought to determine whether a stable NIHSS score represents an adverse or favorable course. Methods Brain magnetic resonance images from a research cohort of acute ischemic stroke patients were analyzed. Using NIHSS scores at baseline and follow-up (day 3-5), patients were categorized into early neurological deterioration (ΔNIHSS ≥ 4), early neurological recovery (ΔNIHSS ≤ -4) or early neurological stability (ΔNIHSS between -3 and 3). The association between these categories and volume of infarct growth, volume of swelling, parenchymal hemorrhage, and 3-month modified Rankin Scale score were evaluated. Results Patients with early neurological deterioration or early neurological stability were less likely to be independent (modified Rankin Scale = 0-2) at 3 months compared to those with early neurological recovery ( P < 0.001). Patients with early neurological deterioration or early neurological stability were observed to have significantly greater infarct growth and swelling volumes than those with early neurological recovery ( P = 0.03; P < 0.001, respectively). Brain edema was more common than the other imaging markers investigated and was independently associated with a stable or worsening NIHSS score after adjustment for age, baseline stroke volume, infarct growth volume, presence of parenchymal hemorrhage, and reperfusion ( P < 0.0001). Conclusions Stable NIHSS score in the subacute period after ischemic stroke may not be benign and is associated with tissue injury, including infarct growth and brain edema. Early improvement is considerably more likely to occur in the absence of these factors.

  20. Prenatal exposure to amphetamines. Risks and adverse outcomes in pregnancy.

    PubMed

    Plessinger, M A

    1998-03-01

    Based on findings in humans and the confirmation of prenatal exposures in animals, amphetamines and methamphetamines increase the risk of an adverse outcome when abused during pregnancy. Clefting, cardiac anomalies, and fetal growth reduction deficits that have been seen in infants exposed to amphetamines during pregnancy have all been reproduced in animal studies involving prenatal exposures to amphetamines. The differential effects of amphetamines between genetic strains of mice and between species demonstrate that pharmacokinetics and the genetic disposition of the mother and developing embryo can have an enormous influence on enhancing or reducing these potential risks. The effects of prenatal exposure to amphetamines in producing altered behavior in humans appear less compelling when one considers other confounding variables of human environment, genetics, and polydrug abuse. In view of the animal data concerning altered behavior and learning tasks in comparison with learning deficits observed in humans, the influence of the confounding variables in humans may serve to increase the sensitivity of the developing embryo/fetus to prenatal exposure to amphetamines. These factors and others may predispose the developing conceptus to the damaging effects of amphetamines by actually lowering the threshold of susceptibility at the sites where damage occurs. Knowledge of the effects of prenatal exposure of the fetus and the mother to designer amphetamines is lacking. Based on the few studies in which designer drugs have been examined in animal models, more questions are raised than answered. Possible reasons why no malformations or significant fetal effects were found in the study by St. Omer include the genetic strain of rat used, the conservative exposure profile, or the fact that the placenta metabolized MDMA before reaching the embryo. These questions underscore the need for further investigations concerning the prenatal exposure effects of designer compounds and

  1. Adverse Outcome Pathways for Embryonic Vascular Disruption and Alternative Methods to Identify Chemical Vascular Disruptor

    EPA Science Inventory

    Chemically induced vascular toxicity during embryonic development can result in a wide range of adverse prenatal outcomes. We used information from genetic mouse models linked to phenotypic outcomes and a vascular toxicity knowledge base to construct an embryonic vascular disrupt...

  2. Hypoplastic Left Heart Syndrome is not Associated with Worse Clinical or Neurodevelopmental Outcomes Than Other Cardiac Pathologies After the Norwood-Sano Operation.

    PubMed

    Martin, Billie-Jean; De Villiers Jonker, I; Joffe, Ari R; Bond, Gwen Y; Acton, Bryan V; Ross, David B; Robertson, Charlene M T; Rebeyka, Ivan M; Atallah, Joseph

    2017-03-24

    There is evidence to suggest that patients undergoing a Norwood for non-HLHS anatomy may have lower mortality than classic HLHS, but differences in neurodevelopmental outcome have not been assessed. Our objective was to compare survival and neurodevelopmental outcome during the same surgical era in a large, well-described cohort. All subjects who underwent a Norwood-Sano operation between 2005 and 2014 were included. Follow-up clinical, neurological, and developmental data were obtained from the Western Canadian Complex Pediatric Therapies Follow-up Program database. Developmental outcomes were assessed at 2 years of age using the Bayley Scales of Infant and Toddler Development (Bayley-III). Survival was assessed using Kaplan-Meier analysis. Baseline characteristics, survival, and neurodevelopmental outcomes were compared between those with HLHS and those with non-HLHS anatomy (non-HLHS). The study comprised 126 infants (75 male), 87 of whom had HLHS. Five-year survival was the same for subjects with HLHS and those with non-HLHS (HLHS 71.8%, non-HLHS 76.9%; p = 0.592). Ninety-three patients underwent neurodevelopmental assessment including Bayley-III scores. The overall mean cognitive composite score was 91.5 (SD 14.6), language score was 86.6 (SD 16.7) and overall mean motor composite score was 85.8 (SD 14.5); being lower than the American normative population mean score of 100 (SD 15) for each (p-value for each comparison, <0.0001). None of the cognitive, language, or motor scores differed between those with HLHS and non-HLHS (all p > 0.05). In the generalized linear models, dominant right ventricle anatomy (present in 117 (93%) of patients) was predictive of lower language and motor scores. Comparative analysis of the HLHS and non-HLHS groups undergoing single ventricle palliation including a Norwood-Sano, during the same era, showed comparable 2-year survival and neurodevelopmental outcomes.

  3. The Association between Rural-Urban Continuum, Maternal Education and Adverse Birth Outcomes in Quebec, Canada

    ERIC Educational Resources Information Center

    Auger, Nathalie; Authier, Marie-Andree; Martinez, Jerome; Daniel, Mark

    2009-01-01

    Context: Rural relative to urban area and low socioeconomic status (SES) are associated with adverse birth outcomes. Whether a graded association of increasing magnitude is present across the urban-rural continuum, accounting for SES, is unclear. We examined the association between rural-urban continuum, SES and adverse birth outcomes. Methods:…

  4. PUTATIVE ADVERSE OUTCOME PATHWAY FOR INHIBITON OF BRAIN AROMATASE IN FISH LEADING TO REPRODUCTIVE IMPAIRMENT

    EPA Science Inventory

    The adverse outcome pathway (AOP) provides a framework for organizing knowledge to define links between a molecular initiating event (MIE) and an adverse outcome (AO) occurring at a higher level of biological organization, such as the individual or population. The AOP framework p...

  5. Evaluation of hypothesized adverse outcome pathway linking thyroid peroxidase inhibition to fish early life stage toxicity

    EPA Science Inventory

    There is an interest in developing alternatives to the fish early-life stage (FELS) test (OECD test guideline 210), for predicting adverse outcomes (e.g., impacts on growth and survival) using less resource-intensive methods. Development and characterization of adverse outcome pa...

  6. Development of an adverse outcome pathway for acetylcholinesterase inhibition leading to acute mortality

    EPA Science Inventory

    Adverse outcome pathways (AOPs) are designed to describe linkages of key events (KEs) within a biological pathway that result in an adverse outcome associated with chemical perturbation of a well-defined molecular initiating event (MIE). Risk assessors have traditionally relied ...

  7. An “ADME Module” in the Adverse Outcome Pathway Knowledgebase

    EPA Science Inventory

    The Adverse Outcome Pathway (AOP) framework has generated intense interest for its utility to organize knowledge on the toxicity mechanisms, starting from a molecular initiating event (MIE) to an adverse outcome across various levels of biological organization. While the AOP fra...

  8. Development of Quantitative Adverse Outcome Pathways Using Health-Protective Assumptions to Fill Data Gaps

    EPA Science Inventory

    In an adverse outcome pathway (AOP), the target site dose participates in a molecular initiating event (MIE), which in turn triggers a sequence of key events leading to an adverse outcome (AO). Quantitative AOPs (QAOP) are needed if AOP characterization is to address risk as well...

  9. Maternal Obesity in Early Pregnancy and Risk of Adverse Outcomes

    PubMed Central

    Bautista-Castaño, Inmaculada; Henriquez-Sanchez, Patricia; Alemán-Perez, Nestor; Garcia-Salvador, Jose J.; Gonzalez-Quesada, Alicia; García-Hernández, Jose A.; Serra-Majem, Luis

    2013-01-01

    Objectives To assess the role of the health consequences of maternal overweight and obesity at the start of pregnancy on gestational pathologies, delivery and newborn characteristics. Methods A cohort of pregnant women (n = 6.558) having delivered at the Maternal & Child University Hospital of Gran Canaria (HUMIGC) in 2008 has been studied. Outcomes were compared using multivariate analyses controlling for confounding variables. Results Compared to normoweight, overweight and obese women have greater risks of gestational diabetes mellitus (RR = 2.13 (95% CI: 1.52–2.98) and (RR = 2.85 (95% CI: 2.01–4.04), gestational hypertension (RR = 2.01 (95% CI: 1.27–3.19) and (RR = 4.79 (95% CI: 3.13–7.32) and preeclampsia (RR = 3.16 (95% CI: 1.12–8.91) and (RR = 8.80 (95% CI: 3.46–22.40). Obese women have also more frequently oligodramnios (RR = 2.02 (95% CI: 1.25–3.27), polyhydramnios. (RR = 1.76 (95% CI: 1.03–2.99), tearing (RR = 1.24 (95% CI: 1.05–1.46) and a lower risk of induced deliveries (RR = 0.83 (95% CI: 0.72–0.95). Both groups have more frequently caesarean section (RR = 1.36 (95% CI: 1.14–1.63) and (RR = 1.84 (95% CI: 1.53–2.22) and manual placenta extraction (RR = 1.65 (95% CI: 1.28–2.11) and (RR = 1.77 (95% CI: 1.35–2.33). Newborns from overweight and obese women have higher weight (p<0.001) and a greater risk of being macrosomic (RR = 2.00 (95% CI: 1.56–2.56) and (RR = 2.74 (95% CI: 2.12–3.54). Finally, neonates from obese mother have a higher risk of being admitted to special care units (RR = 1.34 (95% CI: 1.01–1.77). Apgar 1 min was significantly higher in newborns from normoweight mothers: 8.65 (95% CI: 8.62–8.69) than from overweight: 8.56 (95% CI: 8.50–8.61) or obese mothers: 8.48 (95% CI: 8.41–8.54). Conclusion Obesity and overweight status at the beginning of pregnancy increase the adverse outcomes of the pregnancy. It is important to promote

  10. Area-level risk factors for adverse birth outcomes: trends in urban and rural settings

    PubMed Central

    2013-01-01

    Background Significant and persistent racial and income disparities in birth outcomes exist in the US. The analyses in this manuscript examine whether adverse birth outcome time trends and associations between area-level variables and adverse birth outcomes differ by urban–rural status. Methods Alabama births records were merged with ZIP code-level census measures of race, poverty, and rurality. B-splines were used to determine long-term preterm birth (PTB) and low birth weight (LBW) trends by rurality. Logistic regression models were used to examine differences in the relationships between ZIP code-level percent poverty or percent African-American with either PTB or LBW. Interactions with rurality were examined. Results Population dense areas had higher adverse birth outcome rates compared to other regions. For LBW, the disparity between population dense and other regions increased during the 1991–2005 time period, and the magnitude of the disparity was maintained through 2010. Overall PTB and LBW rates have decreased since 2006, except within isolated rural regions. The addition of individual-level socioeconomic or race risk factors greatly attenuated these geographical disparities, but isolated rural regions maintained increased odds of adverse birth outcomes. ZIP code-level percent poverty and percent African American both had significant relationships with adverse birth outcomes. Poverty associations remained significant in the most population-dense regions when models were adjusted for individual-level risk factors. Conclusions Population dense urban areas have heightened rates of adverse birth outcomes. High-poverty African American areas have higher odds of adverse birth outcomes in urban versus rural regions. These results suggest there are urban-specific social or environmental factors increasing risk for adverse birth outcomes in underserved communities. On the other hand, trends in PTBs and LBWs suggest interventions that have decreased adverse

  11. Adverse outcome pathways (AOPs): A framework to support predictive toxicology

    EPA Science Inventory

    High throughput and in silico methods are providing the regulatory toxicology community with capacity to rapidly and cost effectively generate data concerning a chemical’s ability to initiate one or more biological perturbations that may culminate in an adverse ecological o...

  12. Adolescent Friendships Mediating Childhood Adversity and Adult Outcome.

    ERIC Educational Resources Information Center

    Pawlby, Susan J.; Mills, Alice; Taylor, Alan; Quinton, David

    1997-01-01

    Compares the friendships of girls (N=50) at risk for difficulties in early adult partnerships with those of 50 girls of the same age. Results indicate key differences in both romantic and non-romantic adolescent friendships between the two groups. Findings offer a clearer understanding of processes linking childhood adversity and poor adult…

  13. Altered small-world topology of structural brain networks in infants with intrauterine growth restriction and its association with later neurodevelopmental outcome.

    PubMed

    Batalle, Dafnis; Eixarch, Elisenda; Figueras, Francesc; Muñoz-Moreno, Emma; Bargallo, Nuria; Illa, Miriam; Acosta-Rojas, Ruthy; Amat-Roldan, Ivan; Gratacos, Eduard

    2012-04-02

    Intrauterine growth restriction (IUGR) due to placental insufficiency affects 5-10% of all pregnancies and it is associated with a wide range of short- and long-term neurodevelopmental disorders. Prediction of neurodevelopmental outcomes in IUGR is among the clinical challenges of modern fetal medicine and pediatrics. In recent years several studies have used magnetic resonance imaging (MRI) to demonstrate differences in brain structure in IUGR subjects, but the ability to use MRI for individual predictive purposes in IUGR is limited. Recent research suggests that MRI in vivo access to brain connectivity might have the potential to help understanding cognitive and neurodevelopment processes. Specifically, MRI based connectomics is an emerging approach to extract information from MRI data that exhaustively maps inter-regional connectivity within the brain to build a graph model of its neural circuitry known as brain network. In the present study we used diffusion MRI based connectomics to obtain structural brain networks of a prospective cohort of one year old infants (32 controls and 24 IUGR) and analyze the existence of quantifiable brain reorganization of white matter circuitry in IUGR group by means of global and regional graph theory features of brain networks. Based on global and regional analyses of the brain network topology we demonstrated brain reorganization in IUGR infants at one year of age. Specifically, IUGR infants presented decreased global and local weighted efficiency, and a pattern of altered regional graph theory features. By means of binomial logistic regression, we also demonstrated that connectivity measures were associated with abnormal performance in later neurodevelopmental outcome as measured by Bayley Scale for Infant and Toddler Development, Third edition (BSID-III) at two years of age. These findings show the potential of diffusion MRI based connectomics and graph theory based network characteristics for estimating differences in the

  14. Spontaneous Intestinal Perforation in Extremely Low Birth Weight Infants: Association with Indometacin Therapy and Effects on Neurodevelopmental Outcomes at 18-22 months Corrected Age

    PubMed Central

    Wadhawan, Rajan; Oh, William; Vohr, Betty R.; Saha, Shampa; Das, Abhik; Bell, Edward F.; Laptook, Abbot R.; Shankaran, Seetha; Stoll, Barbara J.; Walsh, Michele C.; Higgins, Rosemary D.

    2013-01-01

    Background Spontaneous intestinal perforation (SIP) is associated with the use of postnatal glucocorticoids and indometacin in extremely low birth weight (ELBW) infants. We hypothesized: 1) an association of SIP with the use of antenatal steroids (ANS) and indometacin either as prophylaxis for IVH (P Indo) or for treatment of PDA (Indo/PDA) and 2) an increased risk of death or abnormal neurodevelopmental outcomes in infants with SIP at 18-22 months corrected age. Design/Methods We retrospectively identified ELBW infants with SIP in the Neonatal Research Network’s generic database. Unadjusted analysis identified the differences in maternal, neonatal and clinical variables between infants with and without SIP. Logistic regression analysis identified the adjusted odds ratio for SIP with reference to ANS, P Indo and Indo/PDA. Neurodevelopmental outcomes were assessed among survivors at 18 to 22 months corrected age. Results Indo/PDA was associated with an increased risk of SIP (adjusted OR 1.61; 95% CI 1.25,2.08), while P Indo and ANS were not. SIP was independently associated with an increased risk of death or NDI (adjusted OR−1.85; 95% CI 1.32,2.60) and NDI among survivors (adjusted OR−1.75, 95% CI 1.20,2.55). Conclusion Indometacin used for IVH prophylaxis and ANS were not associated with the occurrence of SIP in ELBW infants. Indometacin used for treatment of symptomatic PDA was however associated with an increased risk of SIP. ELBW infants with SIP have an increased risk of poor neurodevelopmental outcomes. PMID:22684157

  15. Interventions designed to prevent adverse programming outcomes resulting from exposure to maternal obesity during development

    PubMed Central

    Nathanielsz, PW; Ford, SP; Long, NM; Vega, CC; Reyes-Castro, LA; Zambrano, E

    2013-01-01

    Maternal obesity is a global epidemic affecting the developed and developing world. Human and animal studies indicate that maternal obesity programs development predisposing offspring to later-life chronic diseases. Several mechanisms act together to produce these adverse health problems. There is a need for effective interventions that prevent these outcomes and guide management in human pregnancy. We report here dietary and exercise intervention studies in both altricial and precocial species, rats and sheep, designed to prevent adverse offspring outcomes. Both interventions present exciting opportunities to at least in part prevent adverse metabolic and other outcomes in mother and offspring. PMID:24147928

  16. VIOLENT CRIME EXPOSURE CLASSIFICATION AND ADVERSE BIRTH OUTCOMES: A GEOGRAPHICALLY-DEFINED COHORT STUDY

    EPA Science Inventory

    Background

    Area-level socioeconomic disparities have long been associated with adverse pregnancy outcomes. Crime is an important element of the neighborhood environment inadequately investigated in the public health literature. Using geocoded linked birth, crime and cens...

  17. Adverse Outcome Pathways and Extrapolation Tools to Advance the Three Rs in Ecotoxicology

    EPA Science Inventory

    Adverse outcome pathways (AOPs) are conceptual frameworks for identifying and organizing predictive and causal linkages between cellular-level responses and endpoints conventionally considered in ecological risk assessment (e.g., effects on survival, growth/development, and repro...

  18. Overview of an internationally-harmonized program for adverse outcome pathway development

    EPA Science Inventory

    Adverse outcome pathways (AOPs) are critical frameworks for organizing knowledge concerning the scientifically-credible predictive linkages between toxicological observations made at molecular and cellular levels (e.g., via molecular screening assays, biomarker responses, or chem...

  19. Establishing Adverse Outcome Pathways of Thyroid Hormone Disruption in an Amphibian Model

    EPA Science Inventory

    The Adverse Outcome Pathway (AOP) provides a framework for understanding the relevance of toxicology data in ecotoxicological hazard assessments. The AOP concept can be applied to many toxicological pathways including thyroid hormone disruption. Thyroid hormones play a critical r...

  20. Development & Use of Adverse Outcome Pathways for 21st Century Decision Support

    EPA Science Inventory

    The Adverse Outcome Pathway has emerged as an internationally harmonized mechanism for organizing biological information in a chemical agnostic manner. This construct is valuable for interpreting the results from high-throughput toxicity (HTT) assessment by providing a mechanisti...

  1. Experimental Approaches to Systematic Discovery and Development of Reproductive Adverse Outcome Pathways in Fish

    EPA Science Inventory

    Adverse outcome pathways (AOPs) are conceptual frameworks that portray causal and predictive linkages between key events at multiple scales of biological organization that connect molecular initiating events and early cellular perturbations (e.g., initiation of toxicity pathways)...

  2. Adverse outcome pathways linked to population models as a methodology for investigating effects of chemical stressors

    EPA Science Inventory

    In addressing the complexity and toxicity of chemical contaminants in Great Lakes ecosystems, we describe an approach to link chemically induced alterations in molecular and biochemical endpoints to adverse outcomes in whole organisms and populations. Analysis of population impac...

  3. Near-Infrared Spectroscopy Monitoring, Superior Vena Cava Flow, and Neurodevelopmental Outcome at 2 years in a Cohort of Very Low-Birth-Weight Infants.

    PubMed

    Cerbo, Rosa Maria; Orcesi, Simona; Scudeller, Luigia; Borellini, Martina; Croci, Carolina; Ravelli, Claudia; Masa, Giulia; Paolillo, Piermichele; Manzoni, Paolo; Balottin, Umberto; Stronati, Mauro

    2016-09-01

    Objective We aimed at assessing the association between superior vena cava flow (SVCf), regional (cerebral) tissue oxygen saturation (rSO2), and cerebral fractional oxygen extraction (CFOE) during the first 48 hours of life and 2-years neurodevelopmental outcome of very low-birth-weight infants (VLBW). Methods We prospectively studied 60 VLBW infants admitted to our neonatal intensive care unit; rSO2 was continuously monitored with near-infrared spectroscopy during the first 48 hours of life, SVCf was measured at 4 to 6, 12, 24, and 48 hours, and CFOE was calculated. Neurodevelopmental outcome was assessed at 24 months corrected age. Results The mean gestational age at birth was 27.9 weeks (standard deviation: 2.4); 8 infants died in the first 3 months of life, 6 were lost to follow-up, 46 survived and were followed up. At 24 months, 6 (13%) and 7 (15.2%) infants developed minor and major sequelae, respectively. Infants who died had higher CFOE (p < 0.001) and lower SVCf (p < 0.001) than infants surviving with sequelae. In turn, these had higher SVCf between 24 and 48 hours than those without sequelae (p < 0.001). Conclusion SVCf, rSO2, and CFOE patterns in the first days of life suggest cerebral hyperperfusion, related to loss of autoregulation and/or use of inotropic drugs, as a potential mechanism of cerebral injury.

  4. Candida Virulence Properties and Adverse Clinical Outcomes in Neonatal Candidiasis

    PubMed Central

    Bliss, Joseph M.; Wong, Angela Y.; Bhak, Grace; Laforce-Nesbitt, Sonia S.; Taylor, Sarah; Tan, Sylvia; Stoll, Barbara J.; Higgins, Rosemary D.; Shankaran, Seetha; Benjamin, Daniel K.

    2012-01-01

    Objective To determine if premature infants with invasive Candida infection caused by strains with increased virulence properties have worse clinical outcomes than those infected with less virulent strains. Study design Clinical isolates were studied from 2 populations; premature infants colonized with Candida (commensal, n=27), and those with invasive candidiasis (n=81). Individual isolates of C. albicans and C. parapsilosis were tested for virulence in each of 3 assays: phenotypic switching, adhesion, and cytotoxicity. Invasive isolates were considered to have enhanced virulence if they measured more than 1 SD above the mean for the commensal isolates in at least 1 assay. Outcomes of patients with invasive isolates with enhanced virulence were compared with those with invasive isolates lacking enhanced virulence characteristics. Results 61% of invasive isolates of C. albicans and 42% of invasive isolates of C. parapsilosis had enhanced virulence. All C. albicans cerebrospinal fluid (CSF) isolates (n=6) and 90% of urine isolates (n=10) had enhanced virulence, compared with 48% of blood isolates (n=40). Infants with more virulent isolates were younger at the time of positive culture and had higher serum creatinine. Conclusions Individual isolates of Candida species vary in their virulence properties. Strains with higher virulence are associated with certain clinical outcomes. PMID:22504098

  5. Betel quid chewing and risk of adverse pregnancy outcomes among aborigines in southern Taiwan.

    PubMed

    Yang, M S; Chang, F T; Chen, S S; Lee, C H; Ko, Y C

    1999-07-01

    It is known that substance use is associated with increased risk of adverse pregnancy, outcomes. The aims of this study were to estimate the prevalence of alcohol, cigarette, betel quid and drug use during pregnancy and to assess the risk of adverse effects of betel quid chewing on pregnancy outcomes in aboriginal women in southern Taiwan. The study population included 62 women with adverse pregnancy outcomes and 124 age-matched women. Subjects were interviewed at their homes by trained interviewers using a structure questionnaire. Prevalences of various substance use in aborigines with adverse pregnancy outcomes were estimated as follows: alcohol, 43.6%; smoking, 14.5%; betel quid chewing, 43.6% and over-the-counter drug use, 8.1%; whereas in the comparison group it was alcohol, 38.7%; smoking, 8.1%; betel quid chewing, 28.2% and none used drugs. Univariate analysis revealed that adverse pregnancy outcomes were associated with maternal betel quid chewing, maternal illness during pregnancy, and the number of pregnancies (gravidity) experienced. After adjusting for maternal illness and number of previous pregnancies covariates, the prevalence of adverse pregnancy outcome was computed to be 2.8-fold higher among betel quid chewing women as compared to non-chewers (AOR=2.8, 95% CI=1.2-6.8). Among the aboriginal women, prenatal care is essential not only for routine care, but also to focus health education on the harmful effects of substance use, especially betel quid use during pregnancy.

  6. [Relationship between lipid alterations during pregnancy and adverse pregnancy outcomes].

    PubMed

    Ferriols, Elena; Rueda, Carolina; Gamero, Rocío; Vidal, Mar; Payá, Antonio; Carreras, Ramón; Flores-le Roux, Juana A; Pedro-Botet, Juan

    Lipids play an important role during pregnancy, and in this period major changes occur in lipoprotein metabolism. During the third trimester plasma cholesterol and triglyceride levels are substantially increased, returning to normal after delivery. Described associations between increased morbidity during pregnancy and excessive increases in plasma cholesterol and triglycerides. For this reason we have reviewed the relationship between lipid alterations, preeclampsia, gestational diabetes and preterm birth. The overall metabolic control can improve pregnancy outcomes, and the assessment of supraphysiological changes in lipid profile will classify pregnancy risk at a higher level, which would entail a stricter control.

  7. Attention-deficit/hyperactivity disorder and adverse health outcomes

    PubMed Central

    Nigg, Joel

    2015-01-01

    Attention-deficit/hyperactivity disorder (ADHD) is defined by extreme levels of inattention–disorganization and/or hyperactivity–impulsivity. In DSM-IV, the diagnostic criteria required impairment in social, academic, or occupational functioning. With DSM-5 publication imminent in 2013, further evaluation of impairment in ADHD is timely. This article reviews the current state of knowledge on health-related impairments of ADHD, including smoking, drug abuse, accidental injury, sleep, obesity, hypertension, diabetes, and suicidal behavior. It concludes by suggesting the need for new avenues of research on mechanisms of association and the potential for ADHD to be an early warning sign for secondary prevention of some poor health outcomes. PMID:23298633

  8. Use of Adverse Outcome Pathways for Assessing Effects of the Fungicide Propiconazole on Fish Reproduction

    EPA Science Inventory

    Adverse outcome pathways (AOP) are used to describe the linkage of biological events from a molecular initiating point, to individual-level-endpoints relevant to risk assessment. This study was done to assess toxicity outcomes for the conazole fungicide propiconazole based on a p...

  9. Cortisol Reactivity to Social Stress as a Mediator of Early Adversity on Risk and Adaptive Outcomes

    ERIC Educational Resources Information Center

    Conradt, Elisabeth; Abar, Beau; Lester, Barry M.; LaGasse, Linda L.; Shankaran, Seetha; Bada, Henrietta; Bauer, Charles R.; Whitaker, Toni M.; Hammond, Jane A.

    2014-01-01

    Children chronically exposed to stress early in life are at increased risk for maladaptive outcomes, though the physiological mechanisms driving these effects are unknown. Cortisol reactivity was tested as a mediator of the relation between prenatal substance exposure and/or early adversity on adaptive and maladaptive outcomes. Data were drawn…

  10. Theoretical Framework to Extend Adverse Outcome Pathways to Include Pharmacokinetic Considerations

    EPA Science Inventory

    Adverse Outcome Pathways (AOPs) have generated intense interest for their utility in linking known population outcomes to a molecular initiating event (MIE) that can be quantified using in vitro methods. While there are tens of thousands of chemicals in commercial use, biology h...

  11. Occupational and environmental exposure correlates of adverse live-birth outcomes among 1032 US Navy women.

    PubMed

    Hourani, L; Hilton, S

    2000-12-01

    The integration of women into non-traditional military occupations raises questions concerning the impact of such jobs on women's reproductive health. This study examines the extent to which US Navy women in their reproductive years report exposures to potential occupational and environmental hazards, and the degree to which such exposures are associated with self-reported adverse live-birth outcomes. Data from a survey of pregnant Navy women provided both maternal and paternal exposure information on more than 1000 active-duty women. Self-reported exposures to heavy metals, pesticides, petroleum products, and other chemicals were associated with adverse live-birth outcomes at the bivariate level. Only a father's exposure to pesticides at work predicted an adverse live-birth outcome (preterm delivery) in multivariate models. Maternal occupational exposures may exert their influence through maternal health and/or pregnancy complications and may act as mediators of health-reproductive outcome relationships.

  12. Targeting brain serotonin synthesis: insights into neurodevelopmental disorders with long-term outcomes related to negative emotionality, aggression and antisocial behaviour.

    PubMed

    Lesch, Klaus-Peter; Araragi, Naozumi; Waider, Jonas; van den Hove, Daniel; Gutknecht, Lise

    2012-09-05

    Aggression, which comprises multi-faceted traits ranging from negative emotionality to antisocial behaviour, is influenced by an interaction of biological, psychological and social variables. Failure in social adjustment, aggressiveness and violence represent the most detrimental long-term outcome of neurodevelopmental disorders. With the exception of brain-specific tryptophan hydroxylase-2 (Tph2), which generates serotonin (5-HT) in raphe neurons, the contribution of gene variation to aggression-related behaviour in genetically modified mouse models has been previously appraised (Lesch 2005 Novartis Found Symp. 268, 111-140; Lesch & Merschdorf 2000 Behav. Sci. Law 18, 581-604). Genetic inactivation of Tph2 function in mice led to the identification of phenotypic changes, ranging from growth retardation and late-onset obesity, to enhanced conditioned fear response, increased aggression and depression-like behaviour. This spectrum of consequences, which are amplified by stress-related epigenetic interactions, are attributable to deficient brain 5-HT synthesis during development and adulthood. Human data relating altered TPH2 function to personality traits of negative emotionality and neurodevelopmental disorders characterized by deficits in cognitive control and emotion regulation are based on genetic association and are therefore not as robust as the experimental mouse results. Mouse models in conjunction with approaches focusing on TPH2 variants in humans provide unexpected views of 5-HT's role in brain development and in disorders related to negative emotionality, aggression and antisocial behaviour.

  13. Targeting brain serotonin synthesis: insights into neurodevelopmental disorders with long-term outcomes related to negative emotionality, aggression and antisocial behaviour

    PubMed Central

    Lesch, Klaus-Peter; Araragi, Naozumi; Waider, Jonas; van den Hove, Daniel; Gutknecht, Lise

    2012-01-01

    Aggression, which comprises multi-faceted traits ranging from negative emotionality to antisocial behaviour, is influenced by an interaction of biological, psychological and social variables. Failure in social adjustment, aggressiveness and violence represent the most detrimental long-term outcome of neurodevelopmental disorders. With the exception of brain-specific tryptophan hydroxylase-2 (Tph2), which generates serotonin (5-HT) in raphe neurons, the contribution of gene variation to aggression-related behaviour in genetically modified mouse models has been previously appraised (Lesch 2005 Novartis Found Symp. 268, 111–140; Lesch & Merschdorf 2000 Behav. Sci. Law 18, 581–604). Genetic inactivation of Tph2 function in mice led to the identification of phenotypic changes, ranging from growth retardation and late-onset obesity, to enhanced conditioned fear response, increased aggression and depression-like behaviour. This spectrum of consequences, which are amplified by stress-related epigenetic interactions, are attributable to deficient brain 5-HT synthesis during development and adulthood. Human data relating altered TPH2 function to personality traits of negative emotionality and neurodevelopmental disorders characterized by deficits in cognitive control and emotion regulation are based on genetic association and are therefore not as robust as the experimental mouse results. Mouse models in conjunction with approaches focusing on TPH2 variants in humans provide unexpected views of 5-HT's role in brain development and in disorders related to negative emotionality, aggression and antisocial behaviour. PMID:22826343

  14. Increased incidence of adverse perinatal outcome with low maternal blood viscosity in preeclampsia.

    PubMed

    Pepple, D J; Mullings, A M; Reid, H L

    2004-01-01

    Hyperviscosity of the maternal blood has been reported to be associated with an increased incidence of adverse perinatal outcome in preeclampsia. We related the changes in maternal blood viscosity to perinatal outcome in 47 preeclamptic, nulliparous, black Jamaican women. A group of 49 non-preeclamptic, nulliparous, gestation-matched women acted as controls. Perinatal outcome was also compared between the women with high blood viscosity (> or = 5 mPa.s) and those with low blood viscosity (< 5 mPa.s) in both the preeclamptic and non-preeclamptic groups. Data was analysed by the comparison of two proportions, the chi-squared test, the Fisher's exact test and the Pearson's correlation method. The level of statistical significance was taken at p < 0.05. The incidence of adverse perinatal outcome was significantly (p < 0.001) higher in the preeclamptic women as compared with that of the non-preeclamptic controls. However, of interest, was the fact that within the preeclamptic group, the incidence of adverse perinatal outcome was significantly (p = 0.001, Fisher's exact test) higher in those with low blood viscosity as compared with those with high blood viscosity. These results suggest that low maternal blood viscosity may be related to increased incidence of adverse perinatal outcome in Jamaican women with preeclampsia.

  15. Frequency, Risk Factors, and Adverse Fetomaternal Outcomes of Placenta Previa in Northern Tanzania

    PubMed Central

    Senkoro, Elizabeth Eliet; Mwanamsangu, Amasha H.; Chuwa, Fransisca Seraphin; Msuya, Sia Emmanuel; Mnali, Oresta Peter

    2017-01-01

    Background and Objective. Placenta previa (PP) is a potential risk factor for obstetric hemorrhage, which is a major cause of fetomaternal morbidity and mortality in developing countries. This study aimed to determine frequency, risk factors, and adverse fetomaternal outcomes of placenta previa in Northern Tanzania. Methodology. A retrospective cohort study was conducted using maternally-linked data from Kilimanjaro Christian Medical Centre birth registry spanning 2000 to 2015. All women who gave birth to singleton infants were studied. Adjusted odds ratios (ORs) with 95% confidence intervals for risk factors and adverse fetomaternal outcomes associated with PP were estimated in multivariable logistic regression models. Result. A total of 47,686 singleton deliveries were analyzed. Of these, the frequency of PP was 0.6%. Notable significant risk factors for PP included gynecological diseases, alcohol consumption during pregnancy, malpresentation, and gravidity ≥5. Adverse maternal outcomes were postpartum haemorrhage, antepartum haemorrhage, and Caesarean delivery. PP increased odds of fetal Malpresentation and early neonatal death. Conclusion. The prevalence of PP was comparable to that found in past research. Multiple independent risk factors were identified. PP was found to have associations with several adverse fetomaternal outcomes. Early identification of women at risk of PP may help clinicians prevent such complications. PMID:28321338

  16. Defining Adverse Outcome Pathways for Effects of the Fungicide Propiconazole of Fish Reproduction

    EPA Science Inventory

    Adverse outcome pathways (AOPs) are used to describe the linkage of chemical interactions in terms of molecular initiating events to whole organism responses suitable for risk assessment. This study was conducted to develop AOPs for the model fungicide propiconazole relative to r...

  17. Exposure and Dosimetry Considerations for Adverse Outcome Pathways (AOPs) (NIH-AOP)

    EPA Science Inventory

    Risk is a function of both of hazard and exposure. Toxicokinetic (TK) models can determine whether chemical exposures produce potentially hazardous tissue concentrations. Whether or not the initial molecular event (MIE) in an Adverse Outcome Pathway (AOP) occurs depends on both e...

  18. Physical Performance Characteristics of Assisted Living Residents and Risk for Adverse Health Outcomes

    ERIC Educational Resources Information Center

    Giuliani, Carol A.; Gruber-Baldini, Ann L.; Park, Nan S.; Schrodt, Lori A.; Rokoske, Franzi; Sloane, Philip D.; Zimmerman, Sheryl

    2008-01-01

    Purpose: Researchers know little about the physical performance ability of residential care/assisted living (RC/AL) residents and its relationship to adverse outcomes such as fracture, nursing home placement, functional decline, and death. The purposes of this article are to (a) describe the functional characteristics of RC/AL residents, (b)…

  19. Studying Biology to Understand Risk: Dosimetry Models and Quantitative Adverse Outcome Pathways

    EPA Science Inventory

    Confidence in the quantitative prediction of risk is increased when the prediction is based to as great an extent as possible on the relevant biological factors that constitute the pathway from exposure to adverse outcome. With the first examples now over 40 years old, physiologi...

  20. Constructing Adverse Outcome Pathways: a Demonstration of an Ontology-based Semantics Mapping Approach

    EPA Science Inventory

    Adverse outcome pathway (AOP) provides a conceptual framework to evaluate and integrate chemical toxicity and its effects across the levels of biological organization. As such, it is essential to develop a resource-efficient and effective approach to extend molecular initiating ...

  1. Periodontal treatment during pregnancy decreases the rate of adverse pregnancy outcome: a controlled clinical trial

    PubMed Central

    SANT’ANA, Adriana Campos Passanezi; de CAMPOS, Marinele R.; PASSANEZI, Selma Campos; de REZENDE, Maria Lúcia Rubo; GREGHI, Sebastião Luiz Aguiar; PASSANEZI, Euloir

    2011-01-01

    Objectives The aim of this study was to evaluate the effects of non-surgical treatment of periodontal disease during the second trimester of gestation on adverse pregnancy outcomes. Material and Methods Pregnant patients during the 1st and 2nd trimesters at antenatal care in a Public Health Center were divided into 2 groups: NIG – "no intervention" (n=17) or IG- "intervention" (n=16). IG patients were submitted to a non-surgical periodontal treatment performed by a single periodontist consisting of scaling and root planning (SRP), professional prophylaxis (PROPH) and oral hygiene instruction (OHI). NIG received PROPH and OHI during pregnancy and were referred for treatment after delivery. Periodontal evaluation was performed by a single trained examiner, blinded to periodontal treatment, according to probing depth (PD), clinical attachment level (CAL), plaque index (PI) and sulcular bleeding index (SBI) at baseline and 35 gestational weeks-28 days post-partum. Primary adverse pregnancy outcomes were preterm birth (<37 weeks), low birth weight (<2.5 kg), late abortion (14-24 weeks) or abortion (<14 weeks). The results obtained were statistically evaluated according to OR, unpaired t test and paired t test at 5% significance level. Results No significant differences were observed between groups at baseline examination. Periodontal treatment resulted in stabilization of CAL and PI (p>0.05) at IG and worsening of all periodontal parameters at NIG (p<0.0001), except for PI. Significant differences in periodontal conditions of IG and NIG were observed at 2nd examination (p<0.001). The rate of adverse pregnancy outcomes was 47.05% in NIG and 6.25% in IG. Periodontal treatment during pregnancy was associated to a decreased risk of developing adverse pregnancy outcomes [OR=13.50; CI: 1.47-123.45; p=0.02]. Conclusions Periodontal treatment during the second trimester of gestation contributes to decrease adverse pregnancy outcomes. PMID:21552714

  2. Cortisol Reactivity to Social Stress as a Mediator of Early Adversity on Risk and Adaptive Outcomes

    PubMed Central

    Conradt, Elisabeth; Abar, Beau; Lester, Barry M.; LaGasse, Linda L.; Shankaran, Seetha; Bada, Henrietta; Bauer, Charles R.; Whitaker, Toni M.; Hammond, Jane A.

    2014-01-01

    Children chronically exposed to stress early in life are at increased risk for maladaptive outcomes, though the physiological mechanisms driving these effects are unknown. Cortisol reactivity was tested as a mediator of the relation between prenatal substance exposure and/or early adversity on adaptive and maladaptive outcomes. Data were drawn from a prospective longitudinal study of prenatal substance exposure (N = 860). Cortisol reactivity was assessed at age 11. Among African-Americans, prenatal substance exposure exerted an indirect effect through early adversity and cortisol reactivity to predict externalizing behavior, delinquency, and a positive student-teacher relationship at age 11. Decreased cortisol reactivity was related to maladaptive outcomes, and increased cortisol reactivity predicted better executive functioning and a more positive student-teacher relationship. PMID:25376131

  3. Adverse Outcome Pathway for Embryonic Vascular Disruption and Alternative Methods to Identify Chemical Vascular Disruptors During Development

    EPA Science Inventory

    Chemically induced vascular toxicity during embryonic development can result in a wide range of adverse prenatal outcomes. We used information from genetic mouse models linked to phenotypic outcomes and a vascular toxicity knowledge base to construct an embryonic vascular disrupt...

  4. Prognostic indicators of adverse renal outcome and death in acute kidney injury hospital survivors

    PubMed Central

    Hamzić-Mehmedbašić, Aida; Rašić, Senija; Balavac, Merima; Rebić, Damir; Delić-Šarac, Marina; Durak-Nalbantić, Azra

    2016-01-01

    Introduction: Data regarding prognostic factors of post-discharge mortality and adverse renal function outcome in acute kidney injury (AKI) hospital survivors are scarce and controversial. Objectives: We aimed to identify predictors of post-discharge mortality and adverse renal function outcome in AKI hospital survivors. Patients and Methods: The study group consisted of 84 AKI hospital survivors admitted to the tertiary medical center during 2-year period. Baseline clinical parameters, with renal outcome 3 months after discharge and 6-month mortality were evaluated. According survival and renal function outcome, patients were divided into two groups. Results: Patients who did not recover renal function were statistically significantly older (P < 0.007) with higher Charlson comorbidity index (CCI) score (P < 0.000) and more likely to have anuria and oliguria (P = 0.008) compared to those with recovery. Deceased AKI patients were statistically significantly older (P < 0.000), with higher CCI score (P < 0.000), greater prevalence of sepsis (P =0.004), higher levels of C-reactive protein (CRP) (P < 0.017) and ferritin (P < 0.051) and lower concentrations of albumin (P<0.01) compared to survivors. By multivariate analysis, independent predictors of adverse renal outcome were female gender (P =0.033), increasing CCI (P =0.000), presence of pre-existing chronic kidney disease (P =0.000) and diabetes mellitus (P =0.019) as well as acute decompensated heart failure (ADHF) (P =0.032), while protective factor for renal function outcome was higher urine output (P =0.009). Independent predictors of post-discharge mortality were female gender (P =0.04), higher CCI score (P =0.001) and sepsis (P =0.034). Conclusion: Female AKI hospital survivors with increasing burden of comorbidities, diagnosis of sepsis and ADHF seem to be at high-risk for poor post-discharge outcome. PMID:27471736

  5. Periodontal Disease: A Possible Risk-Factor for Adverse Pregnancy Outcome

    PubMed Central

    Parihar, Anuj Singh; Katoch, Vartika; Rajguru, Sneha A; Rajpoot, Nami; Singh, Pinojj; Wakhle, Sonal

    2015-01-01

    Bacterial invasion in subgingival sites especially of gram-negative organisms are initiators for periodontal diseases. The periodontal pathogens with persistent inflammation lead to destruction of periodontium. In recent years, periodontal diseases have been associated with a number of systemic diseases such as rheumatoid arthritis, cardiovascular-disease, diabetes mellitus, chronic respiratory diseases and adverse pregnancy outcomes including pre-term low-birth weight (PLBW) and pre-eclampsia. The factors like low socio-economic status, mother's age, race, multiple births, tobacco and drug-abuse may be found to increase risk of adverse pregnancy outcome. However, the same are less correlated with PLBW cases. Even the invasion of both aerobic and anerobic may lead to inflammation of gastrointestinal tract and vagina hence contributing to PLBW. The biological mechanism involved between PLBW and Maternal periodontitis is the translocation of chemical mediators of inflammation. Pre-eclampsia is one of the commonest cause of both maternal and fetal morbidity as it is characterized by hypertension and hyperprotenuria. Improving periodontal health before or during pregnancy may prevent or reduce the occurrences of these adverse pregnancy outcomes and, therefore, reduce the maternal and perinatal morbidity and mortality. Hence, this article is an attempt to review the relationship between periodontal condition and altered pregnancy outcome. PMID:26229389

  6. Low socioeconomic status, adverse gene expression profiles, and clinical outcomes in hematopoietic stem cell transplant recipients

    PubMed Central

    Knight, Jennifer M.; Rizzo, J. Douglas; Logan, Brent R.; Wang, Tao; Arevalo, Jesusa M.G.; Ma, Jeffrey; Cole, Steve W.

    2015-01-01

    Purpose Low socioeconomic status (SES) is associated with adverse outcomes among unrelated donor hematopoietic stem cell transplant (HCT) recipients, but the biological mechanisms contributing to this health disparity are poorly understood. Therefore, we examined whether social environment affects expression of a stress-related gene expression profile known as the conserved transcriptional response to adversity (CTRA), which involves up-regulation of pro-inflammatory genes and down-regulation of genes involved in type I IFN response and antibody synthesis. Experimental Design We compared pre-transplant leukocyte CTRA gene expression between a group of 78 high vs. low SES recipients of unrelated donor HCT for acute myelogenous leukemia in first remission. Post hoc exploratory analyses also evaluated whether CTRA gene expression was associated with poor clinical outcomes. Results Peripheral blood mononuclear cells collected pre-HCT from low SES individuals demonstrated significant CTRA up-regulation compared to matched HCT recipients of high SES. Promoter-based bioinformatics implicated distinct patterns of transcription factor activity including increased CREB signaling and decreased IRF and GR signaling. High expression of the CTRA gene profile was also associated with increased relapse risk and decreased leukemia-free survival. Conclusions Low SES is associated with increased expression of the CTRA gene profile, and CTRA gene expression is associated with adverse HCT clinical outcomes. These findings provide a biologic framework within which to understand how social environmental conditions may influence immune function and clinical outcomes in allogeneic HCT. PMID:26286914

  7. Baby on board: do responses to stress in the maternal brain mediate adverse pregnancy outcome?

    PubMed

    Douglas, Alison J

    2010-07-01

    Stress and adverse environmental surroundings result in suboptimal conditions in a pregnant mother such that she may experience poor pregnancy outcome including complete pregnancy failure and preterm labor. Furthermore her developing baby is at risk of adverse programming, which confers susceptibility to long term ill health. While some mechanisms at the feto-maternal interface underlying these conditions are understood, the underlying cause for their adverse adaptation is often not clear. Progesterone plays a key role at many levels, including control of neuroendocrine responses to stress, procuring the required immune balance and controlling placental and decidual function, and lack of progesterone can explain many of the unwanted consequences of stress. How stress that is perceived by the mother inhibits progesterone secretion and action is beginning to be investigated. This overview of maternal neuroendocrine responses to stress throughout pregnancy analyses how they interact to compromise progesterone secretion and precipitate undesirable effects in mother and offspring.

  8. Adverse Pregnancy Outcomes: Opportunity for Analysis of Biospecimens and Co-development of Prognostics | NCI Technology Transfer Center | TTC

    Cancer.gov

    The Eunice Kennedy Shriver National Institute of Child Health and Human Development’s Pregnancy and Perinatology Branch seeks partners interested in collaborative research to: (i) evaluate data and samples taken from women for potential biomarkers indicative for adverse pregnancy outcomes and (ii) co-develop diagnostic kits useful as predictors of adverse pregnancy outcomes.

  9. Predictors of Adverse Cosmetic Outcome in the RAPID Trial: An Exploratory Analysis

    SciTech Connect

    Peterson, David; Truong, Pauline T.; Parpia, Sameer; Olivotto, Ivo A.; Berrang, Tanya; Kim, Do-Hoon; Kong, Iwa; Germain, Isabelle; Nichol, Alan; Akra, Mohamed; Roy, Isabelle; Reed, Melanie; Fyles, Anthony; Trotter, Theresa; Perera, Francisco; Balkwill, Susan; Lavertu, Sophie; Elliott, Elizabeth; and others

    2015-04-01

    Purpose: To evaluate factors associated with adverse cosmesis outcome in breast cancer patients randomized to accelerated partial breast irradiation (APBI) using 3-dimensional conformal radiation therapy or whole-breast irradiation in the RAPID (Randomized Trial of Accelerated Partial Breast Irradiation) trial. Methods and Materials: Subjects were trial participants with nurse-assessed global cosmetic scores at baseline and at 3 years. Adverse cosmesis was defined as a score of fair or poor. Cosmetic deterioration was defined as any adverse change in score from baseline to 3 years. The analysis is based on data from the previously reported interim analysis. Logistic regression models were used to assess the association of risk factors for these outcomes among all patients and those treated with APBI only. Results: Clinicopathologic characteristics were similar between subjects randomized to APBI (n=569) or whole-breast irradiation (n=539). For all subjects, factors associated with adverse cosmesis at 3 years were older age, central/inner tumor location, breast infection, smoking, seroma volume, breast volume, and use of APBI; factors associated with cosmetic deterioration were smoking, seroma volume, and use of APBI (P<.05). For APBI subjects, tumor location, smoking, age, and seroma volume were associated with adverse cosmesis (P<.05), and smoking was associated with cosmetic deterioration (P=.02). An independent association between the V95/whole-breast volume ratio and adverse cosmesis (P=.28) or cosmetic deterioration (P=.07) was not detected. On further exploration a V95/whole-breast volume ratio <0.15 was associated with a lower risk of cosmetic deterioration (p=.04), but this accounted for only 11% of patients. Conclusion: In the RAPID trial, a number of patient tumor and treatment-related factors, including the use of APBI, were associated with adverse cosmesis and cosmetic deterioration. For patients treated with APBI alone, the high-dose treatment

  10. Development of computationally predicted Adverse Outcome Pathway (AOP) networks through data mining and integration of publicly available in vivo, in vitro, phenotype, and biological pathway data

    EPA Science Inventory

    The Adverse Outcome Pathway (AOP) framework is increasingly being adopted as a tool for organizing and summarizing the mechanistic information connecting molecular perturbations by environmental stressors with adverse outcomes relevant for ecological and human health outcomes. Ho...

  11. The adverse outcome pathway for skin sensitisation: Moving closer to replacing animal testing.

    PubMed

    Schultz, Terry W; Dimitrova, Gergana; Dimitrov, Sabcho; Mekenyan, Ovanes G

    2016-10-01

    This article outlines the work of the Organisation for Economic Co-operation and Development (OECD) that led to being jointly awarded the 2015 Lush Black Box Prize. The award-winning work centred on the development of 'The Adverse Outcome Pathway for Skin Sensitisation Initiated by Covalent Binding to Proteins'. This Adverse Outcome Pathway (AOP) has provided the mechanistic basis for the integration of skin sensitisation-related information. Recent developments in integrated approaches to testing and assessment, based on the AOP, are summarised. The impact of the AOP on regulatory policy and on the Three Rs are discussed. An overview of the next generation of the skin sensitisation AOP module in the OECD QSAR Toolbox, based on more-recent work at the Laboratory of Mathematical Chemistry, is also presented.

  12. Population versus Customized Fetal Growth Norms and Adverse Outcomes in an Intrapartum Cohort

    PubMed Central

    Costantine, Maged M.; Lai, Yinglei; Bloom, Steven L.; Spong, Catherine Y.; Varner, Michael W.; Rouse, Dwight J.; Ramin, Susan M.; Caritis, Steve N.; Peaceman, Alan M.; Sorokin, Yoram; Sciscione, Anthony; Mercer, Brian M.; Thorp, John M.; Malone, Fergal D.; Harper, Margaret; Iams, Jay D.

    2013-01-01

    Objective To compare population versus customized fetal growth norms in identifying neonates at risk for adverse outcomes (APO) associated with small for gestational age (SGA). Study Design Secondary analysis of an intrapartum fetal pulse oximetry trial in nulliparous women at term. Birthweight percentiles were calculated using ethnicity- & gender-specific population norms and customized norms (Gardosi). Results 508 (9.9%) and 584 (11.3%) neonates were SGA by population (SGApop) and customized (SGAcust) norms. SGApop infants were significantly associated with a composite adverse neonatal outcome, neonatal intensive care admission, low fetal oxygen saturation and reduced risk of cesarean delivery; while both SGApop and SGAcust were associated with a 5-minute Apgar score < 4. The ability of customized and population birthweight percentiles in predicting APO was poor (12 out of 14 APOs had AUC <0.6). Conclusion In this intrapartum cohort, neither customized nor normalized-population norms adequately identify neonates at risk of APO related to SGA. PMID:22893556

  13. Decline in adverse outcomes and death in tuberculosis patients in Malawi: association with HIV interventions.

    PubMed

    Kanyerere, H; Mganga, A; Harries, A D; Tayler-Smith, K; Zachariah, R; Jahn, A; Chimbwandira, F M; Mpunga, J

    2015-06-21

    Between 2000 and 2012, the annual numbers of patients treated for tuberculosis (TB) in Malawi declined by 28%, from 28 234 to 20 463. During this time, the proportion of TB patients tested for the human immunodeficiency virus (HIV) increased from 6% to 87%. Most HIV-infected patients received cotrimoxazole preventive therapy, and the proportion receiving antiretroviral therapy increased to 88%. Between 2000 and 2008 there was a significant decline in all adverse outcomes (from 31% to 14%), and particularly in deaths (from 23% to 10%) and loss to follow-up (from 5.2% to 1.9%, P < 0.001). After 2008, there was no decrease in any adverse outcome. Ways to further reduce TB-associated mortality are discussed.

  14. Risk factors for adverse life outcomes in fetal alcohol syndrome and fetal alcohol effects.

    PubMed

    Streissguth, Ann P; Bookstein, Fred L; Barr, Helen M; Sampson, Paul D; O'Malley, Kieran; Young, Julia Kogan

    2004-08-01

    Clinical descriptions of patients with Fetal Alcohol Syndrome (FAS) and Fetal Alcohol Effects (FAE) suggest major problems with adaptive behavior. Five operationally defined adverse outcomes and 18 associated risk/protective factors were examined using a Life History Interview with knowledgeable informants of 415 patients with FAS or FAE (median age 14 years, range 6-51; median IQ 86, range 29-126). Eighty percent of these patients were not raised by their biological mothers. For adolescents and adults, the life span prevalence was 61% for Disrupted School Experiences, 60% for Trouble with the Law, 50% for Confinement (in detention, jail, prison, or a psychiatric or alcohol/drug inpatient setting), 49% for Inappropriate Sexual Behaviors on repeated occasions, and 35% for Alcohol/Drug Problems. The odds of escaping these adverse life outcomes are increased 2- to 4-fold by receiving the diagnosis of FAS or FAE at an earlier age and by being reared in good stable environments.

  15. Explaining the Association between Early Adversity and Young Adults' Diabetes Outcomes: Physiological, Psychological, and Behavioral Mechanisms.

    PubMed

    Wickrama, Kandauda A S; Bae, Dayoung; O'Neal, Catherine Walker

    2017-01-31

    Previous studies have documented that early adversity increases young adults' risk for diabetes resulting in morbidity and comorbidity with adverse health conditions. However, less is known about how inter-related physiological (e.g., body mass index [BMI]), psychological (e.g., depressive symptoms), and behavioral mechanisms (e.g., unhealthy eating and sedentary behavior) link early adversity to young adults' diabetes outcomes, although these mechanisms appear to stem from early stressful experiences. The current study tested the patterning of these longitudinal pathways leading to young adults' diabetes using a nationally representative sample of 13,286 adolescents (54% female) over a period of 13 years. The findings indicated that early adversity contributed to elevated BMI, depressive symptoms, and stress-related health behaviors. The impact of these linking mechanisms on hierarchical diabetes outcomes (i.e., prediabetes and diabetes) remained significant after taking their associations with each other into account, showing that these mechanisms operate concurrently. The findings emphasize the importance of early detection for risk factors of young adults' diabetes in order to minimize their detrimental health effects.

  16. Incident opioid drug use and adverse respiratory outcomes among older adults with COPD.

    PubMed

    Vozoris, Nicholas T; Wang, Xuesong; Fischer, Hadas D; Bell, Chaim M; O'Donnell, Denis E; Austin, Peter C; Stephenson, Anne L; Gill, Sudeep S; Rochon, Paula A

    2016-09-01

    We evaluated risk of adverse respiratory outcomes associated with incident opioid use among older adults with chronic obstructive pulmonary diseases (COPD).This was a retrospective population-based cohort study using a validated algorithm applied to health administrative data to identify adults aged 66 years and older with COPD. Inverse probability of treatment weighting using the propensity score was used to estimate hazard ratios comparing adverse respiratory outcomes within 30 days of incident opioid use compared to controls.Incident opioid use was associated with significantly increased emergency room visits for COPD or pneumonia (HR 1.14, 95% CI 1.00-1.29; p=0.04), COPD or pneumonia-related mortality (HR 2.16, 95% CI 1.61-2.88; p<0.0001) and all-cause mortality (HR 1.76, 95% CI 1.57-1.98; p<0.0001), but significantly decreased outpatient exacerbations (HR 0.88, 95% CI 0.83-0.94; p=0.0002). Use of more potent opioid-only agents was associated with significantly increased outpatient exacerbations, emergency room visits and hospitalisations for COPD or pneumonia, and COPD or pneumonia-related and all-cause mortality.Incident opioid use, and in particular use of the generally more potent opioid-only agents, was associated with increased risk for adverse respiratory outcomes, including respiratory-related mortality, among older adults with COPD. Potential adverse respiratory outcomes should be considered when prescribing new opioids in this population.

  17. Patient versus professional based psychosocial risk factor screening for adverse pregnancy outcomes.

    PubMed

    Quispel, Chantal; van Veen, Mieke J; Zuijderhoudt, Christianne; Steegers, Eric A P; Hoogendijk, Witte J G; Birnie, Erwin; Bonsel, Gouke J; Lambregtse-van den Berg, Mijke P

    2014-11-01

    To identify Psychopathology, Psychosocial problems and substance use (PPS) as predictors of adverse pregnancy outcomes, two screen-and-advice instruments were developed: Mind2Care (M2C, self-report) and Rotterdam Reproductive Risk Reduction (R4U, professional's checklist). To decide on the best clinical approach of these risks, the performance of both instruments was compared. Observational study of 164 pregnant women who booked at two midwifery practices in Rotterdam. Women were consecutively screened with M2C and R4U. For referral to tailored care based on specific PPS risks, inter-test agreement of single risks was performed in terms of overall accuracy and positive accuracy (risk present according to both instruments). With univariate regression analysis we explored determinants of poor agreement (<90 %). For triage based on risk accumulation and for detecting women-at-risk for adverse birth outcomes, M2C and R4U sum scores were compared. Overall accuracy of single risks was high (mean 93 %). Positive accuracy was lower (mean 46 %) with poorest accuracy for current psychiatric symptoms. Educational level and ethnicity partly explained poor accuracy (p < 0.05). Overall low PPS prevalence decreased the statistical power. For triage, M2C and R4U sum scores were interchangeable from sum scores of five or more (difference <1 %). The probability of adverse birth outcomes similarly increased with risk accumulation for both instruments, identifying 55-75 % of women-at-risk. The self-report M2C and the professional's R4U checklist seem interchangeable for triage of women-at-risk for PPS or adverse birth outcomes. However, the instruments seem to provide complementary information if used as a guidance to tailored risk-specific care.

  18. Optimal screening for increased risk for adverse outcomes in hospitalised older adults

    PubMed Central

    Heim, Noor; van Fenema, Ester M.; Weverling-Rijnsburger, Annelies W. E.; Tuijl, Jolien P.; Jue, Peter; Oleksik, Anna M.; Verschuur, Margot J.; Haverkamp, Jasper S.; Blauw, Gerard Jan; van der Mast, Roos C.; Westendorp, Rudi G. J.

    2015-01-01

    Background: screening for frailty might help to prevent adverse outcomes in hospitalised older adults. Objective: to identify the most predictive and efficient screening tool for frailty. Design and setting: two consecutive observational prospective cohorts in four hospitals in the Netherlands. Subjects: patients aged ≥70 years, electively or acutely hospitalised for ≥2 days. Methods: screening instruments included in the Dutch Safety Management Programme [VeiligheidsManagementSysteem (VMS)] on four geriatric domains (ADL, falls, undernutrition and delirium) were used and the Identification of Seniors At Risk, the 6-item Cognitive Impairment Test and the Mini-Mental State Examination were assessed. Three months later, adverse outcomes including functional decline, high-healthcare demand or death were determined. Correlation and regression tree analyses were performed and predictive capacities were assessed. Results: follow-up data were available of 883 patients. All screening instruments were similarly predictive for adverse outcome (predictive power 0.58–0.66), but the percentage of positively screened patients (13–72%), sensitivity (24–89%) and specificity (35–91%) highly differed. The strongest predictive model for frailty was scoring positive on ≥3 VMS domains if aged 70–80 years; or being aged ≥80 years and scoring positive on ≥1 VMS domains. This tool classified 34% of the patients as frail with a sensitivity of 68% and a specificity of 74%. Comparable results were found in the validation cohort. Conclusions: the VMS-tool plus age (VMS+) offers an efficient instrument to identify frail hospitalised older adults at risk for adverse outcome. In clinical practice, it is important to weigh costs and benefits of screening given the rather low-predictive power of screening instruments. PMID:25432981

  19. Significance of frailty for predicting adverse clinical outcomes in different patient groups with specific medical conditions.

    PubMed

    Ritt, Martin; Gaßmann, Karl-Günter; Sieber, Cornel Christian

    2016-10-01

    Frailty is a major health burden in an aging society. It constitutes a clinical state of reduced physiological reserves that is associated with a diminished ability to withstand internal and external stressors. Frail patients have an increased risk for adverse clinical outcomes, such as mortality, readmission to hospital, institutionalization and falls. Of further clinical interest, frailty might be at least in part reversible in some patients and subject to preventive strategies. In daily clinical practice older patients with a complex health status, who are mostly frail or at least at risk of developing frailty, are frequently cared for by geriatricians. Recently, clinicians and scientists from other medical disciplines, such as cardiology, pulmonology, gastroenterology, nephrology, endocrinology, rheumatology, surgery and critical care medicine also discovered frailty to be an interesting instrument for risk stratification of patients, including younger patients. In this review we highlight the results of recent studies that demonstrated the significance of frailty to predict adverse clinical outcomes in patients with specific medical conditions, such as cardiac, lung, liver and kidney diseases as well as diabetes mellitus, osteoarthritis, trauma patients, patients undergoing surgery and critically ill patients. Multiple studies in patients with the aforementioned specific medical conditions could be identified demonstrating a predictive role of frailty for several adverse clinical outcomes. The association between frailty and adverse clinical outcomes reported in these studies was in part independent of several major potential confounder factors, such as age, sex, race, comorbidities and disabilities and were also detected in younger patients.

  20. Long-term neurodevelopmental outcome of children born to prospectively followed pregnancies of women with systemic lupus erythematosus and/or antiphospholipid syndrome.

    PubMed

    Nalli, C; Iodice, A; Andreoli, L; Galli, J; Lojacono, A; Motta, M; Fazzi, E; Tincani, A

    2017-04-01

    Background Systemic lupus erythematosus (SLE) and antiphospholipid antibody syndrome (APS) are autoimmune diseases that affect women of childbearing age. Maternal IgG antiphospholipid antibodies (aPL) can cross the placenta during pregnancy and theoretically reach the fetal brain. Some studies showed an increased number of learning disabilities in these children. Objectives To evaluate the long-term neurodevelopmental outcome of 40 children (median age 7.4 years) born to mothers with SLE and/or APS carrying positive IgG aPL during the third trimester of pregnancy. Methods Children were checked for neurological physical exam and intellectual/cognitive functioning by the Wechsler scale for corrected age. We submitted to the mothers the Child Behavior CheckList (CBCL) and a homemade set of questions created by pediatric neurologists. Results In all children neurological physical exam and intelligence levels were found to be normal. A cognitive impairment or a discrepant cognitive profile was found in 3 (7%) and 11 (28%) children, respectively. Learning disabilities were diagnosed in 3 children (19% of school-age children), all born to mothers with triple aPL positivity. A history of epilepsy was shown in four children (10%).

  1. A review of nitrates in drinking water: maternal exposure and adverse reproductive and developmental outcomes.

    PubMed

    Manassaram, Deana M; Backer, Lorraine C; Moll, Deborah M

    2006-03-01

    In this review we present an update on maternal exposure to nitrates in drinking water in relation to possible adverse reproductive and developmental effects, and also discuss nitrates in drinking water in the United States. The current standard for nitrates in drinking water is based on retrospective studies and approximates a level that protects infants from methemoglobinemia, but no safety factor is built into the standard. The current standard applies only to public water systems. Drinking water source was related to nitrate exposure (i.e., private systems water was more likely than community system water to have nitrate levels above the maximum contaminant limit). Animal studies have found adverse reproductive effects resulting from higher doses of nitrate or nitrite. The epidemiologic evidence of a direct exposure-response relationship between drinking water nitrate level and adverse reproductive effect is still not clear. However, some reports have suggested an association between exposure to nitrates in drinking water and spontaneous abortions, intrauterine growth restriction, and various birth defects. Uncertainties in epidemiologic studies include the lack of individual exposure assessment that would rule out confounding of the exposure with some other cause. Nitrates may be just one of the contaminants in drinking water contributing to adverse outcomes. We conclude that the current literature does not provide sufficient evidence of a causal relationship between exposure to nitrates in drinking water and adverse reproductive effects. Future studies incorporating individual exposure assessment about users of private wells--the population most at risk--should be considered.

  2. A Review of Nitrates in Drinking Water: Maternal Exposure and Adverse Reproductive and Developmental Outcomes

    PubMed Central

    Manassaram, Deana M.; Backer, Lorraine C.; Moll, Deborah M.

    2006-01-01

    In this review we present an update on maternal exposure to nitrates in drinking water in relation to possible adverse reproductive and developmental effects, and also discuss nitrates in drinking water in the United States. The current standard for nitrates in drinking water is based on retrospective studies and approximates a level that protects infants from methemoglobinemia, but no safety factor is built into the standard. The current standard applies only to public water systems. Drinking water source was related to nitrate exposure (i.e., private systems water was more likely than community system water to have nitrate levels above the maximum contaminant limit). Animal studies have found adverse reproductive effects resulting from higher doses of nitrate or nitrite. The epidemiologic evidence of a direct exposure–response relationship between drinking water nitrate level and adverse reproductive effect is still not clear. However, some reports have suggested an association between exposure to nitrates in drinking water and spontaneous abortions, intrauterine growth restriction, and various birth defects. Uncertainties in epidemiologic studies include the lack of individual exposure assessment that would rule out confounding of the exposure with some other cause. Nitrates may be just one of the contaminants in drinking water contributing to adverse outcomes. We conclude that the current literature does not provide sufficient evidence of a causal relationship between exposure to nitrates in drinking water and adverse reproductive effects. Future studies incorporating individual exposure assessment about users of private wells—the population most at risk—should be considered. PMID:16507452

  3. Vitamin D Deficiency Strongly Predicts Adverse Medical Outcome Across Different Medical Inpatient Populations

    PubMed Central

    Graedel, Lena; Merker, Meret; Felder, Susan; Kutz, Alexander; Haubitz, Sebastian; Faessler, Lukas; Kaeslin, Martha; Huber, Andreas; Mueller, Beat; Schuetz, Philipp

    2016-01-01

    Abstract Vitamin D deficiency has been associated with several adverse outcomes mainly in the outpatient setting. The objective of this study was to examine the prevalence of vitamin D deficiency and its association with risk of adverse clinical outcomes in a large prospective cohort of medical inpatients. We collected clinical data and measured 25(OH)D levels in adult medical patients upon hospital admission and followed them for 30 days. Regression analyses adjusted for age, gender, comorbidities, and main medical diagnosis were performed to study the effect of vitamin D deficiency on several hospital outcomes. Of 4257 included patients, 1510 (35.47%) had 25(OH)D levels of 25 to 50 nmol/L (vitamin D insufficiency) and 797 (18.72%) had levels of <25nmol/L (severe deficiency). Vitamin D insufficiency and severe deficiency were associated (OR/HR, 95%CI) with an increased risk of 30-day mortality (OR 1.70, 1.22–2.36 and 2.70, 1.22–2.36) and increased length of stay (HR 0.88, 0.81–0.97 and 0.72, 0.65–0.81). Severe deficiency was associated with risk of falls (OR 1.77, 1.18–2.63), impaired Barthel index (OR 1.80, 1.42–2.28), and impairment in quality of life. Most associations remained robust after multivariate adjustment and in subgroups stratified by gender, age, comorbidities, and main diagnoses (P for interaction >0.05). In this comprehensive and large medical inpatient cohort, vitamin D deficiency was highly prevalent and strongly associated with adverse clinical outcome. Interventional research is urgently needed to prove the effect of vitamin D supplementation on these outcomes. PMID:27175650

  4. Maternal smoking during pregnancy and adverse outcomes in offspring: genetic and environmental sources of covariance.

    PubMed

    Kuja-Halkola, Ralf; D'Onofrio, Brian M; Larsson, Henrik; Lichtenstein, Paul

    2014-09-01

    Maternal smoking during pregnancy (SDP) has been associated with several psychiatric outcomes in the offspring; studies have questioned whether the associations are causal, however. We analyzed all children born in Sweden between 1983 and 2009 to investigate the effect of SDP on multiple indicators of adverse outcomes in three areas: pregnancy outcomes (birth weight, preterm birth and being born small for gestational age), long-term cognitive abilities (low academic achievement and general cognitive ability) and externalizing behaviors (criminal conviction, violent criminal conviction and drug misuse). SDP was associated with all outcomes. Within-family analyses of the pregnancy outcomes were consistent with a causal interpretation as the associations persisted when siblings discordant for SDP were compared. For the cognitive and externalizing outcomes, the results were not consistent with causal effects; when comparing differentially exposed siblings none of the associations remained significant. In quantitative genetic models genetic factors explained the majority of the associations between SDP and cognitive and externalizing outcomes. The results suggest that the associations between SDP in mothers and cognition and externalizing behaviors in their offspring is primarily due to genetic effects that influence the behaviors in both generations.

  5. Predictors of failure of awake regional anesthesia for neonatal hernia repair: data from the General Anesthesia compared to Spinal anesthesia (GAS) study: comparing apnoea and neurodevelopmental outcomes

    PubMed Central

    Frawley, Geoff; Bell, Graham; Disma, Nicola; Withington, Davinia E.; de Graaff, Jurgen C.; Morton, Neil S.; McCann, Mary Ellen; Arnup, Sarah J.; Bagshaw, Oliver; Wolfler, Andrea; Bellinger, David; Davidson, Andrew J.

    2015-01-01

    Background Awake regional anesthesia (RA) is a viable alternative to general anesthesia (GA) for infants undergoing lower abdominal surgery. Benefits include lower incidence of postoperative apnea and avoidance of anesthetic agents that may increase neuroapoptosis and worsen neurocognitive outcomes. The General Anesthesia compared to Spinal anesthesia (GAS) study compares neurodevelopmental outcomes following awake RA or GA in otherwise healthy infants. Our aim was to describe success and failure rates of RA in this study and report factors associated with failure. Methods This was a nested cohort study within a prospective randomized, controlled, observer blind, equivalence trial. Seven hundred twenty two infants ≤ 60 weeks postmenstrual age, scheduled for herniorrhaphy under anesthesia were randomly assigned to receive RA (spinal, caudal epidural or combined spinal caudal anesthetic) or GA with sevoflurane. The data of 339 infants, where spinal or combined spinal caudal anesthetic was attempted, was analyzed. Possible predictors of failure were assessed including: patient factors, technique, experience of site and anesthetist and type of local anesthetic. Results RA was sufficient for the completion of surgery in 83.2% of patients. Spinal anesthesia was successful in 86.9% of cases and combined spinal caudal anesthetic in 76.1%. Thirty four patients required conversion to GA and an additional 23 (6.8%) required brief sedation. Bloody tap on the first attempt at lumbar puncture was the only risk factor significantly associated with block failure (OR = 2.46). Conclusions The failure rate of spinal anesthesia was low. Variability in application of combined spinal caudal anesthetic limited attempts to compare the success of this technique to spinal alone. PMID:26001028

  6. Fetal sex modifies effects of prenatal stress exposure and adverse birth outcomes.

    PubMed

    Wainstock, Tamar; Shoham-Vardi, Ilana; Glasser, Saralee; Anteby, Eyal; Lerner-Geva, Liat

    2015-01-01

    Prenatal maternal stress is associated with pregnancy complications, poor fetal development and poor birth outcomes. Fetal sex has also been shown to affect the course of pregnancy and its outcomes. The aim of this study was to evaluate whether fetal sex modifies the association between continuous exposure to life-threatening rocket attack alarms and adverse pregnancy outcomes. A retrospective cohort study was conducted in which the exposed group was comprised of 1846 women exposed to rocket-attack alarms before and during pregnancy. The unexposed group, with similar sociodemographic characteristics, delivered during the same period of time at the same medical center, but resided out of rocket-attack range. Multivariable models for each gender separately, controlling for possible confounders, evaluated the risk associated with exposure for preterm births (PTB), low birthweight (LBW), small for gestational age and small head circumference (HC). In both univariable and multivariable analyses exposure status was a significant risk factor in female fetuses only: PTB (adj. OR = 1.43; 1.04-1.96), LBW (adj. OR = 1.41; 1.02-1.95) and HC < 31 cm (adj. OR = 1.78; 1.11-2.88). In addition, regarding all adverse outcomes, the male-to-female ratio was higher in the exposed group than in the unexposed group. The findings support the hypothesis that male and female fetuses respond differentially to chronic maternal stress.

  7. Maternal Ethnic Ancestry and Adverse Perinatal Outcomes in New York City

    PubMed Central

    Stein, Cheryl R.; Savitz, David A.; Janevic, Teresa; Ananth, Cande V.; Kaufman, Jay S.; Herring, Amy H.; Engel, Stephanie M.

    2009-01-01

    Objective To examine the association between narrowly defined subsets of maternal ethnicity and birth outcomes. Study Design Analysis of 1995-2003 New York City birth certificates linked to hospital discharge data for 949,210 singleton births to examine the multivariable associations between maternal ethnicity and preterm birth, subsets of spontaneous and medically indicated preterm birth, term small for gestational age (SGA), and term birthweight. Results Compared to non-Hispanic whites, Puerto Ricans had an elevated odds ratio (OR 1.9, 95% CI 1.9-2.0) for delivering at 32-36 weeks (adjusted for nativity, maternal age, parity, education, tobacco use, pre-pregnancy weight, birth year). We found an excess of adverse outcomes among most Latino groups. Outcomes also varied within regions, with North African infants nearly 100g (adjusted) heavier than sub-Saharan Africans. Conclusions The considerable heterogeneity in risk of adverse perinatal outcomes is obscured in broad categorizations of maternal race/ethnicity, and may help to formulate etiologic hypotheses. PMID:19729145

  8. One-year neurodevelopmental outcome of very and late preterm infants: Risk factors and correlation with maternal stress.

    PubMed

    Coletti, Maria Franca; Caravale, Barbara; Gasparini, Corinna; Franco, Francesco; Campi, Francesca; Dotta, Andrea

    2015-05-01

    Although "late preterm" (LP) newborns (33-36 weeks of gestational age) represent more than 70% of all preterm labors, little is known about the relation between certain risk factors and developmental outcomes in LP compared to "very preterm" (≤32 weeks) children (VP). This study investigates: (1) LP and VP infants' development at 12 months of corrected age (CA) using the Bayley Scales of Infant Development - 3rd Edition (BSID-III); (2) correlation between BSID-III performances and maternal stress (using Parenting Stress Index-Short Form, PSI-SF) among LP and VP at 12 months CA; and (3) the link between known neonatal and demographic risk factors and developmental outcomes of LP and VP infants. For both LP and VP infants the Mean Cognitive (LP: 102.69±7.68; VP: 103.63±10.68), Language (LP: 96.23±10.08; VP: 99.10±10.37) and Motor (LP: 91.11±10.33; VP: 93.85±10.17) composite scores were in the normal range, without significant differences between the groups. Correlations between PSI-SF and BSID-III showed that in the VP group (but not LP), Language score was negatively related to the PSI-SF 'Difficult Child' scale (r=-.34, p<.05). Regression models revealed that cognitive performance was significantly predicted by physical therapy in LP and by cesarean section in VP infants. For VP only maternal education and length of stay predicted Language score, whereas physical therapy predicted Motor score. Results of the study underline the importance of considering cognitive, language and motor developments separately when assessing a preterm child's development. Prediction models of developmental performance confirm the influence of some known neonatal risk factors and indicate the need for further research on the role of sociodemographic risk factors.

  9. Parental drinking and adverse outcomes in children: A scoping review of cohort studies

    PubMed Central

    Felix, Lambert; Keating, Patrick; McCambridge, Jim

    2015-01-01

    Abstract Introduction and Aims There is a growing interest in measuring alcohol's harms to people other than the drinker themselves. ‘Children of alcoholics’ and foetal alcohol spectrum disorder have received widespread attention. Less is known about how children are affected by post‐natal exposure to parental drinking other than alcohol abuse/dependence. In this scoping review, we aim to assemble and map existing evidence from cohort studies on the consequences of parental alcohol use for children, and to identify limitations and gaps in this literature. Design and Methods Systematic review methods were used. Electronic databases were searched (1980 to October 2013) and a total of 3215 abstracts were screened, 326 full text papers examined and 99 eligible for inclusion according to selection criteria including separation of exposure and outcome measurement in time and report of a quantitative effect size. Results The main finding is the large literature available. Adolescent drinking behaviour was the most common outcome measure and outcomes other than substance use were rarely analysed. In almost two of every three published associations, parental drinking was found to be statistically significantly associated with a child harm outcome measure. Several limitations in the literature are noted regarding its potential to address a possible causal role of parental drinking in children's adverse outcomes. Discussion and Conclusions This study identifies targets for further study and provides a platform for more targeted analytic investigations which ascertain risk of bias, and which are capable of considering the appropriateness of causal inferences for the observed associations. [Rossow I, Felix L, Keating P, McCambridge J. Parental drinking and adverse outcomes in children: A scoping review of cohort studies. Drug Alcohol Rev 2016;35:397–405] PMID:26332090

  10. Acculturation and Adverse Birth Outcomes in a Predominantly Puerto Rican Population

    PubMed Central

    de Mendoza, Veronica Barcelona; Harville, Emily; Theall, Katherine; Buekens, Pierre; Chasan-Taber, Lisa

    2016-01-01

    Introduction Latinas in the United States on average have poorer birth outcomes than Whites, yet considerable heterogeneity exists within Latinas. Puerto Ricans have some of the highest rates of adverse outcomes and are understudied. The goal of this study was to determine if acculturation was associated with adverse birth outcomes in a predominantly Puerto Rican population. Methods We conducted a secondary analysis of Proyecto Buena Salud, a prospective cohort study conducted from 2006 to 2011. A convenience sample of pregnant Latina women were recruited from a tertiary care hospital in Massachusetts. Acculturation was measured in early pregnancy; directly via the Psychological Acculturation Scale, and via proxies of language preference and generation in the United States. Birth outcomes (gestational age and birthweight) were abstracted from medical records (n = 1362). Results After adjustment, psychological acculturation, language preference, and generation was not associated with odds of preterm birth. However, every unit increase in psychological acculturation score was associated with an increase in gestational age of 0.22 weeks (SE = 0.1, p = 0.04) among all births. Women who preferred to speak Spanish (β = −0.39, SE = 0.2, p = 0.02) and who were first generation in the US (β = −0.33, SE = 0.1, p = 0.02) had significantly lower gestational ages than women who preferred English or who were later generation, respectively. Similarly, women who were first generation had babies who weighed 76.11 g less (SE = 35.2, p = 0.03) than women who were later generation. Discussion We observed a small, but statistically significant adverse impact of low acculturation on gestational age and birthweight in this predominantly Puerto Rican population. PMID:26694041

  11. Vitamin D Deficiency Increases the Risk of Adverse Neonatal Outcomes in Gestational Diabetes

    PubMed Central

    Weinert, Letícia Schwerz; Reichelt, Angela Jacob; Schmitt, Leonardo Rauber; Boff, Roberta; Oppermann, Maria Lucia Rocha; Camargo, Joiza Lins; Silveiro, Sandra Pinho

    2016-01-01

    Background Gestational diabetes mellitus (GDM) and vitamin D deficiency have been associated with increased risk of adverse perinatal outcomes but the consequences of both conditions simultaneously present in pregnancy have not yet been evaluated. Our objective was to study the influence of vitamin D deficiency in neonatal outcomes of pregnancies with GDM. Methods 184 pregnant women with GDM referred to specialized prenatal monitoring were included in this cohort and had blood sampled for 25-hydroxyvitamin D measurement. Vitamin D was measured by chemiluminescence and deficiency was defined as < 20 ng/mL. Participants were followed until puerperium and adverse neonatal outcomes were evaluated. Results Newborns of women with vitamin D deficiency had higher incidences of hospitalization in intensive care units (ICU) (32 vs 19%, P = 0.048), of hypoglycemia (any, 17.3 vs 7.1%, P = 0.039requiring ICU, 15.3 vs 3.6%, P = 0.008), and were more frequently small for gestational age (SGA) (17.3 vs 5.9%, P = 0.017). After adjustment, relative risk (RR) for hypoglycemia requiring ICU was 3.63 (95%CI 1.09–12.11) and for SGA was 4.32 (95%CI 1.75–10.66). The incidence of prematurity, jaundice and shoulder dystocia was no statistically different between groups. Conclusions In this cohort of pregnant women with GDM, vitamin D deficiency was associated with a major increase in the incidence of adverse neonatal outcomes such as SGA newborns and neonatal hypoglycemia. PMID:27764194

  12. Associations between Anticholinergic Burden and Adverse Health Outcomes in Parkinson Disease

    PubMed Central

    Crispo, James A. G.; Willis, Allison W.; Thibault, Dylan P.; Fortin, Yannick; Hays, Harlen D.; McNair, Douglas S.; Bjerre, Lise M.; Kohen, Dafna E.; Perez-Lloret, Santiago; Mattison, Donald R.; Krewski, Daniel

    2016-01-01

    Background Elderly adults should avoid medications with anticholinergic effects since they may increase the risk of adverse events, including falls, delirium, and cognitive impairment. However, data on anticholinergic burden are limited in subpopulations, such as individuals with Parkinson disease (PD). The objective of this study was to determine whether anticholinergic burden was associated with adverse outcomes in a PD inpatient population. Methods Using the Cerner Health Facts® database, we retrospectively examined anticholinergic medication use, diagnoses, and hospital revisits within a cohort of 16,302 PD inpatients admitted to a Cerner hospital between 2000 and 2011. Anticholinergic burden was computed using the Anticholinergic Risk Scale (ARS). Primary outcomes were associations between ARS score and diagnosis of fracture and delirium. Secondary outcomes included associations between ARS score and 30-day hospital revisits. Results Many individuals (57.8%) were prescribed non-PD medications with moderate to very strong anticholinergic potential. Individuals with the greatest ARS score (≥4) were more likely to be diagnosed with fractures (adjusted odds ratio (AOR): 1.56, 95% CI: 1.29–1.88) and delirium (AOR: 1.61, 95% CI: 1.08–2.40) relative to those with no anticholinergic burden. Similarly, inpatients with the greatest ARS score were more likely to visit the emergency department (adjusted hazard ratio (AHR): 1.32, 95% CI: 1.10–1.58) and be readmitted (AHR: 1.16, 95% CI: 1.01–1.33) within 30-days of discharge. Conclusions We found a positive association between increased anticholinergic burden and adverse outcomes among individuals with PD. Additional pharmacovigilance studies are needed to better understand risks associated with anticholinergic medication use in PD. PMID:26939130

  13. Short term outcome and risk factors for adverse clinical outcomes in adults with severe acute respiratory syndrome (SARS)

    PubMed Central

    Chan, J; Ng, C; Chan, Y; Mok, T; Lee, S; Chu, S; Law, W; Lee, M; Li, P

    2003-01-01

    Background: Severe acute respiratory syndrome (SARS) was diagnosed in Hong Kong in over 1700 patients between March and early June 2003. Methods: 115 patients diagnosed with SARS were admitted to Queen Elizabeth Hospital, a large regional hospital in Hong Kong, from March 2003, of whom 100 were either discharged or were dead at 31 May. The patients were prospectively studied after admission to assess their short term outcomes and the risk factors associated with adverse outcomes, defined as death or the need for mechanical ventilation Results: At the time of writing 18 patients had died, with a crude mortality rate of 15.7% and a 21 day mortality of 10% (standard error 3%). Thirty nine patients (34%) were admitted to the intensive care unit, 30 of whom (26%) required mechanical ventilation. Multivariate analysis showed that age above 60 (hazards ratio (HR) 3.5, 95% CI 1.2 to 10.2; p=0.02), presence of diabetes mellitus or heart disease (HR 9.1, 95% CI 2.8 to 29.1; p<0.001), and the presence of other comorbid conditions (HR 5.2, 95% CI 1.4 to 19.7; p=0.01) were independently associated with mortality. However, only the presence of diabetes mellitus and/or cardiac disease (HR 7.3, 95% CI 3.1 to 17.4; p<0.001) was associated with adverse outcomes as a whole. Conclusion: SARS is a new disease entity that carries significant morbidity and mortality. Specific clinical and laboratory parameters predicting unfavourable outcomes have been identified. PMID:12885985

  14. B-type natriuretic peptide and cardiac troponin I are associated with adverse outcomes in stable kidney transplant recipients

    Technology Transfer Automated Retrieval System (TEKTRAN)

    BACKGROUND: Approximately 200 000 kidney transplant recipients are living in the United States; they are at increased risk for cardiovascular and other adverse outcomes. Biomarkers predicting these outcomes are needed. Using specimens collected during the Folic Acid for Vascular Outcome Reduction in...

  15. Television viewing associated with adverse dietary outcomes in children ages 2-6.

    PubMed

    Ford, C; Ward, D; White, M

    2012-12-01

    The aim of this paper was to systematically review the evidence for the association between television viewing and diet in children ages 2-6. Data sources included PubMed, PsycINFO, EMBASE, ERIC, SportDISCUS, Sociological Abstracts, Web of Science and hand searches of reference lists of relevant articles. Twelve studies were reviewed in which the relationship between television viewing and diet was assessed in children between the ages of 2 and 6. All but one study reported significant relationship between television viewing time and adverse dietary outcomes. Parent-reported television viewing time was used to assay child television viewing in all included studies. Food frequency survey was the most frequent method of dietary assessment, and parent served as proxies for children in all studies. Lower fruit and/or vegetable intake was the most frequently reported dietary outcome, followed by increased energy intake with increased television viewing. The majority of studies reported adverse dietary outcomes with as little as 1 h of daily television exposure. While these results are consistent with recommendations from child health advocates to limit television viewing in young children, they also suggest that further efforts to limit television viewing in young children may be needed to aid in obesity prevention.

  16. ACE: Health - Neurodevelopmental Disorders

    EPA Pesticide Factsheets

    Information about children reported to have ever been diagnosed with four different neurodevelopmental disorders: attention-deficit/hyperactivity disorder (ADHD), learning disabilities, autism, and intellectual disability.

  17. Systems Toxicology of Male Reproductive Development: Profiling 774 Chemicals for Molecular Targets and Adverse Outcomes

    PubMed Central

    Leung, Maxwell C.K.; Phuong, Jimmy; Baker, Nancy C.; Sipes, Nisha S.; Klinefelter, Gary R.; Martin, Matthew T.; McLaurin, Keith W.; Setzer, R. Woodrow; Darney, Sally Perreault; Judson, Richard S.; Knudsen, Thomas B.

    2015-01-01

    Background: Trends in male reproductive health have been reported for increased rates of testicular germ cell tumors, low semen quality, cryptorchidism, and hypospadias, which have been associated with prenatal environmental chemical exposure based on human and animal studies. Objective: In the present study we aimed to identify significant correlations between environmental chemicals, molecular targets, and adverse outcomes across a broad chemical landscape with emphasis on developmental toxicity of the male reproductive system. Methods: We used U.S. EPA’s animal study database (ToxRefDB) and a comprehensive literature analysis to identify 774 chemicals that have been evaluated for adverse effects on male reproductive parameters, and then used U.S. EPA’s in vitro high-throughput screening (HTS) database (ToxCastDB) to profile their bioactivity across approximately 800 molecular and cellular features. Results: A phenotypic hierarchy of testicular atrophy, sperm effects, tumors, and malformations, a composite resembling the human testicular dysgenesis syndrome (TDS) hypothesis, was observed in 281 chemicals. A subset of 54 chemicals with male developmental consequences had in vitro bioactivity on molecular targets that could be condensed into 156 gene annotations in a bipartite network. Conclusion: Computational modeling of available in vivo and in vitro data for chemicals that produce adverse effects on male reproductive end points revealed a phenotypic hierarchy across animal studies consistent with the human TDS hypothesis. We confirmed the known role of estrogen and androgen signaling pathways in rodent TDS, and importantly, broadened the list of molecular targets to include retinoic acid signaling, vascular remodeling proteins, G-protein coupled receptors (GPCRs), and cytochrome P450s. Citation: Leung MC, Phuong J, Baker NC, Sipes NS, Klinefelter GR, Martin MT, McLaurin KW, Setzer RW, Darney SP, Judson RS, Knudsen TB. 2016. Systems toxicology of male

  18. Adverse inpatient outcomes during the transition to a new electronic health record system: observational study

    PubMed Central

    Barnett, Michael L; Mehrotra, Ateev

    2016-01-01

    Objective To assess the short term association of inpatient implementation of electronic health records (EHRs) with patient outcomes of mortality, readmissions, and adverse safety events. Design Observational study with difference-in-differences analysis. Setting Medicare, 2011-12. Participants Patients admitted to 17 study hospitals with a verifiable “go live” date for implementation of inpatient EHRs during 2011-12, and 399 control hospitals in the same hospital referral region. Main outcome measures All cause readmission within 30 days of discharge, all cause mortality within 30 days of admission, and adverse safety events as defined by the patient safety for selected indicators (PSI)-90 composite measure among Medicare beneficiaries admitted to one of these hospitals 90 days before and 90 days after implementation of the EHRs (n=28 235 and 26 453 admissions), compared with the control group of all contemporaneous admissions to hospitals in the same hospital referral region (n=284 632 and 276 513 admissions). Analyses were adjusted for beneficiaries’ sociodemographic and clinical characteristics. Results Before and after implementation, characteristics of admissions were similar in both study and control hospitals. Among study hospitals, unadjusted 30 day mortality (6.74% to 7.15%, P=0.06) and adverse safety event rates (10.5 to 11.4 events per 1000 admissions, P=0.34) did not significantly change after implementation of EHRs. There was an unadjusted decrease in 30 day readmission rates, from 19.9% to 19.0% post-implementation (P=0.02). In difference-in-differences analysis, however, there was no significant change in any outcome between pre-implementation and post-implementation periods (all P≥0.13). Conclusions Despite concerns that implementation of EHRs might adversely impact patient care during the acute transition period, we found no overall negative association of such implementation on short term inpatient mortality, adverse safety

  19. Longitudinal changes in neurodevelopmental outcomes between 18 and 36 months in children with prenatal triptan exposure: findings from the Norwegian Mother and Child Cohort Study

    PubMed Central

    Wood, Mollie E; Frazier, Jean A; Nordeng, Hedvig M E; Lapane, Kate L

    2016-01-01

    Objective This study sought to determine whether changes in neurodevelopmental outcomes between 18 and 36 months of age were associated with prenatal exposure to triptan medications, a class of 5-HT receptor agonists used in the treatment of migraine. Method Using data from the Norwegian Mother and Child Cohort Study, a prospective birth cohort that includes nearly 40% of all pregnancies in Norway from 1999 to 2008, we identified 50 469 mother–child dyads who met inclusion criteria and were present for at least one follow-up assessment at 18 or 36 months postpartum. Neurodevelopment was assessed using the Child Behaviour Checklist, the Emotionality, Activity, and Shyness Questionnaire, and the Ages and Stages Questionnaire. We used generalised estimating equations to evaluate change from 18 to 36 months for children prenatally exposed to triptans, relative to contrast groups, and used marginal structural models with inverse probability of treatment and censoring weights to address time-varying exposure and confounding as well as loss to follow-up. Results Among eligible participants (n=50 469), 1.0% used a triptan during pregnancy, 2.0% used triptans prior to pregnancy only, 8.0% reported migraine without triptan use and 89.0% had no history of migraine. Children with prenatal triptan exposure had greater increases in emotionality (r-RR 2.18, 95% CI 1.03 to 4.53) and activity problems (r-RR 1.70, 95% CI 1.02 to 2.8) compared to children born to mothers who discontinued triptan use prior to pregnancy. Conclusion Prenatal triptan exposure was associated with changes over time in externalising-type behaviours such as emotionality and activity, but not with internalising-type behaviours. PMID:27625061

  20. Effect of RAAS blockers on adverse clinical outcomes in high CVD risk subjects with atrial fibrillation

    PubMed Central

    Chaugai, Sandip; Sherpa, Lhamo Yanchang; Sepehry, Amir A.; Arima, Hisatomi; Wang, Dao Wen

    2016-01-01

    Abstract Recent studies have demonstrated that atrial fibrillation significantly increases the risk of adverse clinical outcomes in high cardiovascular disease risk subjects. Application of renin–angiotensin–aldosterone system blockers for prevention of recurrence of atrial fibrillation and adverse clinical outcomes in subjects with atrial fibrillation is a theoretically appealing concept. However, results of clinical trials evaluating the effect of renin–angiotensin–aldosterone blockers on adverse clinical outcomes in high cardiovascular disease risk subjects with atrial fibrillation remain inconclusive. A pooled study of 6 randomized controlled trials assessing the efficacy of renin–angiotensin–aldosterone blockers on subjects with atrial fibrillation was performed. A total of 6 randomized controlled trials enrolled a total of 53,510 patients followed for 1 to 5 years. RAAS blockade therapy was associated with 14% reduction in the incidence of heart failure (OR: 0.86, [95%CI: 0.76– 0.97], P=0.018) and 17% reduction in the incidence of CVE (OR: 0.83, [95%CI: 0.70–0.99], P = 0.038). The corresponding decline in absolute risk against heart failure (ARR: 1.4%, [95%CI: 0.2–2.6%], P = 0.018) and CVE (ARR: 3.5%, [95%CI: 0.0–6.9%], P = 0.045) in the AF group was much higher than the non-AF group for heart failure (ARR: 0.4%, [95%CI: 0.0–0.7%], P = 0.057) and CVE (ARR: 1.6%, [95%CI: –0.1% to 3.3%], P = 0.071). No significant effect was noted on all-cause or cardiovascular mortality, stroke, or myocardial infarction. This study suggests that RAAS blockade offers protection against heart failure and cardiovascular events in high cardiovascular disease risk subjects with atrial fibrillation. PMID:27368043

  1. Defining and Modeling Known Adverse Outcome Pathways: Domoic Acid and Neuronal Signaling as a Case Study

    SciTech Connect

    Watanabe, Karen H.; Andersen, Melvin E.; Basu, Nil; Carvan, Michael J.; Crofton, Kevin M.; King, Kerensa A.; Sunol, Cristina; Tiffany-Castiglioni, Evelyn; Schultz, Irvin R.

    2011-01-01

    An adverse outcome pathway (AOP) is a sequence of key events from a molecular-level initiating event and an ensuing cascade of steps to an adverse outcome with population level significance. To implement a predictive strategy for ecotoxicology, the multiscale nature of an AOP requires computational models to link salient processes (e.g., in chemical uptake, toxicokinetics, toxicodynamics, and population dynamics). A case study with domoic acid was used to demonstrate strategies and enable generic recommendations for developing computational models in an effort to move toward a toxicity testing paradigm focused on toxicity pathway perturbations applicable to ecological risk assessment. Domoic acid, an algal toxin with adverse effects on both wildlife and humans, is a potent agonist for kainate receptors (ionotropic glutamate receptors whose activation leads to the influx of Na+ and Ca2+). Increased Ca2+ concentrations result in neuronal excitotoxicity and cell death primarily in the hippocampus, which produces seizures, impairs learning and memory, and alters behavior in some species. Altered neuronal Ca2+ is a key process in domoic acid toxicity which can be evaluated in vitro. Further, results of these assays would be amenable to mechanistic modeling for identifying domoic acid concentrations and Ca2+ perturbations that are normal, adaptive, or clearly toxic. In vitro assays with outputs amenable to measurement in exposed populations can link in vitro to in vivo conditions, and toxicokinetic information will aid in linking in vitro results to the individual organism. Development of an AOP required an iterative process with three important outcomes: (1) a critically reviewed, stressor-specific AOP; (2) identification of key processes suitable for evaluation with in vitro assays; and (3) strategies for model development.

  2. Blood rheology at term in normal pregnancy and in patients with adverse outcome events.

    PubMed

    von Tempelhoff, Georg-Friedrich; Velten, Eva; Yilmaz, Asli; Hommel, Gerhard; Heilmann, Lothar; Koscielny, Jürgen

    2009-01-01

    Plasma volume expansion of more than 1.5 l and sustainable activation of the hemostatic system that results in a steady rise of the fibrinogen/fibrin turnover are contemporary physiological events during normal pregnancy. In contrast, adverse outcome of pregnancy i.e. pre-eclampsia commonly coincide with hemo concentration and over activation of blood coagulation both of which alter blood rheology. On the basis of 4,985 consecutively recorded singleton pregnancies values range of blood rheological parameters in women with normal and complicated outcome of pregnancy at the time of their delivery were compared. Plasma viscosity (pv) was determined using KSPV 1 Fresenius and RBC aggregation (stasis: E0 and low shear: E1) using MA1-Aggregometer; Myrenne. Seventy-nine point four percent (n=3,959) had normal pregnancy outcome and 1,026 with adverse outcome of pregnancy had pre-eclampsia (8.4%; n=423), had newborn with a birth-weight < 2,500 g (9.5%; n=473), had early-birth before week 37 (9.3%; n=464), and/or were diagnosed with intra uterine growth retardation (IUGR) (5.0%; n=250). In women with normal pregnancy outcome mean (+/-SD) of pv was 1.31+/-0.09 mPa s, of E0 was 21.6+/-5.3, and of E1 was 38.4+/-7.9 while in women with adverse outcome means for rheological parameters were statistically significantly different i.e. pv: 1.32+/-0.08 mPa s; p=0.006, E0: 22.1+/-5.5; p=0.002 and E1: 39.5+/-8.5; p=0.0006. Subgroup analysis revealed statistical significant lower pv in women who either had pre term delivery or a low birth-weight child (p<0.005) as compared to women who had normal pregnancy outcome while patients with pre-eclampsia had markedly higher low shear and stasis RBC aggregation (p<0.0001). None of the rheological results at term were correlated with either maternal age (r<0.04), BMI (r<0.09), maternal weight gain until delivery (r<0.04), or fetal outcome such as APGAR-score (r<0.09) art. pH in the umbilical cord (-0.05

  3. Merging Adverse Outcome Pathway (AOP) and Mode of Action (MOA) Frameworks: Assembling Knowledge for Use in Risk Assessment

    EPA Science Inventory

    The Adverse Outcome Pathway has emerged as an internationally harmonized mechanism for organizing biological information in a chemical agnostic manner. This construct is valuable for interpreting the results from high-throughput toxicity (HTT) assessment by providing a mechanisti...

  4. Conceptual Model for Assessing Criteria Air Pollutants in a Multipollutant Context: A Modified Adverse Outcome Pathway Approach

    EPA Science Inventory

    Background: Air pollution consists of a complex mixture of particulate and gaseous components. Individual criteria and other hazardous air pollutants have been linked to adverse respiratory and cardiovascular health outcomes. However, assessing risk of air pollutant mixtures is d...

  5. Use of the adverse outcome pathway framework to represent cross-species consequences of specific pathway perturbations

    EPA Science Inventory

    The adverse outcome pathway (AOP) framework has been developed as a means for assembling scientifically defensible descriptions of how particular molecular perturbations, termed molecular initiating events (MIEs), can evoke a set of predictable responses at different levels of bi...

  6. Maternal Snoring May Predict Adverse Pregnancy Outcomes: A Cohort Study in China

    PubMed Central

    Ge, Xing; Tao, Fangbiao

    2016-01-01

    Objective To examine the prevalence of snoring during pregnancy and its effects on key pregnancy outcomes. Methods Pregnant women were consecutively recruited in their first trimester. Habitual snoring was screened by using a questionnaire in the 1st and 3rd trimester, respectively. According to the time of snoring, participants were divided into pregnancy onset snorers, chronic snorers and non-snorers. Logistic regressions were performed to examine the associations between snoring and pregnancy outcomes. Results Of 3 079 pregnant women, 16.6% were habitual snorers, with 11.7% were pregnancy onset snorers and 4.9% were chronic snorers. After adjusting for potential confounders, chronic snorers were independently associated with gestational diabetes mellitus (GDM) (RR 1.66, 95%CI 1.09–2.53). Both pregnancy onset and chronic snorers were independently associated with placental adhesion (RR 1.96, 95%CI 1.17–3.27, and RR 2.33, 95%CI 1.22–4.46, respectively). Pregnancy onset snorers were at higher risk of caesarean delivery (RR 1.37, 95%CI 1.09–1.73) and having macrosomia (RR 1.54, 95%CI 1.05–2.27) and large for gestational age (LGA) (RR 1.71, 95%CI 1.31–2.24) infants. In addition, being overweight or obese before pregnancy plays an important role in mediating snoring and adverse pregnancy outcomes. Conclusions Maternal snoring may increase the risk of adverse pregnancy outcomes, and being overweight or obese before pregnancy with snoring is remarkable for researchers. Further studies are still needed to confirm our results. PMID:26871434

  7. Generation of computationally predicted Adverse Outcome Pathway networks through integration of publicly available in vivo, in vitro, phenotype, and biological pathway data.

    EPA Science Inventory

    The Adverse Outcome Pathway (AOP) framework is becoming a widely used tool for organizing and summarizing the mechanistic information connecting molecular perturbations by environmental stressors with adverse ecological and human health outcomes. However, the conventional process...

  8. Systems Toxicology of Male Reproductive Development: Profiling 774 Chemicals for Molecular Targets and Adverse Outcomes

    EPA Pesticide Factsheets

    Background: Trends in male reproductive health have been reported for increased rates of testicular germ cell tumors, low semen quality, cryptorchidism, and hypospadias, which have been associated with prenatal environmental chemical exposure based on human and animal studies.Objective: In the present study we aimed to identify significant correlations between environmental chemicals, molecular targets, and adverse outcomes across a broad chemical landscape with emphasis on developmental toxicity of the male reproductive system.Methods: We used U.S. EPA??s animal study database (ToxRefDB) and a comprehensive literature analysis to identify 774 chemicals that have been evaluated for adverse effects on male reproductive parameters, and then used U.S. EPA??s in vitro high-throughput screening (HTS) database (ToxCastDB) to profile their bioactivity across approximately 800 molecular and cellular features. Results: A phenotypic hierarchy of testicular atrophy, sperm effects, tumors, and malformations, a composite resembling the human testicular dysgenesis syndrome (TDS) hypothesis, was observed in 281 chemicals. A subset of 54 chemicals with male developmental consequences had in vitro bioactivity on molecular targets that could be condensed into 156 gene annotations in a bipartite network. Conclusion: Computational modeling of available in vivo and in vitro data for chemicals that produce adverse effects on male reproductive end points revealed a phenotypic hierarch

  9. Photoselective vaporization of the prostate: outcomes and adverse events of 220 consecutive patients

    NASA Astrophysics Data System (ADS)

    Robson, C.; Mueller, E. J.

    2010-02-01

    Purpose: To evaluate the short term outcomes of 220 consecutive patients who underwent the 532 nm KTP photoselective vaporization of the prostate (PVP) procedure and to evaluate and categorize the complications of the procedure. Materials and Methods: A total of 220 patients with symptomatic benign prostatic obstruction were treated with KTP photoselective vaporization of the prostate. Evaluation measures included the AUA Symptom Score (AUASS)/Quality of Life Score (QOL), peak urinary flow rate (Qmax), post void residual urine (PVR) and adverse events. Results: Symptoms were evaluated at 3 months and adverse events at 1 and 3 months. 181 patients returned for their 1 month visit and 152 returned for their 3 month visit. The American Urological Association Symptom Score (AUASS) decreased from 21.8 to 6.7. The Quality of Life Score (QOL) decreased from 3.8 to 0.7. The peak urinary flow rate (Qmax) increased from 10.7 cc/sec to 22.7 cc/sec. And the post void residual urine (PVR) decreased from 262 cc to 105 cc. Most common adverse events lasting more than 10 days were mild hematuria in 45%, dysuria in 32%, and urgency/frequency in31%. Conclusion: These results confirm that photoselective vaporization of the prostate (PVP) is a safe and effective therapy for benign prostatic obstruction. However, there is frequent, but mild, hematuria and irritative voiding symptoms during the early postoperative period.

  10. Common Sleep Disorders Increase Risk of Motor Vehicle Crashes and Adverse Health Outcomes in Firefighters

    PubMed Central

    Barger, Laura K.; Rajaratnam, Shantha M.W.; Wang, Wei; O'Brien, Conor S.; Sullivan, Jason P.; Qadri, Salim; Lockley, Steven W.; Czeisler, Charles A.

    2015-01-01

    Study Objectives: Heart attacks and motor vehicle crashes are the leading causes of death in US firefighters. Given that sleep disorders are an independent risk factor for both of these, we examined the prevalence of common sleep disorders in a national sample of firefighters and their association with adverse health and safety outcomes. Methods: Firefighters (n = 6,933) from 66 US fire departments were assessed for common sleep disorders using validated screening tools, as available. Firefighters were also surveyed about health and safety, and documentation was collected for reported motor vehicle crashes. Results: A total of 37.2% of firefighters screened positive for any sleep disorder including obstructive sleep apnea (OSA), 28.4%; insomnia, 6.0%; shift work disorder, 9.1%; and restless legs syndrome, 3.4%. Compared with those who did not screen positive, firefighters who screened positive for a sleep disorder were more likely to report a motor vehicle crash (adjusted odds ratio 2.00, 95% CI 1.29–3.12, p = 0.0021) and were more likely to self-report falling asleep while driving (2.41, 2.06–2.82, p < 0.0001). Firefighters who screened positive for a sleep disorder were more likely to report having cardiovascular disease (2.37, 1.54–3.66, p < 0.0001), diabetes (1.91, 1.31–2.81, p = 0.0009), depression (3.10, 2.49–3.85, p < 0.0001), and anxiety (3.81, 2.87–5.05, p < 0.0001), and to report poorer health status (p < 0.0001) than those who did not screen positive. Adverse health and safety associations persisted when OSA and non-OSA sleep disorders were examined separately. Conclusions: Sleep disorders are prevalent in firefighters and are associated with increased risk of adverse health and safety outcomes. Future research is needed to assess the efficacy of occupational sleep disorders prevention, screening, and treatment programs in fire departments to reduce these safety and health risks. Citation: Barger LK, Rajaratnam SM, Wang W, O'Brien CS

  11. Preventive Effects of Folic Acid Supplementation on Adverse Maternal and Fetal Outcomes

    PubMed Central

    Kim, Min Woo; Ahn, Ki Hoon; Ryu, Ki-Jin; Hong, Soon-Cheol; Lee, Ji Sung; Nava-Ocampo, Alejandro A.; Oh, Min-Jeong; Kim, Hai-Joong

    2014-01-01

    Although there is accumulating evidence regarding the additional protective effect of folic acid against adverse pregnancy outcomes other than neural tube defects, these effects have not been elucidated in detail. We evaluated whether folic acid supplementation is associated with favorable maternal and fetal outcomes. This was a secondary analysis of 215 pregnant women who were enrolled in our prior study. With additional data from telephone interviews regarding prenatal folic acid supplementation, existing demographic, maternal and fetal data were statistically analyzed. The concentration of folic acid in maternal blood was significantly higher following folic acid supplementation (24.6 ng/mL vs.11.8 ng/mL). In contrast, homocysteine level in maternal blood decreased with folic acid supplementation (5.5 µmol/mL vs. 6.8 µmol/mL). The rates of both preeclampsia (odds ratio [OR], 0.27; 95% confidence interval [CI], 0.09–0.76) and small for gestational age (SGA; 9.2% vs. 20.0%; OR, 0.42; 95% CI, 0.18–0.99) were lower in the folic acid supplementation group than those in the control group. Other pregnancy outcomes had no association with folic acid supplementation. The findings indicate that folic acid supplementation may help to prevent preeclampsia and SGA. Further studies are warranted to elucidate the favorable effects of folic acid supplementation on pregnancy outcomes. PMID:24842467

  12. Infertility, Pregnancy Loss and Adverse Birth Outcomes in Relation to Maternal Secondhand Tobacco Smoke Exposure

    PubMed Central

    Meeker, John D.; Benedict, Merle D.

    2013-01-01

    A substantial proportion of the etiology involved in female infertility and adverse pregnancy outcomes remains idiopathic. Recent scientific research has suggested a role for environmental factors in these conditions. Secondhand tobacco smoke (STS) contains a number of known or suspected reproductive toxins, and human exposure to STS is prevalent worldwide. Robust evidence exists for the toxic effects of active smoking on fertility and pregnancy, but studies of passive exposure are much more limited in number. While the association between maternal STS exposure and declined birth weight has been fairly well-documented, only recently have epidemiologic studies begun to provide suggestive evidence for delayed conception, altered menstrual cycling, early pregnancy loss (e.g. spontaneous abortion), preterm delivery, and congenital malformations in relation to STS exposure. There is also new evidence that developmental exposures to tobacco smoke may be associated with reproductive effects in adulthood. To date, most studies have estimated maternal STS exposure through self-report even though exposure biomarkers are less prone to error and recall bias. In addition to utilizing biomarkers of STS exposure, future studies should aim to identify vital windows of STS exposure, important environmental co-exposures, individual susceptibility factors, and specific STS constituents associated with female infertility and adverse pregnancy outcomes. The role of paternal exposures/factors should also be investigated. PMID:23888128

  13. From pathways to people: applying the adverse outcome pathway (AOP) for skin sensitization to risk assessment.

    PubMed

    MacKay, Cameron; Davies, Michael; Summerfield, Vicki; Maxwell, Gavin

    2013-01-01

    Consumer safety risk assessment of skin sensitization requires information on both consumer exposure to the ingredient through product use and the hazardous properties of the ingredient. Significant progress has been made in determining the hazard potential of ingredients without animal testing. However, hazard identification is insufficient for risk assessment, and an understanding of the dose-response is needed. Obtaining such knowledge without animal testing is challenging and requires applying available mechanistic knowledge to both assay development and the integration of these data. The recent OECD report "The Adverse Outcome Pathway for Skin Sensitization Initiated by Covalent Binding to Proteins" presents the available mechanistic knowledge of the sensitization response within an adverse outcome pathway (AOP). We propose to use this AOP as the mechanistic basis for physiologically- and mechanistically-based toxicokinetic-toxicodynamic models of the sensitization response. The approach would be informed by non-animal data, provide predictions of the dose-response required for risk assessment, and would be evaluated against human clinical data.

  14. The adverse outcome pathway (AOP) for chemical binding to tubulin in oocytes leading to aneuploid offspring.

    PubMed

    Marchetti, Francesco; Massarotti, Alberto; Yauk, Carole L; Pacchierotti, Francesca; Russo, Antonella

    2016-03-01

    The Organisation for Economic Co-operation and Development (OECD) has launched the Adverse Outcome Pathway (AOP) Programme to advance knowledge of pathways of toxicity and improve the use of mechanistic information in risk assessment. An AOP links a molecular initiating event (MIE) to an adverse outcome (AO) through intermediate key events (KE). Here, we present the scientific evidence in support of an AOP whereby chemicals that bind to tubulin cause microtubule depolymerization resulting in spindle disorganization followed by altered chromosome alignment and segregation and the generation of aneuploidy in female germ cells, ultimately leading to aneuploidy in the offspring. Aneuploidy, an abnormal number of chromosomes that is not an exact multiple of the haploid number, is a well-known cause of human disease and represents a major cause of infertility, pregnancy failure, and serious genetic disorders in the offspring. Among chemicals that induce aneuploidy in female germ cells, a large majority impairs microtubule dynamics and spindle function. Colchicine, a prototypical chemical that binds to tubulin and causes microtubule depolymerization, is used here to illustrate the AOP. This AOP is specific to female germ cells exposed during the periovulation period. Although the majority of the data come from rodent studies, the available evidence suggests that the MIE and KEs are conserved across species and would occur in human oocytes. The development of AOPs related to mutagenicity in germ cells is expected to aid the identification of potential hazards to germ cell genomic integrity and support regulatory efforts to protect population health.

  15. Adverse Outcome Pathways-Organizing Toxicological Information to Improve Decision Making.

    PubMed

    Edwards, Stephen W; Tan, Yu-Mei; Villeneuve, Daniel L; Meek, M E; McQueen, Charlene A

    2016-01-01

    The number of chemicals for which environmental regulatory decisions are required far exceeds the current capacity for toxicity testing. High-throughput screening commonly used for drug discovery has the potential to increase this capacity. The adverse outcome pathway (AOP) concept has emerged as a framework for connecting high-throughput toxicity testing (HTT) and other results to potential impacts on human and wildlife populations. As a result of international efforts, the AOP development process is now well-defined and efforts are underway to broaden the participation through outreach and training. One key principle is that AOPs represent the chemical-agnostic portions of pathways to increase the generalizability of their application from early key events to overt toxicity. The closely related mode of action framework extends the AOP as needed when evaluating the potential risk of a specific chemical. This in turn enables integrated approaches to testing and assessment (IATA), which incorporate results of assays at various levels of biologic organization such as in silico; HTT; chemical-specific aspects including absorption, distribution, metabolism, and excretion (ADME); and an AOP describing the biologic basis of toxicity. Thus, it is envisaged that provision of limited information regarding both the AOP for critical effects and the ADME for any chemical associated with any adverse outcome would allow for the development of IATA and permit more detailed AOP and ADME research, where higher precision is needed based on the decision context.

  16. Common variants of the vitamin D binding protein gene and adverse health outcomes

    PubMed Central

    Malik, Suneil; Fu, Lei; Juras, David James; Karmali, Mohamed; Wong, Betty Y. L.; Gozdzik, Agnes

    2013-01-01

    The vitamin D binding protein (DBP) is the major plasma carrier for vitamin D and its metabolites, but it is also an actin scavenger, and is the precursor to the immunomodulatory protein, Gc-MAF. Two missense variants of the DBP gene – rs7041 encoding Asp432Glu and rs4588 encoding Thr436Lys – change the amino acid sequence and alter the protein function. They are common enough to generate population-wide constitutive differences in vitamin D status, based on assay of the serum metabolite, 25-hydroxyvitamin D (25OHD). Whether these variants also influence the role of vitamin D in an immunologic milieu is not known. However, the issue is relevant, given the immunomodulatory effects of DBP and the role of protracted innate immune-related inflammation in response to tissue injury or repeated infection. Indeed, DBP and vitamin D may jointly or independently contribute to a variety of adverse health outcomes unrelated to classical notions of their function in bone and mineral metabolism. This review summarizes the reports to date of associations between DBP variants, and various chronic and infectious diseases. The available information leads us to conclude that DBP variants are a significant and common genetic factor in some common disorders, and therefore, are worthy of closer attention. In view of the heightened interest in vitamin D as a public health target, well-designed studies that look simultaneously at vitamin D and its carrier in relation to genotypes and adverse health outcome should be encouraged. PMID:23427793

  17. Applying Adverse Outcome Pathways (AOPs) to support Integrated Approaches to Testing and Assessment (IATA).

    PubMed

    Tollefsen, Knut Erik; Scholz, Stefan; Cronin, Mark T; Edwards, Stephen W; de Knecht, Joop; Crofton, Kevin; Garcia-Reyero, Natalia; Hartung, Thomas; Worth, Andrew; Patlewicz, Grace

    2014-12-01

    Chemical regulation is challenged by the large number of chemicals requiring assessment for potential human health and environmental impacts. Current approaches are too resource intensive in terms of time, money and animal use to evaluate all chemicals under development or already on the market. The need for timely and robust decision making demands that regulatory toxicity testing becomes more cost-effective and efficient. One way to realize this goal is by being more strategic in directing testing resources; focusing on chemicals of highest concern, limiting testing to the most probable hazards, or targeting the most vulnerable species. Hypothesis driven Integrated Approaches to Testing and Assessment (IATA) have been proposed as practical solutions to such strategic testing. In parallel, the development of the Adverse Outcome Pathway (AOP) framework, which provides information on the causal links between a molecular initiating event (MIE), intermediate key events (KEs) and an adverse outcome (AO) of regulatory concern, offers the biological context to facilitate development of IATA for regulatory decision making. This manuscript summarizes discussions at the Workshop entitled "Advancing AOPs for Integrated Toxicology and Regulatory Applications" with particular focus on the role AOPs play in informing the development of IATA for different regulatory purposes.

  18. Adverse Childhood Experiences and Adult Health Outcomes Among Veteran and Non-Veteran Women

    PubMed Central

    Blosnich, John R.; Dichter, Melissa E.

    2015-01-01

    Abstract Background: Women veterans represent a vulnerable population with unique health needs and disparities in access to care. One constellation of exposures related to subsequent poor health includes adverse childhood experiences (ACEs; e.g., physical and sexual child abuse), though research on impacts of ACEs among women veterans is limited. Methods: Data were drawn from the 2010 Behavioral Risk Factor Surveillance System for the 11 states that included the ACE module (n=36,485). Weighted chi-squared tests and multivariable logistic regression were used to assess the prevalence of ACEs among women veterans compared with women non-veterans and differences in the following outcomes, controlling for ACEs: social support, inadequate sleep, life satisfaction, mental distress, smoking, heavy alcohol use, obesity, diabetes, cardiovascular disease symptoms, asthma, and disability. Results: Women veterans (1.6% of the total sample) reported a higher prevalence of 7 out of 11 childhood adversities and higher mean ACE score than women non-veterans. Women veterans were more likely to be current smokers and report a disability, associations which were attenuated when controlling for ACE. Conclusions: Despite women veterans' higher prevalence of ACE, their health outcomes did not differ substantially from non-veterans. Further research is needed to understand the intersections of traumatic experiences and sources of resilience over the lifecourse among women veterans. PMID:26390379

  19. Time-Dependent Effects in Algae for Chemicals with Different Adverse Outcome Pathways: A Novel Approach.

    PubMed

    Vogs, Carolina; Altenburger, Rolf

    2016-07-19

    Chemicals affect unicellular algae as a result of toxicokinetic and toxicodynamic processes. The internal concentration of chemicals in algae cells typically reaches equilibrium within minutes, while damage cumulatively increases over hours. The time gap between the steady state of internal exposure and damage development is thus suspected to span up to hours, mainly due to toxicodynamic processes. The quantification of rate-limited toxicodynamic processes, aggregated as a progressive effect from an initiating molecular event through biological key events toward the adverse outcome on algae growth inhibition, might discriminate between different adverse outcome pathways (AOPs). To support our hypothesis, we selected six chemicals according to different physicochemical properties and three distinctly dissimilar AOPs. The time courses of internal concentrations were linked to the observed affected Scenedesmus vacuolatus growth using toxicokinetic-toxicodynamic modeling. Effects on cell growth were explained by effect progression and not by the time to reach internal equilibrium concentration. Effect progression rates ranged over 6 orders of magnitude for all chemicals but varied by less than 1 order of magnitude within similar AOP (photosystem II inhibitors > reactive chemicals > lipid biosynthesis inhibitors), meaning that inhibitors of photosystem II advance an effect toward algae growth fastest compared to reactive chemicals and inhibitors of lipid biosynthesis.

  20. Adverse pregnancy outcome in women exposed to acyclovir during pregnancy: a population-based observational study.

    PubMed

    Ratanajamit, Chaveewan; Vinther Skriver, Mette; Jepsen, Peter; Chongsuvivatwong, Virasakdi; Olsen, Jørn; Sørensen, Henrik Toft

    2003-01-01

    This study aimed to examine the risk of adverse pregnancy outcomes in children born to mothers who redeemed a prescription for systemic or topical acyclovir during pregnancy. Data on prescriptions of acyclovir were obtained from the Danish North Jutland Prescription Database and data on pregnancy outcomes from the Danish Medical Birth Registry and the County Hospital Discharge Registry. The risk of malformations, low birth weight, preterm birth and stillbirth in users of acyclovir were compared with non-exposed women using a follow-up design, while the risk of spontaneous abortion was examined using a case-control design. 90 pregnant women had redeemed a prescription for systemic acyclovir, and 995 women for topical acyclovir, during 30 d before conception, or during their pregnancies from 1 January 1990 to 31 December 2001. The odds ratios (95% confidence intervals) of the exposed relative to the non-exposed for the systemic and topical acyclovir were: malformations, 0.69 (0.17-2.82) and 0.84 (0.51, 1.39); low birth weight, 2.03 (0.50-8.35) and 0.48 (0.21-1.07); preterm birth, 1.04 (0.38-2.85) and 0.95 (0.70-1.28); stillbirth (for topical acyclovir), 1.70 (0.80-3.60); and spontaneous abortion, 2.16 (0.60-7.80) and 1.29 (0.80-3.60). There is increasing evidence that the use of systemic acyclovir is not associated with an increased prevalence of malformations at birth and preterm delivery. The data for low birth weight and spontaneous abortion are still inconclusive, although the risk of spontaneous abortion is increased in women exposed to acyclovir during the first month of pregnancy. The use of topical acyclovir does not seem to be associated with any adverse pregnancy outcome, although data on stillbirth are inconclusive.

  1. Correlation of Clinical and Dosimetric Factors With Adverse Pulmonary Outcomes in Children After Lung Irradiation

    SciTech Connect

    Venkatramani, Rajkumar; Kamath, Sunil; Wong, Kenneth; Malvar, Jemily; Sposto, Richard; Goodarzian, Fariba; Freyer, David R.; Keens, Thomas G.; and others

    2013-08-01

    Purpose: To identify the incidence and the risk factors for pulmonary toxicity in children treated for cancer with contemporary lung irradiation. Methods and Materials: We analyzed clinical features, radiographic findings, pulmonary function tests, and dosimetric parameters of children receiving irradiation to the lung fields over a 10-year period. Results: We identified 109 patients (75 male patients). The median age at irradiation was 13.8 years (range, 0.04-20.9 years). The median follow-up period was 3.4 years. The median prescribed radiation dose was 21 Gy (range, 0.4-64.8 Gy). Pulmonary toxic chemotherapy included bleomycin in 58.7% of patients and cyclophosphamide in 83.5%. The following pulmonary outcomes were identified and the 5-year cumulative incidence after irradiation was determined: pneumonitis, 6%; chronic cough, 10%; pneumonia, 35%; dyspnea, 11%; supplemental oxygen requirement, 2%; radiographic interstitial lung disease, 40%; and chest wall deformity, 12%. One patient died of progressive respiratory failure. Post-irradiation pulmonary function tests available from 44 patients showed evidence of obstructive lung disease (25%), restrictive disease (11%), hyperinflation (32%), and abnormal diffusion capacity (12%). Thoracic surgery, bleomycin, age, mean lung irradiation dose (MLD), maximum lung dose, prescribed dose, and dosimetric parameters between V{sub 22} (volume of lung exposed to a radiation dose ≥22 Gy) and V{sub 30} (volume of lung exposed to a radiation dose ≥30 Gy) were significant for the development of adverse pulmonary outcomes on univariate analysis. MLD, maximum lung dose, and V{sub dose} (percentage of volume of lung receiving the threshold dose or greater) were highly correlated. On multivariate analysis, MLD was the sole significant predictor of adverse pulmonary outcome (P=.01). Conclusions: Significant pulmonary dysfunction occurs in children receiving lung irradiation by contemporary techniques. MLD rather than prescribed

  2. The interaction between fluid status and angiopoietin-2 in adverse renal outcomes of chronic kidney disease

    PubMed Central

    Chiu, Yi-Wen; Kuo, Hung-Tien; Lee, Jia-Jung; Lee, Su-Chu; Chen, Tzu-Hui; Lin, Ming-Yen; Hwang, Shang-Jyh; Kuo, Mei-Chuan; Hsu, Ya-Ling; Chen, Hung-Chun

    2017-01-01

    Background Fluid overload is not only the characteristic but also an important complication in chronic kidney disease (CKD) patients. Angiopoietin-2 (Angpt2) disturbs endothelium and vessel permeability, which may induce fluid overload. The aim of this study is to examine the interaction between fluid status and Angpt2 in adverse renal outcomes of CKD. Methods This cohort study enrolled 290 patients with CKD stages 3–5 from January 2011 to December 2011 and followed up until December 2015. Fluid status was presented as overhydration (OH) value measured by body composition monitor, while OH>1.1L was defined as fluid overload. Renal outcomes were defined as commencing dialysis and rapid renal function decline (the slope of estimated glomerular filtration rate < -5 ml/min/1.73 m2/y). Results During a mean follow-up of 38.6±18.3 months, 125 (43.1%) patients progressed to commencing dialysis and 99(34.7%) patients presented rapid renal function decline. All patients were stratified by OH of 1.1L and the median of circulating Angpt2. These patients with both OH>1.1L and high circulating Angpt2 were more likely to reach commencing dialysis compared to other groups. The risks for commencing dialysis and rapid renal function decline were significantly higher in patients with OH>1.1L and high circulating Angpt2 level compared to those with OH≦1.1L and low circulating Angpt2 (2.14, 1.21–3.78, P = 0.009; 4.96, 1.45–16.97, P = 0.01). There was a significant interaction between OH level and circulating Angpt2 in entering dialysis (P-interaction = 0.02). Conclusions Fluid overload and Angpt2 might have a synergistic effect on adverse renal outcomes in CKD patients. PMID:28333979

  3. Selecting measures for the neurodevelopmental assessment of children in low- and middle-income countries.

    PubMed

    Semrud-Clikeman, Margaret; Romero, Regilda Anne A; Prado, Elizabeth L; Shapiro, Elsa G; Bangirana, Paul; John, Chandy C

    2016-09-09

    Diseases affecting millions of children in low- and middle-income countries (LMICs), such as malnutrition, micronutrient deficiency, malaria, and HIV, can lead to adverse neurodevelopmental outcomes. Thus, a key health outcome in children is neurodevelopmental status. In this paper, the neurodevelopmental screening and testing measures most commonly utilized in LMICs are reviewed, and a matrix is presented to help researchers and clinicians determine which measures may be most useful for various LMIC inquiries. The matrix is based on an Internet literature review of 114 publications for the period January 1998 to February 2016, reporting the psychometric properties of instruments tested in LMIC children. The measures are classified as screening tests or more detailed tests that include both comprehensive batteries of general development and tests of specific domains. For completeness, two experts have reviewed this paper, as well as the authors. An overview of the tests used to date is presented, including the benefits and drawbacks of each test, in order to provide researchers and developmental clinicians with a way to decide which tests may be best suited to their developmental assessment goals. Remarkable progress has been made in neurodevelopmental testing in children in LMICs over the past two decades but there remains a need for additional research in this area to develop new tests, better evaluate and adapt current tests, and assess test validity and reliability across cultures.

  4. Elevated Fecal Calprotectin Associates with Adverse Outcomes from Clostridium difficile Infection in Older Adults

    PubMed Central

    Rao, Krishna; Santhosh, Kavitha; Mogle, Jill A.; Higgins, Peter D. R.; Young, Vincent B.

    2016-01-01

    Background Clostridium difficile infection (CDI) causes a mild to moderate colitis in most patients, but some, especially older adults, develop severe, adverse outcomes. Biomarkers predicting outcomes are needed to optimize treatments. This study tested whether fecal calprotectin associated with a composite primary outcome of complicated CDI (intensive care unit admission, colectomy, or death due to CDI within 30 days of diagnosis) and/or 8-week recurrence. Methods Stool was collected in Cary-Blair media at the time of diagnosis from inpatients of age >60 years that tested positive for C. difficile (enzyme immunoassay [EIA] for toxin A/B or polymerase chain reaction for the tcdB gene). Fecal calprotectin was measured and normalized to solid stool weight. Analysis was performed using logistic regression. Variables were selected for the final model using likelihood ratio tests. Results Fifty patients were included with a mean age 72.8 (± 7.5), and 13 (26%) developed the primary outcome. Clinical variables such as age, gender, and comorbid disease did not associate with complicated CDI/recurrence, nor did traditional biomarkers such as serum albumin or white blood cell count. A high normalized fecal calprotectin (>2000 µg/g) associated with the primary outcome in the final model after adjustment for gender and detectable fecal toxin(s) by EIA (OR 24.9, 95% CI 2.4–257.9, P=.007) with a specificity of 91.9%. Conclusion This study provides evidence that fecal calprotectin level associates with complications from CDI in older adults. Further studies are required to validate these findings in larger cohorts and incorporate them into clinical prediction algorithms. PMID:27206404

  5. Antiepileptic drug teratogenesis: what are the risks for congenital malformations and adverse cognitive outcomes?

    PubMed

    Harden, Cynthia L

    2008-01-01

    Antiepileptic drug (AED) exposure in utero has been associated with major congenital malformations (MCMs) and adverse cognitive outcomes in the offspring of women with epilepsy (WWE). However, determining the exact risk and the relative risks of AEDs for these outcomes has been challenging, and only in recent years has improved study designs enabled us to get a clearer picture of the risks. Still, there is a startling lack of information for many of the newer and widely used AEDs. At this point of time, studies clearly show that valproate (VPA) as a part of polytherapy or when used as a monotherapy is associated with an increased risk of MCMs, and that it poses about threefold the risk of carbamazepine (CBZ). It is unclear if any other AEDs studied pose an increased risk of MCM occurrence; in the best available large study the absolute rates of MCMs with other several other AEDs were not different from untreated WWE. The absolute risks have been reported as CBZ 2.2%, lamotrigine (LTG) 3.2%, phenytoin (PHT) 3.7%, untreated WWE 3.5%, with VPA as the outlier at 6.2%. In utero VPA exposure is also associated with a risk of lower verbal intelligence quotient (IQ) in children, at approximately 10 points lower than controls. CBZ appears to pose no risk to cognitive outcome, and there is some evidence that PHT and phenobarbital (PB) may be associated with risk of reduced cognitive outcome. Polytherapy is associated with greater risk than monotherapy for both MCMs and cognitive outcome. Although more information is needed and hopefully will be obtained from ongoing prospective studies, it is clear that WWE taking VPA and planning pregnancy should have a discussion with their physician about considering changing to another AED before pregnancy, if possible.

  6. Racial Discrimination and the Black-White Gap in Adverse Birth Outcomes: A Review

    PubMed Central

    Giurgescu, Carmen; McFarlin, Barbara L.; Lomax, Jeneen; Craddock, Cindy; Albrecht, Amy

    2017-01-01

    Introduction The purpose of this integrative review was to evaluate what is known about the relationship between racial discrimination and adverse birth outcomes. Methods A search of the Cumulative Index of Nursing and Allied Health Literature, MEDLINE, and PsycINFO was conducted. The keywords used were: preterm birth, premature birth, preterm delivery, preterm labor, low birth weight, very low birth weight, racism, racial discrimination, and prejudice. Ten research studies were reviewed. All of the studies included African American women in their samples, were conducted in the United States, and were written in English. We did not limit the year of publication for the studies. Data were extracted based on the birth outcomes of preterm birth, low birth weight, or very low birth weight. Results A consistent positive relationship existed between perceptions of racial discrimination and preterm birth, low birth weight, and very low birth weight. No relationship was found between racial discrimination and gestational age at birth. Discussion Future research should explore the effects of racial discrimination as a chronic stressor contributing to the persistent gap in birth outcomes between racial groups. PMID:21733107

  7. Maternal Vitamin D Status and Adverse Birth Outcomes in Children from Rural Western Kenya

    PubMed Central

    Toko, Eunice N.; Sumba, Odada P.; Daud, Ibrahim I.; Ogolla, Sidney; Majiwa, Maxwel; Krisher, Jesse T.; Ouma, Collins; Dent, Arlene E.; Rochford, Rosemary; Mehta, Saurabh

    2016-01-01

    Maternal plasma 25-hydroxyvitamin D (25(OH)D) status and its association with pregnancy outcomes in malaria holoendemic regions of sub-Saharan Africa is poorly defined. We examined this association and any potential interaction with malaria and helminth infections in an ongoing pregnancy cohort study in Kenya. The association of maternal plasma 25(OH)D status with pregnancy outcomes and infant anthropometric measurements at birth was determined in a subset of women (n = 63). Binomial and linear regression analyses were used to examine associations between maternal plasma 25(OH)D and adverse pregnancy outcomes. Fifty-one percent of the women had insufficient (<75 nmol/L) and 21% had deficient (<50 nmol/L) plasma 25(OH)D concentration at enrollment. At birth, 74.4% of the infants had insufficient and 30% had deficient plasma 25(OH)D concentrations, measured in cord blood. Multivariate analysis controlling for maternal age and body mass index (BMI) at enrollment and gestational age at delivery found that deficient plasma 25(OH)D levels were associated with a four-fold higher risk of stunting in neonates (p = 0.04). These findings add to the existing literature about vitamin D and its association with linear growth in resource-limited settings, though randomized clinical trials are needed to establish causation. PMID:27941597

  8. Maternal Vitamin D Status and Adverse Birth Outcomes in Children from Rural Western Kenya.

    PubMed

    Toko, Eunice N; Sumba, Odada P; Daud, Ibrahim I; Ogolla, Sidney; Majiwa, Maxwel; Krisher, Jesse T; Ouma, Collins; Dent, Arlene E; Rochford, Rosemary; Mehta, Saurabh

    2016-12-07

    Maternal plasma 25-hydroxyvitamin D (25(OH)D) status and its association with pregnancy outcomes in malaria holoendemic regions of sub-Saharan Africa is poorly defined. We examined this association and any potential interaction with malaria and helminth infections in an ongoing pregnancy cohort study in Kenya. The association of maternal plasma 25(OH)D status with pregnancy outcomes and infant anthropometric measurements at birth was determined in a subset of women (n = 63). Binomial and linear regression analyses were used to examine associations between maternal plasma 25(OH)D and adverse pregnancy outcomes. Fifty-one percent of the women had insufficient (<75 nmol/L) and 21% had deficient (<50 nmol/L) plasma 25(OH)D concentration at enrollment. At birth, 74.4% of the infants had insufficient and 30% had deficient plasma 25(OH)D concentrations, measured in cord blood. Multivariate analysis controlling for maternal age and body mass index (BMI) at enrollment and gestational age at delivery found that deficient plasma 25(OH)D levels were associated with a four-fold higher risk of stunting in neonates (p = 0.04). These findings add to the existing literature about vitamin D and its association with linear growth in resource-limited settings, though randomized clinical trials are needed to establish causation.

  9. Association of Chorioamnionitis with Aberrant Neonatal Gut Colonization and Adverse Clinical Outcomes

    PubMed Central

    Ambalavanan, Namasivayam; Schibler, Kurt R.; Morrow, Ardythe L.; Kallapur, Suhas G.

    2016-01-01

    Objective Chorioamnionitis (inflammation of the placenta and fetal membranes) and abnormal gastrointestinal colonization have been associated with an increased risk of sepsis and death in preterm infants, but whether chorioamnionitis causes abnormal pioneering gastrointestinal colonization in infants is not known. We determined the relationship between chorioamnionitis, altered infant fecal microbiome indicating abnormal gastrointestinal colonization, and adverse outcomes. Study Design Preterm infants ≤ 28 weeks at birth were enrolled from 3 level III NICUs in Cincinnati, Ohio and Birmingham, Alabama. Sequencing for 16S microbial gene was performed on stool samples in the first 3 weeks of life. Chorioamnionitis was diagnosed by placental histology. Late onset sepsis and death outcomes were analyzed in relation to fecal microbiota and chorioamnionitis with or without funisitis (inflammation of the umbilical cord). Results Of the 106 enrolled infants, 48 infants had no chorioamnionitis, 32 infants had chorioamnionitis but no funisitis (AC), and 26 infants had chorioamnionitis with funisitis (ACF). The fecal samples from ACF infants collected by day of life 7 had higher relative abundance of family Mycoplasmataceae (phylum Tenericutes), genus Prevotella (phylum Bacteroidetes) and genus Sneathia (phylum Fusobacteria). Further, AC and ACF infants had higher incidence of late-onset sepsis/death as a combined outcome. Presence of specific clades in fecal samples, specifically, order Fusobacteria, genus Sneathia or family Mycoplasmataceae, were significantly associated with higher risk of sepsis or death. Conclusion The results support the hypothesis that specific alterations in the pioneering infant gastrointestinal microbiota induced by chorioamnionitis predispose to neonatal sepsis or death. PMID:27658190

  10. Serum Adiponectin is Associated with Adverse Outcomes of Asthma in Men but Not in Women

    PubMed Central

    Sood, Akshay; Dominic, Elizabeth; Qualls, Clifford; Steffes, Michael W.; Thyagarajan, Bharat; Smith, Lewis J.; Lewis, Cora E.; Jacobs, David R.

    2011-01-01

    Background: Murine studies suggest a beneficial effect of systemic adiponectin on asthma. Our objective was to determine the association between serum adiponectin concentrations and asthma control/severity outcomes in men and women separately. Methods: Cross-sectional and longitudinal analyses of data from years 10, 15, and 20 examinations of the prospective coronary artery risk development in young adults study in the United States were performed. Asthma was defined by self-reported provider diagnosis at or prior to year 15 examination. Outcomes included presence of active disease, number of respiratory symptoms, and number of asthma medications; as well as longitudinal decline in absolute FEV1. Year 15 serum adiponectin concentration was the predictor variable. Results: In a multivariable analysis of 411 eligible subjects, after adjusting for body mass index and covariates, higher serum adiponectin concentrations were associated with more frequent active disease (including more frequent use of any asthma medication), and greater number of respiratory symptoms and asthma medications among men but not among women with asthma (p for interactions between sex and adiponectin for all analyses < 0.05). Conclusions: Higher serum adiponectin concentrations may be independently associated with adverse clinical outcomes of asthma in men but not in women. If biological effect is confirmed in future studies, modification of systemic adiponectin concentrations may open up newer ways to treat asthma in men. PMID:22007173

  11. Hyperglycaemia and risk of adverse perinatal outcomes: systematic review and meta-analysis

    PubMed Central

    Simmonds, Mark; Bryant, Maria; Sheldon, Trevor A; Tuffnell, Derek; Golder, Su; Dunne, Fidelma; Lawlor, Debbie A

    2016-01-01

    Objectives To assess the association between maternal glucose concentrations and adverse perinatal outcomes in women without gestational or existing diabetes and to determine whether clear thresholds for identifying women at risk of perinatal outcomes can be identified. Design Systematic review and meta-analysis of prospective cohort studies and control arms of randomised trials. Data sources Databases including Medline and Embase were searched up to October 2014 and combined with individual participant data from two additional birth cohorts. Eligibility criteria for selecting studies Studies including pregnant women with oral glucose tolerance (OGTT) or challenge (OGCT) test results, with data on at least one adverse perinatal outcome. Appraisal and data extraction Glucose test results were extracted for OGCT (50 g) and OGTT (75 g and 100 g) at fasting and one and two hour post-load timings. Data were extracted on induction of labour; caesarean and instrumental delivery; pregnancy induced hypertension; pre-eclampsia; macrosomia; large for gestational age; preterm birth; birth injury; and neonatal hypoglycaemia. Risk of bias was assessed with a modified version of the critical appraisal skills programme and quality in prognostic studies tools. Results 25 reports from 23 published studies and two individual participant data cohorts were included, with up to 207 172 women (numbers varied by the test and outcome analysed in the meta-analyses). Overall most studies were judged as having a low risk of bias. There were positive linear associations with caesarean section, induction of labour, large for gestational age, macrosomia, and shoulder dystocia for all glucose exposures across the distribution of glucose concentrations. There was no clear evidence of a threshold effect. In general, associations were stronger for fasting concentration than for post-load concentration. For example, the odds ratios for large for gestational age per 1 mmol/L increase of

  12. Intrauterine Zika virus infection of pregnant immunocompetent mice models transplacental transmission and adverse perinatal outcomes

    PubMed Central

    Vermillion, Meghan S.; Lei, Jun; Shabi, Yahya; Baxter, Victoria K.; Crilly, Nathan P.; McLane, Michael; Griffin, Diane E.; Pekosz, Andrew; Klein, Sabra L.; Burd, Irina

    2017-01-01

    Zika virus (ZIKV) crosses the placenta and causes congenital disease. Here we develop an animal model utilizing direct ZIKV inoculation into the uterine wall of pregnant, immunocompetent mice to evaluate transplacental transmission. Intrauterine inoculation at embryonic day (E) 10, but not E14, with African, Asian or American strains of ZIKV reduces fetal viability and increases infection of placental and fetal tissues. ZIKV inoculation at E10 causes placental inflammation, placental dysfunction and reduces neonatal brain cortical thickness, which is associated with increased activation of microglia. Viral antigen localizes in trophoblast and endothelial cells in the placenta, and endothelial, microglial and neural progenitor cells in the fetal brain. ZIKV infection of the placenta increases production of IFNβ and expression of IFN-stimulated genes 48 h after infection. This mouse model provides a platform for identifying factors at the maternal–fetal interface that contribute to adverse perinatal outcomes in a host with an intact immune system. PMID:28220786

  13. Psychoneuroimmunology in pregnancy: immune pathways linking stress with maternal health, adverse birth outcomes, and fetal development.

    PubMed

    Christian, Lisa M

    2012-01-01

    It is well-established that psychological stress promotes immune dysregulation in nonpregnant humans and animals. Stress promotes inflammation, impairs antibody responses to vaccination, slows wound healing, and suppresses cell-mediated immune function. Importantly, the immune system changes substantially to support healthy pregnancy, with attenuation of inflammatory responses and impairment of cell-mediated immunity. This adaptation is postulated to protect the fetus from rejection by the maternal immune system. Thus, stress-induced immune dysregulation during pregnancy has unique implications for both maternal and fetal health, particularly preterm birth. However, very limited research has examined stress-immune relationships in pregnancy. The application of psychoneuroimmunology research models to the perinatal period holds great promise for elucidating biological pathways by which stress may affect adverse pregnancy outcomes, maternal health, and fetal development.

  14. Intrauterine Zika virus infection of pregnant immunocompetent mice models transplacental transmission and adverse perinatal outcomes.

    PubMed

    Vermillion, Meghan S; Lei, Jun; Shabi, Yahya; Baxter, Victoria K; Crilly, Nathan P; McLane, Michael; Griffin, Diane E; Pekosz, Andrew; Klein, Sabra L; Burd, Irina

    2017-02-21

    Zika virus (ZIKV) crosses the placenta and causes congenital disease. Here we develop an animal model utilizing direct ZIKV inoculation into the uterine wall of pregnant, immunocompetent mice to evaluate transplacental transmission. Intrauterine inoculation at embryonic day (E) 10, but not E14, with African, Asian or American strains of ZIKV reduces fetal viability and increases infection of placental and fetal tissues. ZIKV inoculation at E10 causes placental inflammation, placental dysfunction and reduces neonatal brain cortical thickness, which is associated with increased activation of microglia. Viral antigen localizes in trophoblast and endothelial cells in the placenta, and endothelial, microglial and neural progenitor cells in the fetal brain. ZIKV infection of the placenta increases production of IFNβ and expression of IFN-stimulated genes 48 h after infection. This mouse model provides a platform for identifying factors at the maternal-fetal interface that contribute to adverse perinatal outcomes in a host with an intact immune system.

  15. Identifying exposure disparities in air pollution epidemiology specific to adverse birth outcomes

    NASA Astrophysics Data System (ADS)

    Geer, Laura A.

    2014-10-01

    More than 147 million people in the US live in areas where pollutant levels are above regulatory limits and pose a risk to health. Most of the vast network of air pollutant monitors in the US are located in places with higher pollution levels and a higher density of pollutant sources (e.g., point sources from industrial pollution). Vulnerable populations are more likely to live closer to pollutant sources, and thus closer to pollutant monitors. These differential exposures have an impact on maternal and child health; maternal air pollutant exposures have been linked to adverse outcomes such as preterm birth and infant low birth weight. Several studies are highlighted that address methodological approaches in the study of air pollution and health disparities.

  16. Adverse obstetric outcome in women with a history of infertility: a retrospective study.

    PubMed

    Yasmin, H; Hassan, I; Vanga, P; Subramanium, M; Adeghe, J H

    2006-01-01

    Women with a history of infertility are associated with a higher incidence of adverse pregnancy outcome. This retrospective study reviewed 105 women with a known history of infertility; of these 105 women, 77 (73%) conceived spontaneously and 28 (27%) had assisted conception. Our finding confirms higher perinatal complications; relative ratios (RR) for pre-eclampsia was 4.6 (95% CI=2.1-9.9), intrauterine growth restriction 4.8 (95% CI=1.9-12.0), gestational diabetes 1.8 (95% CI=0.5-5.8), pre-term premature rupture of membrane 2.3 (95% CI=0.6-8.8) and pre-term labour 2.6 (95% CI=1.1-5.9). We postulate that women with a history of infertility are at high risk of such obstetric complications and may benefit from intensified antenatal care.

  17. Chlorinated drinking water, cancers and adverse health outcomes in Gangtok, Sikkim, India.

    PubMed

    Sharma, Rabi N; Goel, Sudha

    2007-10-01

    Long-term impacts of drinking chlorinated water on the incidence of cancers and other adverse health outcomes were assessed in a population-based cross-sectional study. The study was conducted by comparing a group exposed to chlorinated drinking water for more than thirty years with control groups with less or no exposure to chlorine. A house-to-house survey was completed to gather information on residential history, age, education, income, source and extent of treatment of water and health characteristics. All residents below thirty years of age were excluded from the database used for analyses to ensure that the groups were comparable. Fourteen cancer cases were found in the long-term exposed groups of 1085 persons and 9 cancer cases in the two control populations of 725 persons. The odds ratio for cancers (OR) was 1.05 (95% CI = 0.43-2.65) and is not statistically significant. Reciprocal or inverse odds [corrected] ratios for gastrointestinal disorders, kidney problems and skin infections were statistically significant ranging from 2.06 (95% CI = 1.01-4.17) to 2.2 (95% CI = 1.45-3.33). These OR values indicate that there is no significant association between the incidence of cancer and exposure to chlorinated water while chlorinating drinking water significantly reduced the incidence of non-carcinogenic adverse health effects like gastrointestinal diseases, skin infections, and kidney diseases.

  18. Fluorene-9-bisphenol is anti-oestrogenic and may cause adverse pregnancy outcomes in mice

    PubMed Central

    Zhang, Zhaobin; Hu, Ying; Guo, Jilong; Yu, Tong; Sun, Libei; Xiao, Xuan; Zhu, Desheng; Nakanishi, Tsuyoshi; Hiromori, Youhei; Li, Junyu; Fan, Xiaolin; Wan, Yi; Cheng, Siyu; Li, Jun; Guo, Xuan; Hu, Jianying

    2017-01-01

    Bisphenol A (BPA) is used in the production of plastic but has oestrogenic activity. Therefore, BPA substitutes, such as fluorene-9-bisphenol (BHPF), have been introduced for the production of so-called ‘BPA-free' plastics. Here we show that BHPF is released from commercial ‘BPA-free' plastic bottles into drinking water and has anti-oestrogenic effects in mice. We demonstrate that BHPF has anti-oestrogenic activity in vitro and, in an uterotrophic assay in mice, induces low uterine weight, atrophic endometria and causes adverse pregnancy outcomes, even at doses lower than those of BPA for which no observed adverse effect have been reported. Female mice given water containing BHPF released from plastic bottles, have detectable levels of BHPF in serum, low uterine weights and show decreased expressions of oestrogen-responsive genes. We also detect BHPF in the plasma of 7/100 individuals, who regularly drink water from plastic bottles. Our data suggest that BPA substitutes should be tested for anti-oestrogenic activity and call for further study of the toxicological effects of BHPF on human health. PMID:28248286

  19. Is growth-discordance in twins a substantial risk factor in adverse neonatal outcomes?

    PubMed

    Frezza, Simonetta; Gallini, Francesca; Puopolo, Maria; De Carolis, Maria P; D'Andrea, Vito; Guidone, Paola I; Luciano, Rita; Zuppa, Antonio A; Romagnoli, Costantino

    2011-10-01

    To evaluate whether growth discordance is an independent risk factor in the neonatal outcome of the smaller twin, all medical records of twin pregnancies delivered between 26 and 41 weeks during a 5-year period (January 2004-December 2008) were reviewed. Among the 49 selected twins, weight discordance was 15-20% in 7 infants, 21-30% in 16 infants, 31-40% in 16 infants and > 40% in 10 infants. No significant differences between the four groups were found with regards to obstetric complications and neonatal disease. Occurrence of birthweight below the 10th percentile and rate of admission to the neonatal intensive care unit significantly increased as intra-pair birthweight difference increased (p = .03). The > 40% discordant group had a significantly lower gestational age (p = .03), lower birthweight (p = .007) and a significantly higher mortality rate (4/10 versus 3/39 p = .04) in comparison with the other discordant groups. Multiple logistic regression analysis showed that birthweight was the single independent and consistent factor associated with elevated risks of mortality. For every 250 g increase in birthweight, the risk for mortality decreased by about 84% [RR 0.16(CI 0.00-0.70)]. Gestational age was the most reliable predictor for major neonatal complications. For every 1-week increase in gestational age a significant decreased risk for all outcomes was found. Discordance alone should not be considered as a predictor for adverse neonatal outcome. Neonatal outcome in discordant twins appears to be related to gestational age and birthweight rather than to the degree of discordance.

  20. Waterlow score as a surrogate marker for predicting adverse outcome in acute pancreatitis

    PubMed Central

    Gillick, K; Elbeltagi, H; Bhattacharya, S

    2016-01-01

    Introduction Introduced originally to stratify risk for developing decubitus ulcers, the Waterlow scoring system is recorded routinely for surgical admissions. It is a composite score, reflecting patients’ general condition and co-morbidities. The aim of this study was to investigate whether the Waterlow score can be used as an independent surrogate marker to predict severity and adverse outcome in acute pancreatitis. Methods In this retrospective analysis, a consecutive cohort was studied of 250 patients presenting with acute pancreatitis, all of whom had their Waterlow score calculated on admission. Primary outcome measures were length of hospital stay and mortality. Secondary outcome measures included rate of intensive care unit (ICU) admission and development of complications such as peripancreatic free fluid, pancreatic necrosis and pseudocyst formation. Correlation of the Waterlow score with some known markers of disease severity and outcomes was also analysed. Results The Waterlow score correlated strongly with the most commonly used marker of disease severity, the Glasgow score (analysis of variance, p=0.0012). Inpatient mortality, rate of ICU admission and length of hospital stay increased with a higher Waterlow score (Mann–Whitney U test, p=0.0007, p=0.049 and p=0.0002 respectively). There was, however, no significant association between the Waterlow score and the incidence of three known complications of pancreatitis: presence of peripancreatic fluid, pancreatic pseudocyst formation and pancreatic necrosis. Receiver operating characteristic curve analysis demonstrated good predictive power of the Waterlow score for mortality (area under the curve [AUC]: 0.73), ICU admission (AUC: 0.65) and length of stay >7 days (AUC: 0.64). This is comparable with the predictive power of the Glasgow score and C-reactive protein. Conclusions The Waterlow score for patients admitted with acute pancreatitis could provide a useful tool in prospective assessment of

  1. Malnutrition in Hospitalized Pediatric Patients: Assessment, Prevalence, and Association to Adverse Outcomes.

    PubMed

    Daskalou, Efstratia; Galli-Tsinopoulou, Assimina; Karagiozoglou-Lampoudi, Thomais; Augoustides-Savvopoulou, Persefone

    2016-01-01

    Malnutrition is a frequent finding in pediatric health care settings in the form of undernutrition or excess body weight. Its increasing prevalence and impact on overall health status, which is reflected in the adverse outcomes, renders imperative the application of commonly accepted and evidence-based practices and tools by health care providers. Nutrition risk screening on admission and nutrition status evaluation are key points during clinical management of hospitalized pediatric patients, in order to prevent health deterioration that can lead to serious complications and growth consequences. In addition, anthropometric data based on commonly accepted universal growth standards can give accurate results for nutrition status. Both nutrition risk screening and nutrition status assessment are techniques that should be routinely implemented, based on commonly accepted growth standards and methodology, and linked to clinical outcomes. The aim of the present review was to address the issue of hospital malnutrition in pediatric settings in terms of prevalence, outline nutrition status evaluation and nutrition screening process using different criteria and available tools, and present its relationship with outcome measures. Key teaching points • Malnutrition-underweight or excess body weight-is a frequent imbalance in pediatric settings that affects physical growth and results in undesirable clinical outcomes. • Anthropometry interpretation through growth charts and nutrition screening are cornerstones for the assessment of malnutrition.To date no commonly accepted anthropometric criteria or nutrition screening tools are used in hospitalized pediatric patients. • Commonly accepted nutrition status and screening processes based on the World Health Organization's growth standards can contribute to the overall hospital nutrition care of pediatric patients.

  2. Interactive associations of depression and sleep apnea with adverse clinical outcomes after acute myocardial infarction

    PubMed Central

    Hayano, Junichiro; Carney, Robert M.; Watanabe, Eiichi; Kawai, Kiyohiro; Kodama, Itsuo; Stein, Phyllis K.; Watkins, Lana L.; Freedland, Kenneth E.; Blumenthal, James A.

    2012-01-01

    Objective Depression and sleep apnea (SA) are common among patients after acute myocardial infarction (AMI), and both are associated with increased risk for adverse outcomes. We tested the hypothesis that there is an interaction between depression and SA in relation to prognosis in post-AMI patients. Methods Participants were 337 depressed and 379 nondepressed post-AMI patients who participated in a substudy of the Enhancing Recovery in Coronary Heart Disease (ENRICHD) clinical trial. SA was identified from Holter ECG at the entry by an algorithm that detects cyclic variation of heart rate. Results During a median follow-up of 25 months, 43 (6.0%) of patients died and 83 (11.6%) either died or experienced a recurrent AMI. Among 94 patients with both depression and SA, these endpoints occurred in 20 (21.3%) and 25 (26.6%), the prevalence that was 6.9 and 3.9 times higher than predicted probabilities by ENRICHD clinical risk scores (P <.001 for both). In the patients with depression alone, SA alone, or neither, the frequencies did not differ significantly from the predicted probability. Although both depression and SA predicted death and the combined endpoint, we observed depression by SA interactions (P = .03 and .02). SA independently predicted these endpoints in depressed (P <.001 and P = .001), but not in nondepressed patients (P = .73 and .84). Similarly, depression independently predicted these endpoints in SA (P <.001 for both), but not in non-SA patients (P = .61 and .12). Conclusion The combination of depression and SA estimated by CVHR is associated with long-term adverse clinical outcomes after AMI. PMID:23023681

  3. Excess risk of adverse pregnancy outcomes in women with porphyria: a population-based cohort study.

    PubMed

    Tollånes, Mette Christophersen; Aarsand, Aasne Karine; Sandberg, Sverre

    2011-02-01

    The porphyrias comprise a heterogeneous group of rare, primarily hereditary, metabolic diseases caused by a partial deficiency in one of the eight enzymes involved in the heme biosynthesis. Our aim was to assess whether acute or cutaneous porphyria has been associated with excess risks of adverse pregnancy outcomes. A population-based cohort study was designed by record linkage between the Norwegian Porphyria Register, covering 70% of all known porphyria patients in Norway, and the Medical Birth Registry of Norway, based on all births in Norway during 1967-2006. The risks of the adverse pregnancy outcomes preeclampsia, delivery by caesarean section, low birth weight, premature delivery, small for gestational age (SGA), perinatal death, and congenital malformations were compared between porphyric mothers and the rest of the population. The 200 mothers with porphyria had 398 singletons during the study period, whereas the 1,100,391 mothers without porphyria had 2,275,317 singletons. First-time mothers with active acute porphyria had an excess risk of perinatal death [adjusted odds ratio (OR) 4.9, 95% confidence interval (CI) 1.5-16.0], as did mothers with the hereditable form of porphyria cutanea tarda (PCT) (3.0, 1.2-7.7). Sporadic PCT was associated with an excess risk of SGA [adjusted relative risk (RR) 2.0, 1.2-3.4], and for first-time mothers, low birth weight (adjusted OR 3.4, 1.2-10.0) and premature delivery (3.5, 1.2-10.5) in addition. The findings suggest women with porphyria should be monitored closely during pregnancy.

  4. The influence of heart developmental anatomy on cardiotoxicity-based adverse outcome pathways in fish.

    PubMed

    Incardona, John P; Scholz, Nathaniel L

    2016-08-01

    The developing fish heart is vulnerable to a diverse array of toxic chemical contaminants in freshwater, estuarine, and marine habitats. Globally occurring examples of cardiotoxic agents include dioxins, polychlorinated biphenyls (PCBs), and polycyclic aromatic hydrocarbons (PAHs). The disruption of cardiac function during the process of heart morphogenesis can lead to adverse outcome pathways (AOPs) that can negatively affect fish survival at hatching as well as later life stages. Proximal impacts include cardiogenic fluid accumulation (edema) and defects of the body axis and jaw that preclude larval feeding. More subtle changes in heart development can produce permanent structural defects in the heart that reduce cardiac output and swimming performance in older fish. In recent decades, the presence of edema in fish embryos and larvae has been a very common bioindicator of cardiotoxicity. However, the different ways that edema forms in fish from different habitats (i.e., freshwater vs. marine, pelagic vs. demersal) has not been rigorously examined. Oil spills are an important source of PAHs in fish spawning areas worldwide, and research is revealing how patterns of cardiogenic edema are shaped by species-specific differences in developmental anatomy and ionoregulatory physiology. Here we review the visible evidence for circulatory disruption across nine freshwater and marine fish species, exposed to crude oils from different parts of the world. We focus on the close interconnectedness of the cardiovascular and osmoregulatory systems during early development, and corresponding implications for fish in hyperosmotic and hyposmotic habitats. Finally, we suggest there may be poorly understood adverse outcomes pathways related to osmotic gradients and water movement within embryos, the latter causing extreme shifts in tissue osmolality.

  5. Assessing Adverse Events of Postprostatectomy Radiation Therapy for Prostate Cancer: Evaluation of Outcomes in the Regione Emilia-Romagna, Italy

    SciTech Connect

    Showalter, Timothy N.; Hegarty, Sarah E.; Rabinowitz, Carol; Maio, Vittorio; Hyslop, Terry; Dicker, Adam P.; Louis, Daniel Z.

    2015-03-15

    Purpose: Although the likelihood of radiation-related adverse events influences treatment decisions regarding radiation therapy after prostatectomy for eligible patients, the data available to inform decisions are limited. This study was designed to evaluate the genitourinary, gastrointestinal, and sexual adverse events associated with postprostatectomy radiation therapy and to assess the influence of radiation timing on the risk of adverse events. Methods: The Regione Emilia-Romagna Italian Longitudinal Health Care Utilization Database was queried to identify a cohort of men who received radical prostatectomy for prostate cancer during 2003 to 2009, including patients who received postprostatectomy radiation therapy. Patients with prior radiation therapy were excluded. Outcome measures were genitourinary, gastrointestinal, and sexual adverse events after prostatectomy. Rates of adverse events were compared between the cohorts who did and did not receive postoperative radiation therapy. Multivariable Cox proportional hazards models were developed for each class of adverse events, including models with radiation therapy as a time-varying covariate. Results: A total of 9876 men were included in the analyses: 2176 (22%) who received radiation therapy and 7700 (78%) treated with prostatectomy alone. In multivariable Cox proportional hazards models, the additional exposure to radiation therapy after prostatectomy was associated with increased rates of gastrointestinal (rate ratio [RR] 1.81; 95% confidence interval [CI] 1.44-2.27; P<.001) and urinary nonincontinence events (RR 1.83; 95% CI 1.83-2.80; P<.001) but not urinary incontinence events or erectile dysfunction. The addition of the time from prostatectomy to radiation therapy interaction term was not significant for any of the adverse event outcomes (P>.1 for all outcomes). Conclusion: Radiation therapy after prostatectomy is associated with an increase in gastrointestinal and genitourinary adverse events. However

  6. Adverse psychosocial outcomes associated with drug use among US high school seniors: a comparison of alcohol and marijuana

    PubMed Central

    Palamar, Joseph J.; Fenstermaker, Michael; Kamboukos, Dimitra; Ompad, Danielle C.; Cleland, Charles M.; Weitzman, Michael

    2015-01-01

    Objectives There is debate about whether marijuana (cannabis) use is more dangerous than alcohol use. Although difficult to make objective comparisons, research is needed to compare relative dangers in order to help inform preventive efforts and policy. Methods Data were analyzed from a nationally representative sample of high school seniors in the Monitoring the Future study (2007–2011; Weighted n = 7437; modal age: 18) who reported lifetime use of alcohol or marijuana. Students were asked to indicate whether they experienced various adverse psychosocial outcomes resulting from use of each substance. We examined which outcomes were more prevalent for each substance. Results Compared to alcohol use, marijuana use was more commonly reported to compromise relationships with teachers or supervisors, result in less energy or interest, and result in lower school or job performance. Compared to marijuana use, alcohol was more commonly reported to compromise relationships with friends and significant others; it was also reported to lead to more regret (particularly among females), and driving unsafely. Marijuana users were more likely to report no adverse outcomes. Females and white students were more likely to report various adverse outcomes and higher frequency use of each substance also increased occurrences of reported adverse outcomes. Conclusions Marijuana and alcohol are associated with unique adverse psychosocial outcomes. Outcomes differ by sex and race/ethnicity, and perception or experience of outcomes may also be related to legal status and associated stigma. Public health interventions may be more effective by focusing on harm reduction strategies for these drug-specific outcomes. PMID:25169838

  7. Child marriage and its association with adverse reproductive outcomes for women in Bangladesh.

    PubMed

    Kamal, S M Mostafa; Hassan, Che Hashim

    2015-03-01

    This study examines the prevalence of child marriage and its effect on reproductive outcomes among women in Bangladesh using the most recent 2011 Bangladesh Demographic and Health Survey data. Both bivariate and multivariate statistical techniques used in the study yielded quantitatively important and reliable estimates of child marriage and its impact on adverse reproductive and health outcomes. Overall, 77% of the marriages among women aged 20 to 49 years old took place before the age of 18 years. Women's education is the most single significant determinant of child marriage. Findings revealed that after being adjusted for sociodemographic factors, child marriage significantly (P < .001) increases the likelihood of stillbirth/miscarriage (odds ratio [OR] = 1.80; 95% confidence interval [CI] = 1.45-2.24) and pregnancy termination (OR = 1.24; 95% CI = 1.12-1.38). Programs should aim to retain girls in school for longer periods not only to raise the age at first marriage but also for sound reproductive health and overall social development of Bangladesh.

  8. Serum 25-Hydroxyvitamin D Levels are not Associated with Adverse Outcomes in Clostridium Difficile Infection

    PubMed Central

    Micic, Dejan; Rao, Krishna; Trindade, Bruno Caetano; Walk, Seth T.; Chenoweth, Elizabeth; Jain, Ruchika; Trivedi, Itishree; Santhosh, Kavitha; Young, Vincent B.; Aronoff, David M.

    2015-01-01

    Clostridium difficile infection (CDI) is a significant source of healthcare-associated morbidity and mortality. This study investigated whether serum 25-hydroxyvitamin D is associated with adverse outcomes from CDI. Patients with CDI were prospectively enrolled. Charts were reviewed and serum 25-hydroxyvitamin D was measured. The primary outcome was a composite definition of severe disease: fever (temperature >38°C), acute organ dysfunction, or serum white blood cell count >15,000 cells/µL within 24-48 hours of diagnosis; lack of response to therapy by day 5; and intensive care unit admission; colectomy; or death within 30 days. Sixty-seven patients were included in the final analysis. Mean (±SD) serum 25-hydroxyvitamin D was 26.1 (±18.54) ng/mL. Severe disease, which occurred in 26 (39%) participants, was not associated with serum 25-hydroxyvitamin D [odds ratio (OR) 1.00; 95% confidence interval (CI) 0.96-1.04]. In the adjusted model for severe disease only serum albumin (OR 0.12; 95%CI 0.02-0.64) and diagnosis by detection of stool toxin (OR 5.87; 95%CI 1.09-31.7) remained independent predictors. We conclude that serum 25-hydroxyvitamin D is not associated with the development of severe disease in patients with CDI. PMID:26500740

  9. Exposing physicians to reduced residency work hours did not adversely affect patient outcomes after residency.

    PubMed

    Jena, Anupam B; Schoemaker, Lena; Bhattacharya, Jay

    2014-10-01

    In 2003, work hours for physicians-in-training (residents) were capped by regulation at eighty hours per week, leading to the hotly debated but unexplored issue of whether physicians today are less well trained as a result of these work-hour reforms. Using a unique database of nearly all hospitalizations in Florida during 2000-09 that were linked to detailed information on the medical training history of the physician of record for each hospitalization, we studied whether hospital mortality and patients' length-of-stay varied according to the number of years a physician was exposed to the 2003 duty-hour regulations during his or her residency. We examined this database of practicing Florida physicians, using a difference-in-differences analysis that compared trends in outcomes of junior physicians (those with one-year post-residency experience) pre- and post-2003 to a control group of senior physicians (those with ten or more years of post-residency experience) who were not exposed to these reforms during their residency. We found that the duty-hour reforms did not adversely affect hospital mortality and length-of-stay of patients cared for by new attending physicians who were partly or fully exposed to reduced duty hours during their own residency. However, assessment of the impact of the duty-hour reforms on other clinical outcomes is needed.

  10. A lifetime experience of violence and adverse reproductive outcomes: findings from population surveys in India.

    PubMed

    Yoshikawa, K; Agrawal, N R; Poudel, K C; Jimba, M

    2012-06-01

    Intimate partner violence (IPV) is a global public health issue that threatens the reproductive health of women. Despite a growing demand for research on the potential threat of IPV in relation to adverse reproductive outcomes, there have been no population-based studies of India. The current study analyzed the National Family Health Survey 3, which contained detailed information on types of violence in relation to the single question of pregnancy outcomes. The dataset was used to assess the association between a lifetime experience of IPV and terminated pregnancies among married Indian women. Multiple logistic regression analysis was then used to assess the association between these variables, controlling for socio-demographic characteristics. Results showed that 39.6% of Indian women have experienced violence by their husbands, while 18.3% of women have terminated a pregnancy during their lifetimes. The odds ratio of a terminated pregnancy among women who had experienced any type of partner violence was 1.62 (95% CI (confidence interval) = 1.51-1.73). All combinations of violence except a combination of emotional and sexual violence were associated with an increased risk of a terminated pregnancy. These results suggest that prevention of IPV would reduce the high incidence of terminated pregnancies, thus improving maternal health in India.

  11. Adverse maternal and perinatal outcomes in women with previous preeclampsia: a prospective study

    PubMed Central

    Bramham, Kate; Briley, Annette L.; Seed, Paul; Poston, Lucilla; Shennan, Andrew H.; Chappell, Lucy C.

    2011-01-01

    Objective The purpose of this study was to assess recurrence rates of preeclampsia and neonatal outcomes in women with a history of preeclampsia that required preterm delivery. Study Design Five hundred women with previous preeclampsia that required delivery at <37 weeks' gestation were followed prospectively. Results Preeclampsia reoccurred in 117 women (23%). Predictive factors included black (odds ratio [OR], 2.29; 95% confidence interval [CI], 1.16–4.53) or Asian (OR, 2.98; 95% CI, 1.33–6.59) ethnicity, enrollment systolic blood pressure of >130 mm Hg (OR, 2.89; 95% CI, 1.52–5.50), current antihypertensive use (OR, 6.39; 95% CI, 2.38–17.16), and proteinuria of ≥2+ on enrollment urinalysis (OR, 12.35; 95% CI, 3.45–44.21). Women who previously delivered at <34 weeks' gestation were more likely to deliver preterm again (29% vs 17%; relative risk, 1.69; 95% CI, 1.19–2.40) than were those women with previous delivery between 34 and 37 weeks' gestation. Conclusion Although this study confirms that women with previous preeclampsia that required early delivery are at high risk of the development of preeclampsia, the study identifies risk factors for recurrence and illustrates that women with previous preeclampsia are at greater risk of adverse neonatal outcome. PMID:21457915

  12. Effects of a Psychosocial Couple-Based Prevention Program on Adverse Birth Outcomes

    PubMed Central

    Roettger, Michael E.; Jones, Damon E.; Paul, Ian M.; Kan, Marni L.

    2015-01-01

    Although maternal stress and depression have been linked to adverse birth outcomes (ABOs), few studies have investigated preventive interventions targeting maternal mental health as a means of reducing ABOs. This randomized controlled study examines the impact of Family Foundations (FF)—a transition to parenthood program for couples focused on promoting coparenting quality, with previously documented impact on maternal stress and depression—on ABOs. We also examine whether intervention buffers birth outcomes from the negative effect of elevated salivary cortisol levels. We use intent-to-treat analyses to assess the main effects of the FF intervention on ABOs (prematurity, birth weight, pregnancy complications, Cesarean section, and days in hospital for mothers and infants) among 148 expectant mothers. We also test the interaction of cortisol with intervention condition status in predicting ABOs. FF participation was associated with reduced risk of C-section (OR .357, p < 0.05, 95 % CI 0.149, 0.862), but did not have main effects on other ABOs. FF significantly buffered (p < 0.05) the negative impact of maternal cortisol on birth weight, gestational age, and days in hospital for infants; that is, among women with relatively higher levels of prenatal cortisol, the intervention reduced ABOs. These results demonstrate that a psycho-educational program for couples reduces incidence of ABOs among higher risk women. Future work should test whether reduced maternal stress and depression mediate these intervention effects. PMID:24969352

  13. Planned Repeat Cesarean Section at Term and Adverse Childhood Health Outcomes: A Record-Linkage Study

    PubMed Central

    Black, Mairead; Bhattacharya, Siladitya; Philip, Sam; Norman, Jane E.; McLernon, David J.

    2016-01-01

    Background Global cesarean section (CS) rates range from 1% to 52%, with a previous CS being the commonest indication. Labour following a previous CS carries risk of scar rupture, with potential for offspring hypoxic brain injury, leading to high rates of repeat elective CS. However, the effect of delivery by CS on long-term outcomes in children is unclear. Increasing evidence suggests that in avoiding exposure to maternal bowel flora during labour or vaginal birth, offspring delivered by CS may be adversely affected in terms of energy uptake from the gut and immune development, increasing obesity and asthma risks, respectively. This study aimed to address the evidence gap on long-term childhood outcomes following repeat CS by comparing adverse childhood health outcomes after (1) planned repeat CS and (2) unscheduled repeat CS with those that follow vaginal birth after CS (VBAC). Methods and Findings A data-linkage cohort study was performed. All second-born, term, singleton offspring delivered between 1 January 1993 and 31 December 2007 in Scotland, UK, to women with a history of CS (n = 40,145) were followed up until 31 January 2015. Outcomes assessed included obesity at age 5 y, hospitalisation with asthma, learning disability, cerebral palsy, and death. Cox regression and binary logistic regression were used as appropriate to compare outcomes following planned repeat CS (n = 17,919) and unscheduled repeat CS (n = 8,847) with those following VBAC (n = 13,379). Risk of hospitalisation with asthma was greater following both unscheduled repeat CS (3.7% versus 3.3%, adjusted hazard ratio [HR] 1.18, 95% CI 1.05–1.33) and planned repeat CS (3.6% versus 3.3%, adjusted HR 1.24, 95% CI 1.09–1.42) compared with VBAC. Learning disability and death were more common following unscheduled repeat CS compared with VBAC (3.7% versus 2.3%, adjusted odds ratio 1.64, 95% CI 1.17–2.29, and 0.5% versus 0.4%, adjusted HR 1.50, 95% CI 1.00–2.25, respectively). Risk of obesity

  14. Food insecurity is associated with adverse health outcomes among human infants and toddlers.

    PubMed

    Cook, John T; Frank, Deborah A; Berkowitz, Carol; Black, Maureen M; Casey, Patrick H; Cutts, Diana B; Meyers, Alan F; Zaldivar, Nieves; Skalicky, Anne; Levenson, Suzette; Heeren, Tim; Nord, Mark

    2004-06-01

    The U.S. Household Food Security Scale, developed with federal support for use in national surveys, is an effective research tool. This study uses these new measures to examine associations between food insecurity and health outcomes in young children. The purpose of this study was to determine whether household food insecurity is associated with adverse health outcomes in a sentinel population ages < or = 36 mo. We conducted a multisite retrospective cohort study with cross-sectional surveys at urban medical centers in 5 states and Washington DC, August 1998-December 2001. Caregivers of 11,539 children ages < or = 36 mo were interviewed at hospital clinics and emergency departments (ED) in central cities. Outcome measures included child's health status, hospitalization history, whether child was admitted to hospital on day of ED visit (for subsample interviewed in EDs), and a composite growth-risk variable. In this sample, 21.4% of households were food insecure (6.8% with hunger). In a logistic regression, after adjusting for confounders, food-insecure children had odds of "fair or poor" health nearly twice as great [adjusted odds ratio (AOR) = 1.90, 95% CI = 1.66-2.18], and odds of being hospitalized since birth almost a third larger (AOR = 1.31, 95% CI = 1.16-1.48) than food-secure children. A dose-response relation appeared between fair/poor health status and severity of food insecurity. Effect modification occurred between Food Stamps and food insecurity; Food Stamps attenuated (but did not eliminate) associations between food insecurity and fair/poor health. Food insecurity is associated with health problems for young, low-income children. Ensuring food security may reduce health problems, including the need for hospitalizations.

  15. Geospatial association between adverse birth outcomes and arsenic in groundwater in New Hampshire, USA

    USGS Publications Warehouse

    Xun Shi,; Ayotte, Joseph; Akikazu Onda,; Stephanie Miller,; Judy Rees,; Diane Gilbert-Diamond,; Onega, Tracy L; Gui, Jiang; Karagas, Margaret R.; Moeschler, John B

    2015-01-01

    There is increasing evidence of the role of arsenic in the etiology of adverse human reproductive outcomes. Because drinking water can be a major source of arsenic to pregnant women, the effect of arsenic exposure through drinking water on human birth may be revealed by a geospatial association between arsenic concentration in groundwater and birth problems, particularly in a region where private wells substantially account for water supply, like New Hampshire, USA. We calculated town-level rates of preterm birth and term low birth weight (term LBW) for New Hampshire, by using data for 1997–2009 stratified by maternal age. We smoothed the rates by using a locally weighted averaging method to increase the statistical stability. The town-level groundwater arsenic probability values are from three GIS data layers generated by the US Geological Survey: probability of local groundwater arsenic concentration >1 µg/L, probability >5 µg/L, and probability >10 µg/L. We calculated Pearson’s correlation coefficients (r) between the reproductive outcomes (preterm birth and term LBW) and the arsenic probability values, at both state and county levels. For preterm birth, younger mothers (maternal age <20) have a statewider = 0.70 between the rates smoothed with a threshold = 2,000 births and the town mean arsenic level based on the data of probability >10 µg/L; for older mothers, r = 0.19 when the smoothing threshold = 3,500; a majority of county level r values are positive based on the arsenic data of probability >10 µg/L. For term LBW, younger mothers (maternal age <25) have a statewide r = 0.44 between the rates smoothed with a threshold = 3,500 and town minimum arsenic concentration based on the data of probability >1 µg/L; for older mothers, r = 0.14 when the rates are smoothed with a threshold = 1,000 births and also adjusted by town median household income in 1999, and the arsenic values are the town minimum based on probability

  16. Predicting adverse outcomes after myocardial infarction among patients with diabetes mellitus

    PubMed Central

    Arnold, Suzanne V.; Spertus, John A.; Jones, Philip G.; McGuire, Darren K.; Lipska, Kasia J.; Xu, Yaping; Stolker, Joshua M.; Goyal, Abhinav; Kosiborod, Mikhail

    2017-01-01

    Background Although patients with diabetes mellitus experience high rates of adverse events after acute myocardial infarction (AMI), including death and recurrent ischemia, some diabetic patients are likely at low risk, while others are at very high risk. We sought to develop prediction models to stratify risk after AMI in patients with diabetes. Methods and Results We developed prediction models for long-term mortality and angina among 1613 patients with diabetes discharged alive after AMI from 24 US hospitals and then validated the models in a separate, multi-center registry of 786 patients with diabetes. Event rates in the derivation cohort were 27% for 5-year mortality and 27% for 1-year angina. Parsimonious prediction models demonstrated good discrimination (c-indices=0.78 and 0.69, respectively) and excellent calibration. Within the context of the predictors we estimated, the strongest predictors for mortality were higher creatinine, not working at the time of the AMI, older age, lower hemoglobin, left ventricular dysfunction, and chronic heart failure. The strongest predictors for angina were angina burden in the 4 weeks prior to the AMI, younger age, history of prior coronary bypass graft surgery, and non-Caucasian race. The lowest and highest deciles of predicted risk ranged from 4–80% for mortality and 12–59% for angina. The models also performed well in external validation (c-indices=0.78 and 0.73, respectively). Conclusion We found a wide range of risk for adverse outcomes after AMI in diabetic patients. Predictive models can identify patients with diabetes for whom closer follow-up and aggressive secondary prevention strategies should be considered. PMID:27220369

  17. Prediction of Neurodevelopmental Sequelae in VLBW Infants.

    ERIC Educational Resources Information Center

    Wolke, Dieter; And Others

    The study examined pre-, peri-, and neonatal factors in 271 British infants (weighing less than 1500 grams at birth), 188 of whom survived to 2 years. The study represented an attempt to define those factors which predict normal neurodevelopmental outcome in very low birth weight (VLBW) infants. Surviving infants were seen at 3, 6, 9, 12, and 24…

  18. North-South Gradients in Adverse Birth Outcomes for First Nations and Others in Manitoba, Canada.

    PubMed

    Martens, Patricia J; Heaman, Maureen; Hart, Lyna; Wilkins, Russell; Smylie, Janet; Wassimi, Spogmai; Simonet, Fabienne; Wu, Yuquan; Fraser, William D; Luo, Zhong-Cheng

    2010-01-01

    OBJECTIVE: to determine the relationship of north-south place of residence to adverse birth outcomes among First Nations and non-First Nations in Manitoba, Canada, a setting with universal health insurance. STUDY DESIGN: Live birth records (n=151,472) for the province of Manitoba, Canada 1991-2000 were analyzed, including 25,743 First Nations and 125,729 non-First Nations infants. North-south and rural-urban residence was determined for each birth through geocoding. RESULTS: Comparing First Nations to non-First Nations, crude rates in North (and South) were: 7.0% versus 8.4% (9.3% versus 7.5%) for preterm birth; 6.1% versus 8.4% (8.7% versus 10.0%) for small-for-gestational-age birth, 4.2% versus 6.5% (6.2% versus 5.7%) for low birth weight, and 20.6% versus 13.7% (17.0% versus 11.0%) for large-for-gestational-age birth; and mortality per 1000 - neonatal 3.2 versus 6.2 (3.8 versus 3.3), post-neonatal 6.4 versus 6.4 (5.8 versus 1.5), and infant 9.5 versus 12.6 (9.6 versus 4.8). Adjusting for observed maternal and infant characteristics and rural versus urban residence, the North was high risk for large-for-gestational-age birth for both First Nations and non-First Nations. First Nations' risk of preterm, small-for-gestational-age and low birth weight was lowest in the North, but for non-First Nations, the North was lower only for small-for-gestational-age. First Nations mortality indicators were similar North to South, but for non-First Nations, the North was high risk. CONCLUSION: North-South place of residence does matter for adverse birth outcomes, but the effects may differ by ethnicity and could require different intervention strategies.

  19. Advancing Age and 30-Day Adverse Outcomes Following Non-Emergent General Surgical Operations

    PubMed Central

    Gajdos, Csaba; Kile, Deidre; Hawn, Mary T.; Finlayson, Emily; Henderson, William G.; Robinson, Thomas N.

    2014-01-01

    Background While some single center studies have demonstrated that major surgical operations are safe to perform in older adults, most multicenter database studies find advancing age to independently predict adverse postoperative outcomes. We hypothesized that thirty-day postoperative mortality, complications, failure to rescue rates and postoperative length of stay will increase with advancing age. Design Retrospective cohort study. Setting Hospitals participating in the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) Participants Patients undergoing non-emergent major general surgical operations between 2005 and 2008 were studied. Measures Postoperative outcomes of interest were complications occurring within 30 days of the index operation, return to OR within 30 days, failure to rescue after a postoperative complication, post-surgical length of stay and 30 day mortality. Results A total of 165,600 patients were studied. The rates of postoperative mortality, overall morbidity, and each type of postoperative complication increased as age increased. The rates of failure to rescue after each type of postoperative complication also increased with age. Mortality rates in patients ≥80 following renal insufficiency (43.3%), stroke (36.5%), myocardial infarction (35.6%), and pulmonary complications (25-39%) were particularly high. Median postoperative length of stay increased with age following surgical site infection, UTI, pneumonia, return to OR, and overall morbidity, but not after venous thromboembolism, stroke, myocardial infarction, renal insufficiency, failure to wean from the ventilator or reintubations. Conclusion Thirty-day mortality, complications and failure to rescue rates increase with advancing age following non-emergent general surgical operations. Patients over 80 years of age have especially high mortality following renal, cardiovascular, and pulmonary complications. As patient age advances, surgeons need to be

  20. Serum Lactate Predicts Adverse Outcomes in Emergency Department Patients With and Without Infection

    PubMed Central

    Oedorf, Kimie; Day, Danielle E.; Lior, Yotam; Novack, Victor; Sanchez, Leon D.; Wolfe, Richard E.; Kirkegaard, Hans; Shapiro, Nathan I.; Henning, Daniel J.

    2017-01-01

    Introduction Lactate levels are increasingly used to risk stratify emergency department (ED) patients with and without infection. Whether a serum lactate provides similar prognostic value across diseases is not fully elucidated. This study assesses the prognostic value of serum lactate in ED patients with and without infection to both report and compare relative predictive value across etiologies. Methods We conducted a prospective, observational study of ED patients displaying abnormal vital signs (AVS) (heart rate ≥130 bpm, respiratory rate ≥24 bpm, shock index ≥1, and/or systolic blood pressure <90 mmHg). The primary outcome, deterioration, was a composite of acute renal failure, non-elective intubation, vasopressor administration or in-hospital mortality. Results Of the 1,152 patients with AVS who were screened, 488 patients met the current study criteria: 34% deteriorated and 12.5% died. The deterioration rate was 88/342 (26%, 95% CI: 21 – 30%) for lactate < 2.5 mmol/L, 47/90 (52%, 42 – 63%) for lactate 2.5 – 4.0 mmol/L, and 33/46 (72%, 59 – 85%) for lactate >4.0mmol/L. Trended stratified lactate levels were associated with deterioration for both infected (p<0.01) and non-infected (p<0.01) patients. In the logistic regression models, lactate > 4mmol/L was an independent predictor of deterioration for patients with infection (OR 4.8, 95% CI: 1.7 – 14.1) and without infection (OR 4.4, 1.7 – 11.5). Conclusion Lactate levels can risk stratify patients with AVS who have increased risk of adverse outcomes regardless of infection status. PMID:28210362

  1. Unplanned Intensive Care Unit Admission following Elective Surgical Adverse Events: Incidence, Patient Characteristics, Preventability, and Outcome

    PubMed Central

    Meziane, Mohammed; El Jaouhari, Sidi Driss; ElKoundi, Abdelghafour; Bensghir, Mustapha; Baba, Hicham; Ahtil, Redouane; Aboulaala, Khalil; Balkhi, Hicham; Haimeur, Charki

    2017-01-01

    Context: Adverse events (AEs) are a persistent and an important reason for Intensive Care Unit (ICU) admission. They lead to death, disability at the time of discharge, unplanned ICU admission (UIA), and prolonged hospital stay. They impose large financial costs on health-care systems. Aims: This study aimed to determine the incidence, patient characteristics, type, preventability, and outcome of UIA following elective surgical AE. Settings and Design: This is a single-center prospective study. Methods: Analysis of 15,372 elective surgical procedures was performed. We defined UIA as an ICU admission that was not anticipated preoperatively but was due to an AE occurring within 5 days after elective surgery. Statistical Analysis: Descriptive analysis using SPSS software version 18 was used for statistical analysis. Results: There were 75 UIA (0.48%) recorded during the 2-year study period. The average age of patients was 54.64 ± 18.02 years. There was no sex predominance, and the majority of our patients had an American Society of Anesthesiologist classes 1 and 2. Nearly 29% of the UIA occurred after abdominal surgery and 22% after a trauma surgery. Regarding the causes of UIA, we observed that 44 UIA (58.7%) were related to surgical AE, 24 (32%) to anesthetic AE, and 7 (9.3%) to postoperative AE caused by care defects. Twenty-three UIA were judged as potentially preventable (30.7%). UIA was associated with negative outcomes, including increased use of ICU-specific interventions and high mortality rate (20%). Conclusions: Our analysis of UIA is a quality control exercise that helps identify high-risk patient groups and patterns of anesthesia or surgical care requiring improvement.

  2. Clonal Hematopoiesis Associated With Adverse Outcomes After Autologous Stem-Cell Transplantation for Lymphoma.

    PubMed

    Gibson, Christopher J; Lindsley, R Coleman; Tchekmedyian, Vatche; Mar, Brenton G; Shi, Jiantao; Jaiswal, Siddhartha; Bosworth, Alysia; Francisco, Liton; He, Jianbo; Bansal, Anita; Morgan, Elizabeth A; Lacasce, Ann S; Freedman, Arnold S; Fisher, David C; Jacobsen, Eric; Armand, Philippe; Alyea, Edwin P; Koreth, John; Ho, Vincent; Soiffer, Robert J; Antin, Joseph H; Ritz, Jerome; Nikiforow, Sarah; Forman, Stephen J; Michor, Franziska; Neuberg, Donna; Bhatia, Ravi; Bhatia, Smita; Ebert, Benjamin L

    2017-01-09

    Purpose Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition characterized by somatic mutations in the blood of otherwise healthy adults. We hypothesized that in patients undergoing autologous stem-cell transplantation (ASCT) for lymphoma, CHIP at the time of ASCT would be associated with an increased risk of myelodysplastic syndrome and acute myeloid leukemia, collectively termed therapy-related myeloid neoplasm (TMN), and other adverse outcomes. Methods We performed whole-exome sequencing on pre- and post-ASCT samples from 12 patients who developed TMN after autologous transplantation for Hodgkin lymphoma or non-Hodgkin lymphoma and targeted sequencing on cryopreserved aliquots of autologous stem-cell products from 401 patients who underwent ASCT for non-Hodgkin lymphoma between 2003 and 2010. We assessed the effect of CHIP at the time of ASCT on subsequent outcomes, including TMN, cause-specific mortality, and overall survival. Results For six of 12 patients in the exome sequencing cohort, mutations found in the TMN specimen were also detectable in the pre-ASCT specimen. In the targeted sequencing cohort, 120 patients (29.9%) had CHIP at the time of ASCT, which was associated with an increased rate of TMN (10-year cumulative incidence, 14.1% v 4.3% for those with and without CHIP, respectively; P = .002). Patients with CHIP had significantly inferior overall survival compared with those without CHIP (10-year overall survival, 30.4% v 60.9%, respectively; P < .001), including increased risk of death from TMN and cardiovascular disease. Conclusion In patients undergoing ASCT for lymphoma, CHIP at the time of transplantation is associated with inferior survival and increased risk of TMN.

  3. Prenatal Exposure to Tetrachloroethylene-Contaminated Drinking Water and the Risk of Adverse Birth Outcomes

    PubMed Central

    Aschengrau, Ann; Weinberg, Janice; Rogers, Sarah; Gallagher, Lisa; Winter, Michael; Vieira, Veronica; Webster, Thomas; Ozonoff, David

    2008-01-01

    Background Prior studies of prenatal exposure to tetrachloroethylene (PCE) have shown mixed results regarding its effect on birth weight and gestational age. Objectives In this retrospective cohort study we examined whether PCE contamination of public drinking-water supplies in Massachusetts influenced the birth weight and gestational duration of children whose mothers were exposed before the child’s delivery. Methods The study included 1,353 children whose mothers were exposed to PCE-contaminated drinking water and a comparable group of 772 children of unexposed mothers. Birth records were used to identify subjects and provide information on the outcomes. Mothers completed a questionnaire to gather information on residential histories and confounding variables. PCE exposure was estimated using EPANET water distribution system modeling software that incorporated a fate and transport model. Results We found no meaningful associations between PCE exposure and birth weight or gestational duration. Compared with children whose mothers were unexposed during the year of the last menstrual period (LMP), adjusted mean differences in birth weight were 20.9, 6.2, 30.1, and 15.2 g for children whose mothers’ average monthly exposure during the LMP year ranged from the lowest to highest quartile. Similarly, compared with unexposed children, adjusted mean differences in gestational age were −0.2, 0.1, −0.1, and −0.2 weeks for children whose mothers’ average monthly exposure ranged from the lowest to highest quartile. Similar results were observed for two other measures of prenatal exposure. Conclusions These results suggest that prenatal PCE exposure does not have an adverse effect on these birth outcomes at the exposure levels experienced by this population. PMID:18560539

  4. Neurobehavioural and neurodevelopmental effects of pesticide exposures

    PubMed Central

    London, Leslie; Beseler, Cheryl; Bouchard, Maryse F.; Bellinger, David C.; Colosio, Claudio; Grandjean, Philippe; Harari, Raul; Kootbodien, Tahira; Kromhout, Hans; Little, Francesca; Meijster, Tim; Moretto, Angelo; Rohlman, Diane S.; Stallones, Lorann

    2012-01-01

    The association between pesticide exposure and neurobehavioral and neurodevelopmental effects is an area of increasing concern. This symposium brought together participants to explore the neurotoxic effects of pesticides across the lifespan. Endpoints examined included neurobehavioral, affective and neurodevelopmental outcomes amongst occupational (both adolescent and adult workers) and non-occupational populations (children). The symposium discussion highlighted many challenges for researchers concerned with the prevention of neurotoxic illness due to pesticides and generated a number of directions for further research and policy interventions for the protection of human health, highlighting the importance of examining potential long-term effects across the lifespan arising from early adolescent, childhood or pre-natal exposure. PMID:22269431

  5. A Workflow to Investigate Exposure and Pharmacokinetic Influences on High-Throughput in Vitro Chemical Screening Based on Adverse Outcome Pathways

    EPA Science Inventory

    Background: Adverse outcome pathways (AOPs) link adverse effects in individuals or populations to a molecular initiating event (MIE) that can be quantified using in vitro methods. Practical application of AOPs in chemical-specific risk assessment requires incorporation of knowled...

  6. Novel adverse outcome pathways revealed by chemical genetics in a developing marine fish

    PubMed Central

    Sørhus, Elin; Incardona, John P; Furmanek, Tomasz; Goetz, Giles W; Scholz, Nathaniel L; Meier, Sonnich; Edvardsen, Rolf B; Jentoft, Sissel

    2017-01-01

    Crude oil spills are a worldwide ocean conservation threat. Fish are particularly vulnerable to the oiling of spawning habitats, and crude oil causes severe abnormalities in embryos and larvae. However, the underlying mechanisms for these developmental defects are not well understood. Here, we explore the transcriptional basis for four discrete crude oil injury phenotypes in the early life stages of the commercially important Atlantic haddock (Melanogrammus aeglefinus). These include defects in (1) cardiac form and function, (2) craniofacial development, (3) ionoregulation and fluid balance, and (4) cholesterol synthesis and homeostasis. Our findings suggest a key role for intracellular calcium cycling and excitation-transcription coupling in the dysregulation of heart and jaw morphogenesis. Moreover, the disruption of ionoregulatory pathways sheds new light on buoyancy control in marine fish embryos. Overall, our chemical-genetic approach identifies initiating events for distinct adverse outcome pathways and novel roles for individual genes in fundamental developmental processes. DOI: http://dx.doi.org/10.7554/eLife.20707.001 PMID:28117666

  7. Mechanisms of lung fibrosis induced by carbon nanotubes: towards an Adverse Outcome Pathway (AOP).

    PubMed

    Vietti, Giulia; Lison, Dominique; van den Brule, Sybille

    2016-02-29

    Several experimental studies have shown that carbon nanotubes (CNT) can induce respiratory effects, including lung fibrosis. The cellular and molecular events through which these effects develop are, however, not clearly elucidated. The purpose of the present review was to analyze the key events involved in the lung fibrotic reaction induced by CNT and to assess their relationships. We thus address current knowledge and gaps with a view to draft an Adverse Outcome Pathway (AOP) concerning the fibrotic potential of CNT.As for many inhaled particles, CNT can indirectly activate fibroblasts through the release of pro-inflammatory (IL-1β) and pro-fibrotic (PDGF and TGF-β) mediators by inflammatory cells (macrophages and epithelial cells) via the induction of oxidative stress, inflammasome or NF-kB. We also highlight here direct effects of CNT on fibroblasts, which appear as a new mode of toxicity relatively specific for CNT. Direct effects of CNT on fibroblasts include the induction of fibroblast proliferation, differentiation and collagen production via ERK 1/2 or Smad signaling. We also point out the physico-chemical properties of CNT important for their toxicity and the relationship between in vitro and in vivo effects. This knowledge provides evidence to draft an AOP for the fibrogenic activity of CNT, which allows developing simple in vitro models contributing to predict the CNT effects in lung fibrosis, and risk assessment tools for regulatory decision.

  8. Internal exposure dynamics drive the Adverse Outcome Pathways of synthetic glucocorticoids in fish

    NASA Astrophysics Data System (ADS)

    Margiotta-Casaluci, Luigi; Owen, Stewart F.; Huerta, Belinda; Rodríguez-Mozaz, Sara; Kugathas, Subramanian; Barceló, Damià; Rand-Weaver, Mariann; Sumpter, John P.

    2016-02-01

    The Adverse Outcome Pathway (AOP) framework represents a valuable conceptual tool to systematically integrate existing toxicological knowledge from a mechanistic perspective to facilitate predictions of chemical-induced effects across species. However, its application for decision-making requires the transition from qualitative to quantitative AOP (qAOP). Here we used a fish model and the synthetic glucocorticoid beclomethasone dipropionate (BDP) to investigate the role of chemical-specific properties, pharmacokinetics, and internal exposure dynamics in the development of qAOPs. We generated a qAOP network based on drug plasma concentrations and focused on immunodepression, skin androgenisation, disruption of gluconeogenesis and reproductive performance. We showed that internal exposure dynamics and chemical-specific properties influence the development of qAOPs and their predictive power. Comparing the effects of two different glucocorticoids, we highlight how relatively similar in vitro hazard-based indicators can lead to different in vivo risk. This discrepancy can be predicted by their different uptake potential, pharmacokinetic (PK) and pharmacodynamic (PD) profiles. We recommend that the development phase of qAOPs should include the application of species-species uptake and physiologically-based PK/PD models. This integration will significantly enhance the predictive power, enabling a more accurate assessment of the risk and the reliable transferability of qAOPs across chemicals.

  9. Taxonomic applicability of inflammatory cytokines in adverse outcome pathway (AOP) development.

    PubMed

    Angrish, Michelle M; Pleil, Joachim D; Stiegel, Matthew A; Madden, Michael C; Moser, Virginia C; Herr, David W

    2016-01-01

    Cytokines, low-molecular-weight messenger proteins that act as intercellular immunomodulatory signals, have become a mainstream preclinical marker for assessing the systemic inflammatory response to external stressors. The challenge is to quantitate from healthy subjects cytokine levels that are below or at baseline and relate those dynamic and complex cytokine signatures of exposures with the inflammatory and repair pathways. Thus, highly sensitive, specific, and precise analytical and statistical methods are critically important. Investigators at the U.S. Environmental Protection Agency (EPA) have implemented advanced technologies and developed statistics for evaluating panels of inflammatory cytokines in human blood, exhaled breath condensate, urine samples, and murine biological media. Advanced multiplex, bead-based, and automated analytical platforms provided sufficient sensitivity, precision, and accuracy over the traditional enzyme-linked immunosorbent assay (ELISA). Thus, baseline cytokine levels can be quantified from healthy human subjects and animals and compared to an in vivo exposure response from an environmental chemical. Specifically, patterns of cytokine responses in humans exposed to environmental levels of ozone and diesel exhaust, and in rodents exposed to selected pesticides (such as fipronil and carbaryl), were used as case studies to generally assess the taxonomic applicability of cytokine responses. The findings in this study may aid in the application of measureable cytokine markers in future adverse outcome pathway (AOP)-based toxicity testing. Data from human and animal studies were coalesced and the possibility of using cytokines as key events (KE) to bridge species responses to external stressors in an AOP-based framework was explored.

  10. Meconium-Associated Umbilical Vascular Myonecrosis: Correlations with Adverse Outcome and Placental Pathology.

    PubMed

    Cimic, Adela; Baergen, Rebecca N

    2016-01-01

    Intrauterine passage of meconium is common, occurring in approximately 10-15% of term births. Uncommonly, long-standing meconium exposure is associated with umbilical vascular myonecrosis, but few studies have evaluated specific clinical and pathologic features. This is a retrospective study of 481 term placentas: 139 with meconium-associated myonecrosis, 139 with meconium in fetal membranes, only 62 with meconium in the cord without myonecrosis, and 139 controls without meconium. We studied clinical factors, including clinical evidence of meconium discharge, fetal distress, APGAR scores, intrauterine growth restriction (IUGR), and intrauterine fetal demise (IUFD), and histologic factors, including acute chorioamnionitis, umbilical cord complications, uteroplacental malperfusion, fetal thrombosis, chorangiosis, and fetal nucleated red blood cells. Meconium myonecrosis was significantly associated with clinical meconium, fetal distress, IUGR, IUFD, acute chorioamnionitis, cord complications, fetal thrombosis, chorangiosis, and nucleated red blood cells when compared to controls (P < 0.05). Compared to cases with meconium in the membranes only, clinical meconium, fetal distress, IUGR, chorioamnionitis, thrombosis, chorangiosis, and nucleated red blood cells remained significant. Compared to cases with meconium in the cord without myonecrosis, only chorioamnionitis retained significance. In conclusion, myonecrosis was associated with adverse clinical outcome and placental lesions associated with hypoxia. Chorioamnionitis was significantly more common in all meconium groups compared to controls. As myonecrosis is an important lesion, a clinical history of meconium should trigger a meticulous search for meconium and specifically myonecrosis.

  11. SOCIOECONOMIC STATUS AND ADVERSE BIRTH OUTCOMES: A POPULATION-BASED CANADIAN SAMPLE.

    PubMed

    Campbell, Emily E; Gilliland, Jason; Dworatzek, Paula D N; De Vrijer, Barbra; Penava, Debbie; Seabrook, Jamie A

    2017-03-08

    This study assessed the strength of the association between socioeconomic status (SES) and low birth weight (LBW) and preterm birth (PTB) in Southwestern Ontario. Utilizing perinatal and neonatal databases at the London Health Science Centre, maternal postal codes were entered into a Geographic Information System to determine home neighbourhoods. Neighbourhoods were defined by dissemination areas (DAs). Median household income for each DA was extracted from the latest Canadian Census and linked to each mother. All singleton infants born between February 2009 and February 2014 were included. Of 26,654 live singleton births, 6.4% were LBW and 9.7% were PTB. Top risk factors for LBW were: maternal amphetamine use, chronic hypertension and maternal marijuana use (OR respectively: 17.51, 3.18, 2.72); previously diagnosed diabetes, maternal narcotic use and insulin-controlled gestational diabetes predicted PTB (OR respectively: 17.95, 2.69, 2.42). Overall, SES had little impact on adverse birth outcomes, although low maternal education increased the likelihood of a LBW neonate (OR: 1.01).

  12. Periodontal disease and some adverse perinatal outcomes in a cohort of low risk pregnant women

    PubMed Central

    2010-01-01

    Objective To evaluate the association of periodontal disease (PD) in pregnancy with some adverse perinatal outcomes. Method This cohort study included 327 pregnant women divided in groups with or without PD. Indexes of plaque and gingival bleeding on probing, probing pocket depth, clinical attachment level and gingival recession were evaluated at one periodontal examination below 32 weeks of gestation. The rates of preterm birth (PTB), low birth weight (LBW), small for gestational age (SGA) neonates and prelabor rupture of membranes (PROM) were evaluated using Risk Ratios (95%CI) and Population Attributable Risk Fractions. Results PD was associated with a higher risk of PTB (RRadj. 3.47 95%CI 1.62-7.43), LBW (RRadj. 2.93 95%CI 1.36-6.34) and PROM (RRadj. 2.48 95%CI 1.35-4.56), but not with SGA neonates (RR 2.38 95%CI 0.93 - 6.10). Conclusions PD was a risk factor for PT, LBW and PROM among Brazilian low risk pregnant women. PMID:21047427

  13. Inhibition of spawning in zebrafish (Danio rerio): Adverse outcome pathways of quinacrine and ethinylestradiol.

    PubMed

    Cosme, Madelyne M; Lister, Andrea L; Van Der Kraak, Glen

    2015-08-01

    This study determined the effects of the estrogen receptor agonist ethinylestradiol (EE2) and the phospholipase A2 inhibitor quinacrine (QUIN) on the pathways controlling follicular development, steroidogenesis, oocyte maturation, ovulation and spawning success in adult zebrafish. Both EE2 and QUIN inhibited spawning but did so through different mechanisms. EE2 affected follicular development (reduced ovarian size and reduction in the proportion of cortical alveolus, vitellogenic and mature follicle stages), steroidogenesis (reduced expression of aromatase), maturation (reduced luteinizing hormone receptor expression) and ovulation (reduced expression of cytosolic phospholipase A2 and the nuclear progesterone receptor). Although EE2 alters the proportion of follicle stages within the ovary, the downregulation of gene expression as a consequence of EE2 exposure was primarily due to a decline in expression of the genes of interest in vitellogenic and mature ovarian follicles. QUIN targeted ovulation via a reduction of the steroid 17α,20β dihydroxy-4-prenen-3-one (17α,20β-P) and decreased expression of the prostaglandin metabolizing enzyme cyclooxygenase 2. This study demonstrates the usefulness in defining the impacts of toxicants at the molecular and cellular, organ and whole organism level and how connections between these impacts can be used to describe the adverse outcome pathways (AOPs) that mediate toxicant action. Histological analysis and gene expression were effective tools in defining the AOPs of QUIN and EE2 while the measurement of reproductive hormones level did not provide much valuable information regarding the toxicant's mode of action.

  14. Change in Motor Function and Adverse Health Outcomes in Older African Americas

    PubMed Central

    Buchman, Aron S.; Wilson, Robert S.; Leurgans, Sue E.; Bennett, David A.; Barnes, Lisa L.

    2015-01-01

    Objective We tested whether declining motor function accelerates with age in older African Americans. Methods Eleven motor performances were assessed annually in 513 older African Americans. Results During follow-up of 5 years, linear mixed-effect models showed that motor function declined by about 0.03 units/yr (Estimate, −0.026, p<0.001); about 4% more rapidly for each additional year of age at baseline. A proportional hazard model showed that both baseline motor function level and its rate of change were independent predictors of death and incident disability (all p’s <0.001). These models showed that the additional annual amount of motor decline in 85 year old persons at baseline versus 65 year old persons was associated with a 1.5-fold higher rate of death and a 3-fold higher rate of developing Katz disability. Conclusions The rate of declining motor function accelerates with increasing age and its rate of decline predicts adverse health outcomes in older African Americans. PMID:26209439

  15. Risk of adverse pregnancy and perinatal outcomes after high technology infertility treatment: a comprehensive systematic review.

    PubMed

    Palomba, Stefano; Homburg, Roy; Santagni, Susanna; La Sala, Giovanni Battista; Orvieto, Raoul

    2016-11-04

    In the literature, there is growing evidence that subfertile patients who conceived after infertility treatments have an increased risk of pregnancy and perinatal complications and this is particularly true for patients who conceived through use of high technology infertility treatments. Moreover, high technology infertility treatments include many concomitant clinical and biological risk factors. This review aims to summarize in a systematic fashion the current evidence regarding the relative effect of the different procedures for high technology infertility treatments on the risk of adverse pregnancy and perinatal outcome. A literature search up to August 2016 was performed in IBSS, SocINDEX, Institute for Scientific Information, PubMed, Web of Science and Google Scholar and an evidence-based hierarchy was used to determine which articles to include and analyze. Data on prepregnancy maternal factors, low technology interventions, specific procedures for male factor, ovarian tissue/ovary and uterus transplantation, and chromosomal abnormalities and malformations of the offspring were excluded. The available evidences were analyzed assessing the level and the quality of evidence according to the Oxford Centre for Evidence-Based Medicine guidelines and the Grading of Recommendations Assessment, Development, and Evaluation system, respectively. Current review highlights that every single procedure of high technology infertility treatments can play a crucial role in increasing the risk of pregnancy and perinatal complications. Due to the suboptimal level and quality of the current evidence, further well-designed studies are needed.

  16. Adverse Outcomes Among Homeless Adolescents and Young Adults Who Report a History of Traumatic Brain Injury

    PubMed Central

    Harpin, Scott B.; Grubenhoff, Joseph A.; Rivara, Frederick P.

    2014-01-01

    Objectives. We examined the prevalence of self-reported traumatic brain injury (TBI) among homeless young people and explored whether sociodemographic characteristics, mental health diagnoses, substance use, exposure to violence, or difficulties with activities of daily living (ADLs) were associated with TBI. Methods. We analyzed data from the Wilder Homelessness Study, in which participants were recruited in 2006 and 2009 from streets, shelters, and locations in Minnesota that provide services to homeless individuals. Participants completed 30-minute interviews to collect information about history of TBI, homelessness, health status, exposure to violence (e.g., childhood abuse, assault), and other aspects of functioning. Results. Of the 2732 participating adolescents and young adults, 43% reported a history of TBI. Participants with TBI became homeless at a younger age and were more likely to report mental health diagnoses, substance use, suicidality, victimization, and difficulties with ADLs. The majority of participants (51%) reported sustaining their first injury prior to becoming homeless or at the same age of their first homeless episode (10%). Conclusions. TBI occurs frequently among homeless young people and is a marker of adverse outcomes such as mental health difficulties, suicidal behavior, substance use, and victimization. PMID:25122029

  17. Adverse outcome pathway and risks of anticoagulant rodenticides to predatory wildlife.

    PubMed

    Rattner, Barnett A; Lazarus, Rebecca S; Elliott, John E; Shore, Richard F; van den Brink, Nico

    2014-01-01

    Despite a long history of successful use, routine application of some anticoagulant rodenticides (ARs) may be at a crossroad due to new regulatory guidelines intended to mitigate risk. An adverse outcome pathway for ARs was developed to identify information gaps and end points to assess the effectiveness of regulations. This framework describes chemical properties of ARs, established macromolecular interactions by inhibition of vitamin K epoxide reductase, cellular responses including altered clotting factor processing and coagulopathy, organ level effects such as hemorrhage, organism responses with linkages to reduced fitness and mortality, and potential consequences to predator populations. Risk assessments have led to restrictions affecting use of some second-generation ARs (SGARs) in North America. While the European regulatory community highlighted significant or unacceptable risk of ARs to nontarget wildlife, use of SGARs in most EU member states remains authorized due to public health concerns and the absence of safe alternatives. For purposes of conservation and restoration of island habitats, SGARs remain a mainstay for eradication of invasive species. There are significant data gaps related to exposure pathways, comparative species sensitivity, consequences of sublethal effects, potential hazards of greater AR residues in genetically resistant prey, effects of low-level exposure to multiple rodenticides, and quantitative data on the magnitude of nontarget wildlife mortality.

  18. Internal exposure dynamics drive the Adverse Outcome Pathways of synthetic glucocorticoids in fish

    PubMed Central

    Margiotta-Casaluci, Luigi; Owen, Stewart F.; Huerta, Belinda; Rodríguez-Mozaz, Sara; Kugathas, Subramanian; Barceló, Damià; Rand-Weaver, Mariann; Sumpter, John P.

    2016-01-01

    The Adverse Outcome Pathway (AOP) framework represents a valuable conceptual tool to systematically integrate existing toxicological knowledge from a mechanistic perspective to facilitate predictions of chemical-induced effects across species. However, its application for decision-making requires the transition from qualitative to quantitative AOP (qAOP). Here we used a fish model and the synthetic glucocorticoid beclomethasone dipropionate (BDP) to investigate the role of chemical-specific properties, pharmacokinetics, and internal exposure dynamics in the development of qAOPs. We generated a qAOP network based on drug plasma concentrations and focused on immunodepression, skin androgenisation, disruption of gluconeogenesis and reproductive performance. We showed that internal exposure dynamics and chemical-specific properties influence the development of qAOPs and their predictive power. Comparing the effects of two different glucocorticoids, we highlight how relatively similar in vitro hazard-based indicators can lead to different in vivo risk. This discrepancy can be predicted by their different uptake potential, pharmacokinetic (PK) and pharmacodynamic (PD) profiles. We recommend that the development phase of qAOPs should include the application of species-species uptake and physiologically-based PK/PD models. This integration will significantly enhance the predictive power, enabling a more accurate assessment of the risk and the reliable transferability of qAOPs across chemicals. PMID:26917256

  19. Adverse pregnancy outcomes in relation to water contamination, Santa Clara County, California, 1980-1981

    SciTech Connect

    Deane, M.; Swan, S.H.; Harris, J.A.; Epstein, D.M.; Neutra, R.R.

    1989-05-01

    An epidemiologic study was conducted to investigate a suspected cluster of adverse outcomes of pregnancies conceived in 1980-1981 among women who resided in a census tract in Santa Clara County, California that was thought to be exposed to drinking water from a well contaminated by an organic solvent, trichloroethane. A comparison census tract that received water from a different source was selected on the basis of demographic comparability. The cluster was confirmed; the odds ratio for spontaneous abortion was 2.3 (95% confidence interval (Cl) 1.3-4.2) after adjustment by multiple logistic regression for maternal risk factors, including maternal age, alcohol consumption, smoking, and prior fetal loss. The relative risk for congenital malformations was 3.1 (95% Cl 1.1-10.4). Because of the lack of precise information on the timing and extent of contamination, the pattern of spontaneous abortion rates throughout the study period cannot be used to either support or refute a causal inference.

  20. Adverse outcome pathway and risks of anticoagulant rodenticides to predatory wildlife

    USGS Publications Warehouse

    Rattner, Barnett A.; Lazarus, Rebecca; Elliott, John E.; Shore, Richard F.; van den Brink, Nico

    2014-01-01

    Despite a long history of successful use, routine application of some anticoagulant rodenticides (ARs) may be at a crossroad due to new regulatory guidelines intended to mitigate risk. An adverse outcome pathway for ARs was developed to identify information gaps and end points to assess the effectiveness of regulations. This framework describes chemical properties of ARs, established macromolecular interactions by inhibition of vitamin K epoxide reductase, cellular responses including altered clotting factor processing and coagulopathy, organ level effects such as hemorrhage, organism responses with linkages to reduced fitness and mortality, and potential consequences to predator populations. Risk assessments have led to restrictions affecting use of some second-generation ARs (SGARs) in North America. While the European regulatory community highlighted significant or unacceptable risk of ARs to nontarget wildlife, use of SGARs in most EU member states remains authorized due to public health concerns and the absence of safe alternatives. For purposes of conservation and restoration of island habitats, SGARs remain a mainstay for eradication of invasive species. There are significant data gaps related to exposure pathways, comparative species sensitivity, consequences of sublethal effects, potential hazards of greater AR residues in genetically resistant prey, effects of low-level exposure to multiple rodenticides, and quantitative data on the magnitude of nontarget wildlife mortality.

  1. Systemic effects of periodontitis: Lessons learned from research on atherosclerotic vascular disease and adverse pregnancy outcomes

    PubMed Central

    Papapanou, Panos N.

    2015-01-01

    Studies conducted over the past 25 years have focused on the role of periodontitis, an inflammatory condition of microbial etiology that destroys the tooth supporting tissues, as a systemic inflammatory stressor that can act as an independent risk factor of atherosclerotic vascular disease (AVSD) and adverse pregnancy outcomes (APOs). It has been suggested that periodontitis-associated bacteremias and systemic dissemination of inflammatory mediators produced in the periodontal tissues may result in systemic inflammation and endothelial dysfunction, while bacteria of oral origin may translocate into the feto-placental unit. Epidemiologic studies largely support an association between periodontitis and ASVD / APOs independent of known confounders; indeed, periodontitis has been shown to confer statistically significantly elevated risk for clinical events associated with ASVD and APOs in multivariable adjustments. On the other hand, intervention studies demonstrate that although periodontal therapy reduces systemic inflammation and improves endothelial function, it has no positive effect on the incidence of APOs. Studies of the effects of periodontal interventions on ASVD-related clinical events are lacking. This review summarizes key findings from mechanistic, association and intervention studies and attempts to reconcile the seemingly contradictory evidence that originates from different lines of investigation. PMID:26388299

  2. Paternal military service in Vietnam and the risk of late adverse pregnancy outcomes.

    PubMed Central

    Aschengrau, A; Monson, R R

    1990-01-01

    To investigate the relationship between paternal military service in Vietnam and the risk of late adverse pregnancy outcomes, we conducted a case-control study of women who delivered infants from August 1977 until March 1980 at Boston Hospital for Women. Paternal military service history among 857 congenital anomaly cases, 61 stillbirth cases, and 48 neonatal death cases were compared with that of 998 normal controls. Military service veterans were identified by crossmatching identifying information from obstetric records with state and national military records. After controlling for confounding variables, we found that the Vietnam veterans' relative risk of fathering an infant with one or more major malformations was 1.7 (95% CI = 0.8, 3.5) compared to non-Vietnam veterans. The increased risk was present in several organ systems and did not seem to be related to a particular type of defect. No associations or highly unstable associations were found between paternal military service in Vietnam and the occurrence of congenital anomalies overall, minor malformations, normal variants, stillbirths, and neonatal deaths. These findings should be viewed with caution since maternal and delivery characteristics appear to have contributed to the etiology of several of the major malformations among the Vietnam veterans' children. PMID:2400033

  3. Advanced paternal age effects in neurodevelopmental disorders—review of potential underlying mechanisms

    PubMed Central

    Janecka, M; Mill, J; Basson, M A; Goriely, A; Spiers, H; Reichenberg, A; Schalkwyk, L; Fernandes, C

    2017-01-01

    Multiple epidemiological studies suggest a relationship between advanced paternal age (APA) at conception and adverse neurodevelopmental outcomes in offspring, particularly with regard to increased risk for autism and schizophrenia. Conclusive evidence about how age-related changes in paternal gametes, or age-independent behavioral traits affect neural development is still lacking. Recent evidence suggests that the origins of APA effects are likely to be multidimensional, involving both inherited predisposition and de novo events. Here we provide a review of the epidemiological and molecular findings to date. Focusing on the latter, we present the evidence for genetic and epigenetic mechanisms underpinning the association between late fatherhood and disorder in offspring. We also discuss the limitations of the APA literature. We propose that different hypotheses relating to the origins of the APA effects are not mutually exclusive. Instead, multiple mechanisms likely contribute, reflecting the etiological complexity of neurodevelopmental disorders. PMID:28140401

  4. Do sugar-sweetened beverages cause adverse health outcomes in children? A systematic review protocol

    PubMed Central

    2014-01-01

    Background Cardiovascular disease and type 2 diabetes are examples of chronic diseases that impose significant morbidity and mortality in the general population worldwide. Most chronic diseases are associated with underlying preventable risk factors, such as elevated blood pressure, high blood glucose or glucose intolerance, high lipid levels, physical inactivity, excessive sedentary behaviours, and overweight/obesity. The occurrence of intermediate outcomes during childhood increases the risk of disease in adulthood. Sugar-sweetened beverages are known to be significant sources of additional caloric intake, and given recent attention to their contribution in the development of chronic diseases, a systematic review is warranted. We will assess whether the consumption of sugar-sweetened beverages in children is associated with adverse health outcomes and what the potential moderating factors are. Methods/Design Of interest are studies addressing sugar-sweetened beverage consumption, taking a broad perspective. Both direct consumption studies as well as those evaluating interventions that influence consumption (e.g. school policy, educational) will be relevant. Non-specific or multi-faceted behavioural, educational, or policy interventions may also be included subject to the level of evidence that exists for the other interventions/exposures. Comparisons of interest and endpoints of interest are pre-specified. We will include randomized controlled trials, controlled clinical trials, interrupted time series studies, controlled before-after studies, prospective and retrospective comparative cohort studies, case–control studies, and nested case–control designs. The MEDLINE®, Embase, The Cochrane Library, CINAHL, ERIC, and PsycINFO® databases and grey literature sources will be searched. The processes for selecting studies, abstracting data, and resolving conflicts are described. We will assess risk of bias using design-specific tools. To determine sets of

  5. Risk of adverse birth outcomes in populations living near landfill sites

    PubMed Central

    Elliott, Paul; Briggs, David; Morris, Sara; de Hoogh, Cornelis; Hurt, Christopher; Jensen, Tina Kold; Maitland, Ian; Richardson, Sylvia; Wakefield, Jon; Jarup, Lars

    2001-01-01

    Objective To investigate the risk of adverse birth outcomes associated with residence near landfill sites in Great Britain. Design Geographical study of risks of adverse birth outcomes in populations living within 2 km of 9565 landfill sites operational at some time between 1982 and 1997 (from a total of 19 196 sites) compared with those living further away. Setting Great Britain. Subjects Over 8.2 million live births, 43 471 stillbirths, and 124 597 congenital anomalies (including terminations). Main outcome measures All congenital anomalies combined, some specific anomalies, and prevalence of low and very low birth weight (<2500 g and <1500 g). Results For all anomalies combined, relative risk of residence near landfill sites (all waste types) was 0.92 (99% confidence interval 0.907 to 0.923) unadjusted, and 1.01 (1.005 to 1.023) adjusted for confounders. Adjusted risks were 1.05 (1.01 to 1.10) for neural tube defects, 0.96 (0.93 to 0.99) for cardiovascular defects, 1.07 (1.04 to 1.10) for hypospadias and epispadias (with no excess of surgical correction), 1.08 (1.01 to 1.15) for abdominal wall defects, 1.19 (1.05 to 1.34) for surgical correction of gastroschisis and exomphalos, and 1.05 (1.047 to 1.055) and 1.04 (1.03 to 1.05) for low and very low birth weight respectively. There was no excess risk of stillbirth. Findings for special (hazardous) waste sites did not differ systematically from those for non-special sites. For some specific anomalies, higher risks were found in the period before opening compared with after opening of a landfill site, especially hospital admissions for abdominal wall defects. Conclusions We found small excess risks of congenital anomalies and low and very low birth weight in populations living near landfill sites. No causal mechanisms are available to explain these findings, and alternative explanations include data artefacts and residual confounding. Further studies are needed to help differentiate between the various

  6. Discovering and annotating fish early life-stage (FELS) adverse outcome pathways: Putting the research strategy into practice

    EPA Science Inventory

    In May 2012, a HESI-sponsored expert workshop yielded a proposed research strategy for systematically discovering, characterizing, and annotating fish early life-stage (FELS) adverse outcome pathways (AOPs) as well as prioritizing AOP development in light of current restrictions ...

  7. Building an Adverse Outcome Pathway Framework through HTS Data and Literature Mining Integration (FutureToxII)

    EPA Science Inventory

    Interpreting EPA’s ToxCast in vitro assay data in the context of Adverse Outcome Pathway (AOP) development is a significant challenge. While chemical activation in these assays may shed light on the molecular initiating event, the downstream effect of these activities at higher ...

  8. Increasing scientific confidence in adverse outcome pathways: Application of tailored Bradford-Hill considerations for evaluating weight of evidence

    EPA Science Inventory

    Systematic consideration of scientific support is a critical element in developing and, ultimately, using adverse outcome pathways (AOPs) for various regulatory applications. Though weight of evidence (WoE) analysis has been proposed as a basis for assessment of the maturity and...

  9. Weight of evidence evaluation of adverse outcome pathways converging at impaired vitellogenin synthesis leading to reproductive impairment

    EPA Science Inventory

    Adverse outcome pathways (AOPs) provide a framework that supports greater use of mechanistic data measured at lower levels of biological organization as a basis for regulatory decision-making. However, it is recognized that different types of regulatory applications and decisions...

  10. Adverse Outcome Pathway (AOP) for a Mutagenic Mode of Action for Cancer: AFB1 and Hepatocellular Carcinoma (HCC)

    EPA Science Inventory

    AOPs provide a framework to describe a sequence of measureable key events (KEs), beginning with a molecular initiating event (MIE), followed by a series of identified KEs linked to one another by KE Relationships (KERs), all anchored by a specific adverse outcome (AO). Each KE/KE...

  11. Physiologically-based Pharmacokinetic(PBPK) Models Application to Screen Environmental Hazards Related to Adverse Outcome Pathways(AOPs)

    EPA Science Inventory

    PBPK models are useful in estimating exposure levels based on in vitro to in vivo extrapolation (IVIVE) calculations. Linkage of large sets of chemically screened vitro signature effects to in vivo adverse outcomes using IVIVE is central to the concepts of toxicology in the 21st ...

  12. Using adverse outcome pathway analysis to guide development of high-throughput screening assays for thyroid-disruptors

    EPA Science Inventory

    Using Adverse Outcome Pathway Analysis to Guide Development of High-Throughput Screening Assays for Thyroid-Disruptors Katie B. Paul1,2, Joan M. Hedge2, Daniel M. Rotroff4, Kevin M. Crofton4, Michael W. Hornung3, Steven O. Simmons2 1Oak Ridge Institute for Science Education Post...

  13. Microbiota and neurodevelopmental windows: implications for brain disorders.

    PubMed

    Borre, Yuliya E; O'Keeffe, Gerard W; Clarke, Gerard; Stanton, Catherine; Dinan, Timothy G; Cryan, John F

    2014-09-01

    Gut microbiota is essential to human health, playing a major role in the bidirectional communication between the gastrointestinal tract and the central nervous system. The microbiota undergoes a vigorous process of development throughout the lifespan and establishes its symbiotic rapport with the host early in life. Early life perturbations of the developing gut microbiota can impact neurodevelopment and potentially lead to adverse mental health outcomes later in life. This review compares the parallel early development of the intestinal microbiota and the nervous system. The concept of parallel and interacting microbial-neural critical windows opens new avenues for developing novel microbiota-modulating based therapeutic interventions in early life to combat neurodevelopmental deficits and brain disorders.

  14. Maternal adverse effects of different antenatal magnesium sulphate regimens for improving maternal and infant outcomes: a systematic review

    PubMed Central

    2013-01-01

    Background Antenatal magnesium sulphate, widely used in obstetrics to improve maternal and infant outcomes, may be associated with adverse effects for the mother sufficient for treatment cessation. This systematic review aimed to quantify maternal adverse effects attributed to treatment, assess how adverse effects vary according to different regimens, and explore women’s experiences with this treatment. Methods Bibliographic databases were searched from their inceptions to July 2012 for studies of any design that reported on maternal adverse effects associated with antenatal magnesium sulphate given to improve maternal or infant outcomes. Primary outcomes were life-threatening adverse effects of treatment (death, cardiac arrest, respiratory arrest). For randomised controlled trials, data were meta-analysed, and risk ratios (RR) pooled using fixed-effects or random-effects models. For non-randomised studies, data were tabulated by design, and presented as RR, odds ratios or percentages, and summarised narratively. Results A total of 143 publications were included (21 randomised trials, 15 non-randomised comparative studies, 32 case series and 75 reports of individual cases), of mixed methodological quality. Compared with placebo or no treatment, magnesium sulphate was not associated with an increased risk of maternal death, cardiac arrest or respiratory arrest. Magnesium sulphate significantly increased the risk of 'any adverse effects’ overall (RR 4.62, 95% CI 2.42-8.83; 4 trials, 13,322 women), and treatment cessation due to adverse effects (RR 2.77; 95% CI 2.32-3.30; 5 trials, 13,666 women). Few subgroup differences were observed (between indications for use and treatment regimens). In one trial, a lower dose regimen (2 g/3 hours) compared with a higher dose regimen (5 g/4 hours) significantly reduced treatment cessation (RR 0.05; 95% CI 0.01-0.39, 126 women). Adverse effect estimates from studies of other designs largely supported data from randomised

  15. Synchronous Aberrant Cerebellar and Opercular Development in Fetuses and Neonates with Congenital Heart Disease: Correlation with Early Communicative Neurodevelopmental Outcomes, Initial Experience

    PubMed Central

    Wong, A.; Chavez, T.; O'Neil, S.; Votava-Smith, J.; Miller, D.; delCastillo, S.; Panigrahy, A.; Paquette, L.

    2017-01-01

    Patients with congenital heart disease (CHD) demonstrate multidomain cognitive delays. Cingulo-opercular and cerebellar brain networks are critical to language functions. This is a description of our initial experience aiming to identify an anatomic correlate for CHD patients with expressive language delays. Fetal CHD patients, prospectively enrolled, underwent serial fetal (1.5T), postnatal pre- and postoperative (3T) MRI. Non-CHD patients were enrolled retrospectively from the same epoch. Comparable fetal and neonatal T2 contrast was used for manual linear cross-sectional measurement. Multivariable analysis was used for adjustments and curve fitting. Neurodevelopment was assessed with Battelle Developmental Inventory, 2nd ed. between 9 and 36 months of age. This interim analysis included patients from our longitudinal CHD study who had fetal, postnatal imaging and neurodevelopmental data—yielding a total of 62 mothers (11 CHD fetuses and 51 non-CHD fetuses). Altered brain trajectories were seen in selected cerebellar and opercular measurements in CHD patients compared with the non-CHD group. Smaller inferior cerebellar vermis measurements were associated with multiple communication-related abnormalities. Altered early structural development of the cerebellum and operculum is present in patients with CHD, which correlates with specific neurodevelopmental abnormalities. PMID:28210520

  16. Impact of Different Childhood Adversities on 1-Year Outcomes of Psychotic Disorder in the Genetics and Psychosis Study.

    PubMed

    Trotta, Antonella; Murray, Robin M; David, Anthony S; Kolliakou, Anna; O'Connor, Jennifer; Di Forti, Marta; Dazzan, Paola; Mondelli, Valeria; Morgan, Craig; Fisher, Helen L

    2016-03-01

    While the role of childhood adversity in increasing the risk of psychosis has been extensively investigated, it is not clear what the impact of early adverse experiences is on the outcomes of psychotic disorders. Therefore, we investigated associations between childhood adversity and 1-year outcomes in 285 first-presentation psychosis patients. Exposure to childhood adversity prior to 17 years of age was assessed using the Childhood Experience of Care and Abuse Questionnaire. Data on illness course, symptom remission, length of psychiatric hospitalization, compliance with medication, employment, and relationship status were extracted from clinical records for the year following first contact with mental health services for psychosis. Seventy-one percent of patients reported exposure to at least 1 type of childhood adversity (physical abuse, sexual abuse, parental separation, parental death, disrupted family arrangements, or being taken into care). No robust associations were found between childhood adversity and illness course or remission. However, childhood physical abuse was associated with almost 3-fold increased odds of not being in a relationship at 1-year follow-up compared to patients who did not report such adverse experiences. There was also evidence of a significant association between parental separation in childhood and longer admissions to psychiatric wards during 1-year follow-up and 2-fold increased odds of noncompliance with medication compared to those not separated from their parents. Therefore, our findings suggest that there may be some specificity in the impact of childhood adversity on service use and social functioning among psychosis patients over the first year following presentation to mental health services.

  17. A meta-analysis of exposure to particulate matter and adverse birth outcomes

    PubMed Central

    2015-01-01

    Objectives The objective of this study was to conduct a systematic review to provide summarized evidence on the association between maternal exposure to particulate air pollution and birth weight (BW) and preterm birth (PTB) after taking into consideration the potential confounding effect of maternal smoking. Methods We systematically searched all published cohort and case-control studies examining BW and PTB association with particulate matter (PM, less than or equal to 2.5μm and 10.0 μm in diameter, PM2.5 and PM10, respectively) from PubMed and Web of Science, from January 1980 to April 2015. We extracted coefficients for continuous BW and odds ratio (OR) for PTB from each individual study, and meta-analysis was used to combine the coefficient and OR of individual studies. The methodological quality of individual study was assessed using a standard protocol proposed by Downs and Black. Forty-four studies met the inclusion criteria. Results In random effects meta-analyses, BW as a continuous outcome was negativelyassociated with 10 μg/m3 increase in PM10 (-10.31 g; 95% confidence interval [CI], -13.57 to -3.13 g; I-squared=0%, p=0.947) and PM2.5 (-22.17 g; 95% CI, -37.93 to -6.41 g; I-squared=92.3%, p <0.001) exposure during entire pregnancy, adjusted for maternal smoking. A significantly increased risk of PTB per 10 μg/m3 increase in PM10 (OR, 1.23; 95% CI, 1.04 to 1.41; I-squared=0%, p =0.977) and PM2.5 (OR, 1.14; 95% CI, 1.06 to 1.22; I-squared=92.5%, p <0.001) exposure during entire pregnancy was observed. Effect size of change in BW per 10 μg/m3 increase in PM tended to report stronger associations after adjustment for maternal smoking. Conclusions While this systematic review supports an adverse impact of maternal exposure to particulate air pollution on birth outcomes, variation in effects by exposure period and sources of heterogeneity between studies should be further explored. PMID:26796890

  18. Do sugar-sweetened beverages cause adverse health outcomes in adults? A systematic review protocol

    PubMed Central

    2014-01-01

    Background Chronic diseases, such as cardiovascular disease and type 2 diabetes, impose significant burden to public health. Most chronic diseases are associated with underlying preventable risk factors, such as elevated blood pressure, blood glucose, and lipids, physical inactivity, excessive sedentary behaviours, overweight and obesity, and tobacco usage. Sugar-sweetened beverages are known to be significant sources of additional caloric intake, and given recent attention to their contribution in the development of chronic diseases, a systematic review is warranted. We will assess whether the consumption of sugar-sweetened beverages in adults is associated with adverse health outcomes and what the potential moderating factors are. Methods/Design Of interest are studies addressing sugar-sweetened beverage consumption, taking a broad perspective. Both direct consumption studies as well as those evaluating interventions that influence consumption (e.g. school policy, educational) will be relevant. Non-specific or multi-faceted behavioural, educational, or policy interventions may also be included subject to the level of evidence that exists for the other interventions/exposures. Comparisons of interest and endpoints of interest are pre-specified. We will include randomized controlled trials, controlled clinical trials, interrupted time series studies, controlled before-after studies, prospective and retrospective comparative cohort studies, case-control studies, and nested case-control designs. The MEDLINE®, Embase, The Cochrane Library, CINAHL, ERIC, and PsycINFO® databases and grey literature sources will be searched. The processes for selecting studies, abstracting data, and resolving conflicts are described. We will assess risk of bias using design-specific tools. To determine sets of confounding variables that should be adjusted for, we have developed causal directed acyclic graphs and will use those to inform our risk of bias assessments. Meta-analysis will

  19. Applying the skin sensitisation adverse outcome pathway (AOP) to quantitative risk assessment.

    PubMed

    Maxwell, Gavin; MacKay, Cameron; Cubberley, Richard; Davies, Michael; Gellatly, Nichola; Glavin, Stephen; Gouin, Todd; Jacquoilleot, Sandrine; Moore, Craig; Pendlington, Ruth; Saib, Ouarda; Sheffield, David; Stark, Richard; Summerfield, Vicki

    2014-02-01

    As documented in the recent OECD report 'the adverse outcome pathway for skin sensitisation initiated by covalent binding to proteins' (OECD, 2012), the chemical and biological events driving the induction of human skin sensitisation have been investigated for many years and are now well understood. Several non-animal test methods have been developed to predict sensitiser potential by measuring the impact of chemical sensitisers on these key events (Adler et al., 2011; Maxwell et al., 2011); however our ability to use these non-animal datasets for risk assessment decision-making (i.e. to establish a safe level of human exposure for a sensitising chemical) remains limited and a more mechanistic approach to data integration is required to address this challenge. Informed by our previous efforts to model the induction of skin sensitisation (Maxwell and MacKay, 2008) we are now developing two mathematical models ('total haptenated protein' model and 'CD8(+) T cell response' model) that will be linked to provide predictions of the human CD8(+) T cell response for a defined skin exposure to a sensitising chemical. Mathematical model development is underpinned by focussed clinical or human-relevant research activities designed to inform/challenge model predictions whilst also increasing our fundamental understanding of human skin sensitisation. With this approach, we aim to quantify the relationship between the dose of sensitiser applied to the skin and the extent of the hapten-specific T cell response that would result. Furthermore, by benchmarking our mathematical model predictions against clinical datasets (e.g. human diagnostic patch test data), instead of animal test data, we propose that this approach could represent a new paradigm for mechanistic toxicology.

  20. The adverse outcome pathway concept: A basis for developing regulatory decision-making tools.

    PubMed

    Delrue, Nathalie; Sachana, Magdalini; Sakuratani, Yuki; Gourmelon, Anne; Leinala, Eeva; Diderich, Robert

    2016-10-01

    The Adverse Outcome Pathway (AOP) concept is expected to guide risk assessors in their work to use all existing information on the effects of chemicals on humans and wildlife, and to target the generation of additional information to the regulatory objective. AOPs will therefore be used in the Organisation for Economic Co-operation and Development (OECD) chemical safety programme, as underlying scientific rationales for the development of alternative methods for hazard assessment, such as read-across, in vitro test methods or the development of integrated testing strategies that have the potential to replace animal tests. As a proof-of-concept, the OECD has developed an AOP for skin sensitisation, and as a follow-up has: a) implemented the AOP into the OECD QSAR Toolbox, so that information related to the Key Events (KEs) in the AOP can be used to group chemicals that are expected to act by the same mechanism and hence have the same skin sensitisation potential; b) developed alternative test methods for the KEs, so that ultimately chemicals can be tested for skin sensitisation without the use of animal tests. The development of integrated testing strategies based on the AOP is ongoing. Building on this proof-of-concept, the OECD has launched an AOP development programme with a first batch of AOPs published in 2016. A number of IT tools, which together form an AOP Knowledge Base, are at various stages of development, and support the construction of AOPs and their use in the development of integrated approaches for testing and assessment. Following the publication of the first batch of AOPs, OECD member countries will decide on priorities for their use in supporting the development of tools for regulatory use.

  1. Maternal Factors and Adverse Perinatal Outcomes in Women with Preeclampsia in Maceió, Alagoas

    PubMed Central

    de Oliveira, Alane Cabral Menezes; Santos, Arianne Albuquerque; Bezerra, Alexandra Rodrigues; de Barros, Amanda Maria Rocha; Tavares, Myrian Cicyanne Machado

    2016-01-01

    Background Preeclampsia has been associated with several risk factors and events. However, it still deserves further investigation, considering the multitude of related factors that affect different populations. Objective To evaluate the maternal factors and adverse perinatal outcomes in a cohort of pregnant women with preeclampsia receiving care in the public health network of the city of Maceió. Methods Prospective cohort study carried out in 2014 in the public health network of the city with a sample of pregnant women calculated based on a prevalence of preeclampsia of 17%, confidence level of 90%, power of 80%, and ratio of 1:1. We applied a questionnaire to collect socioeconomic, personal, and anthropometric data, and retrieved perinatal variables from medical records and certificates of live birth. The analysis was performed with Poisson regression and chi-square test considering p values < 0.05 as significant. Results We evaluated 90 pregnant women with preeclampsia (PWP) and 90 pregnant women without preeclampsia (PWoP). A previous history of preeclampsia (prevalence ratio [PR] = 1.57, 95% confidence interval [95% CI] 1.47 - 1.67, p = 0.000) and black skin color (PR = 1.15, 95% CI 1.00 - 1.33, p = 0.040) were associated with the occurrence of preeclampsia. Among the newborns of PWP and PWoP, respectively, 12.5% and 13.1% (p = 0.907) were small for gestational age and 25.0% and 23.2% (p = 0.994) were large for gestational age. There was a predominance of cesarean delivery. Conclusion Personal history of preeclampsia and black skin color were associated with the occurrence of preeclampsia. There was a high frequency of birth weight deviations and cesarean deliveries. PMID:26761076

  2. The mechanisms of nickel toxicity in aquatic environments: an adverse outcome pathway analysis.

    PubMed

    Brix, Kevin V; Schlekat, Christian E; Garman, Emily R

    2016-12-09

    Current ecological risk assessment and water quality regulations for nickel (Ni) use mechanistically based, predictive tools such as biotic ligand models (BLMs). However, despite many detailed studies, the precise mechanism(s) of Ni toxicity to aquatic organisms remains elusive. This uncertainty in the mechanism(s) of action for Ni has led to concern over the use of tools like the BLM in some regulatory settings. To address this knowledge gap, the authors used an adverse outcome pathway (AOP) analysis, the first AOP for a metal, to identify multiple potential mechanisms of Ni toxicity and their interactions with freshwater aquatic organisms. The analysis considered potential mechanisms of action based on data from a wide range of organisms in aquatic and terrestrial environments on the premise that molecular initiating events for an essential metal would potentially be conserved across taxa. Through this analysis the authors identified 5 potential molecular initiating events by which Ni may exert toxicity on aquatic organisms: disruption of Ca(2+) homeostasis, disruption of Mg(2+) homeostasis, disruption of Fe(2+/3+) homeostasis, reactive oxygen species-induced oxidative damage, and an allergic-type response of respiratory epithelia. At the organ level of biological organization, these 5 potential molecular initiating events collapse into 3 potential pathways: reduced Ca(2+) availability to support formation of exoskeleton, shell, and bone for growth; impaired respiration; and cytotoxicity and tumor formation. At the level of the whole organism, the organ-level responses contribute to potential reductions in growth and reproduction and/or alterations in energy metabolism, with several potential feedback loops between each of the pathways. Overall, the present AOP analysis provides a robust framework for future directed studies on the mechanisms of Ni toxicity and for developing AOPs for other metals. Environ Toxicol Chem 2017;9999:1-10. © 2016 SETAC.

  3. Adverse Outcomes of Tacrolimus Withdrawal in Immune-Quiescent Kidney Transplant Recipients.

    PubMed

    Hricik, Donald E; Formica, Richard N; Nickerson, Peter; Rush, David; Fairchild, Robert L; Poggio, Emilio D; Gibson, Ian W; Wiebe, Chris; Tinckam, Kathryn; Bunnapradist, Suphamai; Samaniego-Picota, Milagros; Brennan, Daniel C; Schröppel, Bernd; Gaber, Osama; Armstrong, Brian; Ikle, David; Diop, Helena; Bridges, Nancy D; Heeger, Peter S

    2015-12-01

    Concerns about adverse effects of calcineurin inhibitors (CNIs) have prompted development of protocols that minimize their use. Whereas previous CNI withdrawal trials in heterogeneous cohorts showed unacceptable rates of acute rejection (AR), we hypothesized that we could identify individuals capable of tolerating CNI withdrawal by targeting immunologically quiescent kidney transplant recipients. The Clinical Trials in Organ Transplantation-09 Trial was a randomized, prospective study of nonsensitized primary recipients of living donor kidney transplants. Subjects received rabbit antithymocyte globulin, tacrolimus, mycophenolate mofetil, and prednisone. Six months post-transplantation, subjects without de novo donor-specific antibodies (DSAs), AR, or inflammation at protocol biopsy were randomized to wean off or remain on tacrolimus. The intended primary end point was the change in interstitial fibrosis/tubular atrophy score between implantation and 24-month protocol biopsies. Serially collected urine CXCL9 ELISA results were correlated with outcomes. The study was terminated prematurely because of unacceptable rates of AR (4 of 14) and/or de novo DSAs (5 of 14) in the tacrolimus withdrawal arm. Positive urinary CXCL9 predated clinical detection of AR by a median of 15 days. Analyses showed that >16 HLA-DQ epitope mismatches and pretransplant, peripheral blood, donor-reactive IFN-γ ELISPOT assay results correlated with development of DSAs and/or AR on tacrolimus withdrawal. Although data indicate that urinary CXCL9 monitoring, epitope mismatches, and ELISPOT assays are potentially informative, complete CNI withdrawal must be strongly discouraged in kidney transplant recipients who are receiving standard-of-care immunosuppression, including those who are deemed to be immunologically quiescent on the basis of current clinical and laboratory criteria.

  4. Cannabis and Neuropsychiatry, 2: The Longitudinal Risk of Psychosis as an Adverse Outcome.

    PubMed

    Andrade, Chittaranjan

    2016-06-01

    Psychosis is one of the most serious among the adverse effects associated with cannabis use. The association between cannabis use and psychosis has been variously explored in a series of recent meta-analyses. The results of these meta-analyses show that persons who develop psychosis experience onset of psychosis about 2-3 years earlier if they are cannabis users; this effect is not observed with alcohol or other substance use. Higher levels of cannabis use are associated with greater risk of psychosis. Current cannabis abuse or dependence (but not past use or lower levels of current use) increases the risk of transition into psychosis in persons at ultrahigh risk of psychosis. About a third of patients with first-episode psychosis are cannabis users, and, at follow-up, about half of these users are found to continue their cannabis use. Continued cannabis use (in those who are treated after developing psychosis) is associated with higher risk of relapse into psychosis, and discontinuation of cannabis use reduces the risk of relapse to that in cannabis nonusers. Finally, persons with psychosis who continue to use cannabis have more severe positive symptoms and poorer levels of functioning. Because experimental studies in humans show that cannabinoids and cannabis can induce psychotic symptoms, it is reasonable to assume that the epidemiologic data indicate a causal effect of cannabis in anticipating, triggering, or exacerbating psychosis in vulnerable individuals and in worsening the course and outcome of the illness in those who continue to use the substance. Given the public health implications of these findings, the trend to legalize medical marijuana must be viewed with concern, and efforts are necessary to educate patients and the public about the serious mental and physical health risks associated with cannabis use and abuse.

  5. Metabolomics for informing adverse outcome pathways: Androgen receptor activation and the pharmaceutical spironolactone.

    PubMed

    Davis, J M; Ekman, D R; Skelton, D M; LaLone, C A; Ankley, G T; Cavallin, J E; Villeneuve, D L; Collette, T W

    2017-03-01

    One objective in developing adverse outcome pathways (AOPs) is to connect biological changes that are relevant to risk assessors (i.e., fecundity) to molecular and cellular-level alterations that might be detectable at earlier stages of a chemical exposure. Here, we examined biochemical responses of fathead minnows (Pimephales promelas) to inform an AOP relevant to spironolactone's activation of the androgen receptor, as well as explore other biological impacts possibly unrelated to this receptor. Liquid chromatography with high resolution mass spectrometry (LC-MS) was used to measure changes in endogenous polar metabolites in livers of male and female fish that were exposed to five water concentrations of spironolactone (0, 0.05, 0.5, 5, or 50μgL(-1)) for 21days. Metabolite profiles were affected at the two highest concentrations (5 and 50μgL(-1)), but not in the lower-level exposures, which agreed with earlier reported results of reduced female fecundity and plasma vitellogenin (VTG) levels. We then applied partial least squares regression to assess whether metabolite alterations covaried with changes in fecundity, VTG gene expression and protein concentrations, and plasma 17β-estradiol and testosterone concentrations. Metabolite profiles significantly covaried with all measured endpoints in females, but only with plasma testosterone in males. Fecundity reductions occurred in parallel with changes in metabolites important in osmoregulation (e.g., betaine), membrane transport (e.g., l-carnitine), and biosynthesis of carnitine (e.g., methionine) and VTG (e.g., glutamate). Based on a network analysis program (i.e., mummichog), spironolactone also affected amino acid, tryptophan, and fatty acid metabolism. Thus, by identifying possible key events related to changes in biochemical pathways, this approach built upon an established AOP describing spironolactone's androgenic properties and highlighted broader implications potentially unrelated to androgen receptor

  6. Porphyromonas gingivalis within Placental Villous Mesenchyme and Umbilical Cord Stroma Is Associated with Adverse Pregnancy Outcome

    PubMed Central

    Vanterpool, Sizzle F.; Been, Jasper V.; Houben, Michiel L.; Nikkels, Peter G. J.; De Krijger, Ronald R.; Zimmermann, Luc J. I.; Kramer, Boris W.; Progulske-Fox, Ann; Reyes, Leticia

    2016-01-01

    Intrauterine presence of Porphyromonas gingivalis (Pg), a common oral pathobiont, is implicated in preterm birth. Our aim was to determine if the location of Pg within placental and/or umbilical cord sections was associated with a specific delivery diagnosis at preterm delivery (histologic chorioamnionitis, chorioamnionitis with funisitis, preeclampsia, and preeclampsia with HELLP-syndrome, small for gestational age). The prevalence and location of Pg within archived placental and umbilical cord specimens from preterm (25 to 32 weeks gestation) and term control cohorts were evaluated by immunofluorescent histology. Detection of Pg was performed blinded to pregnancy characteristics. Multivariate analyses were performed to evaluate independent effects of gestational age, being small for gestational age, specific preterm delivery diagnosis, antenatal steroids, and delivery mode, on the odds of having Pg in the preterm tissue. Within the preterm cohort, 49 of 97 (51%) placentas and 40 of 97 (41%) umbilical cord specimens were positive for Pg. Pg within the placenta was significantly associated with shorter gestation lengths (OR 0.63 (95%CI: 0.48–0.85; p = 0.002) per week) and delivery via caesarean section (OR 4.02 (95%CI: 1.15–14.04; p = 0.03), but not with histological chorioamnionitis or preeclampsia. However, the presence of Pg in the umbilical cord was significantly associated with preeclampsia: OR 6.73 (95%CI: 1.31–36.67; p = 0.02). In the term cohort, 2 of 35 (6%) placentas and no umbilical cord term specimens were positive for Pg. The location of Pg within the placenta was different between preterm and term groups in that Pg within the villous mesenchyme was only detected in the preterm cohort, whereas Pg associated with syncytiotrophoblasts was found in both preterm and term placentas. Taken together, our results suggest that the presence of Pg within the villous stroma or umbilical cord may be an important determinant in Pg-associated adverse pregnancy

  7. Birth malformations and other adverse perinatal outcomes in four U.S. Wheat-producing states.

    PubMed Central

    Schreinemachers, Dina M

    2003-01-01

    Chlorophenoxy herbicides are widely used in the United States and Western Europe for broadleaf weed control in grain farming and park maintenance. Most of the spring and durum wheat produced in the United States is grown in Minnesota, Montana, North Dakota, and South Dakota, with more than 85% of the acreage treated with chlorophenoxy herbicides such as 2,4-dichlorophenoxyacetic acid (2,4-D) and 4-chloro-2-methylphenoxyacetic acid (MCPA). Rates of adverse birth outcomes in rural, agricultural counties of these states during 1995-1997 were studied by comparing counties with a high proportion of wheat acreage and those with a lower proportion. Information routinely collected and made available by federal agencies was used for this ecologic study. Significant increases in birth malformations were observed for the circulatory/respiratory category for combined sexes [odds ratio (OR) = 1.65; 95% confidence interval (CI), 1.07-2.55]. A stronger effect was observed for the subcategory, which excluded heart malformations (OR = 2.03; 95% CI, 1.14-3.59). In addition, infants conceived during April-June--the time of herbicide application--had an increased chance of being diagnosed with circulatory/respiratory (excluding heart) malformations compared with births conceived during other months of the year (OR = 1.75; 95% CI, 1.09-2.80). Musculoskeletal/integumental anomalies increased for combined sexes in the high-wheat counties (OR = 1.50; 95% CI, 1.06-2.12). Infant death from congenital anomalies significantly increased in high-wheat counties for males (OR = 2.66; 95% CI, 1.52-4.65) but not for females (OR = 0.48; 95% CI, 0.20-1.15). These results are especially of concern because of widespread use of chlorophenoxy herbicides. PMID:12842783

  8. Chlorination by-products (CBPs) in drinking water and adverse pregnancy outcomes in Italy.

    PubMed

    Aggazzotti, Gabriella; Righi, Elena; Fantuzzi, Guglielmina; Biasotti, Barbara; Ravera, Gianbattista; Kanitz, Stefano; Barbone, Fabio; Sansebastiano, Giuliano; Battaglia, Mario Alberto; Leoni, Valerio; Fabiani, Leila; Triassi, Maria; Sciacca, Salvatore

    2004-12-01

    Chlorination by-products (CBPs) in drinking water have been associated with an increased risk of adverse pregnancy outcomes, including small for gestational age at term (term-SGA) and preterm delivery. Epidemiological evidence is weakened by a generally inaccurate exposure assessment, often at an ecological level. A case control study with incident cases was performed in nine Italian towns between October 1999 and September 2000. A total of 1,194 subjects were enrolled: 343 preterm births (26th-37th not completed week of pregnancy), 239 term-SGA (from 37th completed week, and weight less than the lowest 10th percentile) and 612 controls. Exposure was assessed both by applying a questionnaire on mothers' personal habits during pregnancy and by water sampling directly at mothers' homes. Levels of trihalomethanes (THMs) were low (median: 1.10 microg l(-1)), while chlorite and chlorate concentrations were relatively high (median: 216.5 microg l(-1) for chlorites and 76.5 microg l(-1) for chlorates). Preterm birth showed no association with CBPs, while term-SGA, when chlorite levels > or =200 microg l(-1) combined with low and high levels of inhalation exposure are considered, suggested a dose-response relationship (adjusted-Odds Ratios (ORs): 1.52, 95%CI: 0.91-2.54 and 1.70, 95%CI: 0.97-3.0, respectively). A weak association with high exposure levels of either THMs (> or =30 microg l(-1)), or chlorite or chlorate (> or =200 microg l(-1)) was also found (adjusted-OR: 1.38, 95%CI: 0.92-2.07). Chlorine dioxide treatment is widespread in Italy; therefore, chlorite levels should be regularly and carefully monitored and their potential effects on pregnancy further evaluated and better understood.

  9. Pediatric Neurodevelopmental Treatment

    ERIC Educational Resources Information Center

    Camacho, Ricardo; McCauley, Brandon; Szczech Moser, Christy

    2016-01-01

    Over 70 years ago Dr. Karel Bobath and his wife Bertha Bobath began to craft the therapeutic intervention now known as neurodevelopmental treatment (NDT). This edition of Reviews, Tools, and Resources will highlight a historical review of research studies that have been completed, current websites, books, and blogs focusing on NDT.

  10. Adverse School Context Moderates the Outcomes of Selective Interventions for Aggressive Children

    ERIC Educational Resources Information Center

    Hughes, Jan N.; Cavell, Timothy A.; Meehan, Barbara T.; Zhang, Duan; Collie, Claire

    2005-01-01

    Drawing on social ecological theory and empirical studies on the role of school context in aggression, the authors argue that school adversity is an important consideration in choosing selective interventions for aggressive children. The moderating role of school adversity on intervention effectiveness is illustrated with data from a randomized…

  11. Predictive validity of parent- and self-rated ADHD symptoms in adolescence on adverse socioeconomic and health outcomes.

    PubMed

    Du Rietz, Ebba; Kuja-Halkola, Ralf; Brikell, Isabell; Jangmo, Andreas; Sariaslan, Amir; Lichtenstein, Paul; Kuntsi, Jonna; Larsson, Henrik

    2017-02-10

    There is scarcity of research investigating the validity of self-report of attention deficit hyperactivity disorder (ADHD) symptoms compared to other informants, such as parents. This study aimed to compare the predictive associations of ADHD symptoms rated by parents and their children across adolescence on a range of adverse socioeconomic and health outcomes in early adulthood. Parent- and self-rated ADHD symptoms were assessed in 2960 individuals in early (13-14 years) and late adolescence (16-17 years). Logistic regression analyses were used to compare the associations between parent- and self-rated ADHD symptoms at both time points and adverse life outcomes in young adulthood obtained from Swedish national registries. Both parent- and self-ratings of ADHD symptoms were associated with increased risk for adverse outcomes, although associations of parent-ratings were more often statistically significant and were generally stronger (OR = 1.12-1.49, p < 0.05) than self-ratings (OR = 1.07-1.17, p < 0.05). After controlling for the other informant, parent-ratings of ADHD symptoms in both early and late adolescence significantly predicted academic and occupational failure, criminal convictions and traffic-related injuries, while self-ratings of ADHD symptoms only in late adolescence predicted substance use disorder and academic failure. Our findings suggest that both parent- and self-ratings of ADHD symptoms in adolescence provides valuable information on risk of future adverse socioeconomic and health outcomes, however, self-ratings are not valuable once parent-ratings have been taken into account in predicting most outcomes. Thus, clinicians and researchers should prioritize parent-ratings over self-ratings.

  12. A single serum glucose measurement predicts adverse outcomes across the whole range of acute coronary syndromes

    PubMed Central

    Foo, K; Cooper, J; Deaner, A; Knight, C; Suliman, A; Ranjadayalan, K; Timmis, A D

    2003-01-01

    Objectives: To analyse the relation between serum glucose concentration and hospital outcome across the whole spectrum of acute coronary syndromes. Methods: This was a prospective cohort study of 2127 patients presenting with acute coronary syndromes. The patients were stratified into quartile groups (Q1 to Q4) defined by serum glucose concentrations of 5.8, 7.2, and 10.0 mmol/l. The relation between quartile group and major in-hospital complications was analysed. Results: The proportion of patients with acute myocardial infarction increased incrementally across the quartile groups, from 21.4% in Q1 to 47.9% in Q4 (p < 0.0001). The trend for frequency of in-hospital major complications was similar, particularly left ventricular failure (LVF) (Q1 6.4%, Q4 25.2%, p < 0.0001) and cardiac death (Q1 0.7%, Q4 6.1%, p < 0.0001). The relations were linear, each glucose quartile increment being associated with an odds ratio of 1.46 (95% confidence interval (CI) 1.27 to 1.70) for LVF and 1.52 (95% CI 1.17 to 1.97) for cardiac death. Although complication rates were higher for a discharge diagnosis of acute myocardial infarction than for unstable angina, there was no evidence that the effects of serum glucose concentration were different for the two groups, there being no significant interaction with discharge diagnosis in the associations between glucose quartile and LVF (p = 0.69) or cardiac death (p = 0.17). Similarly there was no significant interaction with diabetic status in the associations between glucose quartile and LVF (p = 0.08) or cardiac death (p = 0.09). Conclusion: Admission glycaemia stratified patients with acute coronary syndromes according to their risk of in-hospital LVF and cardiac mortality. There was no detectable glycaemic threshold for these adverse effects. The prognostic correlates of admission glycaemia were unaffected by diabetic status and did not differ significantly between patients with acute myocardial infarction and those with unstable

  13. Weight status in the first 2 years of life and neurodevelopmental impairment in extremely low gestational age newborns

    PubMed Central

    Belfort, Mandy B.; Kuban, Karl C.K.; O'Shea, T. Michael; Allred, Elizabeth N.; Ehrenkranz, Richard A.; Engelke, Stephen C.; Leviton, Alan

    2015-01-01

    Objective To examine the extent to which weight gain and weight status in the first 2 years of life relate to the risk of neurodevelopmental impairment in extremely preterm infants. Study Design In a cohort of 1070 infants born between 23 and 27 weeks’ gestation, we examined weight gain from 7-28 days of life (in quartiles) and weight z-score at 12 and 24 months corrected age (in categories: <−2; ≥−2, <−1; ≥1, <1; ≥1) in relation to these adverse neurodevelopmental outcomes: Bayley-II mental development index <55, Bayley-II psychomotor development index <55, cerebral palsy, Gross Motor Function Classification System (GMFCS) ≥1 (cannot walk without assistance), microcephaly. We adjusted for confounders in logistic regression, stratified by sex, and performed separate analyses including the entire sample, and excluding children unable to walk without assistance (motor impairment). Results Weight gain in the lowest quartile from 7-28 days was not associated with higher risk of adverse outcomes. Children with a 12-month weight z-score <−2 were at increased risk for all adverse outcomes in girls, and for microcephaly and GMFCS ≥1 in boys. However, excluding children with motor impairment attenuated all associations except that of weight z-score <−2 with microcephaly in girls. Similarly, most associations of low weight z-score at 24 months with adverse outcomes were attenuated with exclusion of children with motor impairment. Conclusion Excluding children who have gross motor impairment appears to eliminate the association of low weight status with neurodevelopmental impairments at 2 years in extremely preterm infants. PMID:26470687

  14. TOXICOLOGY OF MALE REPRODUCTIVE DEVELOPMENT: PROFILING 774 CHEMICALS FOR MOLECULAR TARGETS AND ADVERSE OUTCOMES (SOT)

    EPA Science Inventory

    Adverse trends in male reproductive health have been reported for increased rates of testicular germ cell tumor, low semen quality, cryptorchidism, and hypospadias. An association with prenatal environmental exposure has been inferred from human and animal studies underlying male...

  15. Systems Toxicology of Male Reproductive Development: Profiling 774 Chemicals for Molecular Targets and Adverse Outcomes

    EPA Science Inventory

    Adverse trends in male reproductive health have been reported for increased rates of testicular germ cell tumor, low semen quality, cryptorchidism, and hypospadias. An association with prenatal environmental exposure has been inferred from human and animal studies underlying male...

  16. Can aircraft noise less than or equal 115 to dBA adversely affect reproductive outcome in USAF women?

    NASA Astrophysics Data System (ADS)

    Brubaker, P. A.

    1985-06-01

    It has been suggested, mainly through animal studies, that exposure to high noise levels may be associated with lower birth weight, reduced gestational length and other adverse reproductive outcomes. Few studies have been done on humans to show this association. The Air Force employs pregnant women in areas where there is a high potential for exposure to high noise levels. This study proposes a method to determine if there is an association between high frequency noise levels or = 115 dBA and adverse reproductive outcomes through a review of records and self-administered questionnaires in a case-comparison design. Prevelance rates will be calculated and a multiple logistic regression analysis computed for the independent variables that can affect reproduction.

  17. Renal systolic time intervals derived from intra-renal artery Doppler as a novel predictor of adverse cardiac outcomes

    PubMed Central

    Lee, Wen-Hsien; Hsu, Po-Chao; Chu, Chun-Yuan; Chen, Szu-Chia; Lee, Hung-Hao; Lee, Meng-Kuang; Lee, Chee-Siong; Yen, Hsueh-Wei; Lin, Tsung-Hsien; Voon, Wen-Chol; Lai, Wen-Ter; Sheu, Sheng-Hsiung; Kuo, Po-Lin; Su, Ho-Ming

    2017-01-01

    The aim of this study was to evaluate the use of renal systolic time intervals measured by electrocardiographic gated Doppler ultrasonography for predicting adverse cardiac events. This longitudinal observation study enrolled 205 patients. Renal systolic time intervals, including pre-ejection period (PEP) and ejection time (ET), and ratio of renal PEP to ET, were measured by electrocardiographic gated Doppler ultrasound. The 14 adverse cardiac events identified in this population included 9 cardiac deaths and 5 hospitalizations for heart failure during an average follow up of 30.9 months (25th–75th percentile: 30–33 months). Renal PEP (hazard ratio = 1.023, P = 0.001), renal ET (hazard ratio = 0.975, P = 0.001) and renal PEP/ET (per 0.01 unit increase, hazard ratio = 1.060, P < 0.001) were associated with poor cardiac outcomes. The addition of renal PEP/ET to a Cox model containing important clinical variables and renal resistive index further improved the value in predicting adverse cardiac events (Chi-square increase, 9.996; P = 0.002). This study showed that parameters of intra-renal hemodynamics were potential predictors of adverse cardiac outcomes. However, the generalizability of these indicators need to be investigated in future large-scale studies. PMID:28266644

  18. Risk of adverse pregnancy outcome in women exposed to livestock: a study within the Danish National Birth Cohort.

    PubMed

    Nielsen, S Y; Henriksen, T B; Hjøllund, N H; Mølbak, K; Andersen, A M N

    2014-07-01

    Maternal infection in pregnancy is a known risk factor for adverse pregnancy outcome, and a number of zoonotic pathogens may constitute a risk to pregnant women and their fetuses. With animal contact as a proxy for the risk of zoonotic infection, this study aimed to evaluate pregnancy outcome in women with self-reported occupational or domestic contact with livestock compared to pregnant women without such contact. The Danish National Birth Cohort collected information on pregnancy outcome from 100 418 pregnant women (1996-2002) from which three study populations with occupational and/or domestic exposure to livestock and a reference group of women with no animal contact was sampled. Outcome measures were miscarriage, very preterm birth (before gestational week 32), preterm birth (before 37 gestational weeks), small for gestational age (SGA), and perinatal death. Adverse reproductive outcomes were assessed in four different exposure groups of women with occupational or domestic exposure to livestock with no association found between exposure to livestock and miscarriage, preterm birth, SGA or perinatal death. These findings should diminish general occupational health concerns for pregnant women with exposures to a range of different farm animals.

  19. Neurodevelopmental effects of fetal antiepileptic drug exposure.

    PubMed

    Velez-Ruiz, Naymee J; Meador, Kimford J

    2015-03-01

    Many studies investigating cognitive outcomes in children of women with epilepsy report an increased risk of mental impairment. Verbal scores on neuropsychometric measures may be selectively more involved. While a variety of factors contribute to the cognitive problems of children of women with epilepsy, antiepileptic drugs (AEDs) appear to play a major role. The mechanisms by which AEDs affect neurodevelopmental outcomes remain poorly defined. Animal models suggest that AED-induced apoptosis, altered neurotransmitter environment, and impaired synaptogenesis are some of the mechanisms responsible for cognitive and behavioral teratogenesis. AEDs that are known to induce apoptosis, such as valproate, appear to affect children's neurodevelopment in a more severe fashion. Fetal valproate exposure has dose-dependent associations with reduced cognitive abilities across a range of domains, and these appear to persist at least until the age of 6. Some studies have shown neurodevelopmental deficiencies associated with the use of phenobarbital and possibly phenytoin. So far, most of the investigations available suggest that fetal exposures to lamotrigine or levetiracetam are safer with regard to cognition when compared with other AEDs. Studies on carbamazepine show contradictory results, but most information available suggests that major poor cognitive outcomes should not be attributed to this medication. Overall, children exposed to polytherapy prenatally appear to have worse cognitive and behavioral outcomes compared with children exposed to monotherapy, and with the unexposed. There is an increase risk of neurodevelopmental deficits when polytherapy involves the use of valproate versus other agents.

  20. Nutritional indicators of adverse pregnancy outcomes and mother-to-child transmission of HIV among HIV-infected women2

    PubMed Central

    Mehta, Saurabh; Manji, Karim P; Young, Alicia M; Brown, Elizabeth R; Chasela, Charles; Taha, Taha E; Read, Jennifer S; Goldenberg, Robert L; Fawzi, Wafaie W

    2008-01-01

    Background Poor nutrition may be associated with mother-to-child transmission (MTCT) of HIV and other adverse pregnancy outcomes. Objective The objective was to examine the relation of nutritional indicators with adverse pregnancy outcomes among HIV-infected women in Tanzania, Zambia, and Malawi. Design Body mass index (BMI; in kg/m2) and hemoglobin concentrations at enrollment and weight change during pregnancy were prospectively related to fetal loss, neonatal death, low birth weight, preterm birth, and MTCT of HIV. Results In a multivariate analysis, having a BMI < 21.8 was significantly associated with preterm birth [odds ratio (OR): 1.82; 95% CI: 1.34, 2.46] and low birth weight (OR: 2.09; 95% CI: 1.41, 3.08). A U-shaped relation between weight change during pregnancy and preterm birth was observed. Severe anemia was significantly associated with fetal loss or stillbirth (OR: 3.67; 95% CI: 1.16, 11.66), preterm birth (OR: 2.08; 95% CI: 1.39, 3.10), low birth weight (OR: 1.76; 95% CI: 1.07, 2.90), and MTCT of HIV by the time of birth (OR: 2.26; 95% CI: 1.18, 4.34) and by 4−6 wk among those negative at birth (OR: 2.33; 95% CI: 1.15, 4.73). Conclusions Anemia, poor weight gain during pregnancy, and low BMI in HIV-infected pregnant women are associated with increased risks of adverse infant outcomes and MTCT of HIV. Interventions that reduce the risk of wasting or anemia during pregnancy should be evaluated to determine their possible effect on the incidence of adverse pregnancy outcomes and MTCT of HIV. PMID:18541551

  1. Intersections of poverty, race/ethnicity, and sex: alcohol consumption and adverse outcomes in the United States.

    PubMed

    Glass, Joseph E; Rathouz, Paul J; Gattis, Maurice; Joo, Young Sun; Nelson, Jennifer C; Williams, Emily C

    2017-03-27

    We examine whether intersectionality theory-which formalizes the notion that adverse health outcomes owing to having a marginalized social status, identity, or characteristic, may be magnified for individuals with an additional marginalized social status, identity, or characteristic-can be applied using quantitative methods to describe the differential effects of poverty on alcohol consumption across sex and race/ethnicity. Using the National Epidemiologic Survey on Alcohol and Related Conditions, we analyze longitudinal data from Black, Hispanic, and White drinkers (n = 21,140) to assess multiplicative interactions between poverty, as defined by the US Census Bureau, sex, and race/ethnicity, on adverse alcohol outcomes. Findings indicated that the effect of poverty on the past-year incidence of heavy episodic drinking was stronger among Black men and Black women in comparison to men and women of other racial/ethnic groups. Poverty reduction programs that are culturally informed may help reduce racial/ethnic disparities in the adverse outcomes of alcohol consumption.

  2. Systematic review of methods used in meta-analyses where a primary outcome is an adverse or unintended event

    PubMed Central

    2012-01-01

    Background Adverse consequences of medical interventions are a source of concern, but clinical trials may lack power to detect elevated rates of such events, while observational studies have inherent limitations. Meta-analysis allows the combination of individual studies, which can increase power and provide stronger evidence relating to adverse events. However, meta-analysis of adverse events has associated methodological challenges. The aim of this study was to systematically identify and review the methodology used in meta-analyses where a primary outcome is an adverse or unintended event, following a therapeutic intervention. Methods Using a collection of reviews identified previously, 166 references including a meta-analysis were selected for review. At least one of the primary outcomes in each review was an adverse or unintended event. The nature of the intervention, source of funding, number of individual meta-analyses performed, number of primary studies included in the review, and use of meta-analytic methods were all recorded. Specific areas of interest relating to the methods used included the choice of outcome metric, methods of dealing with sparse events, heterogeneity, publication bias and use of individual patient data. Results The 166 included reviews were published between 1994 and 2006. Interventions included drugs and surgery among other interventions. Many of the references being reviewed included multiple meta-analyses with 44.6% (74/166) including more than ten. Randomised trials only were included in 42.2% of meta-analyses (70/166), observational studies only in 33.7% (56/166) and a mix of observational studies and trials in 15.7% (26/166). Sparse data, in the form of zero events in one or both arms where the outcome was a count of events, was found in 64 reviews of two-arm studies, of which 41 (64.1%) had zero events in both arms. Conclusions Meta-analyses of adverse events data are common and useful in terms of increasing the power to

  3. Early intervention in neurodevelopmental disorders: underlying neural mechanisms.

    PubMed

    Cioni, Giovanni; Inguaggiato, Emanuela; Sgandurra, Giuseppina

    2016-03-01

    Neurodevelopmental disorders affect motor, cognitive, language, learning, and behavioural development with lifelong consequences. Early identification of infants at risk for neurodevelopmental disorders is a major prerequisite for intervention programmes. This ensures that interventions which aim to positively modify the natural history of these disorders can start in the first weeks or months of life. As indicated by recent scientific evidence, gene abnormalities or congenital brain lesions are not the sole determinants for the neurodevelopmental outcome of affected infants. In fact, environment and experience may modify brain development and improve the outcome in infants at risk for neurodevelopmental disorders. In this review, we analyse the complexity and sensitivity of the brain to environmental stimuli, highlighting clinical effects of early intervention, mainly reported so far in preterm infants, and summarizing the effects of enriched environment on human and animal models. Finally, we discuss some new approaches to early intervention, based on recent neurophysiological theories and new breakthroughs in biotechnologies for diagnosis and rehabilitation.

  4. Circulating angiogenic factors are related to the severity of gestational hypertension and preeclampsia, and their adverse outcomes.

    PubMed

    Leaños-Miranda, Alfredo; Méndez-Aguilar, Francisco; Ramírez-Valenzuela, Karla Leticia; Serrano-Rodríguez, Marilyn; Berumen-Lechuga, Guadalupe; Molina-Pérez, Carlos José; Isordia-Salas, Irma; Campos-Galicia, Inova

    2017-01-01

    Gestational hypertension (GH) and preeclampsia (PE) are characterized by an imbalance in angiogenic factors. However, the relationship among these factors with the severity of hypertensive disorders of pregnancy (HDP) and adverse outcomes are not fully elucidated. We examined whether these biomarkers are related with the severity of HDP and adverse outcomes.Using a cross-sectional design, serum concentrations of placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), and soluble endoglin were determined in 764 pregnant women: 75 healthy pregnant, 83 with mild GH (mGH), 105 with severe GH (sGH), 122 with mild PE (mPE), and 379 with severe PE (sPE).All angiogenic factors' concentrations were significantly different (P ≤ 0.041) in HDP than in healthy pregnancy. In addition, these factors were markedly different in sPE than in mPE, sGH, or mGH (P ≤ 0.027) and in patients with sGH that in those with mPE or mGH (P < 0.05). As compared to mGH and mPE, patients with sGH and sPE had higher rates of both preterm delivery at <34 weeks of gestation and small-for-gestational age infants. Moreover, patients with sPE had higher rates of adverse maternal outcomes (P < 0.001) when compared to patients with mGH, sGH, or mPE. In all cases, levels of sFlt-1/PlGF ratio were significantly higher in patients with sGH and sPE who had adverse perinatal and maternal outcomes than in those with sGH and sPE who did not (P ≤ 0.016).Circulating concentrations of angiogenic factors appear to be suitable markers to assess the severity of GH and PE, and adverse outcomes.

  5. Circulating angiogenic factors are related to the severity of gestational hypertension and preeclampsia, and their adverse outcomes

    PubMed Central

    Leaños-Miranda, Alfredo; Méndez-Aguilar, Francisco; Ramírez-Valenzuela, Karla Leticia; Serrano-Rodríguez, Marilyn; Berumen-Lechuga, Guadalupe; Molina-Pérez, Carlos José; Isordia-Salas, Irma; Campos-Galicia, Inova

    2017-01-01

    Abstract Gestational hypertension (GH) and preeclampsia (PE) are characterized by an imbalance in angiogenic factors. However, the relationship among these factors with the severity of hypertensive disorders of pregnancy (HDP) and adverse outcomes are not fully elucidated. We examined whether these biomarkers are related with the severity of HDP and adverse outcomes. Using a cross-sectional design, serum concentrations of placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), and soluble endoglin were determined in 764 pregnant women: 75 healthy pregnant, 83 with mild GH (mGH), 105 with severe GH (sGH), 122 with mild PE (mPE), and 379 with severe PE (sPE). All angiogenic factors’ concentrations were significantly different (P ≤ 0.041) in HDP than in healthy pregnancy. In addition, these factors were markedly different in sPE than in mPE, sGH, or mGH (P ≤ 0.027) and in patients with sGH that in those with mPE or mGH (P < 0.05). As compared to mGH and mPE, patients with sGH and sPE had higher rates of both preterm delivery at <34 weeks of gestation and small-for-gestational age infants. Moreover, patients with sPE had higher rates of adverse maternal outcomes (P < 0.001) when compared to patients with mGH, sGH, or mPE. In all cases, levels of sFlt-1/PlGF ratio were significantly higher in patients with sGH and sPE who had adverse perinatal and maternal outcomes than in those with sGH and sPE who did not (P ≤ 0.016). Circulating concentrations of angiogenic factors appear to be suitable markers to assess the severity of GH and PE, and adverse outcomes. PMID:28121958

  6. Association between Intimate Partner Violence during Pregnancy and Adverse Pregnancy Outcomes in Vietnam: A Prospective Cohort Study

    PubMed Central

    Van, Toan Ngo; Gammeltoft, Tine; W. Meyrowitsch, Dan; Nguyen Thi Thuy, Hanh; Rasch, Vibeke

    2016-01-01

    Background Violence against pregnant women is an increasing public health concern particularly in low- and middle-income countries. The purpose of this study was to measure the association between intimate partner violence (IPV) during pregnancy and the risk of adverse birth outcomes. Methods Prospective cohort study of 1276 pregnant women in Dong Anh district, Vietnam. Women with gestational age less than 24 weeks were enrolled and interviewed. Repeated interviews were performed at 30–34 weeks gestation to assess experience of IPV during pregnancy and again 48 hours post-delivery to assess the birth outcome including birth weight and gestational age at delivery. Results There was a statistically significant association between exposure to physical violence during pregnancy and preterm birth (PTB) or low birth weight (LBW). After adjustment for age, education, occupation, body mass index (BMI), haemoglobin level, previous adverse pregnancy outcomes, the pregnant women who were exposed to physical violence during pregnancy were five times more likely to have PTB (AOR = 5.5; 95%CI: 2.1–14.1) and were nearly six times more likely to give birth to a child of LBW (AOR = 5.7; 95%CI: 2.2–14.9) as compared to those who were not exposed to physical violence. Conclusion Exposure to IPV during pregnancy increases the risk of PTB and LBW. Case-finding for violence in relation to antenatal care may help protect pregnant women and improve pregnancy outcomes. PMID:27631968

  7. Household and community-level Adverse Childhood Experiences and adult health outcomes in a diverse urban population.

    PubMed

    Wade, Roy; Cronholm, Peter F; Fein, Joel A; Forke, Christine M; Davis, Martha B; Harkins-Schwarz, Mary; Pachter, Lee M; Bair-Merritt, Megan H

    2016-02-01

    Adverse Childhood Experiences (ACEs), which include family dysfunction and community-level stressors, negatively impact the health and well being of children throughout the life course. While several studies have examined the impact of these childhood exposures amongst racially and socially diverse populations, the contribution of ACEs in the persistence of socioeconomic disparities in health is poorly understood. To determine the association between ACEs and health outcomes amongst a sample of adults living in Philadelphia and examine the moderating effect of Socioeconomic Status (SES) on this association, we conducted a cross-sectional survey of 1,784 Philadelphia adults, ages 18 and older, using random digit dialing methodology to assess Conventional ACEs (experiences related to family dysfunction), Expanded ACEs (community-level stressors), and health outcomes. Using weighted, multivariable logistic regression analyses along with SES stratified models, we examined the relationship between ACEs and health outcomes as well as the modifying effect of current SES. High Conventional ACE scores were significantly associated with health risk behaviors, physical and mental illness, while elevated Expanded ACE scores were associated only with substance abuse history and sexually transmitted infections. ACEs did have some differential impacts on health outcomes based on SES. Given the robust impact of Conventional ACEs on health, our results support prior research highlighting the primacy of family relationships on a child's life course trajectory and the importance of interventions designed to support families. Our findings related to the modifying effect of SES may provide additional insight into the complex relationship between poverty and childhood adversity.

  8. A Swedish Population-based Study of Adverse Birth Outcomes among Pregnant Women Treated with Buprenorphine or Methadone: Preliminary Findings

    PubMed Central

    Wurst, Keele E.; Zedler, Barbara K.; Joyce, Andrew R.; Sasinowski, Maciek; Murrelle, E. Lenn

    2016-01-01

    BACKGROUND Untreated opioid dependence in pregnant women is associated with adverse birth outcomes. Buprenorphine and methadone are options for opioid agonist medication-assisted treatment during pregnancy. OBJECTIVE The aim of this study was to describe adverse birth outcomes observed with buprenorphine or methadone treatment compared to the general population in Sweden. METHODS Pregnant women and their corresponding births during 2005–2011 were identified in the Swedish Medical Birth Register. Data on stillbirth, neonatal/infant death, mode of delivery, gestational age at birth, Apgar score, growth outcomes, neonatal abstinence syndrome, and congenital malformations were examined. Frequencies were compared using two-sided Fisher’s exact tests. Unadjusted estimates of birth outcomes for women treated with buprenorphine or methadone were compared to the registered general population. RESULTS A total of 746,257 pregnancies among 538,178 unique women resulted in 746,485 live births. Among the 194 women treated with buprenorphine (N = 176) or methadone (N = 52), no stillbirths or neonatal/infant deaths occurred. Neonatal abstinence syndrome developed in 23.3% and 38.5% of infants born to mothers treated with buprenorphine and methadone, respectively. The frequency of the selected adverse birth outcomes assessed in women treated with buprenorphine as compared to the general population was not significantly different. However, a significantly higher frequency of preterm birth and congenital malformations was observed in women treated with methadone as compared to the general population. Compared with the general population, methadone-treated women were significantly older than buprenorphine-treated women, and both treatment groups began prenatal care later, were more likely to smoke cigarettes, and did not cohabitate with the baby’s father. CONCLUSIONS An increased frequency of the selected adverse birth outcomes was not observed with buprenorphine treatment

  9. Role of adverse outcome pathways in developing computational models for regulatory toxicology

    EPA Science Inventory

    Regulatory toxicology for both human health and the environment increasingly is moving from a sole reliance on direct observation of apical toxicity outcomes in whole organism toxicity tests, to predictive approaches in which unacceptable outcomes and risk are inferred from mecha...

  10. Childhood Adverse Events and Health Outcomes among Methamphetamine-Dependent Men and Women

    ERIC Educational Resources Information Center

    Messina, Nena P.; Marinelli-Casey, Patricia; Hillhouse, Maureen; Ang, Alfonso; Hunter, Jeremy; Rawson, Richard

    2008-01-01

    To describe the prevalence of childhood adverse events (CAEs) among methamphetamine-dependent men and women, and assess the relationship of cumulative CAEs to health problems. Data for 236 men and 351 women were analyzed assessing CAEs. Dependent variables included 14 self-reported health problems or psychiatric symptom domains. Mental health was…

  11. A review of nitrates in drinking water: maternal exposure and adverse reproductive and developmental outcomes.

    PubMed

    Manassaram, Deana M; Backer, Lorraine C; Moll, Deborah M

    2007-01-01

    In this review, we present an update on maternal exposure to nitrates in drinking water in relation to possible adverse reproductive and developmental effects, and discuss nitrates in drinking water in the United States. The current standard for nitrates in drinking water is based on retrospective studies and approximates a level that protects infants from methemoglobinemia, but no safety factor is built into the standard. The current standard applies only to public water systems. Animal studies have found adverse reproductive effects resulting from higher doses of nitrate or nitrite. The epidemiologic evidence of a direct exposure-response relationship between drinking water nitrate level and adverse reproductive effect is still not clear. However, some reports have suggested an association between exposure to nitrates in drinking water and spontaneous abortions, intrauterine growth restriction, and various birth defects. Uncertainties in epidemiologic studies include the lack of individual exposure assessment that would rule out confounding of the exposure with some other cause. We conclude that the current literature does not provide sufficient evidence of a causal relationship between exposure to nitrates in drinking water and adverse reproductive effects.

  12. Potential roles of omics data in the use of adverse outcome pathways for environmental risk assessment

    EPA Science Inventory

    The current approach to assessing adverse effects of chemicals in the environment is largely based on a battery of in-vivo study methods and a limited number of accepted in-silico approaches. For most substances the pool of data from which to predict ecosystem effects is limited ...

  13. Adverse outcome pathways (AOPs): A framework to support predictive toxicology (presentation)

    EPA Science Inventory

    High throughput and in silico methods are providing the regulatory toxicology community with capacity to rapidly and cost effectively generate data concerning a chemical’s ability to initiate one or more biological perturbations that may culminate in an adverse ecological o...

  14. Mental stress-induced left ventricular dysfunction and adverse outcome in ischemic heart disease patients.

    PubMed

    Sun, Julia L; Boyle, Stephen H; Samad, Zainab; Babyak, Michael A; Wilson, Jennifer L; Kuhn, Cynthia; Becker, Richard C; Ortel, Thomas L; Williams, Redford B; Rogers, Joseph G; O'Connor, Christopher M; Velazquez, Eric J; Jiang, Wei

    2017-04-01

    Aims Mental stress-induced myocardial ischemia (MSIMI) occurs in up to 70% of patients with clinically stable ischemic heart disease and is associated with increased risk of adverse prognosis. We aimed to examine the prognostic value of indices of MSIMI and exercise stress-induced myocardial ischemia (ESIMI) in a population of ischemic heart disease patients that was not confined by having a recent positive physical stress test. Methods and results The Responses of Mental Stress Induced Myocardial Ischemia to Escitalopram Treatment (REMIT) study enrolled 310 subjects who underwent mental and exercise stress testing and were followed annually for a median of four years. Study endpoints included time to first and total rate of major adverse cardiovascular events, defined as all-cause mortality and hospitalizations for cardiovascular causes. Cox and negative binomial regression adjusting for age, sex, resting left ventricular ejection fraction, and heart failure status were used to examine associations of indices of MSIMI and ESIMI with study endpoints. The continuous variable of mental stress-induced left ventricular ejection fraction change was significantly associated with both endpoints (all p values < 0.05). For every reduction of 5% in left ventricular ejection fraction induced by mental stress, patients had a 5% increase in the probability of a major adverse cardiovascular event at the median follow-up time and a 20% increase in the number of major adverse cardiovascular events endured over the follow-up period of six years. Indices of ESIMI did not predict endpoints ( ps > 0.05). Conclusion In patients with stable ischemic heart disease, mental, but not exercise, stress-induced left ventricular ejection fraction change significantly predicts risk of future adverse cardiovascular events.

  15. Predicting neurodevelopmental outcomes for at-risk infants: reliability and predictive validity using a Chinese version of the INFANIB at 3, 7 and 10 months

    PubMed Central

    2012-01-01

    Background Chinese primary care settings have a heavy patient load, shortage of physicians, limited medical resources and low medical literacy, making it difficult to screen for developmental disorders in infants. The Infant Neurological International Battery (INFANIB) for the assessment of neuromotor developmental disorders in infants aged 0 ~ 18 months is widely applied in community health service centers because of its simplicity, time-saving advantages and short learning curve. We aimed to develop and assess a Chinese version of the INFANIB. Methods A Chinese version of the INFANIB was developed. Fifty-five preterm and 49 full-term infants with high risk of neurodevelopmental delays were assessed using the Chinese version of the INFANIB at 3, 7 and 10 months after birth. The Peabody Developmental Motor Scale (PDMS) was simultaneously used to assess the children with abnormalities and diagnose cerebral palsy. The sensitivity, specificity, positive predictive value and negative predictive value of the scale were calculated. Results At birth, a higher proportion of full-term infants had asphyxia (p < 0.001), brain damage ( p = 0.003) and hyperbilirubinemia ( p = 0.022). The interclass correlation coefficient and intraclass correlation coefficient values for the INFANIB at 3, 7 and 10 months were >0.8, indicating excellent reliability with regard to inter- and intraobserver differences. The specificity, sensitivity, positive predictive value and negative predictive value were high for both high-risk premature infants and full-term infants at the age of 10 months. For premature infants at the age of 7 months or below, INFANIB had low validity for detecting abnormalities. Conclusions The Chinese version of the INFANIB can be useful for screening infants with high-risk for neuromotor abnormality in Chinese primary care settings. PMID:22697283

  16. Associations between maternal serum free beta human chorionic gonadotropin (β-hCG) levels and adverse pregnancy outcomes.

    PubMed

    Sirikunalai, P; Wanapirak, C; Sirichotiyakul, S; Tongprasert, F; Srisupundit, K; Luewan, S; Traisrisilp, K; Tongsong, T

    2016-01-01

    The objective was to determine the strength of relationship between maternal free beta human chorionic gonadotropin (β-hCG) concentrations and rates of adverse pregnancy outcomes. Consecutive records of the database of our Down screening project were assessed for free β-hCG levels and pregnancy outcomes. Pregnancies with foetal chromosomal or structural anomalies and those with underlying disease were excluded. Free β-hCG levels of < 0.5, > 0.5 and < 2.0, and ≥ 2.0 MoM were categorised as low, normal and high, respectively. Of 17,082 screened women, 13,620 were available for analysis. In the first trimester (n = 8150), low β-hCG levels significantly increased risk for intrauterine growth restriction (IUGR), preterm birth, low birth weight (LBW) and low Apgar score with relative risk of 1.66, 1.43, 1.83 and 2.89; whereas high β-hCG group had a significant decreased risk of preterm birth and GDM with relative risk of 0.73 and 0.62. In the second trimester (n = 5470), both low and high β-hCG groups had significant increased risks of the most common adverse outcomes, i.e. spontaneous abortion, IUGR and preterm birth. In conclusion, abnormally low (< 0.5MoM) or high (> 2.0 MoM) free β-hCG levels are generally associated with an increased risk of adverse pregnancy outcomes. Nevertheless, high free β-hCG levels in the first trimester may possibly decrease risk of preterm delivery and GDM.

  17. Risks of adverse pregnancy outcomes among Inuit and North American Indian women in Quebec, 1985-97.

    PubMed

    Luo, Zhong-Cheng; Wilkins, Russell; Platt, Robert W; Kramer, Michael S

    2004-01-01

    We used Statistics Canada's linked stillbirth, live birth and infant death files to assess the risks of adverse pregnancy outcomes among Inuit and North American Indian vs. other ethnic women in Quebec, 1985-97 (1 125 462 singleton births). Mother tongue was used to define ethnicity, with the largest French language group as the reference. Main outcome measures are adjusted odds ratios (AOR) for preterm birth, small-for-gestational-age (SGA), stillbirth, neonatal and postneonatal death controlled for maternal age, education, marital status, parity, infant sex, community size, and community-level random effects using multilevel logit models. Inuit women had higher risks of preterm birth (AOR = 1.49, 95% CI [1.25, 1.78]) and immaturity-related infant mortality (AOR = 3.03 [1.36, 6.74]), while Indian women did not. Infants of Inuit (AOR = 0.39 [0.31, 0.49]) and Indian (AOR = 0.27 [0.24, 0.31]) women had substantially lower risks of SGA. Elevated risks of stillbirth were observed among Indian women [AOR = 1.53 (1.09, 2.15)], and of postneonatal death among both Inuit (AOR = 4.45 [2.74, 7.22]) and Indian (AOR = 1.86 [1.28, 2.70]) infants. Both Inuit and Indian infants had much higher risks of sudden infant death syndrome (SIDS) and infection-related mortality. Although the absolute risks of adverse outcomes declined from 1985-87 to 1995-97, the relative disparities between aboriginal and non-aboriginal women changed little over this period. We conclude that Inuit and Indian women have different risk profiles for adverse pregnancy outcomes, and that prevention of preterm birth among Inuit women, and of SIDS and infection-related infant mortality in both aboriginal groups, are important targets for future research and intervention.

  18. Increasing Number and Proportion of Adverse Obstetrical Outcomes among Women Living with HIV in the Ottawa Area: A 20-Year Clinical Case Series

    PubMed Central

    Buchan, Sarah; Spaans, Johanna N.; Balfour, Louise

    2016-01-01

    Background. The prevalence and associated risks with adverse obstetrical outcomes among women living with HIV are not well measured. The objective of this study was to longitudinally investigate the prevalence and correlates of adverse obstetrical outcomes among women with HIV. Methods. This 20-year (1990–2010) clinical case series assessed the prevalence of adverse obstetrical outcomes among pregnant women with HIV receiving care at The Ottawa Hospital (TOH). General estimating equation modeling was used to identify factors independently associated with adverse obstetrical outcomes, while controlling for year of childbirth clustering. Results. At TOH, there were 127 deliveries among 94 women (1990–2010): 22 preterm births, 9 births with low birth weight, 12 births small for gestational age, and 4 stillbirths. Per year, the odds of adverse obstetrical outcomes increased by 15% (OR: 1.15, 95% CI: 1.03–1.30). Psychiatric illness (AOR: 2.64, 95% CI: 1.12–6.24), teen pregnancy (AOR: 3.35, 95% CI: 1.04–1.46), and recent immigrant status (AOR: 7.24, 95% CI: 1.30–40.28) were the strongest correlates of adverse obstetrical outcomes. Conclusions. The increasing number and proportion of adverse obstetrical outcomes among pregnant women with HIV over the past 20 years highlight the need for social supports and maternal and child health interventions, especially among adolescents, new immigrants, and those with a history of mental illness. PMID:27528877

  19. Application of in silico and in vitro methods in the development of adverse outcome pathway constructs in wildlife

    PubMed Central

    Madden, Judith C.; Rogiers, Vera; Vinken, Mathieu

    2014-01-01

    There is a long history of using both in silico and in vitro methods to predict adverse effects in humans and environmental species where toxicity data are lacking. Currently, there is a great deal of interest in applying these methods to the development of so-called ‘adverse outcome pathway’ (AOP) constructs. The AOP approach provides a framework for organizing information at the chemical and biological level, allowing evidence from both in silico and in vitro studies to be rationally combined to fill gaps in knowledge concerning toxicological events. Fundamental to this new paradigm is a greater understanding of the mechanisms of toxicity and, in particular, where these mechanisms may be conserved across taxa, such as between model animals and related wild species. This presents an opportunity to make predictions across diverse species, where empirical data are unlikely to become available as is the case for most species of wildlife. PMID:25405971

  20. Associations between maternal BMI as well as glucose tolerance and adverse pregnancy outcomes in women with polycystic ovary syndrome.

    PubMed

    Li, Ying-Ying; Ye, Su-Qi; Zhong, Zhuo-Hui; Xu, Qiong; Mai, Wei-Bi; Yin, Cai-Xin; Zhu, Zhi-Qin; He, Xiao-Qian; Xiao, Qing

    2017-04-01

    This retrospective, cohort study examined the association between maternal pre-pregnancy body mass index (BMI), independent of glucose tolerance and adverse pregnancy outcomes in women with polycystic ovary syndrome (PCOS), for which there are few previous studies. Medical records from 2012 to 2015 at Guangzhou Women and Children's Medical Center, China were reviewed for women previously diagnosed with PCOS with normal 2-h 75-g oral glucose tolerance test (OGTT) results (n = 1249). The separate and joint effects of maternal BMI and glucose levels on pregnancy outcomes were assessed. Maternal pre-pregnancy BMI was associated with hypertensive disorders of pregnancy (HDP) (OR: 1.22, 95% CI: 1.02-1.45), preterm birth (OR: 1.49, 95% CI: 1.08-2.17), and large for gestational age (LGA) (OR: 1.69, 95% CI: 1.16-2.20). Elevated fasting glucose and maternal pre-pregnancy BMI were jointly associated with increased risks of HDP, preterm birth, and LGA. Therefore, among women with PCOS and normal glucose tolerance, maternal pre-pregnancy BMI is an independent risk factor of adverse pregnancy outcomes.

  1. Review of medicolegal cases for cauda equina syndrome: what factors lead to an adverse outcome for the provider?

    PubMed

    Daniels, Eldra W; Gordon, Zachary; French, Keisha; Ahn, Uri M; Ahn, Nicholas U

    2012-03-07

    Cauda equina syndrome is 1 of a few true surgical emergencies involving the lumbar spine. Although treatment within 48 hours has been found to correlate with improved outcomes, recovery of bowel and bladder control does not always occur, and loss of these functions can be distressing to patients. An understanding of factors affecting the legal outcome can aid the clinician in determining risk management for medicolegal cases of cauda equina syndrome. This study is a retrospective analysis of medicolegal cases involving cauda equina syndrome. The LexisNexis Academic legal search database was used to obtain medicolegal cases of cauda equina syndrome to determine risk factors for adverse decisions for the provider. Outcomes data on trial verdicts were collected, as were associated penalties. Case data were also compiled on age, sex, initial presentation site, initial diagnosis, whether a rectal examination was performed, time to consultation with a specialist, time to completion of advanced imaging study, time to surgery, and neurosurgical vs orthopedic consultation. Based on our study of court cases involving cauda equina syndrome, a positive association was found between time to surgery >48 hours and an adverse decision (P<.05). The actual degree of functional loss did not appear to affect the verdicts. Because 26.7% of the cases involved an initial presentation that included loss of bowel or bladder control, this study emphasizes the importance of cautioning all patients with spinal complaints of the potential risk for cauda equina syndrome.

  2. Young adolescent girls are at high risk for adverse pregnancy outcomes in sub-Saharan Africa: an observational multicountry study

    PubMed Central

    Mombo-Ngoma, Ghyslain; Mackanga, Jean Rodolphe; González, Raquel; Ouedraogo, Smaila; Kakolwa, Mwaka A; Manego, Rella Zoleko; Basra, Arti; Rupérez, María; Cot, Michel; Kabanywany, Abdunoor M; Matsiegui, Pierre-Blaise; Agnandji, Seldiji T; Vala, Anifa; Massougbodji, Achille; Abdulla, Salim; Adegnika, Ayôla A; Sevene, Esperança; Macete, Eusebio; Yazdanbakhsh, Maria; Kremsner, Peter G; Aponte, John J; Menéndez, Clara; Ramharter, Michael

    2016-01-01

    Objectives One of Africa's most important challenges is to improve maternal and neonatal health. The identification of groups at highest risk for adverse pregnancy outcomes is important for developing and implementing targeted prevention programmes. This study assessed whether young adolescent girls constitute a group at increased risk for adverse birth outcomes among pregnant women in sub-Saharan Africa. Setting Data were collected prospectively as part of a large randomised controlled clinical trial evaluating intermittent preventive treatment of malaria in pregnancy (NCT00811421—Clinical Trials.gov), conducted between September 2009 and December 2013 in Benin, Gabon, Mozambique and Tanzania. Participants Of 4749 participants, pregnancy outcomes were collected for 4388 deliveries with 4183 live births including 83 multiple gestations. Of 4100 mothers with a singleton live birth delivery, 24% (975/4100) were adolescents (≤19 years of age) and 6% (248/4100) were aged ≤16 years. Primary and secondary outcome measures Primary outcomes of this predefined analysis were preterm delivery and low birth weight. Results The overall prevalence of low birthweight infants and preterm delivery was 10% (371/3851) and 4% (159/3862), respectively. Mothers aged ≤16 years showed higher risk for the delivery of a low birthweight infant (OR: 1.96; 95% CI 1.35 to 2.83). Similarly, preterm delivery was associated with young maternal age (≤16 years; OR: 2.62; 95% CI 1.59 to 4.30). In a subanalysis restricted to primiparous women: preterm delivery, OR 4.28; 95% CI 2.05 to 8.93; low birth weight, OR: 1.29; 95% CI 0.82 to 2.01. Conclusions Young maternal age increases the risk for adverse pregnancy outcomes and it is a stronger predictor for low birth weight and preterm delivery than other established risk factors in sub-Saharan Africa. This finding highlights the need to improve adolescent reproductive health in sub-Saharan Africa. Trial registration number NCT00811421

  3. Antibiotic Prevention for Maternal Group B Streptococcal Colonization on Neonatal GBS-Related Adverse Outcomes: A Meta-Analysis

    PubMed Central

    Li, Shunming; Huang, Jingya; Chen, Zhiyao; Guo, Dan; Yao, Zhenjiang; Ye, Xiaohua

    2017-01-01

    Maternal colonization with group B Streptococcus (GBS) during pregnancy increases the risk of neonatal infection by vertical transmission. However, it remains unclear whether treating all colonized women during labor exposes a large number of their neonates to possible adverse effects without benefit. We performed a meta-analysis to assess the effect of intrapartum antibiotic prophylaxis on neonatal adverse outcomes. We identified studies by searching several English and Chinese electronic databases and reviewing relevant articles. Data were pooled using fixed-effects or random-effects meta-analysis, and for each outcome both risk ratio (RR) and 95% confidence intervals (95% CIs) were calculated. Fourteen studies (2,051 pregnant women and 2,063 neonates) were included, comprising 13 randomized clinical trials and 1 cohort study. Antibiotic prophylaxis is associated with a significant reduced risk of all cause infections (RR = 0.28, 95% CI = 0.18–0.42), GBS infection (RR = 0.24, 95% CI = 0.13–0.44), early-onset GBS infection (RR = 0.24, 95% CI = 0.13–0.45), non-GBS infections (RR = 0.34, 95% CI = 0.20–0.59), and GBS colonization (RR = 0.10, 95% CI = 0.06–0.16). But no significant reduction was observed in late-onset GBS infection, mortality from early-onset GBS infection or from non-GBS infections. Notably, no significant differences were found between ampicillin and penicillin prevention for neonatal adverse outcomes. Our findings suggest that antibiotic prophylaxis is effective in reducing neonatal GBS colonization and infection. PMID:28367139

  4. In vitro testing of basal cytotoxicity: Establishment of an adverse outcome pathway from chemical insult to cell death.

    PubMed

    Vinken, Mathieu; Blaauboer, Bas J

    2017-03-01

    In this paper, an in vitro basal cytotoxicity testing strategy is described for new chemical entities that lack any pre-existing information on potential toxicity. Special attention is paid to the selection of the cellular system, cytotoxicity assay and exposure conditions. This approach is based on a newly proposed generic adverse outcome pathway from chemical insult to cell death that consists of 3 steps, including initial cell injury, mitochondrial dysfunction and cell demise. The suggested strategy to consider in vitro basal cytotoxicity as a first step in evaluating the toxicity of new chemical entities can be placed in a tiered strategy that could be continued by evaluating more specific types of toxicity.

  5. Risk of Performance Decrements and Adverse Health Outcomes Resulting from Sleep Loss, Circadian Desynchronization, and Work Overload

    NASA Technical Reports Server (NTRS)

    Evans-Flynn, Erin; Gregory, Kevin; Arsintescu, Lucia; Whitmire, Alexandra; Leveton, Lauren B.; Vessey, William

    2015-01-01

    Sleep loss, circadian desynchronization, and work overload occur to some extent for ground and flight crews, prior to and during spaceflight missions. Ground evidence indicates that such risk factors may lead to performance decrements and adverse health outcomes, which could potentially compromise mission objectives. Efforts are needed to identify the environmental and mission conditions that interfere with sleep and circadian alignment, as well as individual differences in vulnerability and resiliency to sleep loss and circadian desynchronization. Specifically, this report highlights a collection of new evidence to better characterize the risk and reveals new gaps in this risk.

  6. Using patient safety indicators to estimate the impact of potential adverse events on outcomes.

    PubMed

    Rivard, Peter E; Luther, Stephen L; Christiansen, Cindy L; Shibei Zhao; Loveland, Susan; Elixhauser, Anne; Romano, Patrick S; Rosen, Amy K

    2008-02-01

    The authors estimated the impact of potentially preventable patient safety events, identified by Agency for Healthcare Research and Quality (AHRQ) Patient Safety Indicators (PSIs), on patient outcomes: mortality, length of stay (LOS), and cost. The PSIs were applied to all acute inpatient hospitalizations at Veterans Health Administration (VA) facilities in fiscal 2001. Two methods-regression analysis and multivariable case matching- were used independently to control for patient and facility characteristics while predicting the effect of the PSI on each outcome. The authors found statistically significant (p < .0001) excess mortality, LOS, and cost in all groups with PSIs. The magnitude of the excess varied considerably across the PSIs. These VA findings are similar to those from a previously published study of nonfederal hospitals, despite differences between VA and non-VA systems. This study contributes to the literature measuring outcomes of medical errors and provides evidence that AHRQ PSIs may be useful indicators for comparison across delivery systems.

  7. Investigation of the relationship between idiopathic microscopic hematuria (in the first and second trimesters) and major adverse outcomes of pregnancy

    PubMed Central

    Shahraki, Azar Danesh; Bardeh, Mahboobeh Esteki; Najarzadegan, Mohammad Reza

    2016-01-01

    Background: The aim of this study was to investigate the relationship between idiopathic microscopic hematuria (in the first and second trimesters) and major adverse outcomes of pregnancy. Materials and Methods: Urinalysis was done for 700 pregnant women before 24 weeks of pregnancy. Those who had 3–5 red blood cells per milliliter in urinalysis were considered positive urinalysis. Then, all individuals were examined for blood pressure and other alarm signs of pregnancy complications in each visit. All mothers were followed for the incidence of preeclampsia, preterm delivery, and pregnancy outcome until the end of pregnancy. Results: The results of this study showed that no significant difference in terms of incident of pregnancy complications between the pregnant women with and without hematuria and the only abortions and neonatal deaths differed between the two groups. Conclusion: These results suggest that further studies are needed to determine whether idiopathic microscopic hematuria can be a predictive value for pregnancy complications or not. PMID:28028526

  8. Women with Intellectual Disability at Risk of Adverse Pregnancy and Birth Outcomes

    ERIC Educational Resources Information Center

    Mcconnell, D.; Mayes, R.; Llewellyn, G.

    2008-01-01

    Background: An increasing number of women with intellectual disability (ID) have children. Cross-sectional, clinical population data suggest that these women face an increased risk of delivering preterm and/or low birthweight babies. The aim of this study was to explore the prevalence of poor pregnancy and birth outcomes in women with ID and/or…

  9. Human adverse reproductive outcomes and electromagnetic field exposures: review of epidemiologic studies.

    PubMed Central

    Shaw, G M; Croen, L A

    1993-01-01

    Concerns have been raised regarding a relation between residential and occupational electromagnetic (EM) field exposures and adverse reproductive effects. This paper reviews the epidemiologic evidence for this possible relation, including some pertinent methodologic issues, notes relevant findings from the experimental literature, and discusses areas for future research. Evidence is lacking for a strong association between a woman's use of a video display terminal (VDT) during pregnancy and spontaneous abortion. The evidence for a strong association between a women's use of a VDT and other adverse reproductive endpoints is also lacking, with some suggestive findings for congenital malformations and too few data to reach a conclusion about other endpoints. With respect to low-level EM field exposures other than VDTs, the paucity of data prevents one from determining whether there are reproductive health risks associated with such exposures. Therefore, this is an area that needs further investigation. Given that altered growth may be an underlying biologic effect of EM field exposures, endpoints that might be pursued in future studies include congenital malformations not associated with chromosomal anomalies, intrauterine growth retardation, and chromosomally normal spontaneous abortions. PMID:8206019

  10. The Placenta as a Mediator of Stress Effects on Neurodevelopmental Reprogramming

    PubMed Central

    Bronson, Stefanie L; Bale, Tracy L

    2016-01-01

    Adversity experienced during gestation is a predictor of lifetime neuropsychiatric disease susceptibility. Specifically, maternal stress during pregnancy predisposes offspring to sex-biased neurodevelopmental disorders, including schizophrenia, attention deficit/hyperactivity disorder, and autism spectrum disorders. Animal models have demonstrated disease-relevant endophenotypes in prenatally stressed offspring and have provided unique insight into potential programmatic mechanisms. The placenta has a critical role in the deleterious and sex-specific effects of maternal stress and other fetal exposures on the developing brain. Stress-induced perturbations of the maternal milieu are conveyed to the embryo via the placenta, the maternal–fetal intermediary responsible for maintaining intrauterine homeostasis. Disruption of vital placental functions can have a significant impact on fetal development, including the brain, outcomes that are largely sex-specific. Here we review the novel involvement of the placenta in the transmission of the maternal adverse environment and effects on the developing brain. PMID:26250599

  11. Cognitive load imposed by ultrasound-facilitated teaching does not adversely affect gross anatomy learning outcomes.

    PubMed

    Jamniczky, Heather A; Cotton, Darrel; Paget, Michael; Ramji, Qahir; Lenz, Ryan; McLaughlin, Kevin; Coderre, Sylvain; Ma, Irene W Y

    2017-03-01

    Ultrasonography is increasingly used in medical education, but its impact on learning outcomes is unclear. Adding ultrasound may facilitate learning, but may also potentially overwhelm novice learners. Based upon the framework of cognitive load theory, this study seeks to evaluate the relationship between cognitive load associated with using ultrasound and learning outcomes. The use of ultrasound was hypothesized to facilitate learning in anatomy for 161 novice first-year medical students. Using linear regression analyses, the relationship between reported cognitive load on using ultrasound and learning outcomes as measured by anatomy laboratory examination scores four weeks after ultrasound-guided anatomy training was evaluated in consenting students. Second anatomy examination scores of students who were taught anatomy with ultrasound were compared with historical controls (those not taught with ultrasound). Ultrasound's perceived utility for learning was measured on a five-point scale. Cognitive load on using ultrasound was measured on a nine-point scale. Primary outcome was the laboratory examination score (60 questions). Learners found ultrasound useful for learning. Weighted factor score on "image interpretation" was negatively, but insignificantly, associated with examination scores [F (1,135) = 0.28, beta = -0.22; P = 0.61]. Weighted factor score on "basic knobology" was positively and insignificantly associated with scores; [F (1,138) = 0.27, beta = 0.42; P = 0.60]. Cohorts exposed to ultrasound had significantly higher scores than historical controls (82.4% ± SD 8.6% vs. 78.8% ± 8.5%, Cohen's d = 0.41, P < 0.001). Using ultrasound to teach anatomy does not negatively impact learning and may improve learning outcomes. Anat Sci Educ 10: 144-151. © 2016 American Association of Anatomists.

  12. Eating disorder behaviours amongst adolescents: investigating classification, persistence and prospective associations with adverse outcomes using latent class models.

    PubMed

    Micali, Nadia; Horton, N J; Crosby, R D; Swanson, S A; Sonneville, K R; Solmi, F; Calzo, J P; Eddy, K T; Field, A E

    2017-02-01

    Diagnostic criteria for eating disorders (ED) remain largely based on clinical presentations, but do not capture the full range of behaviours in the population. We aimed to derive an empirically based ED behaviour classification using behavioural and body mass index (BMI) indicators at three time-points in adolescence, and to validate classes investigating prospective associations with adverse outcomes. Adolescents from the Avon Longitudinal Study of Parents and Children (ALSPAC) provided data on ED at age 14 (n = 6615), 16 (n = 5888), and 18 years (n = 5100), and had weight and height measured. Psychological and behavioural outcomes were assessed at 15.5/16 and 17.5/18 years. We fit gender- and age-stratified latent class models, and employed logistic regression to investigate associations between classes and later outcomes. One asymptomatic and two symptomatic (largely representing higher and lower frequency ED behaviours) classes were observed at each time-point, although their relative prevalence varied by age and gender. The majority of girls in symptomatic classes remained symptomatic at subsequent assessments. Girls in symptomatic classes had higher odds of subsequent anxiety and depressive disorders, binge drinking, drug use, and deliberate self-harm. Data analyses were underpowered amongst boys. The presence of two symptomatic classes (characterised by different ED behaviour frequency) and their prospective association with adverse outcomes suggest a need to refine diagnostic thresholds based on empirical data. Despite some instability of classes, particularly in mid-adolescence, evidence that half of girls in symptomatic classes remained symptomatic suggests persistence of ED behaviours in adolescence, and highlights a need for early identification to reduce chronicity.

  13. Gestational diabetes mellitus treatment reduces obesity-induced adverse pregnancy and neonatal outcomes: the St. Carlos gestational study

    PubMed Central

    Assaf-Balut, Carla; Familiar, Cristina; García de la Torre, Nuria; Rubio, Miguel A; Bordiú, Elena; del Valle, Laura; Lara, Miriam; Ruiz, Teresa; Ortolá, Ana; Crespo, Irene; Duran, Alejandra; Herraiz, Miguel A; Izquierdo, Nuria; Perez, Noelia; Torrejon, Maria J; Runkle, Isabelle; Montañez, Carmen; Calle-Pascual, Alfonso L

    2016-01-01

    Background Obesity and gestational diabetes mellitus (GDM) increase the morbidity of the mother and newborn, which could increase further should they coexist. We aimed to determine the risk of adverse pregnancy and neonatal outcomes associated with excess weight (EW), and within this group identify potential differences between those with and without GDM. Methods We carried out a post-hoc analysis of the St. Carlos Gestational Study which included 3312 pregnant women, arranged in 3 groups: normal-weight women (NWw) (2398/72.4%), overweight women (OWw) (649/19.6%) and obese women (OBw) (265/8%). OWw and OBw were grouped as EW women (EWw). We analyzed variables related to adverse pregnancy and neonatal outcomes. Results The relative risk (95% CI) for GDM was 1.82 (1.47 to 2.25; p<0.0001) for OWw, and 3.26 (2.45 to 4.35; p<0.0001) in OBw. Univariate analysis showed associations of EW to higher rates of prematurity, birth weight >90th centile, newborns admitted to neonatal intensive care unit (NICU), instrumental delivery and cesarean delivery (all p<0.005). Multivariate analysis, adjusted for parity and ethnicity, showed that EW increased the risk of prematurity, admission to NICU, cesarean and instrumental delivery, especially in EWw without GDM. NWw with GDM had a significantly lower risk of admission to NICU and cesarean delivery, compared with NWw without GDM. Conclusions EW is detrimental for pregnancy and neonatal outcomes, and treatment of GDM contributes to lowering the risk in EWw and NWw. Applying the same lifestyle changes to all pregnant women, independent of their weight or GDM condition, could improve these outcomes. PMID:28074143

  14. Frequency of changing enteral alimentation bags and tubing, and adverse clinical outcomes in patients in a long term care facility.

    PubMed

    Graham, S; McIntyre, M; Chicoine, J; Gerard, B; Laughren, R; Cowley, G; Morrison, J; Aoki, F Y; Nicolle, L E

    1993-01-01

    Enteral alimentation, given via nasogastric or gastrostomy tubes, is a well established practice to provide nutrition for patients with significant neurological injury. The frequency with which enteral feeding bags and tubes require change and potential adverse effects associated with bacterial contamination of tube feeds remain controversial. The authors studied different times between enteral feeding bag and tube changes, and the effect on adverse clinical outcomes in residents of a long term care facility. In the first study, residents were randomized to 24 h (n = 2), 48 h (n = 3) or 72 h (n = 6) tube feeding and bag changes with clinical status monitored in a standardized fashion for six months. In the second study, patients were randomized to 24 h (n = 6) or 72 h (n = 6) changes. Patient-days of follow-up were 382, 574 and 1000 for the three arms of the first study period and 556 and 496 for the two arms of the second study. No differences in potential clinical adverse events--including fever, gastrointestinal symptoms or pneumonia--were observed with different durations of tubing change. This study suggests it is appropriate to change alimentation tube and feeding bags every 72 h (rather than every 24 h). The less frequent changes will decrease supply costs and free nursing time for other activities.

  15. Associations of meteorology with adverse pregnancy outcomes: a systematic review of preeclampsia, preterm birth and birth weight.

    PubMed

    Beltran, Alyssa J; Wu, Jun; Laurent, Olivier

    2013-12-20

    The relationships between meteorology and pregnancy outcomes are not well known. This article reviews available evidence on the relationships between seasonality or meteorology and three major pregnancy outcomes: the hypertensive disorders of pregnancy (including preeclampsia, eclampsia and gestational hypertension), gestational length and birth weight. In total 35, 28 and 27 studies were identified for each of these outcomes. The risks of preeclampsia appear higher for women with conception during the warmest months, and delivery in the coldest months of the year. Delivery in the coldest months is also associated with a higher eclampsia risk. Patterns of decreased gestational lengths have been observed for births in winter, as well as summer months. Most analytical studies also report decreases in gestational lengths associated with heat. Birth weights are lower for deliveries occurring in winter and in summer months. Only a limited number of studies have investigated the effects of barometric pressure on gestational length or the effects of temperature and sunshine exposure on birth weight, but these questions appear worth investigating further. Available results should encourage further etiological research aiming at enhancing our understanding of the relationships between meteorology and adverse pregnancy outcomes, ideally via harmonized multicentric studies.

  16. Associations of Meteorology with Adverse Pregnancy Outcomes: A Systematic Review of Preeclampsia, Preterm Birth and Birth Weight

    PubMed Central

    Beltran, Alyssa J.; Wu, Jun; Laurent, Olivier

    2013-01-01

    The relationships between meteorology and pregnancy outcomes are not well known. This article reviews available evidence on the relationships between seasonality or meteorology and three major pregnancy outcomes: the hypertensive disorders of pregnancy (including preeclampsia, eclampsia and gestational hypertension), gestational length and birth weight. In total 35, 28 and 27 studies were identified for each of these outcomes. The risks of preeclampsia appear higher for women with conception during the warmest months, and delivery in the coldest months of the year. Delivery in the coldest months is also associated with a higher eclampsia risk. Patterns of decreased gestational lengths have been observed for births in winter, as well as summer months. Most analytical studies also report decreases in gestational lengths associated with heat. Birth weights are lower for deliveries occurring in winter and in summer months. Only a limited number of studies have investigated the effects of barometric pressure on gestational length or the effects of temperature and sunshine exposure on birth weight, but these questions appear worth investigating further. Available results should encourage further etiological research aiming at enhancing our understanding of the relationships between meteorology and adverse pregnancy outcomes, ideally via harmonized multicentric studies. PMID:24362545

  17. How Does the Fast Track Intervention Prevent Adverse Outcomes in Young Adulthood?

    PubMed Central

    Sorensen, Lucy C.; Dodge, Kenneth A.

    2015-01-01

    Numerous studies have shown that childhood interventions can foster improved outcomes in adulthood. Less well understood is precisely how – that is, through which developmental pathways – these interventions work. This study assesses mechanisms by which the Fast Track project (n=891), a randomized intervention in the early 1990s for high-risk children in four communities (Durham, NC; Nashville, TN; rural PA; and Seattle, WA), reduced delinquency, arrests, and health and mental health service utilization in adolescence through young adulthood (ages 12–20). A decomposition of treatment effects indicates that about a third of Fast Track’s impact on later crime outcomes can be accounted for by improvements in social and self-regulation skills during childhood (ages 6–11), such as prosocial behavior, emotion regulation and problem solving. These skills proved less valuable for the prevention of mental and physical health problems. PMID:26670938

  18. Current Perspectives on Arthroplasty in Systemic Lupus Erythematosus: Rates, Outcomes, and Adverse Events.

    PubMed

    Kasturi, Shanthini; Goodman, Susan

    2016-09-01

    Systemic lupus erythematosus (SLE) is a chronic debilitating condition with significant impact on the musculoskeletal system. Arthroplasty may be indicated for damage related to active lupus or its treatment. As therapies for SLE have advanced, morbidity and mortality have declined, while the rate of joint replacement has increased. The age of SLE patients undergoing arthroplasty is increasing, and the indication for surgery is evolving-while avascular necrosis was previously the predominant indication for arthroplasty, osteoarthritis now accounts for a larger proportion of surgeries. Pain and functional outcomes of arthroplasty in SLE patients are comparable to those of the general population with osteoarthritis, but lupus remains an independent risk factor for post-hip arthroplasty complications and mortality. Further research is needed to characterize the impact of lupus disease activity and severity on arthroplasty outcomes.

  19. Proposing a scientific confidence framework to help support the application of adverse outcome pathways for regulatory purposes.

    PubMed

    Patlewicz, Grace; Simon, Ted W; Rowlands, J Craig; Budinsky, Robert A; Becker, Richard A

    2015-04-01

    An adverse outcome pathway (AOP) describes the causal linkage between initial molecular events and an adverse outcome at individual or population levels. Whilst there has been considerable momentum in AOP development, far less attention has been paid to how AOPs might be practically applied for different regulatory purposes. This paper proposes a scientific confidence framework (SCF) for evaluating and applying a given AOP for different regulatory purposes ranging from prioritizing chemicals for further evaluation, to hazard prediction, and ultimately, risk assessment. The framework is illustrated using three different AOPs for several typical regulatory applications. The AOPs chosen are ones that have been recently developed and/or published, namely those for estrogenic effects, skin sensitisation, and rodent liver tumor promotion. The examples confirm how critical the data-richness of an AOP is for driving its practical application. In terms of performing risk assessment, human dosimetry methods are necessary to inform meaningful comparisons with human exposures; dosimetry is applied to effect levels based on non-testing approaches and in vitro data. Such a comparison is presented in the form of an exposure:activity ratio (EAR) to interpret biological activity in the context of exposure and to provide a basis for product stewardship and regulatory decision making.

  20. Practical approaches to adverse outcome pathway (AOP) development and weight of evidence evaluation as illustrated by ecotoxicological case studies.

    PubMed

    Fay, Kellie A; Villeneuve, Daniel L; LaLone, Carlie A; Song, You; Tollefsen, Knut Erik; Ankley, Gerald T

    2017-02-15

    Adverse Outcome Pathways (AOPs) describe toxicant effects as a sequential chain of causally linked events beginning with a molecular perturbation and culminating in an adverse outcome at an individual or population level. Strategies for developing AOPs are still evolving and depend largely on the intended use or motivation for development and data availability. Four ecotoxicological AOP case studies, developed for different purposes, are described herein. In each situation, creation of the AOP began in a manner determined by the initial motivation for its creation, and expanded either to include additional components of the pathway, or to address the domains of applicability in terms of chemical initiators, susceptible species, life stages, etc. From these case studies, some general strategies can be gleaned which a developer may find useful for supporting an existing AOP or creating a new one. Several web-based tools which can aid in AOP assembly and evaluation of weight of evidence for scientific robustness of AOP components are highlighted. This article is protected by copyright. All rights reserved.

  1. Maternal Influenza Immunization and Adverse Birth Outcomes: Using Data and Practice to Inform Theory and Research Design

    PubMed Central

    Phadke, Varun K.; Steinhoff, Mark C.; Omer, Saad B.; MacDonald, Noni E.

    2016-01-01

    Maternal influenza immunization can reduce influenza-attributable morbidity and mortality among pregnant women and infants who are too young to be vaccinated. Data from empirical studies also support the hypothesis that immunization can protect the fetus against adverse outcomes if the mother is exposed to influenza. In their theoretical analysis in the Journal, Hutcheon et al. (Am J Epidemiol. 2016;184(3):227–232) critiqued the existing evidence of the fetal benefits of maternal influenza immunization by calculating the sample sizes needed to demonstrate hypothetical reductions in risk and concluded that the benefits observed in empirical studies are likely implausible. However, in their analysis, they did not take into account multiple fundamental characteristics of influenza epidemiology, including the time-variable effects of influenza illness and vaccination during pregnancy, or well-known differences in disease epidemiology between seasons, populations, and geographic regions. Although these and other factors might affect the magnitude of fetal benefit conferred by maternal influenza immunization, studies in which investigators have accounted for influenza circulation have demonstrated a consistent protective effect against a variety of adverse birth outcomes; those studies include the only randomized controlled trial designed a priori and adequately powered to do so. Only a comprehensive and nuanced assessment of the evidence base will allow for effective translation of these data into a global immunization policy. PMID:27784657

  2. Cilostazol increases patency and reduces adverse outcomes in percutaneous femoropopliteal revascularisation: a meta-analysis of randomised controlled trials

    PubMed Central

    Benjo, Alexandre M; Garcia, Daniel C; Jenkins, J Stephen; Cardoso, Rhanderson M N; Molina, Taina P; El-Hayek, Georges E; Nadkarni, Girish N; Aziz, Emad F; Dinicolantonio, James J; Collins, Tyrone

    2014-01-01

    Background Cilostazol is an oral antiplatelet agent currently indicated for treatment of intermittent claudication. There is evidence that cilostazol may reduce femoropopliteal restenosis after percutaneous endovascular intervention. Methods We searched PubMed, Scopus and Cochrane databases from 1966 through September 2013 for randomised controlled trials (RCTs) evaluating the addition of cilostazol to standard care in patients receiving femoropopliteal endovascular treatment. Restenosis, target lesion revascularisation and combined adverse outcomes (death, revascularisation and amputation) within 1–2 years postprocedure were evaluated. Results Of 205 articles, three RCTs were included in the analysis. The pooled data provided a total of 396 patients, 195 of whom received cilostazol. When compared to standard medical therapy alone, cilostazol significantly reduced the risk of restenosis (risk difference −0.20; 95% CI −0.29 to −0.11; p<0.0001; number needed to treat 5), target lesion revascularisation (risk difference −0.17; 95% CI −0.25 to −0.09; p<0.0001; number needed to treat 6). Death and amputation were not different in between groups. Conclusions and limitation Cilostazol significantly increases femoropopliteal patency and decreases adverse outcomes in percutaneous endovascular intervention. However, further RCTs are needed because of limited sample size; this meta-analysis represents the best current evidence. PMID:25392738

  3. Platelet to lymphocyte ratio in the prediction of adverse outcomes after acute coronary syndrome: a meta-analysis

    PubMed Central

    Li, Wenzhang; Liu, Qianqian; Tang, Yin

    2017-01-01

    Recent studies have shown platelet to lymphocyte ratio (PLR) to be a potential inflammatory marker in cardiovascular diseases. We performed a meta-analysis to systematically evaluate the prognostic role of PLR in acute coronary syndrome (ACS). A comprehensive literature search up to May 18, 2016 was conducted from PUBMED, EMBASE and Web of science to identify related studies. The risk ratio (RR) with 95% confidence interval (CI) was extracted or calculated for effect estimates. Totally ten studies involving 8932 patients diagnosed with ACS were included in our research. We demonstrated that patients with higher PLR level had significantly higher risk of in-hospital adverse outcomes (RR = 2.24, 95%CI = 1.81–2.77) and long-term adverse outcomes (RR = 2.32, 95%CI = 1.64–3.28). Sensitivity analyses confirmed the stability of our results. We didn’t detect significant publication bias by Begg’s and Egger’s test (p > 0.05). In conclusion, our meta-analysis revealed that PLR is promising biomarker in predicting worse prognosis in ACS patients. The results should be validated by future large-scale, standard investigations. PMID:28071752

  4. Serum metabolomics identifies citrulline as a predictor of adverse outcomes in an equine model of gut-derived sepsis.

    PubMed

    Steelman, Samantha M; Johnson, Philip; Jackson, Amy; Schulze, James; Chowdhary, Bhanu P

    2014-05-15

    Acute laminitis is an inflammatory disease of the equine foot that often occurs secondarily to sepsis or systemic inflammation associated with gastrointestinal disease. It has been suggested that laminitis is similar to multiple organ dysfunction syndrome in humans, although in horses the weight-bearing laminar epithelium of the foot appears to be the tissue most sensitive to insult and the first "organ" to fail. Metabolomics performed on serum samples collected before (Con) and after (Lmn) experimental induction of gastrointestinal-associated sepsis in six horses detected 1,177 metabolites of both mammalian and bacterial origin in equine serum. Network and correlation analyses suggested a dysregulation of fatty acid metabolism in the Lmn group, as well as an accumulation of organic acids such as lactate. Furthermore, concentrations of the amino acid citrulline were decreased in Lmn samples from all study animals, suggesting that citrulline might be useful as a biomarker to identify critically ill animals that are at risk of developing laminitis. We therefore established normal ranges of plasma citrulline concentrations in a separate group of horses (n = 36) and tested the ability of citrulline to predict adverse outcomes (laminitis or death) in critically ill horses (n = 23). Plasma citrulline was significantly lower in critically ill horses that went on to experience adverse outcomes (n = 6). Further study is required to accurately determine a diagnostic cutoff, but the present data are suggestive of the predictive value of citrulline as a biomarker for laminar failure in equine sepsis.

  5. Combined approaches using adverse outcome pathways and big data to find potential diseases associated with humidifier disinfectant.

    PubMed

    Leem, Jong-Han; Chung, Kyu Hyuck

    2016-01-01

    According to previous survey, about two million of people were expected to suffer from toxic effects due to humidifier disinfectant (HD), regardless of healing or not. Extremely small group are recognized as HDs' victims. Up to now, previous research tried to focus on interstitial fibrosis on terminal bronchiole because it is specific finding, compared with other diseases. To figure out overall effects from HDs, we recommend adverse outcome pathways (AOPs) as new approach. Reactive oxygen species (ROS) generation, decreased T-cell and pro-inflammatory cytokine release from macrophage could be key events between the exposure to HDs and diseases. ROS generation, decreased cell and pro-inflammatory cytokine release from macrophage could be cause of interstitial fibrosis, pneumonia and many other diseases such as asthma, allergic rhinitis, allergic dermatitis, fetal death, premature baby, autoimmune disease, hepatic toxicity, renal toxicity, cancer, and so on. We predict potential disease candidate by AOPs. We can validate the real risk of the adverse outcome by epidemiologic and toxicologic study using big data such as National Health Insurance data and AOPs knowledge base. Application of these kinds of new methods can find the potential disease list from the exposure to HD.

  6. Combined approaches using adverse outcome pathways and big data to find potential diseases associated with humidifier disinfectant

    PubMed Central

    2017-01-01

    According to previous survey, about two million of people were expected to suffer from toxic effects due to humidifier disinfectant (HD), regardless of healing or not. Extremely small group are recognized as HDs’ victims. Up to now, previous research tried to focus on interstitial fibrosis on terminal bronchiole because it is specific finding, compared with other diseases. To figure out overall effects from HDs, we recommend adverse outcome pathways (AOPs) as new approach. Reactive oxygen species (ROS) generation, decreased T-cell and pro-inflammatory cytokine release from macrophage could be key events between the exposure to HDs and diseases. ROS generation, decreased cell and pro-inflammatory cytokine release from macrophage could be cause of interstitial fibrosis, pneumonia and many other diseases such as asthma, allergic rhinitis, allergic dermatitis, fetal death, premature baby, autoimmune disease, hepatic toxicity, renal toxicity, cancer, and so on. We predict potential disease candidate by AOPs. We can validate the real risk of the adverse outcome by epidemiologic and toxicologic study using big data such as National Health Insurance data and AOPs knowledge base. Application of these kinds of new methods can find the potential disease list from the exposure to HD. PMID:28111421

  7. Adverse Outcome Pathways for Regulatory Applications: Examination of Four Case Studies With Different Degrees of Completeness and Scientific Confidence.

    PubMed

    Perkins, Edward J; Antczak, Philipp; Burgoon, Lyle; Falciani, Francesco; Garcia-Reyero, Natàlia; Gutsell, Steve; Hodges, Geoff; Kienzler, Aude; Knapen, Dries; McBride, Mary; Willett, Catherine

    2015-11-01

    Adverse outcome pathways (AOPs) offer a pathway-based toxicological framework to support hazard assessment and regulatory decision-making. However, little has been discussed about the scientific confidence needed, or how complete a pathway should be, before use in a specific regulatory application. Here we review four case studies to explore the degree of scientific confidence and extent of completeness (in terms of causal events) that is required for an AOP to be useful for a specific purpose in a regulatory application: (i) Membrane disruption (Narcosis) leading to respiratory failure (low confidence), (ii) Hepatocellular proliferation leading to cancer (partial pathway, moderate confidence), (iii) Covalent binding to proteins leading to skin sensitization (high confidence), and (iv) Aromatase inhibition leading to reproductive dysfunction in fish (high confidence). Partially complete AOPs with unknown molecular initiating events, such as 'Hepatocellular proliferation leading to cancer', were found to be valuable. We demonstrate that scientific confidence in these pathways can be increased though the use of unconventional information (eg, computational identification of potential initiators). AOPs at all levels of confidence can contribute to specific uses. A significant statistical or quantitative relationship between events and/or the adverse outcome relationships is a common characteristic of AOPs, both incomplete and complete, that have specific regulatory uses. For AOPs to be useful in a regulatory context they must be at least as useful as the tools that regulators currently possess, or the techniques currently employed by regulators.

  8. Elevated depressive affect is associated with adverse cardiovascular outcomes among African Americans with chronic kidney disease.

    PubMed

    Fischer, Michael J; Kimmel, Paul L; Greene, Tom; Gassman, Jennifer J; Wang, Xuelei; Brooks, Deborah H; Charleston, Jeanne; Dowie, Donna; Thornley-Brown, Denyse; Cooper, Lisa A; Bruce, Marino A; Kusek, John W; Norris, Keith C; Lash, James P

    2011-09-01

    This study was designed to examine the impact of elevated depressive affect on health outcomes among participants with hypertensive chronic kidney disease in the African-American Study of Kidney Disease and Hypertension (AASK) Cohort Study. Elevated depressive affect was defined by Beck Depression Inventory II (BDI-II) thresholds of 11 or more, above 14, and by 5-Unit increments in the score. Cox regression analyses were used to relate cardiovascular death/hospitalization, doubling of serum creatinine/end-stage renal disease, overall hospitalization, and all-cause death to depressive affect evaluated at baseline, the most recent annual visit (time-varying), or average from baseline to the most recent visit (cumulative). Among 628 participants at baseline, 42% had BDI-II scores of 11 or more and 26% had a score above 14. During a 5-year follow-up, the cumulative incidence of cardiovascular death/hospitalization was significantly greater for participants with baseline BDI-II scores of 11 or more compared with those with scores <11. The baseline, time-varying, and cumulative elevated depressive affect were each associated with a significant higher risk of cardiovascular death/hospitalization, especially with a time-varying BDI-II score over 14 (adjusted HR 1.63) but not with the other outcomes. Thus, elevated depressive affect is associated with unfavorable cardiovascular outcomes in African Americans with hypertensive chronic kidney disease.

  9. Adverse Outcomes after Non-Chest Surgeries in Patients with Pulmonary Tuberculosis: A Nationwide Study

    PubMed Central

    Lin, Chao-Shun; Yeh, Chun-Chieh; Chung, Chi-Li; Hung, Chih-Jen; Chen, Ta-Liang

    2015-01-01

    Background The association between pulmonary tuberculosis (TB) and postoperative outcomes remains unknown. This study investigated outcomes following non-chest surgeries in patients with previous pulmonary TB. Methods Using Taiwan’s National Health Insurance Research Database, we analyzed 6911 patients (aged ≥ 20 years) with preoperative diagnosis of pulmonary TB and 6911 propensity score-matched controls receiving non-chest surgeries in 2008–2010. Postoperative outcomes were compared between patients with or without pulmonary TB by calculating adjusted odds ratios (ORs) and 95% confidence intervals (CIs) in the multivariate logistic regressions. Results Surgical patients with pulmonary TB had a significantly higher postoperative complication rates than controls, including septicemia, pneumonia, acute renal failure, deep wound infection, overall complications, and 30-day postoperative mortality (OR 1.41; 95% CI 1.07–1.86). The ORs of patients with low-income status were as high as 2.27 (95% CI 1.03–5.03). Preoperative use of TB drugs and TB-related medical expenditure also associated with higher postoperative mortality among surgical patients with pulmonary TB. Conclusions Surgical patients with pulmonary TB have significantly increased risks of postoperative complications and mortality after non-chest surgeries. This study suggests the need to improve postoperative care for surgical patients with pulmonary TB. PMID:26172153

  10. The use of multiple respiratory inhalers requiring different inhalation techniques has an adverse effect on COPD outcomes

    PubMed Central

    Bosnic-Anticevich, Sinthia; Chrystyn, Henry; Costello, Richard W; Dolovich, Myrna B; Fletcher, Monica J; Lavorini, Federico; Rodríguez-Roisin, Roberto; Ryan, Dermot; Wan Yau Ming, Simon; Price, David B

    2017-01-01

    Background Patients with COPD may be prescribed multiple inhalers as part of their treatment regimen, which require different inhalation techniques. Previous literature has shown that the effectiveness of inhaled treatment can be adversely affected by incorrect inhaler technique. Prescribing a range of device types could worsen this problem, leading to poorer outcomes in COPD patients, but the impact is not yet known. Aims To compare clinical outcomes of COPD patients who use devices requiring similar inhalation technique with those who use devices with mixed techniques. Methods A matched cohort design was used, with 2 years of data from the Optimum Patient Care Research Database. Matching variables were established from a baseline year of follow-up data, and two cohorts were formed: a “similar-devices cohort” and a “mixed-devices cohort”. COPD-related events were recorded during an outcome year of follow-up. The primary outcome measure was an incidence rate ratio (IRR) comparing the rate of exacerbations between study cohorts. A secondary outcome compared average daily use of short-acting beta agonist (SABA). Results The final study sample contained 8,225 patients in each cohort (mean age 67 [SD, 10], 57% males, 37% current smokers). Patients in the similar-devices cohort had a lower rate of exacerbations compared with those in the mixed-devices cohort (adjusted IRR 0.82, 95% confidence interval [CI] 0.80–0.84) and were less likely to be in a higher-dose SABA group (adjusted proportional odds ratio 0.54, 95% CI 0.51–0.57). Conclusion COPD patients who were prescribed one or more additional inhaler devices requiring similar inhalation techniques to their previous device(s) showed better outcomes than those who were prescribed devices requiring different techniques. PMID:28053517

  11. Sex-Specific and Strain-Dependent Effects of Early Life Adversity on Behavioral and Epigenetic Outcomes

    PubMed Central

    Kundakovic, Marija; Lim, Sean; Gudsnuk, Kathryn; Champagne, Frances A.

    2013-01-01

    Early life adversity can have a significant long-term impact with implications for the emergence of psychopathology. Disruption to mother-infant interactions is a form of early life adversity that may, in particular, have profound programing effects on the developing brain. However, despite converging evidence from human and animal studies, the precise mechanistic pathways underlying adversity-associated neurobehavioral changes have yet to be elucidated. One approach to the study of mechanism is exploration of epigenetic changes associated with early life experience. In the current study, we examined the effects of postnatal maternal separation (MS) in mice and assessed the behavioral, brain gene expression, and epigenetic effects of this manipulation in offspring. Importantly, we included two different mouse strains (C57BL/6J and Balb/cJ) and both male and female offspring to determine strain- and/or sex-associated differential response to MS. We found both strain-specific and sex-dependent effects of MS in early adolescent offspring on measures of open-field exploration, sucrose preference, and social behavior. Analyses of cortical and hippocampal mRNA levels of the glucocorticoid receptor (Nr3c1) and brain-derived neurotrophic factor (Bdnf) genes revealed decreased hippocampal Bdnf expression in maternally separated C57BL/6J females and increased cortical Bdnf expression in maternally separated male and female Balb/cJ offspring. Analyses of Nr3c1and Bdnf (IV and IX) CpG methylation indicated increased hippocampal Nr3c1 methylation in maternally separated C57BL/6J males and increased hippocampal Bdnf IX methylation in male and female maternally separated Balb/c mice. Overall, though effect sizes were modest, these findings suggest a complex interaction between early life adversity, genetic background, and sex in the determination of neurobehavioral and epigenetic outcomes that may account for differential vulnerability to later-life disorder. PMID:23914177

  12. Social deprivation and adverse perinatal outcomes among Western and non-Western pregnant women in a Dutch urban population.

    PubMed

    Poeran, Jashvant; Maas, Arno F G; Birnie, Erwin; Denktas, Semiha; Steegers, Eric A P; Bonsel, Gouke J

    2013-04-01

    Social deprivation is considered a key factor in adverse perinatal outcomes. Rotterdam, the second largest city in The Netherlands, has large inequalities in perinatal health and a high number of deprived neighbourhoods. Social deprivation is measured here through a composite variable: 'Social Index' (SI). We studied the impact of the SI (2008-2009; 5 categories) in terms of perinatal mortality, congenital anomalies, preterm birth, small for gestational age (SGA) and low 5-minute Apgar score as registered in The Netherlands Perinatal Registry (Rotterdam 2000-2007, n = 56,443 singleton pregnancies). We applied ethnic dichotomisation as Western (European/North-American/Australian) vs. Non-Western (all others) ethnicity was expected to interact with the impact of SI. Tests for trend and multilevel regression analysis were applied. Gradually decreasing prevalence of adverse perinatal outcomes was observed in Western women from the lowest SI category (low social quality) to the highest SI category (high social quality). In Western women the low-high SI gradient for prevalence of spontaneous preterm birth (per 1000) changed from 57.2 to 34.1, for iatrogenic preterm birth from 35.2 to 19.0, for SGA from 119.6 to 59.4, for low Apgar score from 10.9 to 8.2, and for perinatal mortality from 14.9 to 7.6. These trends were statistically confirmed by Chi2-tests for trend (p < 0.001). For non-Western women such trends were absent. These strong effects for Western women were confirmed by significant odds ratios for almost all adverse perinatal outcomes estimated from multilevel regression analysis. We conclude social deprivation to play a different role among Western vs. non-Western women. Our results suggest that improvements in social quality may improve perinatal outcomes in Western women, but alternative approaches may be necessary for non-Western groups. Suggested explanations for non-Western 'migrant' groups include the presence of 'protective' effects through knowledge

  13. Background Rates of Adverse Pregnancy Outcomes for Assessing the Safety of Maternal Vaccine Trials in Sub-Saharan Africa

    PubMed Central

    Orenstein, Lauren A. V.; Orenstein, Evan W.; Teguete, Ibrahima; Kodio, Mamoudou; Tapia, Milagritos; Sow, Samba O.; Levine, Myron M.

    2012-01-01

    Background Maternal immunization has gained traction as a strategy to diminish maternal and young infant mortality attributable to infectious diseases. Background rates of adverse pregnancy outcomes are crucial to interpret results of clinical trials in Sub-Saharan Africa. Methods We developed a mathematical model that calculates a clinical trial's expected number of neonatal and maternal deaths at an interim safety assessment based on the person-time observed during different risk windows. This model was compared to crude multiplication of the maternal mortality ratio and neonatal mortality rate by the number of live births. Systematic reviews of severe acute maternal morbidity (SAMM), low birth weight (LBW), prematurity, and major congenital malformations (MCM) in Sub-Saharan African countries were also performed. Findings Accounting for the person-time observed during different risk periods yields lower, more conservative estimates of expected maternal and neonatal deaths, particularly at an interim safety evaluation soon after a large number of deliveries. Median incidence of SAMM in 16 reports was 40.7 (IQR: 10.6–73.3) per 1,000 total births, and the most common causes were hemorrhage (34%), dystocia (22%), and severe hypertensive disorders of pregnancy (22%). Proportions of liveborn infants who were LBW (median 13.3%, IQR: 9.9–16.4) or premature (median 15.4%, IQR: 10.6–19.1) were similar across geographic region, study design, and institutional setting. The median incidence of MCM per 1,000 live births was 14.4 (IQR: 5.5–17.6), with the musculoskeletal system comprising 30%. Interpretation Some clinical trials assessing whether maternal immunization can improve pregnancy and young infant outcomes in the developing world have made ethics-based decisions not to use a pure placebo control. Consequently, reliable background rates of adverse pregnancy outcomes are necessary to distinguish between vaccine benefits and safety concerns. Local studies that

  14. Recent immigration and adverse pregnancy outcomes in an urban setting in Spain.

    PubMed

    Garcia-Subirats, Irene; Pérez, Glòria; Rodríguez-Sanz, Maica; Salvador, Joaquín; Jané, Mireia

    2011-07-01

    To describe social and economic inequalities in non-fatal pregnancy outcomes (low birth weight, preterm birth and small for gestational age births) in the neighbourhoods of the city of Barcelona (Spain), according to maternal age and maternal country of origin, between 1991 and 2005. A cross-sectional ecological study was carried out using the 38 neighbourhoods of Barcelona as the unit of analysis. The study population comprises the 192,921 live births to resident women aged 12-49 residing from 1991 to 2005. Information was gathered from births registry. Prevalence of low birth-weight, preterm birth and small for gestational age, was calculated for each of the 38 neighbourhoods of mothers' residence, stratifying results by maternal age and country of origin. The indicator of neighbourhood socio-economic level was the unemployment rate. Quartile maps along with Spearman correlation coefficients and linear regression were performed between indicators. The present study reports socio-economic inequalities in pregnancy outcomes among neighbourhoods in Barcelona (Spain): the more disadvantaged neighbourhoods have worse pregnancy outcomes (low birth weight, preterm birth and small for gestational age births) in all women age groups. These inequalities do not exist among immigrant women, and some groups of foreign mothers even have lower rates of low birth weight, preterm birth, and small for gestational age births than autochthonous women. The existing inequalities suggest that policy efforts to reduce these inequalities are not entirely successful and should focus on improving pregnancy and delivery care in less privileged women in a country with universal access to health care.

  15. Smallpox Vaccine and Adverse Reproductive Health Outcomes in Military Service Members

    DTIC Science & Technology

    2005-01-01

    disease to bioterrorist threat. Obstet Gynecol 2002;100(1):87-93 4. Levine MM. Live-virus vaccines in pregnancy: risks and recommendations. Lancet 1974;2...vaccination and outcome of pregnancy. AJPH Nations Health 1968;58(10)1910-21. 12. Luisi M. Smallpox vaccination and pregnancy. Am J Obstet Gynecol 1977;128...Valero J, Luna S, Dominguez-Rojas V. Risk factors in miscarriage: a review. Eur J Obstet Gynecol Reprod Biol 2002;102(2):111-9 14. Ellish NJ, Saboda K

  16. Multidimensional system biology: genetic markers and proteomic biomarkers of adverse pregnancy outcome in preterm birth.

    PubMed

    Buhimschi, Catalin S; Rosenberg, Victor A; Dulay, Antonette T; Thung, Stephen; Sfakianaki, Anna K; Bahtiyar, Mert-Ozan; Buhimschi, Irina A

    2008-03-01

    Premature birth before 37 weeks of gestation is a significant public health problem. Each year, 4.5 million premature infants are born worldwide. Despite extensive research and a variety of interventions, the rate of preterm birth has steadily increased over the past 20 years and reached a high of 12.8% in 2006. The etiology of most preterm births remains elusive and is likely multifactorial, with many pathophysiological pathways involved, such as excessive stretching, oxidative stress, decidual hemorrhage, and infection. Genomics and proteomics have emerged to provide a better comprehension of the pathophysiological conditions leading to preterm birth, thereby providing a perspective for improving neonatal outcome.

  17. Durations of second stage of labor and pushing, and adverse neonatal outcomes: a population-based cohort study

    PubMed Central

    Sandström, A; Altman, M; Cnattingius, S; Johansson, S; Ahlberg, M; Stephansson, O

    2017-01-01

    Objective: The associations between duration of second stage of labor, pushing time and risk of adverse neonatal outcomes are not fully established. Therefore, we aimed to examine such relationships. Study design: A population-based cohort study including 42 539 nulliparous women with singleton infants born in cephalic presentation at ⩾37 gestational weeks, using the Stockholm-Gotland Obstetric Cohort, Sweden, and the Swedish Neonatal Quality Register, 2008 to 2013. Poisson regression was used to analyze estimated adjusted relative risks (RRs), with 95% confidence intervals (CIs). Outcome measures were umbilical artery acidosis (pH <7.05 and base excess <−12), birth asphyxia-related complications (including any of the following conditions: hypoxic ischemic encephalopathy, hypothermia treatment, neonatal seizures, meconium aspiration syndrome or advanced resuscitation after birth) and admission to neonatal intensive care unit (NICU). Results: Overall rates of umbilical artery acidosis, birth asphyxia-related complications and admission to NICU were 1.08, 0.63 and 6.42%, respectively. Rate of birth asphyxia-related complications gradually increased with duration of second stage: from 0.42% at <1 h to 1.29% at ≥4 h (adjusted RR 2.46 (95% CI 1.66 to 3.66)). For admission to NICU, corresponding rates were 4.97 and 9.45%, and adjusted RR (95% CI) was 1.80 (95% CI 1.58 to 2.04). Compared with duration of pushing <15 min, a duration of pushing ⩾60 min increased rates of acidosis from 0.57 to 1.69% (adjusted RR 2.55 (95% CI 1.51 to 4.30)). Conclusion: Prolonged durations of second stage of labor and pushing are associated with increased RRs of adverse neonatal outcomes. Clinical assessment of fetal well-being is essential when durations of second stage and pushing increases. PMID:27929527

  18. Clinical Characteristics and Predictors of Adverse Outcome in Adult and Pediatric Patients With Healthcare-Associated Ventriculitis and Meningitis

    PubMed Central

    Srihawan, Chanunya; Castelblanco, Rodrigo Lopez; Salazar, Lucrecia; Wootton, Susan H.; Aguilera, Elizabeth; Ostrosky-Zeichner, Luis; Sandberg, David I.; Choi, HuiMahn A.; Lee, Kiwon; Kitigawa, Ryan; Tandon, Nitin; Hasbun, Rodrigo

    2016-01-01

    Background. Healthcare-associated meningitis or ventriculitis is a serious and life-threatening complication of invasive neurosurgical procedures or penetrating head trauma. Methods. We performed a retrospective study of adults and children with the diagnosis of healthcare-associated meningitis or ventriculitis, as defined by the 2015 Centers of Disease Control and Prevention case definition, at 2 large tertiary care hospitals in Houston, Texas from July 2003 to November 2014. Patients were identified by infection control practitioners and by screening cerebrospinal fluid samples sent to the central laboratory. We collected data on demographics, clinical presentations, laboratory results, imaging studies, treatments, and outcomes. Results. A total of 215 patients were included (166 adults and 49 children). A positive cerebrospinal fluid culture was seen in 106 (49%) patients, with the majority of the etiologies being Staphylococcus and Gram-negative rods. An adverse clinical outcome was seen in 167 patients (77.7%) and was defined as death in 20 patients (9.3%), persistent vegetative state in 31 patients (14.4%), severe disability in 77 patients (35.8%), or moderate disability in 39 patients (18.1%). On logistic regression analysis, age >45 years (adjusted odds ratio [OR], 6.47; 95% confidence interval [CI], 2.31–18.11; P ≤ .001), abnormal neurological exam (adjusted OR, 3.04; 95% CI, 1.27–7.29; P = .013), and mechanical ventilation (adjusted OR, 5.34; 95% CI, 1.51–18.92; P = .01) were associated with an adverse outcome. Conclusions. Healthcare-associated meningitis or ventriculitis is associated with significant morbidity and mortality. PMID:27419154

  19. Adverse Birth Outcomes and Maternal Exposure to Trichloroethylene and Tetrachloroethylene through Soil Vapor Intrusion in New York State

    PubMed Central

    Lewis-Michl, Elizabeth L.; Gomez, Marta I.

    2011-01-01

    Background: Industrial spills of volatile organic compounds (VOCs) in Endicott, New York (USA), have led to contamination of groundwater, soil, and soil gas. Previous studies have reported an increase in adverse birth outcomes among women exposed to VOCs in drinking water. Objective: We investigated the prevalence of adverse birth outcomes among mothers exposed to trichloroethylene (TCE) and tetrachloroethylene [or perchloroethylene (PCE)] in indoor air contaminated through soil vapor intrusion. Methods: We examined low birth weight (LBW), preterm birth, fetal growth restriction, and birth defects among births to women in Endicott who were exposed to VOCs, compared with births statewide. We used Poisson regression to analyze births and malformations to estimate the association between maternal exposure to VOCs adjusting for sex, mother’s age, race, education, parity, and prenatal care. Two exposure areas were identified based on environmental sampling data: one area was primarily contaminated with TCE, and the other with PCE. Results: In the TCE-contaminated area, adjusted rate ratios (RRs) were significantly elevated for LBW [RR = 1.36; 95% confidence interval (CI): 1.07, 1.73; n = 76], small for gestational age (RR = 1.23; 95% CI: 1.03, 1.48; n = 117), term LBW (RR = 1.68; 95% CI: 1.20, 2.34; n = 37), cardiac defects (RR = 2.15; 95% CI: 1.27, 3.62; n = 15), and conotruncal defects (RR = 4.91; 95% CI: 1.58, 15.24; n = 3). In the PCE-contaminated area, RRs for cardiac defects (five births) were elevated but not significantly. Residual socioeconomic confounding may have contributed to elevations of LBW outcomes. Conclusions: Maternal residence in both areas was associated with cardiac defects. Residence in the TCE area, but not the PCE area, was associated with LBW and fetal growth restriction. PMID:22142966

  20. Adverse Outcomes After Palliative Radiation Therapy for Uncomplicated Spine Metastases: Role of Spinal Instability and Single-Fraction Radiation Therapy

    SciTech Connect

    Lam, Tai-Chung; Krishnan, Monica; Groff, Michael; Cheney, Matthew; Balboni, Tracy

    2015-10-01

    Purpose: Level I evidence demonstrates equivalent pain response after single-fraction (SF) or multifraction (MF) radiation therapy (RT) for bone metastases. The purpose of this study is to provide additional data to inform the incidence and predictors of adverse outcomes after RT for spine metastases. Methods and Materials: At a single institution, 299 uncomplicated spine metastases (without cord compression, prior RT, or surgery) treated with RT from 2008 to 2013 were retrospectively reviewed. The spinal instability neoplastic score (SINS) was used to assess spinal instability. The primary outcome was time to first spinal adverse event (SAE) at the site, including symptomatic vertebral fracture, hospitalization for site-related pain, salvage surgery, interventional procedure, new neurologic symptoms, or cord compression. Fine and Gray's multivariable model assessed associations of the primary outcome with SINS, SF RT, and other significant baseline factors. Propensity score matched analysis further assessed the relationship of SF RT to first SAEs. Results: The cumulative incidence of first SAE after SF RT (n=66) was 6.8% at 30 days, 16.9% at 90 days, and 23.6% at 180 days. For MF RT (n=233), the incidence was 3.5%, 6.4%, and 9.2%, respectively. In multivariable analysis, SF RT (hazard ratio [HR] = 2.8, 95% confidence interval [CI] 1.5-5.2, P=.001) and SINS ≥11 (HR=2.5 , 95% CI 1.3-4.9, P=.007) were predictors of the incidence of first SAE. In propensity score matched analysis, first SAEs had developed in 22% of patients with SF RT versus 6% of those with MF RT cases (HR=3.9, 95% CI 1.6-9.6, P=.003) at 90 days after RT. Conclusion: In uncomplicated spinal metastases treated with RT alone, spinal instability with SINS ≥11 and SF RT were associated with a higher rate of SAEs.

  1. Sleep apnoea adversely affects the outcome in patients who undergo posterior lumbar fusion

    PubMed Central

    Stundner, O.; Chiu, Y-L.; Sun, X.; Ramachandran, S-K.; Gerner, P.; Vougioukas, V.; Mazumdar, M.; Memtsoudis, S. G.

    2014-01-01

    Despite the increasing prevalence of sleep apnoea, little information is available regarding its impact on the peri-operative outcome of patients undergoing posterior lumbar fusion. Using a national database, patients who underwent lumbar fusion between 2006 and 2010 were identified, sub-grouped by diagnosis of sleep apnoea and compared. The impact of sleep apnoea on various outcome measures was assessed by regression analysis. The records of 84 655 patients undergoing posterior lumbar fusion were identified and 7.28% also had a diagnostic code for sleep apnoea. Compared with patients without sleep apnoea, these patients were older, more frequently female, had a higher comorbidity burden and higher rates of peri-operative complications, post-operative mechanical ventilation, blood transfusion, and intensive care. Patients with sleep apnoea also had longer and more costly periods of hospitalisation. In the regression analysis, sleep apnoea emerged as an independent risk factor for the development of peri-operative complications (Odds Ratio (OR) 1.50, Confidence Interval (CI) 1.38;1.62), blood transfusions (OR 1.12, CI 1.03;1.23), mechanical ventilation (OR 6.97, CI 5.90;8.23), critical care services (OR 1.86, CI 1.71;2.03), prolonged hospitalisation and increased cost (OR 1.28, CI 1.19;1.37; OR 1.10, CI 1.03;1.18). Patients with sleep apnoea who undergo posterior lumbar fusion pose significant challenges to clinicians. PMID:24493191

  2. Plasma glutathione peroxidase activity in kidney recipients with and without adverse outcome.

    PubMed

    Eftekhar, Ebrahim; Hajirahimkhan, Athie; Taghizadeh Afshari, Ali; Nourooz-Zadeh, Jaffar

    2012-01-01

    Kidney function is routinely monitored utilizing classic biochemical parameters including serum or plasma creatinine (Cr), and blood urea nitrogen (BUN) concentrations. This study demonstrates that the simultaneous assessment of plasma glutathione peroxidase (pGPx) and Cr levels provides a better strategy for the immediate follow-up of kidney function in organ recipients. Kidney recipients (Krs; n = 22) were recruited. Blood sampling schedule commenced at day 1 (pre-transplantation) and post-transplantation days (i.e., everyday from 1 until day 14, and thereafter on days 21, 28, 35, 42, 49, and 56). pGPx was measured spectrophotometrically. Candidates for transplantation exhibited lower pGPx than control subjects (42 ± 24 vs. 143 ± 31 U/L; p < 0.005). In Krs with a stable post-transplant outcome, pGPx increased to a maximum at day 28 (214 ± 61 U/L). In a Kr diagnosed with acute tubulonecrosis, pGPx provided a better predictive value (threefold increase) than Cr. In a Kr diagnosed with acute rejection, the increment in Cr values was found to be more pronounced than in pGPx values. The pGPx test is simple, inexpensive and automatable, and should be a valuable diagnostic tool of kidney function in organ recipients with and without troublesome outcome for the follow-up during hospitalization period.

  3. Two pathways through adversity: Predicting well-being and housing outcomes among homeless service users.

    PubMed

    Walter, Zoe C; Jetten, Jolanda; Dingle, Genevieve A; Parsell, Cameron; Johnstone, Melissa

    2016-06-01

    People who experience homelessness face many challenges and disadvantages that negatively impact health and well-being and form barriers to achieving stable housing. Further, people who are homeless often have limited social connections and support. Building on previous research that has shown the beneficial effect of group identification on health and well-being, the current study explores the relationship between two social identity processes - multiple group memberships and service identification - and well-being and positive housing outcomes. Measures were collected from 76 participants while they were residing in a homeless accommodation service (T1) and again 2-4 weeks after leaving the service (or 3 months after T1 if participants had not left the service). Mediation analyses revealed that multiple group memberships and service identification at T1 independently predicted well-being at T2 indirectly, via social support. Further, both social identity processes also indirectly predicted housing outcomes via social support. The implications of these findings are twofold. First, while belonging to multiple social groups may provide a pathway to gaining social support and well-being, group belonging may not necessarily be beneficial to achieve stable housing. Second, fostering identification with homeless services may be particularly important as a source of support that contributes to well-being.

  4. Maternal characteristics, pregnancy complications and adverse birth outcomes among women with disabilities

    PubMed Central

    Clements, Karen M.; Zhang, Jianying; Iezzoni, Lisa I.; Smeltzer, Suzanne C.; Long-Bellil, Linda M.

    2015-01-01

    Objectives The objective of this study is to describe the maternal characteristics, pregnancy complications, and birth outcomes among a representative sample of Rhode Island women with disabilities who recently gave birth. Methods Data from the 2002–2011 Rhode Island Pregnancy Risk Assessment Monitoring System (PRAMS) survey were analyzed. Results Approximately 7% of women in Rhode Island reported a disability. Women with disabilities reported significant disparities in their health care utilization, health behaviors and health status before and during pregnancy and during the postpartum period. Compared to nondisabled women, they were significantly more likely to report stressful life events and medical complications during their most recent pregnancy, were less likely to receive prenatal care in the first trimester, and more likely to have preterm births (13.4%; 95% CI, 11.6–15.6 compared to 8.9%; 95% CI, 8.5–9.3 for women without disabilities) and low birth weight babies (10.3%; 95% CI, 9.4–11.2 compared to 6.8%; 95% CI, 6.8–6.9). There was no difference in the rates of cesarean section between women with and without disabilities. Conclusion These findings support the need for clinicians providing care to pregnant women with disabilities to be aware of the increased risk for medical problems during pregnancy and factors that increase the risk for poor infant outcomes. PMID:26492209

  5. An Elevated Glycemic Gap is Associated with Adverse Outcomes in Diabetic Patients with Acute Myocardial Infarction

    PubMed Central

    Liao, Wen-I; Lin, Chin-Sheng; Lee, Chien-Hsing; Wu, Ya-Chieh; Chang, Wei-Chou; Hsu, Chin-Wang; Wang, Jen-Chun; Tsai, Shih-Hung

    2016-01-01

    Acute hyperglycemia is a frequent finding in patients presenting to the emergency department (ED) with acute myocardial infarction (AMI). The prognostic role of hyperglycemia in diabetic patients with AMI remains controversial. We retrospectively reviewed patients’ medical records to obtain demographic data, clinical presentation, major adverse cardiac events (MACEs), several clinical scores and laboratory data, including the plasma glucose level at initial presentation and HbA1c levels. The glycemic gap, which represents changes in serum glucose levels during the index event, was calculated from the glucose level upon ED admission minus the HbA1c-derived average glucose (ADAG). We enrolled 331 patients after the review of medical records. An elevated glycemic gap between admission serum glucose levels and ADAG were associated with an increased risk of mortality in patients. The glycemic gap showed superior discriminative power regarding the development of MACEs when compared with the admission glucose level. The calculation of the glycemic gap may increase the discriminative powers of established clinical scoring systems in diabetic patients presenting to the ED with AMI. In conclusion, the glycemic gap could be used as an adjunct parameter to assess the severity and prognosis of diabetic patients presenting with AMI. However, the usefulness of the glycemic gap should be further explored in prospective longitudinal studies. PMID:27291987

  6. Sleep Disturbances in Neurodevelopmental Disorders.

    PubMed

    Robinson-Shelton, Althea; Malow, Beth A

    2016-01-01

    Sleep disturbances are extremely prevalent in children with neurodevelopmental disorders compared to typically developing children. The diagnostic criteria for many neurodevelopmental disorders include sleep disturbances. Sleep disturbance in this population is often multifactorial and caused by the interplay of genetic, neurobiological and environmental overlap. These disturbances often present either as insomnia or hypersomnia. Different sleep disorders present with these complaints and based on the clinical history and findings from diagnostic tests, an appropriate diagnosis can be made. This review aims to provide an overview of causes, diagnosis, and treatment of sleep disturbances in neurodevelopmental disorders that present primarily with symptoms of hypersomnia and/or insomnia.

  7. Patient-Reported Outcomes in Cancer Clinical Trials: Measuring Symptomatic Adverse Events With the National Cancer Institute's Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE).

    PubMed

    Kluetz, Paul G; Chingos, Diana T; Basch, Ethan M; Mitchell, Sandra A

    2016-01-01

    Systematic capture of the patient perspective can inform the development of new cancer therapies. Patient-reported outcomes (PROs) are commonly included in cancer clinical trials; however, there is heterogeneity in the constructs, measures, and analytic approaches that have been used making these endpoints challenging to interpret. There is renewed effort to identify rigorous methods to obtain high-quality and informative PRO data from cancer clinical trials. In this setting, PROs are used to address specific research objectives, and an important objective that spans the product development life cycle is the assessment of safety and tolerability. The U.S. Food and Drug Administration's (FDA) Office of Hematology and Oncology Products (OHOP) has identified symptomatic adverse events (AEs) as a central PRO concept, and a systematic assessment of patient-reported symptomatic AEs can provide data to complement clinician reporting. The National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) is being evaluated by multiple stakeholders, including the FDA, and is considered a promising tool to provide a standard yet flexible method to assess symptomatic AEs from the patient perspective. In this article, we briefly review the FDA OHOP's perspective on PROs in cancer trials submitted to the FDA and focus on the assessment of symptomatic AEs using PRO-CTCAE. We conclude by discussing further work that must be done to broaden the use of PRO-CTCAE as a method to provide patient-centered data that can complement existing safety and tolerability assessments across cancer clinical trials.

  8. Adverse outcome analyses of observational data: assessing cardiovascular risk in HIV disease.

    PubMed

    Triant, V A; Josephson, F; Rochester, C G; Althoff, K N; Marcus, K; Munk, R; Cooper, C; D'Agostino, R B; Costagliola, D; Sabin, C A; Williams, P L; Hughes, S; Post, W S; Chandra-Strobos, N; Guaraldi, G; Young, S S; Obenchain, R; Bedimo, R; Miller, V; Strobos, J

    2012-02-01

    Clinical decisions are ideally based on randomized trials but must often rely on observational data analyses, which are less straightforward and more influenced by methodology. The authors, from a series of expert roundtables convened by the Forum for Collaborative HIV Research on the use of observational studies to assess cardiovascular disease risk in human immunodeficiency virus infection, recommend that clinicians who review or interpret epidemiological publications consider 7 key statistical issues: (1) clear explanation of confounding and adjustment; (2) handling and impact of missing data; (3) consistency and clinical relevance of outcome measurements and covariate risk factors; (4) multivariate modeling techniques including time-dependent variables; (5) how multiple testing is addressed; (6) distinction between statistical and clinical significance; and (7) need for confirmation from independent databases. Recommendations to permit better understanding of potential methodological limitations include both responsible public access to de-identified source data, where permitted, and exploration of novel statistical methods.

  9. Adverse impact of intermittent portal clamping on long-term postoperative outcomes in hepatocellular carcinoma.

    PubMed

    Hao, S; Chen, S; Yang, X; Wan, C

    2017-01-01

    Introduction To evaluate the impact of intermittent portal clamping (IPC) on long-term postoperative outcomes in patients with hepatocellular carcinoma (HCC). Methods Clinical records of 355 patients underwent curative liver resection for HCC in January 2007 to December 2010 were retrospectively reviewed. According to how portal clamping was performed, patients were grouped as: IPC, n=113; other portal clamping (OPC), n=190; and no portal clamping (NPC), n=52. Results Median recurrence-free survival (RFS) was statistically significantly shorter in the IPC (39.4 months) than OPC (47.3 months, p=0.010) and NPC groups (51.4 months, p=0.008). Median overall survival (OS) was also significantly shorter with IPC (46.3 months), versus 52.9 months with OPC (p=0.022) and 56.2 months with NPC (p=0.015). Kaplan-Meier survival analysis revealed that 5-year cumulative RFS was much lower in the IPC (42.5%) than OPC (50.9%, p=0.014) and NPC groups (49.6%, p=0.013). Five-year cumulative OS was also much lower in the IPC (44.9%) than OPC (58.0%, p=0.020) and NPC groups (57.7%, p=0.025). On univariate analysis, tumour grade, size and number, TNM stage, blood transfusion, vascular invasion and IPC were significantly inversely correlated with RFS and OS. On multivariate analysis, tumour size and number, blood transfusion, vascular invasion and IPC remained significant. Conclusions Our study suggests that IPC is an independent risk factor for poor long-term postoperative outcomes in patients with HCC.

  10. How Adverse Outcome Pathways Can Aid the Development and Use of Computational Prediction Models for Regulatory Toxicology.

    PubMed

    Wittwehr, Clemens; Aladjov, Hristo; Ankley, Gerald; Byrne, Hugh J; de Knecht, Joop; Heinzle, Elmar; Klambauer, Günter; Landesmann, Brigitte; Luijten, Mirjam; MacKay, Cameron; Maxwell, Gavin; Meek, M E Bette; Paini, Alicia; Perkins, Edward; Sobanski, Tomasz; Villeneuve, Dan; Waters, Katrina M; Whelan, Maurice

    2017-02-01

    Efforts are underway to transform regulatory toxicology and chemical safety assessment from a largely empirical science based on direct observation of apical toxicity outcomes in whole organism toxicity tests to a predictive one in which outcomes and risk are inferred from accumulated mechanistic understanding. The adverse outcome pathway (AOP) framework provides a systematic approach for organizing knowledge that may support such inference. Likewise, computational models of biological systems at various scales provide another means and platform to integrate current biological understanding to facilitate inference and extrapolation. We argue that the systematic organization of knowledge into AOP frameworks can inform and help direct the design and development of computational prediction models that can further enhance the utility of mechanistic and in silico data for chemical safety assessment. This concept was explored as part of a workshop on AOP-Informed Predictive Modeling Approaches for Regulatory Toxicology held September 24-25, 2015. Examples of AOP-informed model development and its application to the assessment of chemicals for skin sensitization and multiple modes of endocrine disruption are provided. The role of problem formulation, not only as a critical phase of risk assessment, but also as guide for both AOP and complementary model development is described. Finally, a proposal for actively engaging the modeling community in AOP-informed computational model development is made. The contents serve as a vision for how AOPs can be leveraged to facilitate development of computational prediction models needed to support the next generation of chemical safety assessment.

  11. How Adverse Outcome Pathways Can Aid the Development and Use of Computational Prediction Models for Regulatory Toxicology

    PubMed Central

    Aladjov, Hristo; Ankley, Gerald; Byrne, Hugh J.; de Knecht, Joop; Heinzle, Elmar; Klambauer, Günter; Landesmann, Brigitte; Luijten, Mirjam; MacKay, Cameron; Maxwell, Gavin; Meek, M. E. (Bette); Paini, Alicia; Perkins, Edward; Sobanski, Tomasz; Villeneuve, Dan; Waters, Katrina M.; Whelan, Maurice

    2017-01-01

    Efforts are underway to transform regulatory toxicology and chemical safety assessment from a largely empirical science based on direct observation of apical toxicity outcomes in whole organism toxicity tests to a predictive one in which outcomes and risk are inferred from accumulated mechanistic understanding. The adverse outcome pathway (AOP) framework provides a systematic approach for organizing knowledge that may support such inference. Likewise, computational models of biological systems at various scales provide another means and platform to integrate current biological understanding to facilitate inference and extrapolation. We argue that the systematic organization of knowledge into AOP frameworks can inform and help direct the design and development of computational prediction models that can further enhance the utility of mechanistic and in silico data for chemical safety assessment. This concept was explored as part of a workshop on AOP-Informed Predictive Modeling Approaches for Regulatory Toxicology held September 24–25, 2015. Examples of AOP-informed model development and its application to the assessment of chemicals for skin sensitization and multiple modes of endocrine disruption are provided. The role of problem formulation, not only as a critical phase of risk assessment, but also as guide for both AOP and complementary model development is described. Finally, a proposal for actively engaging the modeling community in AOP-informed computational model development is made. The contents serve as a vision for how AOPs can be leveraged to facilitate development of computational prediction models needed to support the next generation of chemical safety assessment. PMID:27994170

  12. How Adverse Outcome Pathways Can Aid the Development and Use of Computational Prediction Models for Regulatory Toxicology

    SciTech Connect

    Wittwehr, Clemens; Aladjov, Hristo; Ankley, Gerald; Byrne, Hugh J.; de Knecht, Joop; Heinzle, Elmar; Klambauer, Günter; Landesmann, Brigitte; Luijten, Mirjam; MacKay, Cameron; Maxwell, Gavin; Meek, M. E.; Paini, Alicia; Perkins, Edward; Sobanski, Tomasz; Villeneuve, Dan; Waters, Katrina M.; Whelan, Maurice

    2016-12-19

    Efforts are underway to transform regulatory toxicology and chemical safety assessment from a largely empirical science based on direct observation of apical toxicity outcomes in whole organism toxicity tests to a predictive one in which outcomes and risk are inferred from accumulated mechanistic understanding. The adverse outcome pathway (AOP) framework has emerged as a systematic approach for organizing knowledge that supports such inference. We argue that this systematic organization of knowledge can inform and help direct the design and development of computational prediction models that can further enhance the utility of mechanistic and in silico data for chemical safety assessment. Examples of AOP-informed model development and its application to the assessment of chemicals for skin sensitization and multiple modes of endocrine disruption are provided. The role of problem formulation, not only as a critical phase of risk assessment, but also as guide for both AOP and complementary model development described. Finally, a proposal for actively engaging the modeling community in AOP-informed computational model development is made. The contents serve as a vision for how AOPs can be leveraged to facilitate development of computational prediction models needed to support the next generation of chemical safety assessment.

  13. The effect of maternal betel quid exposure during pregnancy on adverse birth outcomes among aborigines in Taiwan.

    PubMed

    Yang, Mei-Sang; Lee, Chien-Hung; Chang, Shun-Jen; Chung, Tieh-Chi; Tsai, Eing-Mei; Ko, Allen Min-Jen; Ko, Ying-Chin

    2008-05-01

    In considering documented developmental toxicity and teratogenicity found in earlier research, maternal betel quid chewing may very well be linked to a higher risk of adverse birth outcomes. The aim of this study was to investigate the significance of betel quid chewing, together with the use of cigarettes or alcohol, either independently or combined, on birth-related outcomes. A total of 1264 aboriginal women who had just given birth in 10 hospitals in Southern and Eastern Taiwan were recruited. Information on their maternal and newborn characteristics was obtained from medical charts and by performing personal interviews using a validated questionnaire. Maternal areca nut chewing during pregnancy was found to be significantly associated with both birth weight loss (-89.54 g) and birth length reduction (-0.43 cm). A significantly lower male newborn rate (aOR=0.62) was observed among aboriginal women with a habit of betel quid chewing during pregnancy. The use of this substance conveyed a 2.40- and 3.67-fold independent risk of low birth weight and full-term low birth weight, respectively. An enhanced risk (aOR=3.26-5.99) of low birth weight was observed among women concomitantly using betel quid, cigarette and alcohol during gestation. Our findings suggest that betel quid chewing during pregnancy has a substantial effect on a number of birth outcomes, including sex ratio at birth, lower birth weight and reduced birth length.

  14. The adverse outcome pathway for rodent liver tumor promotion by sustained activation of the aryl hydrocarbon receptor.

    PubMed

    Becker, Richard A; Patlewicz, Grace; Simon, Ted W; Rowlands, J Craig; Budinsky, Robert A

    2015-10-01

    An Adverse Outcome Pathway (AOP) represents the existing knowledge of a biological pathway leading from initial molecular interactions of a toxicant and progressing through a series of key events (KEs), culminating with an apical adverse outcome (AO) that has to be of regulatory relevance. An AOP based on the mode of action (MOA) of rodent liver tumor promotion by dioxin-like compounds (DLCs) has been developed and the weight of evidence (WoE) of key event relationships (KERs) evaluated using evolved Bradford Hill considerations. Dioxins and DLCs are potent aryl hydrocarbon receptor (AHR) ligands that cause a range of species-specific adverse outcomes. The occurrence of KEs is necessary for inducing downstream biological responses and KEs may occur at the molecular, cellular, tissue and organ levels. The common convention is that an AOP begins with the toxicant interaction with a biological response element; for this AOP, this initial event is binding of a DLC ligand to the AHR. Data from mechanistic studies, lifetime bioassays and approximately thirty initiation-promotion studies have established dioxin and DLCs as rat liver tumor promoters. Such studies clearly show that sustained AHR activation, weeks or months in duration, is necessary to induce rodent liver tumor promotion--hence, sustained AHR activation is deemed the molecular initiating event (MIE). After this MIE, subsequent KEs are 1) changes in cellular growth homeostasis likely associated with expression changes in a number of genes and observed as development of hepatic foci and decreases in apoptosis within foci; 2) extensive liver toxicity observed as the constellation of effects called toxic hepatopathy; 3) cellular proliferation and hyperplasia in several hepatic cell types. This progression of KEs culminates in the AO, the development of hepatocellular adenomas and carcinomas and cholangiolar carcinomas. A rich data set provides both qualitative and quantitative knowledge of the progression of

  15. Plasma neutrophil gelatinase-associated lipocalin as a potential predictor of adverse renal outcomes in immunoglobulin A nephropathy

    PubMed Central

    Park, Ga-Young; Yu, Chung-Hoon; Kim, Jun-Seop; Kang, Yun-Jeong; Kwon, Owen; Choi, Ji-Young; Cho, Jang-Hee; Kim, Chan-Duck; Kim, Yong-Lim

    2015-01-01

    Background/Aims Neutrophil gelatinase-associated lipocalin (NGAL) is a well-known biomarker of acute kidney injury. We evaluated the value of plasma NGAL (pNGAL) as an independent predictor of prognosis in immunoglobulin A nephropathy (IgAN). Methods In total, 91 patients with biopsy-proven IgAN at a single center were evaluated. pNGAL was measured using a commercial enzyme-linked immunosorbent assay kit (R&D Systems). Adverse renal outcome was defined as chronic kidney disease (CKD) stage 3 or above at the last follow-up. Pearson correlation coefficient and Cox regression were used for analyses. Results The mean age of all patients (male:female, 48:43) was 35 years (range, 18 to 77). pNGAL ranged between 21.68 and 446.40 ng/mL (median, 123.97) and showed a correlation with age (r = 0.332, p = 0.001), creatinine (r = 0.336, p = 0.001), estimated glomerular filtration rate (r = -0.397, p < 0.001), uric acid (r = 0.289, p = 0.006), and the protein-to-creatinine ratio (r = 0.288, p = 0.006). During a mean follow-up period of 37.6 months, 11 patients (12.1%) had CKD stage 3 or above. In a multivariate Cox regression model, hypertension (hazard ratio [HR], 8.779; 95% confidence interval [CI], 1.526 to 50.496; p = 0.015), proteinuria > 1 g/day (HR, 5.184; 95% CI, 1.124 to 23.921; p = 0.035), and pNGAL (HR, 1.012; 95% CI, 1.003 to 1.022; p = 0.013) were independent predictors associated with adverse renal outcome. Conclusions pNGAL showed strong correlations with other clinical prognostic factors and was also an independent predictor of adverse renal outcome. We suggest pNGAL as a potential predictor for prognosis in IgAN, while further studies are needed to confirm the clinical value. PMID:25995665

  16. A workflow to investigate exposure and pharmacokinetic influences on high-throughput in vitro chemical screening based on adverse outcome pathways, OpenTox USA 2015 Poster

    EPA Science Inventory

    Adverse outcome pathways (AOP) link known population outcomes to a molecular initiating event (MIE) that can be quantified using high-throughput in vitro methods. Practical application of AOPs in chemical-specific risk assessment requires consideration of exposure and absorption,...