PARENTAL CHILDHOOD ADVERSITY, DEPRESSIVE SYMPTOMS, AND PARENTING QUALITY: EFFECTS ON TODDLER SELF-REGULATION IN CHILD WELFARE SERVICES INVOLVED FAMILIES.

PubMed

Spieker, Susan J; Oxford, Monica L; Fleming, Charles B; Lohr, Mary Jane

2018-01-01

Parents who are involved with child welfare services (CWSI) often have a history of childhood adversity and depressive symptoms. Both affect parenting quality, which in turn influences child adaptive functioning. We tested a model of the relations between parental depression and child regulatory outcomes first proposed by K. Lyons-Ruth, R. Wolfe, A. Lyubchik, and R. Steingard (2002). We hypothesized that both parental depression and parenting quality mediate the effects of parental early adversity on offspring regulatory outcomes. Participants were 123 CWSI parents and their toddlers assessed three times over a period of 6 months. At Time 1, parents reported on their childhood adversity and current depressive symptoms. At Time 2, parents' sensitivity to their child's distress and nondistress cues was rated from a videotaped teaching task. At Time 3, observers rated children's emotional regulation, orientation/engagement, and secure base behavior. The results of a path model partly supported the hypotheses. Parent childhood adversity was associated with current depressive symptoms, which in turn related to parent sensitivity to child distress, but not nondistress. Sensitivity to distress also predicted secure base behavior. Depression directly predicted orientation/engagement, also predicted by sensitivity to nondistress. Sensitivity to distress predicted emotion regulation and orientation/engagement. Results are discussed in terms of intervention approaches for CWSI families. © 2017 Michigan Association for Infant Mental Health.

Predicting effects of climate and land use change on human well-being via changes in ecosystem services

EPA Science Inventory

Landuse and climate change have affected biological systems in many parts of the world, and are projected to further adversely affect associated ecosystem goods and services, including provisioning of clean air, clean water, food, and biodiversity. Such adverse effects on ecosyst...

Using human genetics to predict the effects and side-effects of drugs.

PubMed

Stender, Stefan; Tybjærg-Hansen, Anne

2016-04-01

'Genetic proxies' are increasingly being used to predict the effects of drugs. We present an up-to-date overview of the use of human genetics to predict effects and adverse effects of lipid-targeting drugs. LDL cholesterol lowering variants in HMG-Coenzyme A reductase and Niemann-Pick C1-like protein 1, the targets for statins and ezetimibe, protect against ischemic heart disease (IHD). However, HMG-Coenzyme A reductase and Niemann-Pick C1-Like Protein 1-variants also increase the risk of type 2 diabetes and gallstone disease, respectively. Mutations in proprotein convertase subtilisin kexin 9 (PCSK9), apolipoprotein B, and microsomal triglyceride transfer protein cause low LDL cholesterol and protect against IHD. In addition, mutations in apolipoprotein B and microsomal triglyceride transfer protein cause hepatic steatosis, in concordance with drugs that inhibit these targets. Both mutations in PCSK9 and PCSK9-inhibition seem without adverse effects. Mutations in APOC3 cause low triglycerides and protect against IHD, and recent pharmacological APOC3-inhibition reported major reductions in plasma triglycerides. Human genetics support that low lipoprotein(a) protects against IHD, without adverse effects, and the first trial of lipoprotein(a) inhibition reduced lipoprotein(a) up to 78%. Recent genetic studies have confirmed the efficacy of statins and ezetimibe in protecting against IHD. Results from human genetics support that several lipid-lowering drugs currently under development are likely to prove efficacious in protecting against IHD, without major adverse effects.

Minimizing AED adverse effects: improving quality of life in the interictal state in epilepsy care.

PubMed

St Louis, Erik K; Louis, Erik K

2009-06-01

The goals of epilepsy therapy are to achieve seizure freedom while minimizing adverse effects of treatment. However, producing seizure-freedom is often overemphasized, at the expense of inducing adverse effects of treatment. All antiepileptic drugs (AEDs) have the potential to cause dose-related, "neurotoxic" adverse effects (i.e., drowsiness, fatigue, dizziness, blurry vision, and incoordination). Such adverse effects are common, especially when initiating AED therapy and with polytherapy. Dose-related adverse effects may be obviated in most patients by dose reduction of monotherapy, reduction or elimination of polytherapy, or substituting for a better tolerated AED. Additionally, all older and several newer AEDs have idiosyncratic adverse effects which usually require withdrawal in an affected patient, including serious rash (i.e., Stevens-Johnson Syndrome, toxic epidermal necrolysis), hematologic dyscrasias, hepatotoxicity, teratogenesis in women of child bearing potential, bone density loss, neuropathy, and severe gingival hyperplasia. Unfortunately, occurrence of idiosyncratic AED adverse effects cannot be predicted or, in most cases, prevented in susceptible patients. This article reviews a practical approach for the definition and identification of adverse effects of epilepsy therapies, and reviews the literature demonstrating that adverse effects result in detrimental quality of life in epilepsy patients. Strategies for minimizing AED adverse effects by reduction or elimination of AED polytherapy, appropriately employing drug-sparing therapies, and optimally administering AEDs are outlined, including tenets of AED selection, titration, therapeutic AED laboratory monitoring, and avoidance of chronic idiosyncratic adverse effects.

Lifespan adversity and later adulthood telomere length in the nationally representative US Health and Retirement Study

PubMed Central

Gemmill, Alison; Weir, David; Adler, Nancy E.; Prather, Aric A.

2016-01-01

Stress over the lifespan is thought to promote accelerated aging and early disease. Telomere length is a marker of cell aging that appears to be one mediator of this relationship. Telomere length is associated with early adversity and with chronic stressors in adulthood in many studies. Although cumulative lifespan adversity should have bigger impacts than single events, it is also possible that adversity in childhood has larger effects on later life health than adult stressors, as suggested by models of biological embedding in early life. No studies have examined the individual vs. cumulative effects of childhood and adulthood adversities on adult telomere length. Here, we examined the relationship between cumulative childhood and adulthood adversity, adding up a range of severe financial, traumatic, and social exposures, as well as comparing them to each other, in relation to salivary telomere length. We examined 4,598 men and women from the US Health and Retirement Study. Single adversities tended to have nonsignificant relations with telomere length. In adjusted models, lifetime cumulative adversity predicted 6% greater odds of shorter telomere length. This result was mainly due to childhood adversity. In adjusted models for cumulative childhood adversity, the occurrence of each additional childhood event predicted 11% increased odds of having short telomeres. This result appeared mainly because of social/traumatic exposures rather than financial exposures. This study suggests that the shadow of childhood adversity may reach far into later adulthood in part through cellular aging. PMID:27698131

Lifespan adversity and later adulthood telomere length in the nationally representative US Health and Retirement Study.

PubMed

Puterman, Eli; Gemmill, Alison; Karasek, Deborah; Weir, David; Adler, Nancy E; Prather, Aric A; Epel, Elissa S

2016-10-18

Stress over the lifespan is thought to promote accelerated aging and early disease. Telomere length is a marker of cell aging that appears to be one mediator of this relationship. Telomere length is associated with early adversity and with chronic stressors in adulthood in many studies. Although cumulative lifespan adversity should have bigger impacts than single events, it is also possible that adversity in childhood has larger effects on later life health than adult stressors, as suggested by models of biological embedding in early life. No studies have examined the individual vs. cumulative effects of childhood and adulthood adversities on adult telomere length. Here, we examined the relationship between cumulative childhood and adulthood adversity, adding up a range of severe financial, traumatic, and social exposures, as well as comparing them to each other, in relation to salivary telomere length. We examined 4,598 men and women from the US Health and Retirement Study. Single adversities tended to have nonsignificant relations with telomere length. In adjusted models, lifetime cumulative adversity predicted 6% greater odds of shorter telomere length. This result was mainly due to childhood adversity. In adjusted models for cumulative childhood adversity, the occurrence of each additional childhood event predicted 11% increased odds of having short telomeres. This result appeared mainly because of social/traumatic exposures rather than financial exposures. This study suggests that the shadow of childhood adversity may reach far into later adulthood in part through cellular aging.

Predicting the clinical efficacy and potential adverse effects of a humanized anticocaine monoclonal antibody

PubMed Central

Norman, Andrew B; Ball, William J

2012-01-01

The effects of a humanized monoclonal antibody (mAb) having high affinity and specificity for cocaine in animal models are reviewed. The mAb reduced the concentration of cocaine in the brain of mice after intravenous injection of cocaine. In addition, the mAb increased the concentration of cocaine required to reinstate cocaine self-administration. These effects may predict clinical efficacy of a passive immunotherapy for reducing the probability of cocaine-induced relapse. However, in the presence of the mAb, once cocaine self-administration was reinstated, the consumption rate of cocaine was increased. This effect is hypothesized to result from a pharmacokinetic/pharmacodynamic interaction. A humanized mAb should minimize adverse events related to the immunogenicity of the mAb protein, and the specificity for cocaine should avoid adverse events related to interactions with physiologically relevant endogenous proteins. PMID:22401638

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 ...

[Adverse Effect Predictions Based on Computational Toxicology Techniques and Large-scale Databases].

PubMed

Uesawa, Yoshihiro

2018-01-01

　Understanding the features of chemical structures related to the adverse effects of drugs is useful for identifying potential adverse effects of new drugs. This can be based on the limited information available from post-marketing surveillance, assessment of the potential toxicities of metabolites and illegal drugs with unclear characteristics, screening of lead compounds at the drug discovery stage, and identification of leads for the discovery of new pharmacological mechanisms. This present paper describes techniques used in computational toxicology to investigate the content of large-scale spontaneous report databases of adverse effects, and it is illustrated with examples. Furthermore, volcano plotting, a new visualization method for clarifying the relationships between drugs and adverse effects via comprehensive analyses, will be introduced. These analyses may produce a great amount of data that can be applied to drug repositioning.

A path analysis of gender differences in adolescent onset of alcohol, tobacco and other drug use (ATOD), reported ATOD use and adverse consequences of ATOD use.

PubMed

Thomas, B S

1996-01-01

Gender differences in the ways a risk factor approach explains onset of using alcohol, tobacco and other drugs (ATOD), reported use of ATOD and adverse consequences from ATOD use were investigated by means of separate path analyses for male and female adolescents. A fully recursive model was specified in which alienation, trait anger, interaction anxiety and cognitive motivation for ATOD use comprised the first column variables which were used to predict earliness of onset. For the second step, column one variables plus onset were used to predict ATOD use. In the final step, column one variables plus onset and ATOD use were used to predict adverse consequences of ATOD use. An ex post facto design was used in surveying 796 high school students in a single Midwestern community. The data from this sample supported the predictive validity of the theoretical model. In addition to the expected indirect or mediated effects of the risk factors via onset of ATOD use on ATOD use and via onset and ATOD use on adverse consequences of ATOD use, there were direct effects of column on risk factors on both ATOD use and on adverse consequences of ATOD use for both males and females, lending support to the concept of multiple pathway risk factors. The three gender differences that emerged in the separate path analyses were entirely consistent with the gendered deviance model.

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...

Childhood abuse affects emotional closeness with family in mid- and later life.

PubMed

Savla, J Tina; Roberto, Karen A; Jaramillo-Sierra, Ana L; Gambrel, Laura Eubanks; Karimi, Hassan; Butner, L Michelle

2013-06-01

Knowledge about the effects of early life adversity on kin relationships in later years is sparse. The purpose of this study was to examine if childhood abuse and adversity negatively influences emotional closeness with family in mid- and later life. A second goal was to determine the role of psychosocial resources and personality traits in buffering the effects of early adversities. Gender and cohort differences were explored to see if men were differentially affected than women and whether middle-aged adults (35-49 years old) were differentially affected than older adults (50-74 years old) by the effects of childhood abuse and adversity. Using retrospective accounts of early family abuse and adversities of 1,266 middle aged adults and 1,219 older adults from a large population-based survey, the National Survey of Midlife Development in United States (MIDUS), separate multiple regression analyses were conducted for the two cohorts to examine the effects of childhood emotional and physical abuse and family adversities on perceived emotional closeness with family. Interaction effects between childhood abuse and adversity (e.g., being expelled from school, death of sibling, parental divorce, losing a home to a natural disaster) with psychosocial resources (perceived control and self acceptance), personality characteristics (extraversion and neuroticism), and gender were examined. Results of OLS regressions suggest emotional and physical abuse predicted family closeness in middle-aged adults. Conversely, only emotional abuse predicted family closeness in older adults. Moderation models revealed that high levels of self acceptance were associated with better maintenance of emotional closeness among middle-aged adults who were emotionally and physically abused as children. Older adults with lower extraversion who experienced emotional abuse or reported greater number of adversities in childhood were found to be at higher risk for lower emotional closeness with family. Early life adversities were more detrimental for women. Findings suggest that the aftermath of childhood abuse does not dissipate with time, but continues to influence family relationships in mid- and later life. Identifying the links between childhood adversities and adult relationships can help identify strategic points for intervention to reduce the long-term effects of accumulated adverse experiences over the life course. Published by Elsevier Ltd.

Baseline Hemodynamics and Response to Contrast Media During Diagnostic Cardiac Catheterization Predict Adverse Events in Heart Failure Patients.

PubMed

Denardo, Scott J; Vock, David M; Schmalfuss, Carsten M; Young, Gregory D; Tcheng, James E; O'Connor, Christopher M

2016-07-01

Contrast media administered during cardiac catheterization can affect hemodynamic variables. However, little is documented about the effects of contrast on hemodynamics in heart failure patients or the prognostic value of baseline and changes in hemodynamics for predicting subsequent adverse events. In this prospective study of 150 heart failure patients, we measured hemodynamics at baseline and after administration of iodixanol or iopamidol contrast. One-year Kaplan-Meier estimates of adverse event-free survival (death, heart failure hospitalization, and rehospitalization) were generated, grouping patients by baseline measures of pulmonary capillary wedge pressure (PCWP) and cardiac index (CI), and by changes in those measures after contrast administration. We used Cox proportional hazards modeling to assess sequentially adding baseline PCWP and change in CI to 5 validated risk models (Seattle Heart Failure Score, ESCAPE [Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness], CHARM [Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity], CORONA [Controlled Rosuvastatin Multinational Trial in Heart Failure], and MAGGIC [Meta-Analysis Global Group in Chronic Heart Failure]). Median contrast volume was 109 mL. Both contrast media caused similarly small but statistically significant changes in most hemodynamic variables. There were 39 adverse events (26.0%). Adverse event rates increased using the composite metric of baseline PCWP and change in CI (P<0.01); elevated baseline PCWP and decreased CI after contrast correlated with the poorest prognosis. Adding both baseline PCWP and change in CI to the 5 risk models universally improved their predictive value (P≤0.02). In heart failure patients, the administration of contrast causes small but significant changes in hemodynamics. Calculating baseline PCWP with change in CI after contrast predicts adverse events and increases the predictive value of existing models. Patients with elevated baseline PCWP and decreased CI after contrast merit greatest concern. © 2016 American Heart Association, Inc.

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...

Childhood adversity, early-onset depressive/anxiety disorders, and adult-onset asthma.

PubMed

Scott, Kate M; Von Korff, Michael; Alonso, Jordi; Angermeyer, Matthias C; Benjet, Corina; Bruffaerts, Ronny; de Girolamo, Giovanni; Haro, Josep Maria; Kessler, Ronald C; Kovess, Viviane; Ono, Yutaka; Ormel, Johan; Posada-Villa, José

2008-11-01

To investigate a) whether childhood adversity predicts adult-onset asthma; b) whether early-onset depressive/anxiety disorders predict adult-onset asthma; and c) whether childhood adversity and early-onset depressive/anxiety disorders predict adult-onset asthma independently of each other. Previous research has suggested, but not established, that childhood adversity may predict adult-onset asthma and, moreover, that the association between mental disorders and asthma may be a function of shared risk factors, such as childhood adversity. Ten cross-sectional population surveys of household-residing adults (>18 years, n = 18,303) assessed mental disorders with the Composite International Diagnostic Interview (CIDI 3.0) as part of the World Mental Health surveys. Assessment of a range of childhood family adversities was included. Asthma was ascertained by self-report of lifetime diagnosis and age of diagnosis. Survival analyses calculated hazard ratios (HRs) for risk of adult-onset (>age 20 years) asthma as a function of number and type of childhood adversities and early-onset (

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...

Pretreatment Predictors of Adverse Radiation Effects After Radiosurgery for Arteriovenous Malformation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hayhurst, Caroline; Monsalves, Eric; Prooijen, Monique van

Purpose: To identify vascular and dosimetric predictors of symptomatic T2 signal change and adverse radiation effects after radiosurgery for arteriovenous malformation, in order to define and validate preexisting risk models. Methods and Materials: A total of 125 patients with arteriovenous malformations (AVM) were treated at our institution between 2005 and 2009. Eighty-five patients have at least 12 months of clinical and radiological follow-up. Any new-onset headaches, new or worsening seizures, or neurological deficit were considered adverse events. Follow-up magnetic resonance images were assessed for new onset T2 signal change and the volume calculated. Pretreatment characteristics and dosimetric variables were analyzedmore » to identify predictors of adverse radiation effects. Results: There were 19 children and 66 adults in the study cohort, with a mean age of 34 (range 6-74). Twenty-three (27%) patients suffered adverse radiation effects (ARE), 9 patients with permanent neurological deficit (10.6%). Of these, 5 developed fixed visual field deficits. Target volume and 12 Gy volume were the most significant predictors of adverse radiation effects on univariate analysis (p < 0.001). Location and cortical eloquence were not significantly associated with the development of adverse events (p = 0.12). No additional vascular parameters were identified as predictive of ARE. There was a significant target volume threshold of 4 cm{sup 3}, above which the rate of ARE increased dramatically. Multivariate analysis target volume and the absence of prior hemorrhage are the only significant predictors of ARE. The volume of T2 signal change correlates to ARE, but only target volume is predictive of a higher volume of T2 signal change. Conclusions: Target volume and the absence of prior hemorrhage is the most accurate predictor of adverse radiation effects and complications after radiosurgery for AVMs. A high percentage of permanent visual field defects in this series suggest the optic radiation is a critical radiosensitive structure.« less

Predicting Occurrence of Spine Surgery Complications Using "Big Data" Modeling of an Administrative Claims Database.

PubMed

Ratliff, John K; Balise, Ray; Veeravagu, Anand; Cole, Tyler S; Cheng, Ivan; Olshen, Richard A; Tian, Lu

2016-05-18

Postoperative metrics are increasingly important in determining standards of quality for physicians and hospitals. Although complications following spinal surgery have been described, procedural and patient variables have yet to be incorporated into a predictive model of adverse-event occurrence. We sought to develop a predictive model of complication occurrence after spine surgery. We used longitudinal prospective data from a national claims database and developed a predictive model incorporating complication type and frequency of occurrence following spine surgery procedures. We structured our model to assess the impact of features such as preoperative diagnosis, patient comorbidities, location in the spine, anterior versus posterior approach, whether fusion had been performed, whether instrumentation had been used, number of levels, and use of bone morphogenetic protein (BMP). We assessed a variety of adverse events. Prediction models were built using logistic regression with additive main effects and logistic regression with main effects as well as all 2 and 3-factor interactions. Least absolute shrinkage and selection operator (LASSO) regularization was used to select features. Competing approaches included boosted additive trees and the classification and regression trees (CART) algorithm. The final prediction performance was evaluated by estimating the area under a receiver operating characteristic curve (AUC) as predictions were applied to independent validation data and compared with the Charlson comorbidity score. The model was developed from 279,135 records of patients with a minimum duration of follow-up of 30 days. Preliminary assessment showed an adverse-event rate of 13.95%, well within norms reported in the literature. We used the first 80% of the records for training (to predict adverse events) and the remaining 20% of the records for validation. There was remarkable similarity among methods, with an AUC of 0.70 for predicting the occurrence of adverse events. The AUC using the Charlson comorbidity score was 0.61. The described model was more accurate than Charlson scoring (p < 0.01). We present a modeling effort based on administrative claims data that predicts the occurrence of complications after spine surgery. We believe that the development of a predictive modeling tool illustrating the risk of complication occurrence after spine surgery will aid in patient counseling and improve the accuracy of risk modeling strategies. Copyright © 2016 by The Journal of Bone and Joint Surgery, Incorporated.

A hierarchical anatomical classification schema for prediction of phenotypic side effects

PubMed Central

Kanji, Rakesh

2018-01-01

Prediction of adverse drug reactions is an important problem in drug discovery endeavors which can be addressed with data-driven strategies. SIDER is one of the most reliable and frequently used datasets for identification of key features as well as building machine learning models for side effects prediction. The inherently unbalanced nature of this data presents with a difficult multi-label multi-class problem towards prediction of drug side effects. We highlight the intrinsic issue with SIDER data and methodological flaws in relying on performance measures such as AUC while attempting to predict side effects.We argue for the use of metrics that are robust to class imbalance for evaluation of classifiers. Importantly, we present a ‘hierarchical anatomical classification schema’ which aggregates side effects into organs, sub-systems, and systems. With the help of a weighted performance measure, using 5-fold cross-validation we show that this strategy facilitates biologically meaningful side effects prediction at different levels of anatomical hierarchy. By implementing various machine learning classifiers we show that Random Forest model yields best classification accuracy at each level of coarse-graining. The manually curated, hierarchical schema for side effects can also serve as the basis of future studies towards prediction of adverse reactions and identification of key features linked to specific organ systems. Our study provides a strategy for hierarchical classification of side effects rooted in the anatomy and can pave the way for calibrated expert systems for multi-level prediction of side effects. PMID:29494708

A hierarchical anatomical classification schema for prediction of phenotypic side effects.

PubMed

Wadhwa, Somin; Gupta, Aishwarya; Dokania, Shubham; Kanji, Rakesh; Bagler, Ganesh

2018-01-01

Prediction of adverse drug reactions is an important problem in drug discovery endeavors which can be addressed with data-driven strategies. SIDER is one of the most reliable and frequently used datasets for identification of key features as well as building machine learning models for side effects prediction. The inherently unbalanced nature of this data presents with a difficult multi-label multi-class problem towards prediction of drug side effects. We highlight the intrinsic issue with SIDER data and methodological flaws in relying on performance measures such as AUC while attempting to predict side effects.We argue for the use of metrics that are robust to class imbalance for evaluation of classifiers. Importantly, we present a 'hierarchical anatomical classification schema' which aggregates side effects into organs, sub-systems, and systems. With the help of a weighted performance measure, using 5-fold cross-validation we show that this strategy facilitates biologically meaningful side effects prediction at different levels of anatomical hierarchy. By implementing various machine learning classifiers we show that Random Forest model yields best classification accuracy at each level of coarse-graining. The manually curated, hierarchical schema for side effects can also serve as the basis of future studies towards prediction of adverse reactions and identification of key features linked to specific organ systems. Our study provides a strategy for hierarchical classification of side effects rooted in the anatomy and can pave the way for calibrated expert systems for multi-level prediction of side effects.

The Effects of Childhood and Adolescent Adversity on Substance Use Disorders and Poor Health in Early Adulthood

PubMed Central

Wolitzky-Taylor, Kate; Sewart, Amy; Vrshek-Schallhorn, Suzanne; Zinbarg, Richard; Mineka, Susan; Hammen, Constance; Bobova, Lyuba; Adam, Emma K.; Craske, Michelle G.

2016-01-01

Childhood and adolescent adversity have been shown to predict later mental and physical health outcomes. Understanding which aspects and developmental timings of adversity are important, and the mechanisms by which they have their impact may help guide intervention approaches. A large subset of adolescents (N = 457; Female 68.9%) from the 10-year longitudinal Youth Emotion Project was examined to better understand the associations among childhood/adolescent adversity, substance use disorder, and later health quality. Adolescent (but not childhood) adversities were associated with poorer health in late adolescence/early adulthood, adolescent adversities were associated with subsequent onset of substance use disorder, and adolescent adversities continued to be associated with poorer health in late adolescence/early adulthood after accounting for the variance explained by substance use disorder onset. These associations were observed after statistically accounting for emotional disorders and socioeconomic status. Specific domains of adversity uniquely predicted substance use disorder and poorer health outcomes. In contrast with current recent research, our findings suggest the association between childhood/adolescent adversity and poorer health outcomes in late adolescence and emerging adulthood are not entirely accounted for by substance use disorder, suggesting efforts to curtail family-based adolescent adversity may have downstream health benefits. PMID:27613006

The Effects of Childhood and Adolescent Adversity on Substance Use Disorders and Poor Health in Early Adulthood.

PubMed

Wolitzky-Taylor, Kate; Sewart, Amy; Vrshek-Schallhorn, Suzanne; Zinbarg, Richard; Mineka, Susan; Hammen, Constance; Bobova, Lyuba; Adam, Emma K; Craske, Michelle G

2017-01-01

Childhood and adolescent adversity have been shown to predict later mental and physical health outcomes. Understanding which aspects and developmental timings of adversity are important, and the mechanisms by which they have their impact may help guide intervention approaches. A large subset of adolescents (N = 457; Female 68.9 %) from the 10-year longitudinal Youth Emotion Project was examined to better understand the associations among childhood/adolescent adversity, substance use disorder, and later health quality. Adolescent (but not childhood) adversities were associated with poorer health in late adolescence/early adulthood, adolescent adversities were associated with subsequent onset of substance use disorder, and adolescent adversities continued to be associated with poorer health in late adolescence/early adulthood after accounting for the variance explained by substance use disorder onset. These associations were observed after statistically accounting for emotional disorders and socioeconomic status. Specific domains of adversity uniquely predicted substance use disorder and poorer health outcomes. In contrast with current recent research, our findings suggest the association between childhood/adolescent adversity and poorer health outcomes in late adolescence and emerging adulthood are not entirely accounted for by substance use disorder, suggesting efforts to curtail family-based adolescent adversity may have downstream health benefits.

Empirical testing AOP network-based hazard prediction combined effect of aromatase inhibition & androgen receptor agonism

EPA Science Inventory

Adverse outcome pathways (AOPs) describe linkages between a specific molecular perturbation resulting from interaction of a chemical with a biomolecule in an organism and one possible adverse outcome of regulatory significance. While individual AOPs have utility, it is recognized...

Cumulative adversity in childhood and emergent risk factors for long-term health.

PubMed

Slopen, Natalie; Koenen, Karestan C; Kubzansky, Laura D

2014-03-01

To examine whether and when effects of cumulative adversity in the first 7 years of life are evident in relation to 3 childhood markers of risk for poor adult physical health. The study data are from an English birth cohort. Parental reports of 8 social risk factors were obtained during the child's first 7 years, and scores were created to reflect cumulative adversity at 4 developmental periods. At age 7 and 11 years, weight, height, and blood pressure (BP) were measured by clinic staff, and caregivers reported behavior problems. Linear regression was used to estimate associations of cumulative adversity with each outcome (n = 4361) and changes in these outcomes between 7 and 11 years (n = 3348). At age 7 years, mean adversity and chronic exposure to high adversity were associated with elevated body mass index (BMI) and internalizing and externalizing symptoms (P < .05), but not elevated BP. Adversity in all developmental periods was associated with elevated numbers of internalizing and externalizing symptoms (P < .0001), but associations were less robust for BMI. Adversity did not predict change in BMI or BP between age 7 and 11 years, however, it predicted increases in internalizing and externalizing symptoms (P < .0001). Cumulative adversity was associated with BMI and behavior problems at age 7 years, and our data indicate that timing and chronicity of exposure to adversity differentially influence diverse indicators of long-term health risk commonly measured in childhood. This research suggests the hypothesis that interventions to address adversity could reduce the development of multiple chronic disease risk factors and limit their effects on health. Copyright © 2014 Mosby, Inc. All rights reserved.

Children's Executive Function in a CPS-Involved Sample: Effects of Cumulative Adversity and Specific Types of Adversity.

PubMed

Roos, Leslie E; Kim, Hyoun K; Schnabler, Simone; Fisher, Philip A

2016-12-01

Prior research has identified the presence of executive function (EF) deficits in child protective service (CPS) involved (versus non-involved) children but minimal work has examined predictors that might explain individual differences within these CPS-involved children. Here, we sought to characterize EF in a large sample (N=694) of CPS-involved children and examine how specific adversities (physical abuse, neglect, caregiver domestic violence, and caregiver substance dependence) and cumulative adversity (at ages 0-3 and 3-6 years) predict EF (at approximately 5-6 years). It was expected that the sample would exhibit low EF overall based on previous research in maltreated children. Specific adversity and cumulative adversity analyses were largely exploratory given the limited previous work in this area. Results indicated poor EF overall, with 43.5% of children performing worse than chance. Amongst children who performed greater than chance, higher cumulative adversity, physical abuse, and caregiver substance use (at ages 3-6 years) predicted better EF. These findings join literature documenting that, within CPS-involved children, the presence of certain adversities predicts variable cognitive function. Findings highlight the potential relevance of evolutionary psychology to understanding how alterations in behavior linked to harsh and unpredictable early environments may cue accelerated brain development underlying relative cognitive advantages, within at-risk, low performing samples. Longitudinal studies are critical to determine if the relative EF advantages linked to higher adversity persist over time or result in lower EF later on, reflecting a more rapid, but overall limited, trajectory of cognitive development.

Short-term effects of air pollution, markers of endothelial activation, and coagulation to predict major adverse cardiovascular events in patients with acute coronary syndrome: insights from AIRACOS study.

PubMed

Dominguez-Rodriguez, Alberto; Abreu-Gonzalez, Pedro; Rodríguez, Sergio; Avanzas, Pablo; Juarez-Prera, Ruben A

2017-07-01

The aim of this study was to determine whether markers of inflammation and coagulation are associated with short-term particulate matter exposure and predict major adverse cardiovascular events at 360 d in patients with acute coronary syndrome (ACS). We included 307 consecutive patients, and assessed the average concentrations of data on atmospheric pollution in ambient air and meteorological variables from 1 d up to 7 d prior to admission. In patients with ACS, the markers of endothelial activation and coagulation, but not black carbon exposure, are associated with major adverse cardiovascular events at one-year follow-up.

Predictors of local adverse effects caused by topical tretinoin cream 0·1% in the Veterans Affairs Topical Tretinoin Chemoprevention trial.

PubMed

Pomerantz, H; Weinstock, M A

2014-09-01

Topical tretinoin is commonly prescribed, but its frequent adverse effects are barriers to use. Predictors of resistance or susceptibility to retinoid irritation are not known. To identify baseline patient characteristics associated with adverse effects of topical tretinoin. This cohort study used data collected from 324 participants in the Veterans Affairs Topical Tretinoin Chemoprevention trial who were randomized to apply tretinoin cream on the face and ears. Univariate and multivariate logistic regression models were used to examine the associations between baseline characteristics and local adverse effects. One hundred and ninety-seven patients (61% of those randomized to tretinoin) reported local adverse effects within 6 months. Clinical signs of severe photodamage at baseline [odds ratio (OR) 0·15, 95% confidence interval (CI) 0·04-0·54] and history of acne (OR 0·46, 95% CI 0·27-0·77) were associated with a decreased risk of adverse effects to tretinoin. The use of other topical medications at enrolment (OR 1·88, 95% CI 1·15-3·08) predicted an increase in adverse effects. In this study population, the common indications of topical tretinoin treatment were associated with lower risks of adverse effects. The concurrent use of other topical medications may worsen irritation caused by tretinoin. © 2014 British Association of Dermatologists.

Long-term mucocutaneous adverse effects of imatinib in Indian chronic myeloid leukemia patients.

PubMed

Vinay, Keshavamurthy; Yanamandra, Uday; Dogra, Sunil; Handa, Sanjeev; Suri, Vikas; Kumari, Savita; Khadwal, Alka; Prakash, Gaurav; Lad, Deepesh; Varma, Subhash; Malhotra, Pankaj

2018-03-01

Short-term mucocutaneous adverse effects are well documented with imatinib. However, studies on long-term adverse effects and in the ethnic population are lacking. To study the long-term mucocutaneous adverse effects of imatinib and factors predicting these adverse effects. In this cross-sectional study, consenting adult chronic myeloid leukemia patients on imatinib for more than 250 days were recruited. The details of imatinib treatment were retrieved from hematology clinic records. Four hundred and thirty-eight patients who were on imatinib for a mean duration of 1820 days were recruited. A mean number of 1.42 ± 0.98 cutaneous adverse effects were seen per patient. Melasma-like pigmentation, periorbital edema, oral lichenoid reaction, cutaneous hypopigmentation, and vesicobullous eruptions were seen in 236 (53.9%), 81 (18.5%), 70 (16%), 42 (9.6%), and 12 (2.7%) patients, respectively. Drug-induced cutaneous eruptions (9.1%) and cutaneous hypopigmentation (9.6%) were seen less frequently. Cutaneous hyperpigmentation was more likely seen in younger patients (P = 0.001) and females (P < 0.001). On multivariate analysis, female gender was a significant risk factor for developing cutaneous hyperpigmentation and periorbital edema. Cutaneous hyperpigmentation and periorbital edema are common long-term adverse effects of imatinib in Indian patients. Female gender is a significant risk factor for the development of both these adverse effects. © 2017 The International Society of Dermatology.

Interplay between Schizophrenia Polygenic Risk Score and Childhood Adversity in First-Presentation Psychotic Disorder: A Pilot Study

PubMed Central

Trotta, Antonella; Iyegbe, Conrad; Di Forti, Marta; Sham, Pak C.; Campbell, Desmond D.; Cherny, Stacey S.; Mondelli, Valeria; Aitchison, Katherine J.; Murray, Robin M.

2016-01-01

A history of childhood adversity is associated with psychotic disorder, with an increase in risk according to number or severity of exposures. However, it is not known why only some exposed individuals go on to develop psychosis. One possibility is pre-existing genetic vulnerability. Research on gene-environment interaction in psychosis has primarily focused on candidate genes, although the genetic effects are now known to be polygenic. This pilot study investigated whether the effect of childhood adversity on psychosis is moderated by the polygenic risk score for schizophrenia (PRS). Data were utilised from the Genes and Psychosis (GAP) study set in South London, UK. The GAP sample comprises 285 first-presentation psychosis cases and 256 unaffected controls with information on childhood adversity. We studied only white subjects (80 cases and 110 controls) with PRS data, as the PRS has limited predictive ability in patients of African ancestry. The occurrence of childhood adversity was assessed with the Childhood Experience of Care and Abuse Questionnaire (CECA.Q) and the PRS was based on genome-wide meta-analysis results for schizophrenia from the Psychiatric Genomics Consortium. Higher schizophrenia PRS and childhood adversities each predicted psychosis status. Nevertheless, no evidence was found for interaction as departure from additivity, indicating that the effect of polygenic risk scores on psychosis was not increased in the presence of a history of childhood adversity. These findings are compatible with a multifactorial threshold model in which both genetic liability and exposure to environmental risk contribute independently to the etiology of psychosis. PMID:27648571

Prenatal alcohol and other early childhood adverse exposures: Direct and indirect pathways to adolescent drinking

PubMed Central

Cornelius, Marie D.; De Genna, Natacha M.; Goldschmidt, Lidush; Larkby, Cynthia; Day, Nancy L.

2016-01-01

We examined direct and indirect pathways between adverse environmental exposures during gestation and childhood and drinking in mid-adolescence. Mothers and their offspring (n = 917 mother/child dyads) were followed prospectively from second trimester to a 16-year follow-up assessment. Interim assessments occurred at delivery, 6, 10, and 14 years. Adverse environmental factors included gestational exposures to alcohol, tobacco, and marijuana, exposures to childhood maltreatment and violence, maternal psychological symptoms, parenting practices, economic and home environments, and demographic characteristics of the mother and child. Indirect effects of early child behavioral characteristics including externalizing, internalizing activity, attention, and impulsivity were also examined. Polytomous logistic regression analyses were used to evaluate direct effects of adverse environmental exposures with level of adolescent drinking. Structural equation modeling (SEM) was applied to simultaneously estimate the relation between early adversity variables, childhood characteristics, and drinking level at age 16 while controlling for significant covariates. Level of drinking among the adolescent offspring was directly predicted by prenatal exposure to alcohol, less parental strictness, and exposures to maltreatment and violence during childhood. Whites and offspring with older mothers were more likely to drink at higher levels. There was a significant indirect effect between childhood exposure to violence and adolescent drinking via childhood externalizing behavior problems. All other hypothesized indirect pathways were not significant. Thus most of the early adversity measures directly predicted adolescent drinking and did not operate via childhood behavioral dysregulation characteristics. These results highlight the importance of adverse environmental exposures on pathways to adolescent drinking. PMID:26994529

Warnings of adverse side effects can backfire over time.

PubMed

Steinhart, Yael; Carmon, Ziv; Trope, Yaacov

2013-09-01

Warnings that a promoted product can have adverse side effects (e.g., smoking cigarettes can cause cancer) should dampen the product's allure. We predicted that with temporal distance (e.g., when an ad relates to future consumption or was viewed some time earlier), this common type of warning can have a worrisome alternative consequence: It can ironically boost the product's appeal. Building on construal-level theory, we argue that this is because temporal distance evokes high-level construal, which deemphasizes side effects and emphasizes message trustworthiness. In four studies, we demonstrated this phenomenon. For example, participants could buy cigarettes or artificial sweeteners after viewing an ad promoting the product. Immediately afterward, the quantity that participants bought predictably decreased if the ad they saw included a warning about adverse side effects. With temporal distance (product to be delivered 3 months later, or 2 weeks after the ad was viewed), however, participants who had seen an ad noting the benefits of the product but warning of risky side effects bought more than those who had seen an ad noting only benefits.

Brain neurotransmitter transporter/receptor genomics and efavirenz central nervous system adverse events.

PubMed

Haas, David W; Bradford, Yuki; Verma, Anurag; Verma, Shefali S; Eron, Joseph J; Gulick, Roy M; Riddler, Sharon A; Sax, Paul E; Daar, Eric S; Morse, Gene D; Acosta, Edward P; Ritchie, Marylyn D

2018-05-29

We characterized associations between central nervous system (CNS) adverse events and brain neurotransmitter transporter/receptor genomics among participants randomized to efavirenz-containing regimens in AIDS Clinical Trials Group studies in the USA. Four clinical trials randomly assigned treatment-naive participants to efavirenz-containing regimens. Genome-wide genotype and PrediXcan were used to infer gene expression levels in tissues including 10 brain regions. Multivariable regression models stratified by race/ethnicity were adjusted for CYP2B6/CYP2A6 genotypes that predict plasma efavirenz exposure, age, and sex. Combined analyses also adjusted for genetic ancestry. Analyses included 167 cases with grade 2 or greater efavirenz-consistent CNS adverse events within 48 weeks of study entry, and 653 efavirenz-tolerant controls. CYP2B6/CYP2A6 genotype level was independently associated with CNS adverse events (odds ratio: 1.07; P=0.044). Predicted expression of six genes postulated to mediate efavirenz CNS side effects (SLC6A2, SLC6A3, PGR, HTR2A, HTR2B, HTR6) were not associated with CNS adverse events after correcting for multiple testing, the lowest P value being for PGR in hippocampus (P=0.012), nor were polymorphisms in these genes or AR and HTR2C, the lowest P value being for rs12393326 in HTR2C (P=6.7×10). As a positive control, baseline plasma bilirubin concentration was associated with predicted liver UGT1A1 expression level (P=1.9×10). Efavirenz-related CNS adverse events were not associated with predicted neurotransmitter transporter/receptor gene expression levels in brain or with polymorphisms in these genes. Variable susceptibility to efavirenz-related CNS adverse events may not be explained by brain neurotransmitter transporter/receptor genomics.

Prediction of adverse drug reactions using decision tree modeling.

PubMed

Hammann, F; Gutmann, H; Vogt, N; Helma, C; Drewe, J

2010-07-01

Drug safety is of great importance to public health. The detrimental effects of drugs not only limit their application but also cause suffering in individual patients and evoke distrust of pharmacotherapy. For the purpose of identifying drugs that could be suspected of causing adverse reactions, we present a structure-activity relationship analysis of adverse drug reactions (ADRs) in the central nervous system (CNS), liver, and kidney, and also of allergic reactions, for a broad variety of drugs (n = 507) from the Swiss drug registry. Using decision tree induction, a machine learning method, we determined the chemical, physical, and structural properties of compounds that predispose them to causing ADRs. The models had high predictive accuracies (78.9-90.2%) for allergic, renal, CNS, and hepatic ADRs. We show the feasibility of predicting complex end-organ effects using simple models that involve no expensive computations and that can be used (i) in the selection of the compound during the drug discovery stage, (ii) to understand how drugs interact with the target organ systems, and (iii) for generating alerts in postmarketing drug surveillance and pharmacovigilance.

Ecological Models to Predict and Test the Effects of Chemical Stressors: Integration across 2 EPA STAR cooperative agreements

EPA Science Inventory

Accessible tools to quantify adverse outcomes pathways (AOPs) that can predict the ecological effects of chemicals and other stressors are a major goal of Chemical Safety and Sustainability research within US EPA’s Office of Research and Development. To address this goal, w...

Multiple lines of evidence risk assessment of American robins exposed to polychlorinated dibenzofurans (PCDFS) and polychlorinated dibenzo-P-dioxins (PCDDS) in the Tittabawassee River floodplain, Midland, Michigan, USA.

PubMed

Tazelaar, Dustin L; Fredricks, Timothy B; Seston, Rita M; Coefield, Sarah J; Bradley, Patrick W; Roark, Shaun A; Kay, Denise P; Newsted, John L; Giesy, John P; Bursian, Steven J; Zwiernik, Matthew J

2013-06-01

Concentrations of polychlorinated dibenzofurans (PCDFs) and polychlorinated dibenzo-p-dioxins (PCDDs) in Tittabawassee River floodplain soils and biota downstream of Midland, Michigan, USA, are greater than regional background concentrations. From 2005 to 2008, a multiple lines of evidence approach was utilized to evaluate the potential for effects of PCDD/DFs on American robins (Turdus migratorius) breeding in the floodplains. A dietary-based assessment indicated there was potential for adverse effects for American robins predicted to have the greatest exposures. Conversely, a tissue-based risk assessment based on site-specific PCDD/DF concentrations in American robin eggs indicated minimal potential for adverse effects. An assessment based on reproductive endpoints indicated that measures of hatch success in study areas were significantly less than those of reference areas. However, there was no dose-response relationship between that endpoint and concentrations of PCDD/DF. Although dietary-based exposure and reproductive endpoint assessments predicted potential for adverse effects to resident American robins, the tissue-based assessment indicates minimal to no potential for adverse effects, which is reinforced by the fact the response was not dose related. It is likely that the dietary assessment is overly conservative given the inherent uncertainties of estimating dietary exposure relative to direct tissue-based assessment measures. Based on the available data, it can be concluded that exposure to PCDD/DFs in the Tittabawassee River floodplain would not likely result in adverse population-level effects to American robins. Copyright © 2013 SETAC.

Accidental release of chlorine in Chicago: Coupling of an exposure model with a Computational Fluid Dynamics model

NASA Astrophysics Data System (ADS)

Sanchez, E. Y.; Colman Lerner, J. E.; Porta, A.; Jacovkis, P. M.

2013-01-01

The adverse health effects of the release of hazardous substances into the atmosphere continue being a matter of concern, especially in densely populated urban regions. Emergency responders need to have estimates of these adverse health effects in the local population to aid planning, emergency response, and recovery efforts. For this purpose, models that predict the transport and dispersion of hazardous materials are as necessary as those that estimate the adverse health effects in the population. In this paper, we present the results obtained by coupling a Computational Fluid Dynamics model, FLACS (FLame ACceleration Simulator), with an exposure model, DDC (Damage Differential Coupling). This coupled model system is applied to a scenario of hypothetical release of chlorine with obstacles, such as buildings, and the results show how it is capable of predicting the atmospheric dispersion of hazardous chemicals, and the adverse health effects in the exposed population, to support decision makers both in charge of emergency planning and in charge of real-time response. The results obtained show how knowing the influence of obstacles in the trajectory of the toxic cloud and in the diffusion of the pollutants transported, and obtaining dynamic information of the potentially affected population and of associated symptoms, contribute to improve the planning of the protection and response measures.

Development and evaluation of adverse outcome pathways predicting adverse effects of conazole fungicides on avian species

EPA Science Inventory

Conazoles are a class of fungicides commonly used in agriculture and as pharmaceuticals to prevent the spread of fungus through inhibition of cytochrome P450 14á-demethylase (CYP51). However these fungicides are known to act promiscuously on other cytochrome P450 enzymes (...

Developing confidence in adverse outcome pathway-based toxicity predictions effects of the fungicide imazalil on fathead minnow reproduction

EPA Science Inventory

An adverse outcome pathway (AOP) description linking inhibition of aromatase (cytochrome P450 [cyp] 19) to reproductive dysfunction was reviewed for scientific and technical quality and endorsed by the OECD (https://aopwiki.org/wiki/index.php/Aop:25). An intended application of t...

Developing confidence in adverse outcome pathway-based toxicity predictions effects of the fungicide imazalil on fathead minnow reproduction (Poster)

EPA Science Inventory

An adverse outcome pathway (AOP) description linking inhibition of aromatase (cytochrome P450 [cyp] 19) to reproductive dysfunction was reviewed for scientific and technical quality and endorsed by the OECD. An intended application of the AOP framework is to support the use of me...

The joint contribution of maternal history of early adversity and adulthood depression to socioeconomic status and potential relevance for offspring development.

PubMed

Bouvette-Turcot, Andrée-Anne; Unternaehrer, Eva; Gaudreau, Hélène; Lydon, John E; Steiner, Meir; Meaney, Michael J

2017-01-01

We examined the interactive effects of maternal childhood adversity and later adulthood depression on subsequent socioeconomic status (SES). Our community sample ranged from 230 to 243 mothers (across measures) drawn from a prospective, longitudinal cohort study. Maternal childhood adversity scores were derived using an integrated measure derived from the Childhood Trauma Questionnaire (CTQ) and the Parental Bonding Index (PBI). Maternal depression was measured in the prenatal period with the Center for Epidemiologic Studies Depression Scale (CES-D). SES measures included maternal highest level of education and family income as obtained prenatally. The analyses yielded significant interaction effects between maternal childhood adversity and prenatal depression that predicted income, prenatally. Women who reported higher levels of childhood adversity combined with higher levels of self-reported depressive symptoms were significantly more likely to live in low SES environments. Results also showed that level of education was predicted by childhood adversity independent of maternal symptoms of depression. The results suggest that SES is influenced by a life course pathway that begins in childhood and includes adversity-related mental health outcomes. Since child health and development is influenced by both maternal mental health and SES, this pathway may also contribute to the intergenerational transmission of the risk for psychopathology in the offspring. The results also emphasize the importance of studying potential precursors of low SES, a well-documented environmental risk factor for poor developmental outcomes in the offspring. Copyright © 2016. Published by Elsevier B.V.

Enantiomer specific measurements of current-use pesticides in aquatic systems

EPA Science Inventory

Contrary to predictions, current-use pesticides are adversely affecting aquatic systems in both urban and agricultural watersheds, particularly in California. One possible divergence from fate and effect predictions is that some current-use pesticides are chiral molecules. Increa...

Childhood adversity and social functioning in psychosis: Exploring clinical and cognitive mediators.

PubMed

Palmier-Claus, Jasper; Berry, Katherine; Darrell-Berry, Hannah; Emsley, Richard; Parker, Sophie; Drake, Richard; Bucci, Sandra

2016-04-30

Childhood adversity may increase risk of impaired social functioning across the continuum of psychosis. However, the pathways by which adversity dictates functional outcome remain underexplored. This study investigated the association between childhood adversity and social functioning, and the clinical and cognitive mediators of this relationship. Fifty-four clinical (20 chronic, 20 first episode, 14 at ultra-high risk) and 120 non-clinical participants completed standardised questionnaires, semi-structured interviews and tests of theory of mind ability. The authors used multiple group structural equation modelling to fit mediation models allowing for differential relationships between the clinical and non-clinical samples. When examining each pathway separately, depression, paranoia and anxious attachment mediated the effect of childhood adversity on social functioning. In a combined model, depression was the only significant mediating variable with greater adversity predicting lower mood across groups. Childhood adversity did not significantly predict theory of mind ability in any of the models. This is the first study to indicate that childhood adversity acts on social functioning by increasing levels of depression, suggesting a common mechanism across the spectrum of psychosis. Clinical interventions should target low mood in order to improve social functioning at all stages of psychotic disorder. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Technical evaluation report, AGARD Fluid Dynamics Panel Symposium on Effects of Adverse Weather on Aerodynamics

NASA Technical Reports Server (NTRS)

Reinmann, J. J.

1991-01-01

The purpose of the meeting on Effects of Adverse Weather on Aerodynamics was to provide an update of the stae-of-the-art with respect to the prediction, simulation, and measurement of the effects of icing, anti-icing fluids, and various precipitation on the aerodynamic characteristics of flight vehicles. Sessions were devoted to introductory and survey papers and icing certification issues, to analytical and experimental simulation of ice frost contamination and its effects of aerodynamics, and to the effects of heavy rain and deicing/anti-icing fluids.

One size fits one: pharmacogenetics in gastroenterology.

PubMed

Porayette, Prashanth; Flockhart, David; Gupta, Sandeep K

2014-04-01

Individual variability in response and development of adverse effects to drugs is a major challenge in clinical practice. Pharmacogenomics refers to the aspect of personalized medicine where the patient's genetic information instructs the selection and dosage of therapy while also predicting its adverse effects profile. Sequencing of the entire human genome has given us the opportunity to study commonly used drugs as well as newer therapeutic agents in a new light, opening up opportunities for better drug efficacy and decreased adverse effects. This article highlights developments in pharmacogenomics, relates these to practice of gastroenterology, and outlines roadblocks in translation of this knowledge into clinical practice. Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.

Comparison of in vitro and ex vivo thyroid hormone synthesis inhibition results and in vivo outcomes for a series of benzothiazoles

EPA Science Inventory

Assessing how in vitro data may be used to predict adverse effects in vivo is critical as efforts are advanced to incorporate in vitro assays into a risk assessment framework. Within the context of a thyroid hormone (TH) synthesis inhibition adverse outcome pathway (AOP), in vitr...

Encouraging CPAP adherence: it is everyone's job.

PubMed

Bollig, Suzanne M

2010-09-01

Obstructive sleep apnea (OSA) is a chronic disease treated effectively with the use of continuous positive airway pressure (CPAP) therapy. Patient adherence to prescribed CPAP is variable, however, leaving the undertreated OSA patient at risk of development or worsening of comorbid medical conditions, including hypertension and cardiovascular disease. The severity of disease and the presence of daytime sleepiness appear to have some predictive quality for subsequent adherence, though a search for consistent predictive factors related to CPAP adherence has proven elusive. Other influences, such as sex, age, socioeconomic status, and personality traits are less robust predictors. The use of sophisticated therapy modalities such as auto-titration or bi-level PAP units has been shown to improve adherence in certain subsets of OSA patients. Adverse effects such as nasal congestion, dry mouth, or skin irritation occur in approximately 50% of CPAP users, and addressing these adverse effects may improve adherence in some patients. More encouraging, studies on the use of intensive patient education and behavioral interventions have shown more positive effects on adherence, leading to the conclusion that improvement in patient adherence to CPAP therapy requires a multi-layered approach, using combined technological, behavioral, and adverse-effect interventions.

ACCEPT: Introduction of the Adverse Condition and Critical Event Prediction Toolbox

NASA Technical Reports Server (NTRS)

Martin, Rodney A.; Santanu, Das; Janakiraman, Vijay Manikandan; Hosein, Stefan

2015-01-01

The prediction of anomalies or adverse events is a challenging task, and there are a variety of methods which can be used to address the problem. In this paper, we introduce a generic framework developed in MATLAB (sup registered mark) called ACCEPT (Adverse Condition and Critical Event Prediction Toolbox). ACCEPT is an architectural framework designed to compare and contrast the performance of a variety of machine learning and early warning algorithms, and tests the capability of these algorithms to robustly predict the onset of adverse events in any time-series data generating systems or processes.

The effects of power, leadership and psychological safety on resident event reporting.

PubMed

Appelbaum, Nital P; Dow, Alan; Mazmanian, Paul E; Jundt, Dustin K; Appelbaum, Eric N

2016-03-01

Although the reporting of adverse events is a necessary first step in identifying and addressing lapses in patient safety, such events are under-reported, especially by frontline providers such as resident physicians. This study describes and tests relationships between power distance and leader inclusiveness on psychological safety and the willingness of residents to report adverse events. A total of 106 resident physicians from the departments of neurosurgery, orthopaedic surgery, emergency medicine, otolaryngology, neurology, obstetrics and gynaecology, paediatrics and general surgery in a mid-Atlantic teaching hospital were asked to complete a survey on psychological safety, perceived power distance, leader inclusiveness and intention to report adverse events. Perceived power distance (β = -0.26, standard error [SE] 0.06, 95% confidence interval [CI] -0.37 to 0.15; p < 0.001) and leader inclusiveness (β = 0.51; SE 0.07, 95% CI 0.38-0.65; p < 0.001) both significantly predicted psychological safety, which, in turn, significantly predicted intention to report adverse events (β = 0.34; SE 0.08, 95% CI 0.18-0.49; p < 0.001). Psychological safety significantly mediated the direct relationship between power distance and intention to report adverse events (indirect effect: -0.09; SE 0.02, 95% CI -0.13 to 0.04; p < 0.001). Psychological safety also significantly mediated the direct relationship between leader inclusiveness and intention to report adverse events (indirect effect: 0.17; SE 0.02, 95% CI 0.08-0.27; p = 0.001). Psychological safety was found to be a predictor of intention to report adverse events. Perceived power distance and leader inclusiveness both influenced the reporting of adverse events through the concept of psychological safety. Because adverse event reporting is shaped by relationships and culture external to the individual, it should be viewed as an organisational as much as a personal function. Supervisors and other leaders in health care should ensure that policies, procedures and leadership practices build psychological safety and minimise power distance between low- and high-status members in order to support greater reporting of adverse events. © 2016 John Wiley & Sons Ltd.

A Pathway to Psychological Difficulty: Perceived Chronic Social Adversity and Its Symptomatic Reactions.

PubMed

Ding, Cody; Zhang, Jingqiu; Yang, Dong

2018-01-01

In this paper, we attempt to predict and explain psychological maladjustment or difficulty. Specifically, we discuss the concept of perceived chronic social adversity, and we expect that such perceived chronic social adversity may potentially lead to chronic stress responses. Accordingly, we propose the symptomatic reactions of perceived chronic social adversity. We put forward a set of hypotheses regarding the relationships between perceived chronic social adversity and those chronic stress responses, and we further hypothesize a mediating role of individualized negative essentialism brought by perceived chronical social adversity. Resilience and individual differences in the ability to cope with perceived adversity are discussed. Future research and prevention need to pay more attention to effects of subjective personal experiences on psychological difficulty, focusing on the importance of exploring daily social experiences in improving cognitive construction processes and developing appropriate preventions.

Biological Relevance of Key Events (KE) in utero in The Androgen Adverse Outcome Pathway Network (AOPn) to Adverse Effects in F1 Male Rats

EPA Science Inventory

We are conducting studies to evaluate the biological relevance of changes in KEs and molecular initiating events (MIE) in AOPs to determine if these can accurately predict of the dose levels of chemicals that disrupt the androgen signaling pathway in utero. Herein, we focus on ch...

Detailed assessments of childhood adversity enhance prediction of central obesity independent of gender, race, adult psychosocial risk and health behaviors.

PubMed

Davis, Cynthia R; Dearing, Eric; Usher, Nicole; Trifiletti, Sarah; Zaichenko, Lesya; Ollen, Elizabeth; Brinkoetter, Mary T; Crowell-Doom, Cindy; Joung, Kyoung; Park, Kyung Hee; Mantzoros, Christos S; Crowell, Judith A

2014-02-01

This study examined whether a novel indicator of overall childhood adversity, incorporating number of adversities, severity, and chronicity, predicted central obesity beyond contributions of "modifiable" risk factors including psychosocial characteristics and health behaviors in a diverse sample of midlife adults. The study also examined whether the overall adversity score (number of adversities × severity × chronicity) better predicted obesity compared to cumulative adversity (number of adversities), a more traditional assessment of childhood adversity. 210 Black/African Americans and White/European Americans, mean age=45.8; ±3.3 years, were studied cross-sectionally. Regression analysis examined overall childhood adversity as a direct, non-modifiable risk factor for central obesity (waist-hip ratio) and body mass index (BMI), with and without adjustment for established adult psychosocial risk factors (education, employment, social functioning) and heath behavior risk factors (smoking, drinking, diet, exercise). Overall childhood adversity was an independent significant predictor of central obesity, and the relations between psychosocial and health risk factors and central obesity were not significant when overall adversity was in the model. Overall adversity was not a statistically significant predictor of BMI. Overall childhood adversity, incorporating severity and chronicity and cumulative scores, predicts central obesity beyond more contemporaneous risk factors often considered modifiable. This is consistent with early dysregulation of metabolic functioning. Findings can inform practitioners interested in the impact of childhood adversity and personalizing treatment approaches of obesity within high-risk populations. Prevention/intervention research is necessary to discover and address the underlying causes and impact of childhood adversity on metabolic functioning. © 2013.

Gender differences in the effects of childhood adversity on alcohol, drug, and polysubstance-related disorders.

PubMed

Evans, Elizabeth A; Grella, Christine E; Upchurch, Dawn M

2017-07-01

To examine gender differences in the associations between childhood adversity and different types of substance use disorders and whether gender moderates these relationships. We analyzed data from 19,209 women and 13,898 men as provided by Wave 2 (2004-2005) of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) to examine whether gender moderates the associations between childhood adversity and DSM-IV defined lifetime occurrence of alcohol, drug, and polysubstance-related disorders. We used multinomial logistic regression, weighted to be representative of the US adult civilian, noninstitutionalized population, and we calculated predicted probabilities by gender, controlling for covariates. To test which specific moderation contrasts were statistically significant, we conducted pair-wise comparisons corrected for multiple comparisons using Bonferroni's method. For each type of substance use disorder, risk was increased by more exposure to childhood adversity, and women had a lower risk than men. However, moderation effects revealed that with more experiences of childhood adversity, the gender gap in predicted probability for a disorder narrowed in relation to alcohol, it converged in relation to drugs such that risk among women surpassed that among men, and it widened in relation to polysubstances. Knowledge regarding substance-specific gender differences associated with childhood adversity exposure can inform evidence-based treatments. It may also be useful for shaping other types of gender-sensitive public health initiatives to ameliorate or prevent different types of substance use disorders.

Effects of maternal serum 25-hydroxyvitamin D concentrations in the first trimester on subsequent pregnancy outcomes in an Australian population.

PubMed

Schneuer, Francisco J; Roberts, Christine L; Guilbert, Cyrille; Simpson, Judy M; Algert, Charles S; Khambalia, Amina Z; Tasevski, Vitomir; Ashton, Anthony W; Morris, Jonathan M; Nassar, Natasha

2014-02-01

Low serum 25-hydroxyvitamin D [25(OH)D] concentrations during pregnancy have been associated with adverse pregnancy outcomes in a few studies but not in other studies. We assessed the serum 25(OH)D concentration at 10-14 wk of pregnancy and its association with adverse pregnancy outcomes and examined the predictive accuracy. In this nested case-control study, we measured serum 25(OH)D in 5109 women with singleton pregnancies who were attending first-trimester screening in New South Wales, Australia. Multivariate logistic regression was conducted to examine the association between low 25(OH)D concentrations and adverse pregnancy outcomes (small for gestational age, preterm birth, preeclampsia, gestational diabetes, miscarriage, and stillbirth). The predictive accuracy of models was assessed. The median (IQR) 25(OH)D concentration for the total population was 56.4 nmol/L (43.3-69.8 nmol/L). Serum 25(OH)D concentrations showed significant variation by parity, smoking, weight, season of sampling, country of birth, and socioeconomic status. After adjustment for maternal and clinical risk factors, low 25(OH)D concentrations were not associated with most adverse pregnancy outcomes. The area under the receiver operating characteristic curve (AUC) and likelihood ratio for a composite of severe adverse pregnancy outcomes of 25(OH)D concentrations <25 nmol/L were 0.51 and 1.44, respectively, and, for risk factors alone, were 0.64 and 2.87, respectively. The addition of 25(OH)D information to maternal and clinical risk factors did not improve the ability to predict severe adverse pregnancy outcomes (AUC: 0.64; likelihood ratio: 2.32; P = 0.39). Low 25(OH)D serum concentrations in the first trimester of pregnancy are not associated with adverse pregnancy outcomes and do not predict complications any better than routinely assessed clinical and maternal risk-factor information.

Cumulative early life adversity predicts longevity in wild baboons

PubMed Central

Tung, Jenny; Archie, Elizabeth A.; Altmann, Jeanne; Alberts, Susan C.

2016-01-01

In humans and other animals, harsh circumstances in early life predict morbidity and mortality in adulthood. Multiple adverse conditions are thought to be especially toxic, but this hypothesis has rarely been tested in a prospective, longitudinal framework, especially in long-lived mammals. Here we use prospective data on 196 wild female baboons to show that cumulative early adversity predicts natural adult lifespan. Females who experience ≥3 sources of early adversity die a median of 10 years earlier than females who experience ≤1 adverse circumstances (median lifespan is 18.5 years). Females who experience the most adversity are also socially isolated in adulthood, suggesting that social processes partially explain the link between early adversity and adult survival. Our results provide powerful evidence for the developmental origins of health and disease and indicate that close ties between early adversity and survival arise even in the absence of health habit and health care-related explanations. PMID:27091302

A systematic investigation of computation models for predicting Adverse Drug Reactions (ADRs).

PubMed

Kuang, Qifan; Wang, MinQi; Li, Rong; Dong, YongCheng; Li, Yizhou; Li, Menglong

2014-01-01

Early and accurate identification of adverse drug reactions (ADRs) is critically important for drug development and clinical safety. Computer-aided prediction of ADRs has attracted increasing attention in recent years, and many computational models have been proposed. However, because of the lack of systematic analysis and comparison of the different computational models, there remain limitations in designing more effective algorithms and selecting more useful features. There is therefore an urgent need to review and analyze previous computation models to obtain general conclusions that can provide useful guidance to construct more effective computational models to predict ADRs. In the current study, the main work is to compare and analyze the performance of existing computational methods to predict ADRs, by implementing and evaluating additional algorithms that have been earlier used for predicting drug targets. Our results indicated that topological and intrinsic features were complementary to an extent and the Jaccard coefficient had an important and general effect on the prediction of drug-ADR associations. By comparing the structure of each algorithm, final formulas of these algorithms were all converted to linear model in form, based on this finding we propose a new algorithm called the general weighted profile method and it yielded the best overall performance among the algorithms investigated in this paper. Several meaningful conclusions and useful findings regarding the prediction of ADRs are provided for selecting optimal features and algorithms.

Adverse life events, psychiatric history, and biological predictors of postpartum depression in an ethnically diverse sample of postpartum women.

PubMed

Guintivano, J; Sullivan, P F; Stuebe, A M; Penders, T; Thorp, J; Rubinow, D R; Meltzer-Brody, S

2018-05-01

Race, psychiatric history, and adverse life events have all been independently associated with postpartum depression (PPD). However, the role these play together in Black and Latina women remains inadequately studied. Therefore, we performed a case-control study of PPD, including comprehensive assessments of symptoms and biomarkers, while examining the effects of genetic ancestry. We recruited our sample (549 cases, 968 controls) at 6 weeks postpartum from obstetrical clinics in North Carolina. PPD status was determined using the MINI-plus. Psychiatric history was extracted from medical records. Participants were administered self-report instruments to assess depression (Edinburgh Postnatal Depression Scale) and adverse life events. Levels of estradiol, progesterone, brain-derived neurotrophic factor, oxytocin, and allopregnanalone were assayed. Principal components from genotype data were used to estimate genetic ancestry and logistic regression was used to identify predictors of PPD. This population was racially diverse (68% Black, 13% Latina, 18% European). Genetic ancestry was not a predictor of PPD. Case status was predicted by a history of major depression (p = 4.01E-14), lifetime anxiety disorder diagnosis (p = 1.25E-34), and adverse life events (p = 6.06E-06). There were no significant differences between groups in any hormones or neurosteroids. Psychiatric history and multiple exposures to adverse life events were significant predictors of PPD in a population of minority and low-income women. Genetic ancestry and hormone levels were not predictive of case status. Increased genetic vulnerability in conjunction with risk factors may predict the onset of PPD, whereas genetic ancestry does not appear predictive.

Screening for angiogenic inhibitors in zebrafish to evaluate a predictive model for developmental vascular toxicity

EPA Science Inventory

Chemically-induced vascular toxicity during embryonic development may cause a wide range of adverse effects. To identify putative vascular disrupting chemicals (pVDCs), a predictive signature was constructed from U.S. EPA ToxCast high-throughput screening (HTS) assays that map to...

Pharmacogenetics-based area-under-curve model can predict efficacy and adverse events from axitinib in individual patients with advanced renal cell carcinoma.

PubMed

Yamamoto, Yoshiaki; Tsunedomi, Ryouichi; Fujita, Yusuke; Otori, Toru; Ohba, Mitsuyoshi; Kawai, Yoshihisa; Hirata, Hiroshi; Matsumoto, Hiroaki; Haginaka, Jun; Suzuki, Shigeo; Dahiya, Rajvir; Hamamoto, Yoshihiko; Matsuyama, Kenji; Hazama, Shoichi; Nagano, Hiroaki; Matsuyama, Hideyasu

2018-03-30

We investigated the relationship between axitinib pharmacogenetics and clinical efficacy/adverse events in advanced renal cell carcinoma (RCC) and established a model to predict clinical efficacy and adverse events using pharmacokinetic and gene polymorphisms related to drug metabolism and efflux in a phase II trial. We prospectively evaluated the area under the plasma concentration-time curve (AUC) of axitinib, objective response rate, and adverse events in 44 consecutive advanced RCC patients treated with axitinib. To establish a model for predicting clinical efficacy and adverse events, polymorphisms in genes including ABC transporters ( ABCB1 and ABCG2 ), UGT1A , and OR2B11 were analyzed by whole-exome sequencing, Sanger sequencing, and DNA microarray. To validate this prediction model, calculated AUC by 6 gene polymorphisms was compared with actual AUC in 16 additional consecutive patients prospectively. Actual AUC significantly correlated with the objective response rate ( P = 0.0002) and adverse events (hand-foot syndrome, P = 0.0055; and hypothyroidism, P = 0.0381). Calculated AUC significantly correlated with actual AUC ( P < 0.0001), and correctly predicted objective response rate ( P = 0.0044) as well as adverse events ( P = 0.0191 and 0.0082, respectively). In the validation study, calculated AUC prior to axitinib treatment precisely predicted actual AUC after axitinib treatment ( P = 0.0066). Our pharmacogenetics-based AUC prediction model may determine the optimal initial dose of axitinib, and thus facilitate better treatment of patients with advanced RCC.

Pharmacogenetics-based area-under-curve model can predict efficacy and adverse events from axitinib in individual patients with advanced renal cell carcinoma

PubMed Central

Yamamoto, Yoshiaki; Tsunedomi, Ryouichi; Fujita, Yusuke; Otori, Toru; Ohba, Mitsuyoshi; Kawai, Yoshihisa; Hirata, Hiroshi; Matsumoto, Hiroaki; Haginaka, Jun; Suzuki, Shigeo; Dahiya, Rajvir; Hamamoto, Yoshihiko; Matsuyama, Kenji; Hazama, Shoichi; Nagano, Hiroaki; Matsuyama, Hideyasu

2018-01-01

We investigated the relationship between axitinib pharmacogenetics and clinical efficacy/adverse events in advanced renal cell carcinoma (RCC) and established a model to predict clinical efficacy and adverse events using pharmacokinetic and gene polymorphisms related to drug metabolism and efflux in a phase II trial. We prospectively evaluated the area under the plasma concentration–time curve (AUC) of axitinib, objective response rate, and adverse events in 44 consecutive advanced RCC patients treated with axitinib. To establish a model for predicting clinical efficacy and adverse events, polymorphisms in genes including ABC transporters (ABCB1 and ABCG2), UGT1A, and OR2B11 were analyzed by whole-exome sequencing, Sanger sequencing, and DNA microarray. To validate this prediction model, calculated AUC by 6 gene polymorphisms was compared with actual AUC in 16 additional consecutive patients prospectively. Actual AUC significantly correlated with the objective response rate (P = 0.0002) and adverse events (hand-foot syndrome, P = 0.0055; and hypothyroidism, P = 0.0381). Calculated AUC significantly correlated with actual AUC (P < 0.0001), and correctly predicted objective response rate (P = 0.0044) as well as adverse events (P = 0.0191 and 0.0082, respectively). In the validation study, calculated AUC prior to axitinib treatment precisely predicted actual AUC after axitinib treatment (P = 0.0066). Our pharmacogenetics-based AUC prediction model may determine the optimal initial dose of axitinib, and thus facilitate better treatment of patients with advanced RCC. PMID:29682213

The HEART score for early rule out of acute coronary syndromes in the emergency department: a systematic review and meta-analysis.

PubMed

Van Den Berg, Patricia; Body, Richard

2018-03-01

The objective of this systematic review was to summarise the current evidence on the diagnostic accuracy of the HEART score for predicting major adverse cardiac events in patients presenting with undifferentiated chest pain to the emergency department. Two investigators independently searched Medline, Embase and Cochrane databases between 2008 and May 2016 identifying eligible studies providing diagnostic accuracy data on the HEART score for predicting major adverse cardiac events as the primary outcome. For the 12 studies meeting inclusion criteria, study characteristics and diagnostic accuracy measures were systematically extracted and study quality assessed using the QUADAS-2 tool. After quality assessment, nine studies including data from 11,217 patients were combined in the meta-analysis applying a generalised linear mixed model approach with random effects assumption (Stata 13.1). In total, 15.4% of patients (range 7.3-29.1%) developed major adverse cardiac events after a mean of 6 weeks' follow-up. Among patients categorised as 'low risk' and suitable for early discharge (HEART score 0-3), the pooled incidence of 'missed' major adverse cardiac events was 1.6%. The pooled sensitivity and specificity of the HEART score for predicting major adverse cardiac events were 96.7% (95% confidence interval (CI) 94.0-98.2%) and 47.0% (95% CI 41.0-53.5%), respectively. Patients with a HEART score of 0-3 are at low risk of incident major adverse cardiac events. As 3.3% of patients with major adverse cardiac events are 'missed' by the HEART score, clinicians must ask whether this risk is acceptably low for clinical implementation.

Detailed Assessments of Childhood AdversityEnhance Prediction of Central Obesity Independent of Gender, Race, Adult Psychosocial Risk and Health Behaviors

PubMed Central

Davis, Cynthia R.; Dearing, Eric; Usher, Nicole; Trifiletti, Sarah; Zaichenko, Lesya; Ollen, Elizabeth; Brinkoetter, Mary T.; Crowell-Doom, Cindy; Joung, Kyoung; Park, Kyung Hee; Mantzoros, Christos S.; Crowell, Judith A.

2017-01-01

Objective This study examined whether a novel indicator of overall childhood adversity, incorporating number of adversities, severity, and chronicity, predicted central obesity beyond contributions of “modifiable” risk factors including psychosocial characteristics and health behaviors in a diverse sample of midlife adults. The study also examined whether the overall adversity score (number of adversities X severity X chronicity) better predicted obesity compared to cumulative adversity (number of adversities), a more traditional assessment of childhood adversity. Materials/Methods 210 Black/African Americans and White/European Americans, mean age = 45.8; ±3.3 years, were studied cross-sectionally. Regression analysis examined overall childhood adversity as a direct, non-modifiable risk factor for central obesity (waist-hip ratio) and body mass index (BMI), with and without adjustment for established adult psychosocial risk factors (education, employment, social functioning) and heath behavior risk factors (smoking, drinking, diet, exercise). Results Overall childhood adversity was an independent significant predictor of central obesity, and the relations between psychosocial and health risk factors and central obesity were not significant when overall adversity was in the model. Overall adversity was not a statistically significant predictor of BMI. Conclusions Overall childhood adversity, incorporating severity and chronicity and cumulative scores, predicts central obesity beyond more contemporaneous risk factors often considered modifiable. This is consistent with early dysregulation of metabolic functioning. Findings can inform practitioners interested in the impact of childhood adversity and personalizing treatment approaches of obesity within high-risk populations. Prevention/intervention research is necessary to discover and address the underlying causes and impact of childhood adversity on metabolic functioning. PMID:24211017

A Pathway to Psychological Difficulty: Perceived Chronic Social Adversity and Its Symptomatic Reactions

PubMed Central

Ding, Cody; Zhang, Jingqiu; Yang, Dong

2018-01-01

In this paper, we attempt to predict and explain psychological maladjustment or difficulty. Specifically, we discuss the concept of perceived chronic social adversity, and we expect that such perceived chronic social adversity may potentially lead to chronic stress responses. Accordingly, we propose the symptomatic reactions of perceived chronic social adversity. We put forward a set of hypotheses regarding the relationships between perceived chronic social adversity and those chronic stress responses, and we further hypothesize a mediating role of individualized negative essentialism brought by perceived chronical social adversity. Resilience and individual differences in the ability to cope with perceived adversity are discussed. Future research and prevention need to pay more attention to effects of subjective personal experiences on psychological difficulty, focusing on the importance of exploring daily social experiences in improving cognitive construction processes and developing appropriate preventions. PMID:29755394

The Cumulative Effect of Health Adversities on Children's Later Academic Achievement.

PubMed

Quach, Jon; Nguyen, Cattram; O'Connor, Meredith; Wake, Melissa

We aimed to determine whether the accumulation of physical, psychosocial, and combined health adversities measured at age 8 to 9 years predicts worsening of academic scores cross-sectionally at 8 to 9 and longitudinally at 10 to 11 years. Design: Longitudinal data from Waves 3 and 4 in the Longitudinal Study of Australian Children (83% of 4983 retained). Exposures (8-9 years): Physical health adversities (yes/no; summed range, 0-5): overweight, special health care needs, chronic illness, PedsQL Physical, and global health. Psychosocial health adversities (yes/no; summed range, 0-4): parent- and teacher-reported behavior, PedsQL Psychosocial, sleep problems. Combined health adversities (range 0-9). Outcomes (8-9, and 10-11 years): National academic standardized test scores. Generalized estimating equations, accounting for multiple academic domains in each year and socioeconomic position and cognition. At 8 to 9 years, 23.9%, 9.9%, and 5.3% had 1, 2, or ≥3 physical health adversities, respectively, while 27.2%, 9.5%, and 4.9% had 1, 2, or ≥3 psychosocial health adversities. For each additional health adversity at 8 to 9 years, academic scores fell incrementally in year 3 and year 5 (both P < .001), with reductions of at least 0.4 SDs for ≥3 health adversities. Number was more important than type (physical, psychosocial) of adversity. The accumulation of health adversities predicts poorer academic achievement up to 2 years later. Interventions might need to address multiple domains to improve child academic outcomes and be delivered across the health-education interface. Copyright © 2017 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.

The evolution of predictive adaptive responses in human life history

PubMed Central

Nettle, Daniel; Frankenhuis, Willem E.; Rickard, Ian J.

2013-01-01

Many studies in humans have shown that adverse experience in early life is associated with accelerated reproductive timing, and there is comparative evidence for similar effects in other animals. There are two different classes of adaptive explanation for associations between early-life adversity and accelerated reproduction, both based on the idea of predictive adaptive responses (PARs). According to external PAR hypotheses, early-life adversity provides a ‘weather forecast’ of the environmental conditions into which the individual will mature, and it is adaptive for the individual to develop an appropriate phenotype for this anticipated environment. In internal PAR hypotheses, early-life adversity has a lasting negative impact on the individual's somatic state, such that her health is likely to fail more rapidly as she gets older, and there is an advantage to adjusting her reproductive schedule accordingly. We use a model of fluctuating environments to derive evolveability conditions for acceleration of reproductive timing in response to early-life adversity in a long-lived organism. For acceleration to evolve via the external PAR process, early-life cues must have a high degree of validity and the level of annual autocorrelation in the individual's environment must be almost perfect. For acceleration to evolve via the internal PAR process requires that early-life experience must determine a significant fraction of the variance in survival prospects in adulthood. The two processes are not mutually exclusive, and mechanisms for calibrating reproductive timing on the basis of early experience could evolve through a combination of the predictive value of early-life adversity for the later environment and its negative impact on somatic state. PMID:23843395

Adverse Reactions Associated With Cannabis Consumption as Evident From Search Engine Queries

PubMed Central

Lev-Ran, Shaul

2017-01-01

Background Cannabis is one of the most widely used psychoactive substances worldwide, but adverse drug reactions (ADRs) associated with its use are difficult to study because of its prohibited status in many countries. Objective Internet search engine queries have been used to investigate ADRs in pharmaceutical drugs. In this proof-of-concept study, we tested whether these queries can be used to detect the adverse reactions of cannabis use. Methods We analyzed anonymized queries from US-based users of Bing, a widely used search engine, made over a period of 6 months and compared the results with the prevalence of cannabis use as reported in the US National Survey on Drug Use in the Household (NSDUH) and with ADRs reported in the Food and Drug Administration’s Adverse Drug Reporting System. Predicted prevalence of cannabis use was estimated from the fraction of people making queries about cannabis, marijuana, and 121 additional synonyms. Predicted ADRs were estimated from queries containing layperson descriptions to 195 ICD-10 symptoms list. Results Our results indicated that the predicted prevalence of cannabis use at the US census regional level reaches an R2 of .71 NSDUH data. Queries for ADRs made by people who also searched for cannabis reveal many of the known adverse effects of cannabis (eg, cough and psychotic symptoms), as well as plausible unknown reactions (eg, pyrexia). Conclusions These results indicate that search engine queries can serve as an important tool for the study of adverse reactions of illicit drugs, which are difficult to study in other settings. PMID:29074469

Developing and applying the adverse outcome pathway concept for understanding and predicting neurotoxicity

PubMed Central

Bal-Price, Anna; Lein, Pamela J.; Keil, Kimberly P.; Sethi, Sunjay; Shafer, Timothy; Barenys, Marta; Fritsche, Ellen; Sachana, Magdalini; Meek, M.E. (Bette)

2016-01-01

The Adverse Outcome Pathway (AOP) concept has recently been proposed to support a paradigm shift in regulatory toxicology testing and risk assessment. This concept is similar to the Mode of Action (MOA), in that it describes a sequence of measurable key events triggered by a molecular initiating event in which a stressor interacts with a biological target. The resulting cascade of key events includes molecular, cellular, structural and functional changes in biological systems, resulting in a measurable adverse outcome. Thereby, an AOP ideally provides information relevant to chemical structure-activity relationships as a basis for predicting effects of structurally similar compounds. AOPs could potentially also form the basis for qualitative and quantitative predictive modeling of the human adverse outcome resulting from molecular initiating or other key events for which higher-throughput testing methods are available or can be developed. A variety of cellular and molecular processes are known to be critical for normal function of the central (CNS) and peripheral nervous systems (PNS). Because of the biological and functional complexity of the CNS and PNS, it has been challenging to establish causative links and quantitative relationships between key events that comprise the pathways leading from chemical exposure to an adverse outcome in the nervous system. Following introduction of the principles of MOA and AOPs, examples of potential or putative adverse outcome pathways specific for developmental or adult neurotoxicity are summarized and aspects of their assessment considered. Their possible application in developing mechanistically informed Integrated Approaches to Testing and Assessment (IATA) is also discussed. PMID:27212452

Specific expectancies are associated with symptomatic outcomes and side effect burden in a trial of chamomile extract for Generalized Anxiety Disorder

PubMed Central

Keefe, John R.; Amsterdam, Jay; Li, Qing S; Soeller, Irene; DeRubeis, Robert; Mao, Jun J

2017-01-01

Objective Patient expectancies are hypothesized to contribute to the efficacy and side effects of psychiatric treatments, but little research has investigated this hypothesis in the context of psychopharmacological therapies for anxiety. We prospectively investigated whether expectancies predicted efficacy and adverse events in oral therapy for Generalized Anxiety Disorder (GAD), controlling for confounding patient characteristics correlating with outcomes. Methods Expectancies regarding treatment efficacy and side effects were assessed at baseline of an eight week open-label phase of a trial of chamomile for Generalized Anxiety Disorder (GAD). The primary outcome was patient-reported GAD-7 scores, with clinical response and treatment-emergent side-effects as secondary outcomes. Expectancies were used to predict symptomatic and side-effect outcomes. Results Very few baseline patient characteristics predicted either type of expectancy. Controlling for a patient’s predicted recovery based on their baseline characteristics, higher efficacy expectancies at baseline predicted greater change on the GAD-7 (adjusted β = −0.19, p = 0.011). Efficacy expectancies also predicted a higher likelihood of attaining clinical response (adjusted odds ratio = 1.69, p = 0.002). Patients with higher side effect expectancies reported more side effects (adjusted log expected count = 0.26, p = 0.038). Efficacy expectancies were unrelated to side effect reports (log expected count = −0.05, p = 0.680), and side effect expectancies were unrelated to treatment efficacy (β = 0.08, p = 0.306). Conclusions Patients entering chamomile treatment for GAD with more favorable self-generated expectancies for the treatment experience greater improvement and fewer adverse events. Aligning patient expectancies with treatment selections may optimize outcomes. PMID:27716513

Developing and applying the adverse outcome pathway ...

EPA Pesticide Factsheets

To support a paradigm shift in regulatory toxicology testing and risk assessment, the Adverse Outcome Pathway (AOP) concept has recently been proposed. This concept is similar to that for Mode of Action (MOA), describing a sequence of measurable key events triggered by a molecular initiating event in which a stressor interacts with a biological target. The resulting cascade of key events includes molecular, cellular, structural and functional changes in biological systems, resulting in a measurable adverse outcome. Thereby, an AOP ideally provides information relevant to chemical structure-activity relationships as a basis to predict effects for structurally similar compounds. AOPs could potentially also form the basis for qualitative and quantitative predictive modeling of the human adverse outcome resulting from molecular initiating or other key events for which higher-throughput testing methods are available or can be developed.A variety of cellular and molecular processes are known to be critical to normal function of the central (CNS) and peripheral nervous systems (PNS). Because of the biological and functional complexity of the CNS and PNS, it has been challenging to establish causative links and quantitative relationships between key events that comprise the pathways leading from chemical exposure to an adverse outcome in the nervous system. Following introduction of principles of the description and assessment of MOA and AOPs, examples of adverse out

Positive childhood experiences predict less psychopathology and stress in pregnant women with childhood adversity: A pilot study of the benevolent childhood experiences (BCEs) scale.

PubMed

Narayan, Angela J; Rivera, Luisa M; Bernstein, Rosemary E; Harris, William W; Lieberman, Alicia F

2018-04-01

This pilot study examined the psychometric properties of the Benevolent Childhood Experiences (BCEs) scale, a new instrument designed to assess positive early life experiences in adults with histories of childhood maltreatment and other adversities. A counterpart to the Adverse Childhood Experiences (ACEs) questionnaire, the BCEs was developed to be multiculturally-sensitive and applicable regardless of socioeconomic position, urban-rural background, or immigration status. Higher levels of BCEs were hypothesized to predict lower levels of psychopathology and stress beyond the effects of ACES in a sample of ethnically diverse, low-income pregnant women. BCEs were also expected to show adequate internal validity across racial/ethnic groups and test-retest stability from the prenatal to the postnatal period. Participants were 101 pregnant women (M=29.10years, SD=6.56, range=18-44; 37% Latina, 22% African-American, 20% White, 21% biracial/multiracial/other; 37% foreign-born, 26% Spanish-speaking) who completed the BCEs and ACEs scales; assessments of prenatal depression and post-traumatic stress disorder (PTSD) symptoms, perceived stress, and exposure to stressful life events (SLEs) during pregnancy; and demographic information. Higher levels of BCEs predicted less PTSD symptoms and SLEs, above and beyond ACEs. The BCEs showed excellent test-retest reliability, and mean levels were comparable across racial/ethnic and Spanish-English groups of women. Person-oriented analyses also showed that higher levels of BCEs offset the effects of ACEs on prenatal stress and psychopathology. The BCEs scale indexes promising promotive factors associated with lower trauma-related symptomatology and stress exposure during pregnancy and illuminates how favorable childhood experiences may counteract long-term effects of childhood adversity. Copyright © 2017 Elsevier Ltd. All rights reserved.

Environmental adversity and children's early trajectories of problem behavior: The role of harsh parental discipline.

PubMed

Flouri, Eirini; Midouhas, Emily

2017-03-01

This study was performed to examine the role of harsh parental discipline in mediating and moderating the effects of environmental adversity (family socioeconomic disadvantage and adverse life events) on emotional and behavioral problems across early-to-middle childhood. The sample included 16,916 children (48% female; 24% non-White) from the U.K.'s Millennium Cohort Study. We analyzed trajectories of conduct, hyperactivity, and emotional problems, measured at ages 3, 5, and 7 years, using growth curve models. Harsh parental discipline was measured at these ages with parent-reported items on the frequency of using the physical and verbal discipline tactics of smacking, shouting at, and "telling off" the child. As expected, family socioeconomic disadvantage and adverse life events were significantly associated with emotional and behavioral problems. Harsh parental discipline was related to children's trajectories of problems, and it moderated, but did not explain, the effect of environmental risk on these trajectories. High-risk children experiencing harsh parental discipline had the highest levels of conduct problems and hyperactivity across the study period. In addition, harsh parental discipline predicted an increase in emotional symptoms over time in high-risk children, unseen in their counterparts experiencing low levels of harsh parental discipline. However, children in low-risk families were also negatively affected by harsh parental discipline concurrently and over time. In conclusion, harsh parental discipline predicted emotional and behavioral problems in high- and low-risk children and moderated the effects of family poverty and adversity on these problems. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Rhetorical features facilitate prosodic processing while handicapping ease of semantic comprehension.

PubMed

Menninghaus, Winfried; Bohrn, Isabel C; Knoop, Christine A; Kotz, Sonja A; Schlotz, Wolff; Jacobs, Arthur M

2015-10-01

Studies on rhetorical features of language have reported both enhancing and adverse effects on ease of processing. We hypothesized that two explanations may account for these inconclusive findings. First, the respective gains and losses in ease of processing may apply to different dimensions of language processing (specifically, prosodic and semantic processing) and different types of fluency (perceptual vs. conceptual) and may well allow for an integration into a more comprehensive framework. Second, the effects of rhetorical features may be sensitive to interactions with other rhetorical features; employing a feature separately or in combination with others may then predict starkly different effects. We designed a series of experiments in which we expected the same rhetorical features of the very same sentences to exert adverse effects on semantic (conceptual) fluency and enhancing effects on prosodic (perceptual) fluency. We focused on proverbs that each employ three rhetorical features: rhyme, meter, and brevitas (i.e., artful shortness). The presence of these target features decreased ease of conceptual fluency (semantic comprehension) while enhancing perceptual fluency as reflected in beauty and succinctness ratings that were mainly driven by prosodic features. The rhetorical features also predicted choices for persuasive purposes, yet only for the sentence versions featuring all three rhetorical features; the presence of only one or two rhetorical features had an adverse effect on the choices made. We suggest that the facilitating effects of a combination of rhyme, meter, and rhetorical brevitas on perceptual (prosodic) fluency overcompensated for their adverse effects on conceptual (semantic) fluency, thus resulting in a total net gain both in processing ease and in choices for persuasive purposes. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

[Changes of menstruation patterns and adverse effects during the treatment of LNG-IUS for symptomatic adenomyosis].

PubMed

Li, L; Leng, J H; Zhang, J J; Jia, S Z; Li, X Y; Shi, J H; Dai, Y; Zhang, J R; Li, T; Xu, X X; Liu, Z Z; You, S S; Chang, X Y; Lang, J H

2016-09-25

Objective: To investigate the changes of mestruation patterns and adverse effects during the treatment of levonorgestrel-releasing intrauterine system(LNG-IUS)for symptomatic adenomyosis in a prospective cohort study. Methods: From December, 2006 to December, 2014, patients of symptomatic adenomyosis diagnosed by transvaginal ultrasound in Peking Union Medical College Hospital were given LNG-IUS. Before and after placement of IUS, all patients' parameters were recorded, including carrying status of IUS, symptoms and scores of dysmenorrhea, menstruation scores, biochemical indicators, physical parameters, menstruation patterns and adverse effects. Risk factors for changes of menstruation patterns and adverse effects, and their impact on treatment effects were analyzed. Results: Totally 1 100 cases met inclusion criteria, with median age 36 years(range 20-44 years), median follow-up 35 months(range 1 -108 months). During follow-up changes of menstruation patterns increased significantly with amenorrhea and shortened-menstruation being the most common manifestations. On 3, 6, 12, 24, 36, 48 and 60 months after the placement of LNG-IUS, 0, 5.8%(43/744), 6.9%(47/682), 10.1%(60/595), 17.3%(87/502), 27.2%(104/383)and 29.6%(82/277)patients achieved amenorrhea respectively( P <0.01). Total and subclassification of adverse effects decreased significantly( P <0.01). Within 12 months and >12 months after placement, abdominal pain and body weight increasing ≥5 kg/year were the most common adverse effects. Changes of menstruation patterns, total and subclassifications of adverse effects were neither dependent on patient parameters, treatment modes and treatment effects, nor could predict future LNG-IUS carrying status(all P > 0.05). After taking out of LNG-IUS, most changes of menstruation and adverse effects disappeared. Conclusions: During the treatment of LNG-IUS for symptomatic adenomyosis, changes of menstruation patterns increase gradually with amenorrhea and shortened-menstruation being the most common manifestations, while adverse effects decrease significantly. Changes of menstruation patterns or adverse effects neither have any risk factor nor have impact on treatment effects.

Discriminative ability of commonly used indices to predict adverse outcomes after poster lumbar fusion: a comparison of demographics, ASA, the modified Charlson Comorbidity Index, and the modified Frailty Index.

PubMed

Ondeck, Nathaniel T; Bohl, Daniel D; Bovonratwet, Patawut; McLynn, Ryan P; Cui, Jonathan J; Shultz, Blake N; Lukasiewicz, Adam M; Grauer, Jonathan N

2018-01-01

As research tools, the American Society of Anesthesiologists (ASA) physical status classification system, the modified Charlson Comorbidity Index (mCCI), and the modified Frailty Index (mFI) have been associated with complications following spine procedures. However, with respect to clinical use for various adverse outcomes, no known study has compared the predictive performance of these indices specifically following posterior lumbar fusion (PLF). This study aimed to compare the discriminative ability of ASA, mCCI, and mFI, as well as demographic factors including age, body mass index, and gender for perioperative adverse outcomes following PLF. A retrospective review of prospectively collected data was performed. Patients undergoing elective PLF with or without interbody fusion were extracted from the 2011-2014 American College of Surgeons National Surgical Quality Improvement Program (NSQIP). Perioperative adverse outcome variables assessed included the occurrence of minor adverse events, severe adverse events, infectious adverse events, any adverse event, extended length of hospital stay, and discharge to higher-level care. Patient comorbidity indices and characteristics were delineated and assessed for discriminative ability in predicting perioperative adverse outcomes using an area under the curve analysis from the receiver operating characteristics curves. In total, 16,495 patients were identified who met the inclusion criteria. The most predictive comorbidity index was ASA and demographic factor was age. Of these two factors, age had the larger discriminative ability for three out of the six adverse outcomes and ASA was the most predictive for one out of six adverse outcomes. A combination of the most predictive demographic factor and comorbidity index resulted in improvements in discriminative ability over the individual components for five of the six outcome variables. For PLF, easily obtained patient ASA and age have overall similar or better discriminative abilities for perioperative adverse outcomes than numerically tabulated indices that have multiple inputs and are harder to implement in clinical practice. Copyright © 2017 Elsevier Inc. All rights reserved.

INTEGRATION OF ANIMAL AND HUMAN GENE EXPRESSION DATA TO IMPROVE THE PREDICTIVE VALUE OF EXPOUSRE, EFFECTS AND SUSCEPTIBILITY BIOMARKERS IN ASTHMATIC CHILDREN

EPA Science Inventory

Advances in biomarker development have improved our ability to detect early changes at the molecular, cellular and pre-clinical level that are often predictive of adverse health outcomes. Integration of human and animal studies addresses key concerns about animal-human extrapolat...

External-environmental and internal-health early life predictors of adolescent development.

PubMed

Hartman, Sarah; Li, Zhi; Nettle, Daniel; Belsky, Jay

2017-12-01

A wealth of evidence documents associations between various aspects of the rearing environment and later development. Two evolutionary-inspired models advance explanations for why and how such early experiences shape later functioning: (a) the external-prediction model, which highlights the role of the early environment (e.g., parenting) in regulating children's development, and (b) the internal-prediction model, which emphasizes internal state (i.e., health) as the critical regulator. Thus, by using data from the NICHD Study of Early Child Care and Youth Development, the current project draws from both models by investigating whether the effect of the early environment on later adolescent functioning is subject to an indirect effect by internal-health variables. Results showed a significant indirect effect of internal health on the relation between the early environment and adolescent behavior. Specifically, early environmental adversity during the first 5 years of life predicted lower quality health during childhood, which then led to problematic adolescent functioning and earlier age of menarche for girls. In addition, for girls, early adversity predicted lower quality health that forecasted earlier age of menarche leading to increased adolescent risk taking. The discussion highlights the importance of integrating both internal and external models to further understand the developmental processes that effect adolescent behavior.

Psychopathology, adversity, and creativity: diversifying experiences in the development of eminent African Americans.

PubMed

Damian, Rodica Ioana; Simonton, Dean Keith

2015-04-01

Symptoms associated with mental illness have been hypothesized to relate to creative achievement because they act as diversifying experiences. However, this theory has only been tested on predominantly majority-culture samples. Do tendencies toward mental illness still predict eminent creativity when they coexist with other diversifying experiences, such as early parental death, minority-status, or poverty? These alternative diversifying experiences can be collectively referred to as examples of developmental adversity. This conjecture was tested on a significant sample of 291 eminent African Americans who, by the nature of their status as long-term minorities, would experience more developmental adversity. Replicating majority-culture patterns, African American artists showed higher mental illness rates than African American scientists. Yet the absolute percentages were significantly lower for the African Americans, regardless of profession. Furthermore, mental illness predicted higher eminence levels only for the African American artists, an effect that diminished when controlling for developmental adversity. Because the latter predicted eminence for both artists and scientists, the "madness-to-genius" link probably represents just 1 of several routes by which diversifying experiences can influence eminence. The same developmental ends can be attained by different means. This inference warrants further research using other eminent creators emerging from minority culture populations. (c) 2015 APA, all rights reserved).

Childhood adversities and socioeconomic position as predictors of leisure-time physical inactivity in early adulthood.

PubMed

Kestilä, Laura; Mäki-Opas, Tomi; Kunst, Anton E; Borodulin, Katja; Rahkonen, Ossi; Prättälä, Ritva

2015-02-01

Limited knowledge exists on how childhood social, health-related and economic circumstances predict adult physical inactivity. Our aim was a) to examine how various childhood adversities and living conditions predict leisure-time physical inactivity in early adulthood and b) to find out whether these associations are mediated through the respondent's own education. Young adults aged 18-29 were used from the Health 2000 Study of the Finnish. The cross-sectional data were based on interviews and questionnaires including retrospective information on childhood circumstances. The analyses were carried out on 68% of the original sample (N = 1894). The outcome measure was leisure-time physical inactivity. Only a few of the 11 childhood adversities were related with physical activity in early adulthood. Having been bullied at school was associated with physical inactivity independently of the other childhood circumstances and the respondent's own education. Low parental education predicted leisure-time physical inactivity in men and the association was mediated by the respondent's own education. Respondents with only primary or vocational education were more likely to be physically inactive during leisure-time compared with those with secondary or higher education. There is some evidence that few specific childhood adversities, especially bullying at school, have long-lasting effects on physical activity levels.

Prediction of the cause, effects, and prevention of drug-nutrient interactions using attributes and attribute values.

PubMed

Roe, D A

1985-01-01

Drug-nutrient interactions and their adverse outcomes have previously been identified by observation, investigation, and literature reports. Knowing the attributes of the drugs, availability of knowledge base management systems for microcomputer use can facilitate prediction of the mechanism and the effects of drug-nutrient interactions. Examples used to illustrate this approach are prediction of lactose intolerance in drug-induced malabsorption, and prediction of the mechanism responsible for drug-induced flush reactions. In the future we see that there may be many opportunities to use this system further in the investigation of complex drug-nutrient interactions.

Chemical Risk Assessment: Traditional vs Public Health ...

EPA Pesticide Factsheets

Preventing adverse health impacts from exposures to environmental chemicals is fundamental to protecting individual and public health. When done efficiently and properly, chemical risk assessment enables risk management actions that minimize the incidence and impacts of environmentally-induced diseases related to chemical exposure. However, traditional chemical risk assessment is faced with multiple challenges with respect to predicting and preventing disease in human populations, and epidemiological studies increasingly report observations of adverse health effects at exposure levels predicted from animal studies to be safe for humans. This discordance reinforces concerns about the adequacy of contemporary risk assessment practices (Birnbaum, Burke, & Jones, 2016) for protecting public health. It is becoming clear that to protect public health more effectively, future risk assessments will need to use the full range of available data, draw on innovative methods to integrate diverse data streams, and consider health endpoints that also reflect the range of subtle effects and morbidities observed in human populations. Given these factors, there is a need to reframe chemical risk assessment to be more clearly aligned with the public health goal of minimizing environmental exposures associated with disease. Preventing adverse health impacts from exposures to environmental chemicals is fundamental to protecting individual and public health. Chemical risk assessments

By-product mutualism with evolving common enemies.

PubMed

De Jaegher, Kris

2017-05-07

The common-enemy hypothesis of by-product mutualism states that organisms cooperate when it is in their individual interests to do so, with benefits for other organisms arising as a by-product; in particular, such cooperation is hypothesized to arise when organisms face the common enemy of a sufficiently adverse environment. In an evolutionary game where two defenders can cooperate to defend a common resource, this paper analyzes the common-enemy hypothesis when adversity is endogenous, in that an attacker sets the number of attacks. As a benchmark, we first consider exogenous adversity, where adversity is not subject to evolution. In this case, the common-enemy hypothesis is predicted when the degree of complementarity between defenders' defensive efforts is sufficiently low. When the degree of complementarity is high, the hypothesis is predicted only when cooperation costs are high; when cooperation costs are instead low, a competing hypothesis is predicted, where adversity discourages cooperation. Second, we consider the case of endogenous adversity. In this case, we continue to predict the competing hypothesis for a high degree of complementarity and low cooperation costs. The common-enemy hypothesis, however, only continues to be predicted for the lowest degrees of complementarity. Copyright © 2017 Elsevier Ltd. All rights reserved.

The effect of childhood adversity on 4-year outcome in individuals at ultra high risk for psychosis in the Dutch Early Detection Intervention Evaluation (EDIE-NL) Trial.

PubMed

Kraan, Tamar C; Ising, Helga K; Fokkema, Marjolein; Velthorst, Eva; van den Berg, David P G; Kerkhoven, Margot; Veling, Wim; Smit, Filip; Linszen, Don H; Nieman, Dorien H; Wunderink, Lex; Boonstra, Nynke; Klaassen, Rianne M C; Dragt, Sara; Rietdijk, Judith; de Haan, Lieuwe; van der Gaag, Mark

2017-01-01

Childhood adversity is associated with a range of mental disorders, functional impairment and higher health care costs in adulthood. In this study we evaluated if childhood adversity was predictive of adverse clinical and functional outcomes and health care costs in a sample of patients at ultra-high risk (UHR) for developing a psychosis. Structural Equation Modeling was used to examine the effect of childhood adversity on depression, anxiety, transition to psychosis and overall functioning at 4-year follow-up. In addition, we evaluated economic costs of childhood adversity in terms of health care use and productivity loss. Data pertain to 105 UHR participants of the Dutch Early Detection and Intervention Evaluation (EDIE-NL). Physical abuse was associated with higher depression rates (b=0.381, p=0.012) and lower social functional outcome (b=-0.219, p=0.017) at 4-year follow-up. In addition, emotional neglect was negatively associated with social functioning (b=-0.313, p=0.018). We did not find evidence that childhood adversity was associated with transition to psychosis, but the experience of childhood adversity was associated with excess health care costs at follow-up. The data indicate long-term negative effects of childhood adversity on depression, social functioning and health care costs at follow-up in a sample of UHR patients. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

A Systematic Investigation of Computation Models for Predicting Adverse Drug Reactions (ADRs)

PubMed Central

Kuang, Qifan; Wang, MinQi; Li, Rong; Dong, YongCheng; Li, Yizhou; Li, Menglong

2014-01-01

Background Early and accurate identification of adverse drug reactions (ADRs) is critically important for drug development and clinical safety. Computer-aided prediction of ADRs has attracted increasing attention in recent years, and many computational models have been proposed. However, because of the lack of systematic analysis and comparison of the different computational models, there remain limitations in designing more effective algorithms and selecting more useful features. There is therefore an urgent need to review and analyze previous computation models to obtain general conclusions that can provide useful guidance to construct more effective computational models to predict ADRs. Principal Findings In the current study, the main work is to compare and analyze the performance of existing computational methods to predict ADRs, by implementing and evaluating additional algorithms that have been earlier used for predicting drug targets. Our results indicated that topological and intrinsic features were complementary to an extent and the Jaccard coefficient had an important and general effect on the prediction of drug-ADR associations. By comparing the structure of each algorithm, final formulas of these algorithms were all converted to linear model in form, based on this finding we propose a new algorithm called the general weighted profile method and it yielded the best overall performance among the algorithms investigated in this paper. Conclusion Several meaningful conclusions and useful findings regarding the prediction of ADRs are provided for selecting optimal features and algorithms. PMID:25180585

Childhood bullying involvement predicts low-grade systemic inflammation into adulthood

PubMed Central

Copeland, William E.; Wolke, Dieter; Lereya, Suzet Tanya; Shanahan, Lilly; Worthman, Carol; Costello, E. Jane

2014-01-01

Bullying is a common childhood experience that involves repeated mistreatment to improve or maintain one’s status. Victims display long-term social, psychological, and health consequences, whereas bullies display minimal ill effects. The aim of this study is to test how this adverse social experience is biologically embedded to affect short- or long-term levels of C-reactive protein (CRP), a marker of low-grade systemic inflammation. The prospective population-based Great Smoky Mountains Study (n = 1,420), with up to nine waves of data per subject, was used, covering childhood/adolescence (ages 9–16) and young adulthood (ages 19 and 21). Structured interviews were used to assess bullying involvement and relevant covariates at all childhood/adolescent observations. Blood spots were collected at each observation and assayed for CRP levels. During childhood and adolescence, the number of waves at which the child was bullied predicted increasing levels of CRP. Although CRP levels rose for all participants from childhood into adulthood, being bullied predicted greater increases in CRP levels, whereas bullying others predicted lower increases in CRP compared with those uninvolved in bullying. This pattern was robust, controlling for body mass index, substance use, physical and mental health status, and exposures to other childhood psychosocial adversities. A child’s role in bullying may serve as either a risk or a protective factor for adult low-grade inflammation, independent of other factors. Inflammation is a physiological response that mediates the effects of both social adversity and dominance on decreases in health. PMID:24821813

Childhood bullying involvement predicts low-grade systemic inflammation into adulthood.

PubMed

Copeland, William E; Wolke, Dieter; Lereya, Suzet Tanya; Shanahan, Lilly; Worthman, Carol; Costello, E Jane

2014-05-27

Bullying is a common childhood experience that involves repeated mistreatment to improve or maintain one's status. Victims display long-term social, psychological, and health consequences, whereas bullies display minimal ill effects. The aim of this study is to test how this adverse social experience is biologically embedded to affect short- or long-term levels of C-reactive protein (CRP), a marker of low-grade systemic inflammation. The prospective population-based Great Smoky Mountains Study (n = 1,420), with up to nine waves of data per subject, was used, covering childhood/adolescence (ages 9-16) and young adulthood (ages 19 and 21). Structured interviews were used to assess bullying involvement and relevant covariates at all childhood/adolescent observations. Blood spots were collected at each observation and assayed for CRP levels. During childhood and adolescence, the number of waves at which the child was bullied predicted increasing levels of CRP. Although CRP levels rose for all participants from childhood into adulthood, being bullied predicted greater increases in CRP levels, whereas bullying others predicted lower increases in CRP compared with those uninvolved in bullying. This pattern was robust, controlling for body mass index, substance use, physical and mental health status, and exposures to other childhood psychosocial adversities. A child's role in bullying may serve as either a risk or a protective factor for adult low-grade inflammation, independent of other factors. Inflammation is a physiological response that mediates the effects of both social adversity and dominance on decreases in health.

Consequences of violence across the lifespan: Mental health and sleep quality in pregnant women.

PubMed

Miller-Graff, Laura E; Cheng, Philip

2017-09-01

Research has demonstrated that exposure to violence and adversity has negative effects on both mental health and biobehavioral outcomes, such as sleep health. Research examining the relationship between past and recent violence exposure and mental health suggests that the effects of childhood adversity are especially pernicious, but to date, no studies have attempted to disentangle the direct, indirect and relative effects of past year versus childhood exposure to violence and adversity on sleep. The objective of the current study was to examine the direct effects of adverse childhood experiences (ACEs) and past year intimate partner violence (IPV) on different aspects of sleep health in pregnant women. A sample of high-risk pregnant women (n = 101) were interviewed. Mediation analysis with bias-corrected, bootstrapped confidence intervals was used to evaluate direct and indirect effects. Findings indicated that while ACEs had significant direct effects on mental health, past year IPV had stronger effects on sleep quality, latency, and efficiency. ACEs did, however, indirectly affect subjective sleep quality via past year psychological IPV. These findings suggest that sleep disturbance may be a regulatory stress response that is most clearly linked to past year violence and trauma. That is, though long-term sleep disturbance may be evident following childhood adversity, it is likely that this relationship is better explained by the role of childhood adversity in predicting adulthood revictimization or due to long-term mental health difficulties associated with early trauma. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Partial and no recovery from delirium after hospital discharge predict increased adverse events.

PubMed

Cole, Martin G; McCusker, Jane; Bailey, Robert; Bonnycastle, Michael; Fung, Shek; Ciampi, Antonio; Belzile, Eric

2017-01-08

The implications of partial and no recovery from delirium after hospital discharge are not clear. We sought to explore whether partial and no recovery from delirium among recently discharged patients predicted increased adverse events (emergency room visits, hospitalisations, death) during the subsequent 3 months. Prospective study of recovery from delirium in older hospital inpatients. The Confusion Assessment Method was used to diagnose delirium in hospital and determine recovery status after discharge (T0). Adverse events were determined during the 3 months T0. Survival analysis to the first adverse event and counting process modelling for one or more adverse events were used to examine associations between recovery status (ordinal variable, 0, 1 or 2 for full, partial or no recovery, respectively) and adverse events. Of 278 hospital inpatients with delirium, 172 were discharged before the assessment of recovery status (T0). Delirium recovery status at T0 was determined for 152: 25 had full recovery, 32 had partial recovery and 95 had no recovery. Forty-four patients had at least one adverse event during the subsequent 3 months. In multivariable analysis of one or more adverse events, poorer recovery status predicted increased adverse events; the hazard ratio (HR) (95% confidence interval, CI) was 1.72 (1.09, 2.71). The association of recovery status with adverse events was stronger among patients without dementia. Partial and no recovery from delirium after hospital discharge appear to predict increased adverse events during the subsequent 3 months These findings have potentially important implications for in-hospital and post-discharge management and policy.

Evolution of a Planar Wake in Adverse Pressure Gradient

NASA Technical Reports Server (NTRS)

Driver, David M.; Mateer, George G.

2016-01-01

In the interest of improving the predictability of high-lift systems at maximum lift conditions, a series of fundamental experiments were conducted to study the effects of adverse pressure gradient on a wake flow. Mean and fluctuating velocities were measured with a two-component laser-Doppler velocimeter. Data were obtained for several cases of adverse pressure gradient, producing flows ranging from no reversed flow to massively reversed flow. While the turbulent Reynolds stresses increase with increasing size of the reversed flow region, the gradient of Reynolds stress does not. Computations using various turbulence models were unable to reproduce the reversed flow.

Testing and testing positive: childhood adversities and later life HIV status among Kenyan women and their partners.

PubMed

Goodman, Michael L; Raimer-Goodman, Lauren; Chen, Catherine X; Grouls, Astrid; Gitari, Stanley; Keiser, Philip H

2017-12-01

Adverse childhood experiences are a critical feature of lifelong health. No research assesses whether childhood adversities predict HIV-testing behaviors, and little research analyzes childhood adversities and later life HIV status in sub-Saharan Africa. We use regression models with cross-sectional data from a representative sample (n = 1974) to analyze whether adverse childhood experiences, separately or as cumulative exposures, predict reports of later life HIV testing and testing HIV+ among semi-rural Kenyan women and their partners. No significant correlation was observed between thirteen cumulative childhood adversities and reporting prior HIV testing for respondent or partner. Separately, childhood sexual abuse and emotional neglect predicted lower odds of reporting having previously been tested for HIV. Witnessing household violence during one's childhood predicted significantly higher odds of reporting HIV+. Sexual abuse predicted higher odds of reporting a partner tested HIV+. Preventing sexual abuse and household violence may improve HIV testing and test outcomes among Kenyan women. More research is required to understand pathways between adverse childhood experiences and partner selection within Kenya and sub-Saharan Africa, and data presented here suggest understanding pathways may help improve HIV outcomes. © The Author 2016. Published by Oxford University Press on behalf of Faculty of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Computationally predicted Adverse Outcome Pathway networks for liver-related diseases using publicly available data sources: Case studies and lessons learned

EPA Science Inventory

The Adverse Outcome Pathway (AOP) framework summarizes key information about mechanistic events leading to an adverse health or ecological outcome. In recent years computationally predicted AOPs (cpAOP) making use of publicly available data have been proposed as a means of accele...

The use of adverse outcome pathway-based toxicity predictions: A case study evaluating the effects of imazalil on fathead minnow reproduction

EPA Science Inventory

Product Description: As a means to increase the efficiency of chemical safety assessment, there is an interest in using data from molecular and cellular bioassays, conducted in a highly automated fashion using modern robotics, to predict toxicity in humans and wildlife. The prese...

Maternal employment and the health of low-income young children.

PubMed

Gennetian, Lisa A; Hill, Heather D; London, Andrew S; Lopoo, Leonard M

2010-05-01

This study examines whether maternal employment affects the health status of low-income, elementary-school-aged children using instrumental variables estimation and experimental data from a welfare-to-work program implemented in the early 1990s. Maternal report of child health status is predicted as a function of exogenous variation in maternal employment associated with random assignment to the experimental group. IV estimates show a modest adverse effect of maternal employment on children's health. Making use of data from another welfare-to-work program we propose that any adverse effect on child health may be tempered by increased family income and access to public health insurance coverage, findings with direct relevance to a number of current policy discussions. In a secondary analysis using fixed effects techniques on longitudinal survey data collected in 1998 and 2001, we find a comparable adverse effect of maternal employment on child health that supports the external validity of our primary result.

Adverse Reactions Associated With Cannabis Consumption as Evident From Search Engine Queries.

PubMed

Yom-Tov, Elad; Lev-Ran, Shaul

2017-10-26

Cannabis is one of the most widely used psychoactive substances worldwide, but adverse drug reactions (ADRs) associated with its use are difficult to study because of its prohibited status in many countries. Internet search engine queries have been used to investigate ADRs in pharmaceutical drugs. In this proof-of-concept study, we tested whether these queries can be used to detect the adverse reactions of cannabis use. We analyzed anonymized queries from US-based users of Bing, a widely used search engine, made over a period of 6 months and compared the results with the prevalence of cannabis use as reported in the US National Survey on Drug Use in the Household (NSDUH) and with ADRs reported in the Food and Drug Administration's Adverse Drug Reporting System. Predicted prevalence of cannabis use was estimated from the fraction of people making queries about cannabis, marijuana, and 121 additional synonyms. Predicted ADRs were estimated from queries containing layperson descriptions to 195 ICD-10 symptoms list. Our results indicated that the predicted prevalence of cannabis use at the US census regional level reaches an R 2 of .71 NSDUH data. Queries for ADRs made by people who also searched for cannabis reveal many of the known adverse effects of cannabis (eg, cough and psychotic symptoms), as well as plausible unknown reactions (eg, pyrexia). These results indicate that search engine queries can serve as an important tool for the study of adverse reactions of illicit drugs, which are difficult to study in other settings. ©Elad Yom-Tov, Shaul Lev-Ran. Originally published in JMIR Public Health and Surveillance (http://publichealth.jmir.org), 26.10.2017.

Prognostic accuracy of cerebroplacental ratio and middle cerebral artery Doppler for adverse perinatal outcome: systematic review and meta‐analysis

PubMed Central

De Boer, M. A.; Heymans, M. W.; Schoonmade, L. J.; Bossuyt, P. M. M.; Mol, B. W. J.; De Groot, C. J. M.; Bax, C. J.

2018-01-01

ABSTRACT Objective Doppler ultrasonographic assessment of the cerebroplacental ratio (CPR) and middle cerebral artery (MCA) is widely used as an adjunct to umbilical artery (UA) Doppler to identify fetuses at risk of adverse perinatal outcome. However, reported estimates of its accuracy vary considerably. The aim of this study was to review systematically the prognostic accuracies of CPR and MCA Doppler in predicting adverse perinatal outcome, and to compare these with UA Doppler, in order to identify whether CPR and MCA Doppler evaluation are of added value to UA Doppler. Methods PubMed, EMBASE, the Cochrane Library and ClinicalTrials.gov were searched, from inception to June 2016, for studies on the prognostic accuracy of UA Doppler compared with CPR and/or MCA Doppler in the prediction of adverse perinatal outcome in women with a singleton pregnancy of any risk profile. Risk of bias and concerns about applicability were assessed using the QUADAS‐2 (Quality Assessment of Diagnostic Accuracy Studies‐2) tool. Meta‐analysis was performed for multiple adverse perinatal outcomes. Using hierarchal summary receiver–operating characteristics meta‐regression models, the prognostic accuracy of CPR vs MCA Doppler was compared indirectly, and CPR and MCA Doppler vs UA Doppler compared directly. Results The search identified 4693 articles, of which 128 studies (involving 47 748 women) were included. Risk of bias or suboptimal reporting was detected in 120/128 studies (94%) and substantial heterogeneity was found, which limited subgroup analyses for fetal growth and gestational age. A large variation was observed in reported sensitivities and specificities, and in thresholds used. CPR outperformed UA Doppler in the prediction of composite adverse outcome (as defined in the included studies) (P < 0.001) and emergency delivery for fetal distress (P = 0.003), but was comparable to UA Doppler for the other outcomes. MCA Doppler performed significantly worse than did UA Doppler in the prediction of low Apgar score (P = 0.017) and emergency delivery for fetal distress (P = 0.034). CPR outperformed MCA Doppler in the prediction of composite adverse outcome (P < 0.001) and emergency delivery for fetal distress (P = 0.013). Conclusion Calculating the CPR with MCA Doppler can add value to UA Doppler assessment in the prediction of adverse perinatal outcome in women with a singleton pregnancy. However, it is unclear to which subgroup of pregnant women this applies. The effectiveness of the CPR in guiding clinical management needs to be evaluated in clinical trials. © 2017 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology. PMID:28708272

ENHANCED AIR POLLUTION EPIDEMIOLOGY USING A SOURCE-ORIENTED CHEMICAL TRANSPORT MODEL

EPA Science Inventory

Air quality model predictions describing source-oriented PM component concentrations in multiple size cuts will provide new inputs to examine the effects of acute and chronic PM exposure on mortality and morbidity. Associations between adverse health effects and PM sources/com...

Differences by Veteran/civilian status and gender in associations between childhood adversity and alcohol and drug use disorders.

PubMed

Evans, Elizabeth A; Upchurch, Dawn M; Simpson, Tracy; Hamilton, Alison B; Hoggatt, Katherine J

2018-04-01

To examine differences by US military Veteran status and gender in associations between childhood adversity and DSM-5 lifetime alcohol and drug use disorders (AUD/DUD). We analyzed nationally representative data from 3119 Veterans (n = 379 women; n = 2740 men) and 33,182 civilians (n = 20,066 women; n = 13,116 men) as provided by the 2012-2013 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC-III). We used weighted multinomial logistic regression, tested interaction terms, and calculated predicted probabilities by Veteran status and gender, controlling for covariates. To test which specific moderation contrasts were statistically significant, we conducted pairwise comparisons. Among civilians, women had lower AUD and DUD prevalence than men; however, with more childhood adversity, this gender gap narrowed for AUD and widened for DUD. Among Veterans, in contrast, similar proportions of women and men had AUD and DUD; with more childhood adversity, AUD-predicted probability among men surpassed that of women. Childhood adversity elevated AUD probability among civilian women to levels exhibited by Veteran women. Among men, Veterans with more childhood adversity were more likely than civilians to have AUD, and less likely to have DUD. Childhood adversity alters the gender gap in AUD and DUD risk, and in ways that are different for Veterans compared with civilians. Department of Defense, Veterans Affairs, and community health centers can prevent and ameliorate the harmful effects of childhood adversity by adapting existing behavioral health efforts to be trauma informed, Veteran sensitive, and gender tailored.

Adverse effect of outdoor air pollution on cardiorespiratory fitness in Chinese children

NASA Astrophysics Data System (ADS)

Gao, Yang; Chan, Emily Y. Y.; Zhu, Yingjia; Wong, Tze Wai

2013-01-01

Little is known about the health impact of air pollution on children's cardiovascular health. A cross-sectional study was conducted and data was analysed in 2048 Chinese schoolchildren (aged 8-10 years) in three districts of Hong Kong to examine the association between exposure to outdoor air pollution and cardiorespiratory fitness. Annual means of ambient PM10, SO2, NO2 and O3 from 1996 to 2003 were used to estimate individual exposure of the subjects. Cardiorespiratory fitness was measured for maximal oxygen uptake (VO2max), predicted by the multistage fitness test (MFT). Height and weight were measured and other potential confounders were collected with questionnaires. Analysis of covariance was performed to estimate the impact of air pollution on complete speed in the MFT and predicted VO2max. The results showed that children in high-pollution district had significantly lower complete speed and predicted VO2max compared to those in low- and moderate-pollution districts. Complete speed and predicted VO2max was estimated to reduce 0.327 km h-1 and 1.53 ml kg-1 min-1 per 10 μg m-3 increase in PM10 annual mean respectively, with those in girls being greater than in boys. Being physically active could not significantly result in improved cardiorespiratory fitness in polluted districts. The adverse effect seems to be independent of short-term exposure to air pollution. We concluded that long-term exposure to higher outdoor air pollution levels was negatively associated with cardiorespiratory fitness in Chinese schoolchildren, especially for girls. PM10 is the most relevant pollutant of the adverse effect. Elevated cardiorespiratory fitness observed in physically activate children could be negated by increased amount of inhaled pollutants during exercise.

The Drosophila foraging gene human orthologue PRKG1 predicts individual differences in the effects of early adversity on maternal sensitivity.

PubMed

Sokolowski, H Moriah; Vasquez, Oscar E; Unternaehrer, Eva; Sokolowski, Dustin J; Biergans, Stephanie D; Atkinson, Leslie; Gonzalez, Andrea; Silveira, Patricia P; Levitan, Robert; O'Donnell, Kieran J; Steiner, Meir; Kennedy, James; Meaney, Michael J; Fleming, Alison S; Sokolowski, Marla B

2017-04-01

There is variation in the extent to which childhood adverse experience affects adult individual differences in maternal behavior. Genetic variation in the animal foraging gene, which encodes a cGMP-dependent protein kinase, contributes to variation in the responses of adult fruit flies, Drosophila melanogaster , to early life adversity and is also known to play a role in maternal behavior in social insects. Here we investigate genetic variation in the human foraging gene ( PRKG1 ) as a predictor of individual differences in the effects of early adversity on maternal behavior in two cohorts. We show that the PRKG1 genetic polymorphism rs2043556 associates with maternal sensitivity towards their infants. We also show that rs2043556 moderates the association between self-reported childhood adversity of the mother and her later maternal sensitivity. Mothers with the TT allele of rs2043556 appeared buffered from the effects of early adversity, whereas mothers with the presence of a C allele were not. Our study used the Toronto Longitudinal Cohort (N=288 mother-16 month old infant pairs) and the Maternal Adversity and Vulnerability and Neurodevelopment Cohort (N=281 mother-18 month old infant pairs). Our findings expand the literature on the contributions of both genetics and gene-environment interactions to maternal sensitivity, a salient feature of the early environment relevant for child neurodevelopment.

Job Demands and Job Control as Predictors of Depressive Symptoms: Moderating Effects of Negative Childhood Socioemotional Experiences.

PubMed

Pulkki-Råback, Laura; Elovainio, Marko; Virtanen, Marianna; Kivimäki, Mika; Hintsanen, Mirka; Hintsa, Taina; Jokela, Markus; Puttonen, Sampsa; Joensuu, Matti; Lipsanen, Jari; Raitakari, Olli T; Keltikangas-Järvinen, Liisa

2016-10-01

There have been calls to know more about vulnerability factors that may predispose to adverse health outcomes at work. We examined if childhood adverse experiences would affect vulnerability to psychosocial stress factors at work. A nationally representative sample of 1546 Finnish men and women was followed up from childhood to adulthood. Childhood adverse experiences consisted of socioeconomic and emotional factors. Job demands and job control were measured 21 years later, and depressive symptoms were measured 21 and 27 years after the childhood measurements. Job demands predicted depressive symptoms over 6 years, and the association was modified by childhood emotional adversity. Participants with three or more emotional adversities in childhood had more depressive symptoms in response to high job demands compared with participants with zero or one emotional adversities in childhood (Betas = -1.40 and -2.01, ps < 0.05 and <0.01). No such moderating effect by childhood adverse experiences was found for the association between job control and depressive symptoms. Although modest in effect size, these findings provide a developmental viewpoint for understanding the role of childhood experiences in work-related stress factors. Such knowledge can enhance understanding of individual differences in vulnerability to the demands of working life. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

Childhood adversity, recent life stressors and suicidal behavior in Chinese college students.

PubMed

You, Zhiqi; Chen, Mingxi; Yang, Sen; Zhou, Zongkui; Qin, Ping

2014-01-01

Although the independent effects of childhood adversities and of recent negative events on suicidality have been well-documented, the combinative role of childhood and recent adversities on risk for suicidality is still underexplored, especially in the context of Chinese culture and in consideration of specific types of negative events. 5989 students, randomly sampled from six universities in central China, completed the online survey for this study. Suicidal behavior, life adversity during childhood and stressful events in recent school life were assessed with designed questionnaires. Students experiencing recent stressful life events more often reported an experience of life adversity during childhood. While recent stressful life events and childhood life adversity both were associated with an increased risk for suicidal behavior, the two exposures presented conjunctively and acted interactively to increase the risk. There was noticeable variation of effects associated with specific childhood life adversities, and sexual abuse, poor parental relationship, divorce of parents and loss of a parent were among the adversities associated with the highest increased risk. Recent conflicts with classmates, poor school performance and rupture of romantic relationships were the recent school life stressors associated with the highest increased risk. Childhood adversity and recent school life stressors had a combinative role in predicting suicidality of young people studying in Chinese colleges. Unhappy family life during childhood and recent interpersonal conflicts in school were the most important predictors of suicidality in this population.

Impact of Discordant Views in the Management of Descending Thoracic Aortic Aneurysm.

PubMed

Chiu, Peter; Sailer, Anna-Margaretha; Baiocchi, Michael; Goldstone, Andrew B; Schaffer, Justin M; Trojan, Jeff; Fleischmann, Dominik; Mitchell, R Scott; Miller, D Craig; Dake, Michael D; Woo, Y Joseph; Lee, Jason T; Fischbein, Michael P

2017-01-01

Thoracic endovascular aortic repair has a lower perceived risk than open surgical repair and has become an increasingly popular alternative. Whether general consensus exists regarding candidacy for either operation among open and endovascular specialists is unknown. A retrospective review of isolated descending thoracic aortic aneurysm at our institution between January 2005 and October 2015 was performed, excluding trauma and dissection. Two cardiac surgeons, 2 cardiovascular surgeons, 1 vascular surgeon, and 1 interventional radiologist gave their preference for open vs endovascular repair. Interobserver agreement was assessed with the kappa coefficient. k-means clustering agnostically grouped various patterns of agreement. The mean rating was predicted using least absolute shrinkage and selection operator regression. Negative binomial regression predicted the discrepancy between our panel of raters and the historical operation. Generalized estimating equation modeling was then used to evaluate the association between the extent of discrepancy and the adverse perioperative outcome. There were 77 patients with preoperative imaging studies. Pairwise interobserver agreement was only fair (median weighted kappa 0.270 [interquartile range 0.211-0.404]). Increasing age and proximal neck length predicted an increasing preference for thoracic endovascular aortic repair in our panel; larger proximal neck diameter predicted a general preference for open surgical repair. Increasing proximal neck diameter predicted a larger discrepancy between our panel and the historical operation. Greater discrepancy was associated with adverse outcome. Substantial disagreement existed among our panel, and an exploratory analysis of the effect of increasing discrepancy demonstrated an association with adverse perioperative outcome. An investigation of the effect of a thoracic aortic team with open and endovascular specialists is warranted. Copyright © 2017 Elsevier Inc. All rights reserved.

Dose and Effect Thresholds for Early Key Events in a Mode of PPARa-Mediated Action

EPA Science Inventory

ABSTRACT Strategies for predicting adverse health outcomes of environmental chemicals are centered on early key events in toxicity pathways. However, quantitative relationships between early molecular changes in a given pathway and later health effects are often poorly defined. T...

Measurement and prediction of post-fire erosion at the hillslope scale, Colorado Front Range

Treesearch

Juan de Dios Benavides-Solorio; Lee H. MacDonald

2005-01-01

Post-fire soil erosion is of considerable concern because of the potential decline in site productivity and adverse effects on downstream resources. For the Colorado Front Range there is a paucity of post-fire erosion data and a corresponding lack of predictive models. This study measured hillslope-scale sediment production rates and site characteristics for three wild...

Recent advances, and unresolved issues, in the application of computational modelling to the prediction of the biological effects of nanomaterials

DOE Office of Scientific and Technical Information (OSTI.GOV)

Winkler, David A., E-mail: dave.winkler@csiro.au

2016-05-15

Nanomaterials research is one of the fastest growing contemporary research areas. The unprecedented properties of these materials have meant that they are being incorporated into products very quickly. Regulatory agencies are concerned they cannot assess the potential hazards of these materials adequately, as data on the biological properties of nanomaterials are still relatively limited and expensive to acquire. Computational modelling methods have much to offer in helping understand the mechanisms by which toxicity may occur, and in predicting the likelihood of adverse biological impacts of materials not yet tested experimentally. This paper reviews the progress these methods, particularly those QSAR-based,more » have made in understanding and predicting potentially adverse biological effects of nanomaterials, and also the limitations and pitfalls of these methods. - Highlights: • Nanomaterials regulators need good information to make good decisions. • Nanomaterials and their interactions with biology are very complex. • Computational methods use existing data to predict properties of new nanomaterials. • Statistical, data driven modelling methods have been successfully applied to this task. • Much more must be learnt before robust toolkits will be widely usable by regulators.« less

Neighborhood cohesion and daily well-being: Results from a diary study

PubMed Central

Robinette, Jennifer W.; Charles, Susan T.; Mogle, Jacqueline A.; Almeida, David M.

2013-01-01

Neighborly cohesiveness has documented benefits for health. Furthermore, high perceived neighborhood cohesion offsets the adverse health effects of neighborhood socioeconomic adversity. One potential way neighborhood cohesion influences health is through daily stress processes. The current study uses participants (n = 2022, age 30–84 years) from The Midlife in the United States II and the National Study of Daily Experiences II, collected between 2004–2006, to examine this hypothesis using a within-person, daily diary design. We predicted that people who perceive high neighborhood cohesion are exposed to fewer daily stressors, such as interpersonal arguments, lower daily physical symptoms and negative affect, and higher daily positive affect. We also hypothesized that perceptions of neighborhood cohesion buffer declines in affective and physical well-being on days when daily stressors do occur. Results indicate that higher perceived neighborhood cohesion predicts fewer self-reported daily stressors, higher positive affect, lower negative affect, and fewer physical health symptoms. High perceived neighborhood cohesion also buffers the effects of daily stressors on negative affect, even after adjusting for other sources of social support. Results from the present study suggest interventions focusing on neighborhood cohesion may result in improved well-being and may minimize the adverse effect of daily stressors. PMID:24034965

Adverse Life Experience and Psychological Distress in Adolescence: Moderating and Mediating Effects of Emotion Regulation and Rumination.

PubMed

Boyes, Mark E; Hasking, Penelope A; Martin, Graham

2016-10-01

The current study tested whether emotion regulation and rumination moderated and/or mediated the relationship between accumulated adverse life experience and psychological distress in adolescence. In class, Australian high school students (n = 2637, 12-18 years, 68% female) from 41 schools completed well-validated measures of adverse life experience, emotion regulation, rumination and psychological distress, and were followed up 1 year later (n = 1973, 75% retention rate). Adjusting for age, gender and baseline psychological distress, adverse life experience predicted psychological distress 1 year later. Expressive suppression and rumination were positively associated with psychological distress. Cognitive reappraisal was negatively associated with psychological distress and moderated the relationship between adverse life experience and psychological distress. This relationship was also partially mediated by cognitive reappraisal, expressive suppression and rumination. Promoting cognitive reappraisal and minimizing expressive suppression and rumination may be useful strategies to improve mental health for adolescents who have experienced adverse life events. Future research should examine whether adolescents who have experienced adverse life events can be trained in effective emotion regulation strategies and whether this training can prevent development of psychological maladjustment. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

Childhood personality as a harbinger of competence and resilience in adulthood.

PubMed

Shiner, Rebecca L; Masten, Ann S

2012-05-01

This study examined the significance of childhood Big Five personality traits for competence and resilience in early adulthood. Resilience was defined in terms of adaptive success in age-salient developmental tasks despite significant adversity throughout childhood/adolescence. The Project Competence Longitudinal Study tracked 205 young people from childhood (around age 10) to emerging adulthood (EA, age 20) and young adulthood (YA, age 30; 90% retention). Multimethod composites were created for personality traits, adversity exposure, and adult outcomes of academic achievement, work, rule-abiding conduct, friendship, and romantic relationships. Regressions showed significant main effects of childhood personality predicting adult outcomes, controlling for adversity, with few interaction effects. In person-focused analyses, the resilient group in EA and YA (high competence, high adversity) showed higher childhood conscientiousness, agreeableness, and openness and lower neuroticism than the maladaptive group (low competence, high adversity). The competent (high competence, low adversity) and resilient groups showed similar childhood traits. Turnaround cases, who changed from the maladaptive group in EA to the resilient group in YA, exhibited higher childhood conscientiousness than persistently maladaptive peers. Findings suggest that children on pathways to success in adulthood, whether facing low or high adversity, have capacities for emotion regulation, empathy and connection, dedication to schoolwork, and mastery and exploration.

A summary of wind power prediction methods

NASA Astrophysics Data System (ADS)

Wang, Yuqi

2018-06-01

The deterministic prediction of wind power, the probability prediction and the prediction of wind power ramp events are introduced in this paper. Deterministic prediction includes the prediction of statistical learning based on histor ical data and the prediction of physical models based on NWP data. Due to the great impact of wind power ramp events on the power system, this paper also introduces the prediction of wind power ramp events. At last, the evaluation indicators of all kinds of prediction are given. The prediction of wind power can be a good solution to the adverse effects of wind power on the power system due to the abrupt, intermittent and undulation of wind power.

Infant Parasympathetic and Sympathetic Activity during Baseline, Stress and Recovery: Interactions with Prenatal Adversity Predict Physical Aggression in Toddlerhood.

PubMed

Suurland, J; van der Heijden, K B; Huijbregts, S C J; van Goozen, S H M; Swaab, H

2018-05-01

Exposure to prenatal adversity is associated with aggression later in life. Individual differences in autonomic nervous system (ANS) functioning, specifically nonreciprocal activation of the parasympathetic (PNS) and sympathetic (SNS) nervous systems, increase susceptibility to aggression, especially in the context of adversity. Previous work examining interactions between early adversity and ANS functioning in infancy is scarce and has not examined interaction between PNS and SNS. This study examined whether the PNS and SNS moderate the relation between cumulative prenatal risk and early physical aggression in 124 children (57% male). Cumulative risk (e.g., maternal psychiatric disorder, substance (ab)use, and social adversity) was assessed during pregnancy. Parasympathetic respiratory sinus arrhythmia (RSA) and sympathetic pre-ejection period (PEP) at baseline, in response to and during recovery from emotional challenge were measured at 6 months. Physical aggression and non-physical aggression/oppositional behavior were measured at 30 months. The results showed that cumulative prenatal risk predicted elevated physical aggression and non-physical aggression/oppositional behavior in toddlerhood; however, the effects on physical aggression were moderated by PNS and SNS functioning. Specifically, the effects of cumulative risk on physical aggression were particularly evident in children characterized by low baseline PNS activity and/or by nonreciprocal activity of the PNS and SNS, characterized by decreased activity (i.e., coinhibition) or increased activity (i.e., coactivation) of both systems at baseline and/or in response to emotional challenge. These findings extend our understanding of the interaction between perinatal risk and infant ANS functioning on developmental outcome.

Computational Approach using Mouse Embryonic Stem Cells to Define a Mechanistic Applicability Domain for Prenatal Developmental Toxicity

EPA Science Inventory

Identification of mechanisms responsible for adverse developmental effects is the first step in creating predictive toxicity models. Identification of putative mechanisms was performed by co-analyzing three datasets for the effects of ToxCast phase Ia and II chemicals: 1.In vitro...

22 CFR 217.42 - Admissions and recruitment.

Code of Federal Regulations, 2010 CFR

2010-04-01

... activity in question and (ii) alternate tests or criteria that have a less disproportionate, adverse effect... effects of past discrimination pursuant to § 217.6(a) or when a recipient is taking voluntary action to... base prediction equations on first year grades, but shall conduct periodic validity studies against the...

Climate Change Impacts on Harmful Algal Blooms in U.S. Freshwaters: A Screening-Level Assessment

EPA Science Inventory

Cyanobacterial harmful algal blooms have serious adverse effects on human and environmental health. Herein, we develop a modeling framework that predicts the effect of climate change on cyanobacteria concentrations in reservoirs in the contiguous U.S. The framework, which uses cl...

Specific expectancies are associated with symptomatic outcomes and side effect burden in a trial of chamomile extract for generalized anxiety disorder.

PubMed

Keefe, John R; Amsterdam, Jay; Li, Qing S; Soeller, Irene; DeRubeis, Robert; Mao, Jun J

2017-01-01

Patient expectancies are hypothesized to contribute to the efficacy and side effects of psychiatric treatments, but little research has investigated this hypothesis in the context of psychopharmacological therapies for anxiety. We prospectively investigated whether expectancies predicted efficacy and adverse events in oral therapy for Generalized Anxiety Disorder (GAD), controlling for confounding patient characteristics correlating with outcomes. Expectancies regarding treatment efficacy and side effects were assessed at baseline of an eight week open-label phase of a trial of chamomile for Generalized Anxiety Disorder (GAD). The primary outcome was patient-reported GAD-7 scores, with clinical response and treatment-emergent side-effects as secondary outcomes. Expectancies were used to predict symptomatic and side-effect outcomes. Very few baseline patient characteristics predicted either type of expectancy. Controlling for a patient's predicted recovery based on their baseline characteristics, higher efficacy expectancies at baseline predicted greater change on the GAD-7 (adjusted β = -0.19, p = 0.011). Efficacy expectancies also predicted a higher likelihood of attaining clinical response (adjusted odds ratio = 1.69, p = 0.002). Patients with higher side effect expectancies reported more side effects (adjusted log expected count = 0.26, p = 0.038). Efficacy expectancies were unrelated to side effect reports (log expected count = -0.05, p = 0.680), and side effect expectancies were unrelated to treatment efficacy (β = 0.08, p = 0.306). Patients entering chamomile treatment for GAD with more favorable self-generated expectancies for the treatment experience greater improvement and fewer adverse events. Aligning patient expectancies with treatment selections may optimize outcomes. Trial Number NCT01072344 at ClinicalTrials.gov. Copyright © 2016 Elsevier Ltd. All rights reserved.

Ultrasound predictors of neonatal outcome in intrauterine growth restriction.

PubMed

Craigo, S D; Beach, M L; Harvey-Wilkes, K B; D'Alton, M E

1996-11-01

Our purpose was to assess the value of commonly performed ultrasound parameters in predicting neonatal outcome of fetuses with intrauterine growth restriction (IUGR). One hundred twenty-seven patients were identified on ultrasound examination to have IUGR. Estimated weight percentile, amniotic fluid volume, umbilical artery Doppler velocimetry, and head circumference/abdominal circumference ratio were compared with neonatal outcome. Thirty infants had severely adverse courses. The degree of growth restriction was strongly associated with adverse outcome and neonatal death. Umbilical artery Doppler waveforms with absent or reverse end-diastolic flow were predicted of neonatal death, bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), and adverse outcome in general. Oligohydramnios was predictive of adverse outcome and neonatal death. Logistic regression also showed that absent or reverse end-diastolic flow and oligohydramnios were independent predictors of adverse outcome. Ultrasound findings of low estimated weight percentile, absent or reverse end-diastolic umbilical blood flow, and oligohydramnios are independent predictors of adverse neonatal outcome of growth restricted fetuses.

Elucidation of the molecular mechanisms underlying adverse reactions associated with a kinase inhibitor using systems toxicology

PubMed Central

Amemiya, Takahiro; Honma, Masashi; Kariya, Yoshiaki; Ghosh, Samik; Kitano, Hiroaki; Kurachi, Yoshihisa; Fujita, Ken-ichi; Sasaki, Yasutsuna; Homma, Yukio; Abernethy, Darrel R; Kume, Haruki; Suzuki, Hiroshi

2015-01-01

Background/Objectives: Targeted kinase inhibitors are an important class of agents in anticancer therapeutics, but their limited tolerability hampers their clinical performance. Identification of the molecular mechanisms underlying the development of adverse reactions will be helpful in establishing a rational method for the management of clinically adverse reactions. Here, we selected sunitinib as a model and demonstrated that the molecular mechanisms underlying the adverse reactions associated with kinase inhibitors can efficiently be identified using a systems toxicological approach. Methods: First, toxicological target candidates were short-listed by comparing the human kinase occupancy profiles of sunitinib and sorafenib, and the molecular mechanisms underlying adverse reactions were predicted by sequential simulations using publicly available mathematical models. Next, to evaluate the probability of these predictions, a clinical observation study was conducted in six patients treated with sunitinib. Finally, mouse experiments were performed for detailed confirmation of the hypothesized molecular mechanisms and to evaluate the efficacy of a proposed countermeasure against adverse reactions to sunitinib. Results: In silico simulations indicated the possibility that sunitinib-mediated off-target inhibition of phosphorylase kinase leads to the generation of oxidative stress in various tissues. Clinical observations of patients and mouse experiments confirmed the validity of this prediction. The simulation further suggested that concomitant use of an antioxidant may prevent sunitinib-mediated adverse reactions, which was confirmed in mouse experiments. Conclusions: A systems toxicological approach successfully predicted the molecular mechanisms underlying clinically adverse reactions associated with sunitinib and was used to plan a rational method for the management of these adverse reactions. PMID:28725458

Callous-unemotional traits and early life stress predict treatment effects on stress and sex hormone functioning in incarcerated male adolescents.

PubMed

Johnson, Megan; Vitacco, Michael J; Shirtcliff, Elizabeth A

2018-03-01

The stress response system is highly plastic, and hormone rhythms may "adaptively calibrate" in response to treatment. This investigation assessed whether stress and sex hormone diurnal rhythms changed over the course of behavioral treatment, and whether callous-unemotional (CU) traits and history of early adversity affected treatment results on diurnal hormone functioning in a sample of 28 incarcerated adolescent males. It was hypothesized that the treatment would have beneficial effects, such that healthier diurnal rhythms would emerge post-treatment. Diurnal cortisol, testosterone, and dehydroepiandrosterone (DHEA) were sampled two weeks after admission to the correctional/treatment facility, and again approximately four months later. Positive treatment effects were detected for the whole sample, such that testosterone dampened across treatment. CU traits predicted a non-optimal hormone response to treatment, potentially indicating biological preparedness to respond to acts of social dominance and aggression. The interaction between CU traits and adversity predicted a promising and sensitized response to treatment including increased cortisol and a steeper testosterone drop across treatment. Results suggest that stress and sex hormones are highly receptive to treatment during this window of development.

Chemical Risk Assessment: Traditional vs Public Health Perspectives

PubMed Central

Axelrad, Daniel A.; Bahadori, Tina; Bussard, David; Cascio, Wayne E.; Deener, Kacee; Dix, David; Thomas, Russell S.; Kavlock, Robert J.; Burke, Thomas A.

2017-01-01

Preventing adverse health effects of environmental chemical exposure is fundamental to protecting individual and public health. When done efficiently and properly, chemical risk assessment enables risk management actions that minimize the incidence and effects of environmentally induced diseases related to chemical exposure. However, traditional chemical risk assessment is faced with multiple challenges with respect to predicting and preventing disease in human populations, and epidemiological studies increasingly report observations of adverse health effects at exposure levels predicted from animal studies to be safe for humans. This discordance reinforces concerns about the adequacy of contemporary risk assessment practices for protecting public health. It is becoming clear that to protect public health more effectively, future risk assessments will need to use the full range of available data, draw on innovative methods to integrate diverse data streams, and consider health endpoints that also reflect the range of subtle effects and morbidities observed in human populations. Considering these factors, there is a need to reframe chemical risk assessment to be more clearly aligned with the public health goal of minimizing environmental exposures associated with disease. PMID:28520487

Admission factors can predict the need for ICU monitoring in gallstone pancreatitis.

PubMed

Arnell, T D; de Virgilio, C; Chang, L; Bongard, F; Stabile, B E

1996-10-01

The purpose was 1) to prospectively determine the prevalence of adverse events necessitating intensive care unit (ICU) monitoring in gallstone pancreatitis (GP) and 2) To identify admission prognostic indicators that predict the need for ICU unit monitoring. Prospective laboratory data, physiologic parameters, and APACHE II scores were gathered on 102 patients with GP over 14 months. Adverse events were defined as cardiac, respiratory, or renal failure, gastrointestinal bleeding, stroke, sepsis, and necrotizing pancreatitis. Patients were divided into Group 1 (no adverse events, n=95) and Group 2 (adverse events, n=7). There were no deaths and 7 (7%) adverse events, including necrotizing pancreatitis (3), cholangitis (2), and cardiac (2). APACHE 11 > or = 5 (P < 0.005), blood urea nitrogen (BUN) > or = 12 mmol/L (P < 0.005), white blood cell count (WBC) > or = 14.5 x 10(9)/L, (P < 0.001), heart rate > or = 100 bpm (P < 0.001), and glucose > or = 150 mg/dL (P < 0.005) were each independent predictors of adverse events. The sensitivity and specificity of these criteria for predicting severe complications requiring ICU care varied from 71 to 86 per cent and 78 to 87 per cent, respectively. The prevalence of adverse events necessitating ICU care in GP patients is low. Glucose, BUN, WBC, heart rate, and APACHE II scores are independent predictors of adverse events necessitating ICU care. Single criteria predicting the need for ICU care on admission are readily available on admission.

Childhood adversities and adult psychopathology in the WHO World Mental Health Surveys.

PubMed

Kessler, Ronald C; McLaughlin, Katie A; Green, Jennifer Greif; Gruber, Michael J; Sampson, Nancy A; Zaslavsky, Alan M; Aguilar-Gaxiola, Sergio; Alhamzawi, Ali Obaid; Alonso, Jordi; Angermeyer, Matthias; Benjet, Corina; Bromet, Evelyn; Chatterji, Somnath; de Girolamo, Giovanni; Demyttenaere, Koen; Fayyad, John; Florescu, Silvia; Gal, Gilad; Gureje, Oye; Haro, Josep Maria; Hu, Chi-Yi; Karam, Elie G; Kawakami, Norito; Lee, Sing; Lépine, Jean-Pierre; Ormel, Johan; Posada-Villa, José; Sagar, Rajesh; Tsang, Adley; Ustün, T Bedirhan; Vassilev, Svetlozar; Viana, Maria Carmen; Williams, David R

2010-11-01

Although significant associations of childhood adversities with adult mental disorders are widely documented, most studies focus on single childhood adversities predicting single disorders. To examine joint associations of 12 childhood adversities with first onset of 20 DSM-IV disorders in World Mental Health (WMH) Surveys in 21 countries. Nationally or regionally representative surveys of 51 945 adults assessed childhood adversities and lifetime DSM-IV disorders with the WHO Composite International Diagnostic Interview (CIDI). Childhood adversities were highly prevalent and interrelated. Childhood adversities associated with maladaptive family functioning (e.g. parental mental illness, child abuse, neglect) were the strongest predictors of disorders. Co-occurring childhood adversities associated with maladaptive family functioning had significant subadditive predictive associations and little specificity across disorders. Childhood adversities account for 29.8% of all disorders across countries. Childhood adversities have strong associations with all classes of disorders at all life-course stages in all groups of WMH countries. Long-term associations imply the existence of as-yet undetermined mediators.

Interactive Effect of Stressful Life Events and the Serotonin Transporter 5-HTTLPR Genotype on Posttraumatic Stress Disorder Diagnosis in 2 Independent Populations

PubMed Central

Xie, Pingxing; Kranzler, Henry R.; Poling, James; Stein, Murray B.; Anton, Raymond F.; Brady, Kathleen; Weiss, Roger D.; Farrer, Lindsay; Gelernter, Joel

2010-01-01

Context: The 5-HTTLPR polymorphism in the promoter region of the serotonin transporter gene (SLC6A4) has been found to moderate several categories of emotional response after stressful life events. Previous studies generally focused on its effect on depressive symptoms; little is known about its moderation of the development of post-traumatic stress disorder (PTSD). Objective: To examine the effects of childhood adversity, adult traumatic events, 5-HTTLPR genotypes, and gene×environment interactions on the etiology of PTSD. Design: A cross-sectional study in which participants in several studies investigating the genetics of substance dependence were also screened for lifetime PTSD. The triallelic system of 5-HTTLPR was genotyped. Logistic regression modeling was used in the analyses. Setting: General community. Participants: Five hundred eighty-two European American and 670 African American individuals who reported experiences of childhood adversity, adult traumatic events, or both. Main Outcome Measure: Diagnosis of PTSD, defined by DSM-IV diagnostic criteria and assessed through the Semi-Structured Assessment for Drug Dependence and Alcoholism interview. Results: Childhood adversity and adult traumatic events both predicted PTSD. Although the 5-HTTLPR genotype alone did not predict the onset of PTSD, it interacted with adult traumatic events and childhood adversity to increase the risk for PTSD, especially for those with high rates of both types of trauma exposure (European American: odds ratio [OR], 2.86; 95% confidence interval [CI], 1.50-5.45; P=.002; African American: OR, 1.88; 95% CI, 1.04-3.40; P=.04; pooled: OR, 2.31; 95% CI, 1.50-3.56; P<.001). Conclusions: Participants who had both childhood adversity and adult traumatic events were more likely to develop lifetime PTSD compared with those who experienced either type of adverse event. The risk was increased in individuals with 1 or 2 copies of the S′ (S) allele compared with the L′ (L) homozygotes. Our study provides additional direct evidence that PTSD is influenced by the interactive effect of environmental and genetic factors. PMID:19884608

Childhood Adversity, Recent Life Stressors and Suicidal Behavior in Chinese College Students

PubMed Central

You, Zhiqi; Chen, Mingxi; Yang, Sen; Zhou, Zongkui; Qin, Ping

2014-01-01

Background Although the independent effects of childhood adversities and of recent negative events on suicidality have been well-documented, the combinative role of childhood and recent adversities on risk for suicidality is still underexplored, especially in the context of Chinese culture and in consideration of specific types of negative events. Method 5989 students, randomly sampled from six universities in central China, completed the online survey for this study. Suicidal behavior, life adversity during childhood and stressful events in recent school life were assessed with designed questionnaires. Results Students experiencing recent stressful life events more often reported an experience of life adversity during childhood. While recent stressful life events and childhood life adversity both were associated with an increased risk for suicidal behavior, the two exposures presented conjunctively and acted interactively to increase the risk. There was noticeable variation of effects associated with specific childhood life adversities, and sexual abuse, poor parental relationship, divorce of parents and loss of a parent were among the adversities associated with the highest increased risk. Recent conflicts with classmates, poor school performance and rupture of romantic relationships were the recent school life stressors associated with the highest increased risk. Conclusions Childhood adversity and recent school life stressors had a combinative role in predicting suicidality of young people studying in Chinese colleges. Unhappy family life during childhood and recent interpersonal conflicts in school were the most important predictors of suicidality in this population. PMID:24681891

MATHEMATICAL MODEL OF METABOLIC PATHWAYS OF STEROIDOGENESIS TO PREDICT MOLECULAR RESPONSE FOR ENDOCRINE DISRUPTING CHEMICALS.

EPA Science Inventory

There is increasing evidence that exposure to endocrine disrupting chemicals (EDCs) in the environment can induce adverse effects on reproduction and development in both humans and wildlife, mediated through hormonal disturbances.

Model-based analysis of thromboxane B{sub 2} and prostaglandin E{sub 2} as biomarkers in the safety evaluation of naproxen

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sahota, Tarjinder; Sanderson, Ian; Danhof, Meindert

The assessment of safety in traditional toxicology protocols relies on evidence arising from observed adverse events (AEs) in animals and on establishing their correlation with different measures of drug exposure (e.g., C{sub max} and AUC). Such correlations, however, ignore the role of biomarkers, which can provide further insight into the underlying pharmacological mechanisms. Here we use naproxen as a paradigm drug to explore the feasibility of a biomarker-guided approach for the prediction of AEs in humans. A standard toxicology protocol was set up for the evaluation of effects of naproxen in rat, in which four doses were tested (7.5, 15,more » 40 and 80 mg/kg). In addition to sparse blood sampling for the assessment of exposure, thromboxane B{sub 2} and prostaglandin E{sub 2} were also collected in satellite groups. Nonlinear mixed effects modelling was used to evaluate the predictive performance of the approach. A one-compartmental model with first order absorption was found to best describe the pharmacokinetics of naproxen. A nonlinear relationship between dose and bioavailability was observed which leads to a less than proportional increase in naproxen concentrations with increasing doses. The pharmacodynamics of TXB{sub 2} and PGE{sub 2} was described by direct inhibition models with maximum pharmacological effects achieved at doses > 7.5 mg/kg. The predicted PKPD relationship in humans was within 10-fold of the values previously published. Moreover, our results indicate that biomarkers can be used to assess interspecies differences in PKPD and extrapolated data from animals to humans. Biomarker sampling should be used systematically in general toxicity studies. - Highlights: • Prediction of a drug's safety profile from preclinical protocols remains challenging. • Pharmacokinetic measures of safe exposure (e.g., AUC) ignore the role of biomarkers. • PKPD relationships enable the evaluation of adverse events in a mechanistic manner. • Major differences exist between rats and humans in the effects of naproxen on TXB{sub 2}. • A biomarker-guided approach may facilitate the prediction of adverse events in humans.« less

Mothers’ Employment and Health of Low-Income Children

PubMed Central

Gennetian, Lisa; Hill, Heather; Lopoo, Leonard; London, Andrew

2010-01-01

This study examines whether maternal employment affects the health status of low-income, elementary-school-aged children using instrumental variables estimation and experimental data from a welfare-to-work program implemented in the early 1990s. Mother’s report of child health status is predicted as a function of exogenous variation in maternal employment associated with random assignment to the program group. IV estimates show a modest adverse effect of maternal employment on children’s health. Making use of data from another welfare-to-work program we propose that any adverse effect on child health may be tempered by increased family income and access to public health insurance coverage, findings with direct relevance to a number of current policy discussions. In a secondary analysis using fixed effects techniques on longitudinal survey data collected in 1998 and 2001, we find a comparable adverse effect of maternal employment on child health that supports the external validity of our primary result. PMID:20356641

Applying adverse outcome pathways and species sensitivity-weighted distribution to predicted-no-effect concentration derivation and quantitative ecological risk assessment for bisphenol A and 4-nonylphenol in aquatic environments: A case study on Tianjin City, China.

PubMed

Wang, Ying; Na, Guangshui; Zong, Humin; Ma, Xindong; Yang, Xianhai; Mu, Jingli; Wang, Lijun; Lin, Zhongsheng; Zhang, Zhifeng; Wang, Juying; Zhao, Jinsong

2018-02-01

Adverse outcome pathways (AOPs) are a novel concept that effectively considers the toxic modes of action and guides the ecological risk assessment of chemicals. To better use toxicity data including biochemical or molecular responses and mechanistic data, we further developed a species sensitivity-weighted distribution (SSWD) method for bisphenol A and 4-nonylphenol. Their aquatic predicted-no-effect concentrations (PNECs) were derived using the log-normal statistical extrapolation method. We calculated aquatic PNECs of bisphenol A and 4-nonylphenol with values of 4.01 and 0.721 µg/L, respectively. The ecological risk of each chemical in different aquatic environments near Tianjin, China, a coastal municipality along the Bohai Sea, was characterized by hazard quotient and probabilistic risk quotient assessment techniques. Hazard quotients of 7.02 and 5.99 at 2 municipal sewage sites using all of the endpoints were observed for 4-nonylphenol, which indicated high ecological risks posed by 4-nonylphenol to aquatic organisms, especially endocrine-disrupting effects. Moreover, a high ecological risk of 4-nonylphenol was indicated based on the probabilistic risk quotient method. The present results show that combining the SSWD method and the AOP concept could better protect aquatic organisms from adverse effects such as endocrine disruption and could decrease uncertainty in ecological risk assessment. Environ Toxicol Chem 2018;37:551-562. © 2017 SETAC. © 2017 SETAC.

The Effects of Sleep Deprivation on Item and Associative Recognition Memory

ERIC Educational Resources Information Center

Ratcliff, Roger; Van Dongen, Hans P. A.

2018-01-01

Sleep deprivation adversely affects the ability to perform cognitive tasks, but theories range from predicting an overall decline in cognitive functioning because of reduced stability in attentional networks to specific deficits in various cognitive domains or processes. We measured the effects of sleep deprivation on two memory tasks, item…

Cumulative burden of lifetime adversities: Trauma and mental health in low-SES African Americans and Latino/as.

PubMed

Myers, Hector F; Wyatt, Gail E; Ullman, Jodie B; Loeb, Tamra B; Chin, Dorothy; Prause, Nicole; Zhang, Muyu; Williams, John K; Slavich, George M; Liu, Honghu

2015-05-01

This study examined the utility of a lifetime cumulative adversities and trauma model in predicting the severity of mental health symptoms of depression, anxiety, and posttraumatic stress disorder. We also tested whether ethnicity and gender moderate the effects of this stress exposure construct on mental health using multigroup structural equation modeling. A sample of 500 low-socioeconomic status African American and Latino men and women with histories of adversities and trauma were recruited and assessed with a standard battery of self-report measures of stress and mental health. Multiple-group structural equation models indicated good overall model fit. As hypothesized, experiences of discrimination, childhood family adversities, childhood sexual abuse, other childhood trauma, and chronic stresses all loaded on the latent cumulative burden of adversities and trauma construct (CBAT). The CBAT stress exposure index in turn predicted the mental health status latent variable. Although there were several significant univariate ethnic and gender differences, and ethnic and gender differences were observed on several paths, there were no significant ethnic differences in the final model fit of the data. These findings highlight the deleterious consequences of cumulative stress and trauma for mental health and underscore a need to assess these constructs in selecting appropriate clinical interventions for reducing mental health disparities and improving human health. (c) 2015 APA, all rights reserved).

Testing an explanatory model of nurses' intention to report adverse drug reactions in hospital settings.

PubMed

Angelis, Alessia De; Pancani, Luca; Steca, Patrizia; Colaceci, Sofia; Giusti, Angela; Tibaldi, Laura; Alvaro, Rosaria; Ausili, Davide; Vellone, Ercole

2017-05-01

To test an explanatory model of nurses' intention to report adverse drug reactions in hospital settings, based on the theory of planned behaviour. Under-reporting of adverse drug reactions is an important problem among nurses. A cross-sectional design was used. Data were collected with the adverse drug reporting nurses' questionnaire. Confirmatory factor analysis was performed to test the factor validity of the adverse drug reporting nurses' questionnaire, and structural equation modelling was used to test the explanatory model. The convenience sample comprised 500 Italian hospital nurses (mean age = 43.52). Confirmatory factor analysis supported the factor validity of the adverse drug reporting nurses' questionnaire. The structural equation modelling showed a good fit with the data. Nurses' intention to report adverse drug reactions was significantly predicted by attitudes, subjective norms and perceived behavioural control (R² = 0.16). The theory of planned behaviour effectively explained the mechanisms behind nurses' intention to report adverse drug reactions, showing how several factors come into play. In a scenario of organisational empowerment towards adverse drug reaction reporting, the major predictors of the intention to report are support for the decision to report adverse drug reactions from other health care practitioners, perceptions about the value of adverse drug reaction reporting and nurses' favourable self-assessment of their adverse drug reaction reporting skills. © 2017 John Wiley & Sons Ltd.

Mixture effects in samples of multiple contaminants - An inter-laboratory study with manifold bioassays.

PubMed

Altenburger, Rolf; Scholze, Martin; Busch, Wibke; Escher, Beate I; Jakobs, Gianina; Krauss, Martin; Krüger, Janet; Neale, Peta A; Ait-Aissa, Selim; Almeida, Ana Catarina; Seiler, Thomas-Benjamin; Brion, François; Hilscherová, Klára; Hollert, Henner; Novák, Jiří; Schlichting, Rita; Serra, Hélène; Shao, Ying; Tindall, Andrew; Tolefsen, Knut-Erik; Umbuzeiro, Gisela; Williams, Tim D; Kortenkamp, Andreas

2018-05-01

Chemicals in the environment occur in mixtures rather than as individual entities. Environmental quality monitoring thus faces the challenge to comprehensively assess a multitude of contaminants and potential adverse effects. Effect-based methods have been suggested as complements to chemical analytical characterisation of complex pollution patterns. The regularly observed discrepancy between chemical and biological assessments of adverse effects due to contaminants in the field may be either due to unidentified contaminants or result from interactions of compounds in mixtures. Here, we present an interlaboratory study where individual compounds and their mixtures were investigated by extensive concentration-effect analysis using 19 different bioassays. The assay panel consisted of 5 whole organism assays measuring apical effects and 14 cell- and organism-based bioassays with more specific effect observations. Twelve organic water pollutants of diverse structure and unique known modes of action were studied individually and as mixtures mirroring exposure scenarios in freshwaters. We compared the observed mixture effects against component-based mixture effect predictions derived from additivity expectations (assumption of non-interaction). Most of the assays detected the mixture response of the active components as predicted even against a background of other inactive contaminants. When none of the mixture components showed any activity by themselves then the mixture also was without effects. The mixture effects observed using apical endpoints fell in the middle of a prediction window defined by the additivity predictions for concentration addition and independent action, reflecting well the diversity of the anticipated modes of action. In one case, an unexpectedly reduced solubility of one of the mixture components led to mixture responses that fell short of the predictions of both additivity mixture models. The majority of the specific cell- and organism-based endpoints produced mixture responses in agreement with the additivity expectation of concentration addition. Exceptionally, expected (additive) mixture response did not occur due to masking effects such as general toxicity from other compounds. Generally, deviations from an additivity expectation could be explained due to experimental factors, specific limitations of the effect endpoint or masking side effects such as cytotoxicity in in vitro assays. The majority of bioassays were able to quantitatively detect the predicted non-interactive, additive combined effect of the specifically bioactive compounds against a background of complex mixture of other chemicals in the sample. This supports the use of a combination of chemical and bioanalytical monitoring tools for the identification of chemicals that drive a specific mixture effect. Furthermore, we demonstrated that a panel of bioassays can provide a diverse profile of effect responses to a complex contaminated sample. This could be extended towards representing mixture adverse outcome pathways. Our findings support the ongoing development of bioanalytical tools for (i) compiling comprehensive effect-based batteries for water quality assessment, (ii) designing tailored surveillance methods to safeguard specific water uses, and (iii) devising strategies for effect-based diagnosis of complex contamination. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

Poor mental health among low-income women in the U.S.: The roles of adverse childhood and adult experiences.

PubMed

Mersky, Joshua P; Janczewski, Colleen E; Nitkowski, Jenna C

2018-06-01

It is well established that exposure to a greater number of adverse childhood experiences (ACEs) increases the risk of poor physical and mental health outcomes. Given the predictive validity of ACE scores and other cumulative risk metrics, a similar measurement approach may advance the study of risk in adulthood. We examined the prevalence and interrelations of 10 adverse adult experiences, including household events such as intimate partner violence and extrafamilial events such as crime victimization. We also tested the relation between cumulative adult adversity and later mental health problems, and we examined whether adult adversity mediates the link between childhood adversity and mental health. Data were collected from 501 women in the Families and Children Thriving Study, a longitudinal investigation of low-income families that received home visiting services in Wisconsin. We conducted correlation analyses to assess interrelations among study measures along with multivariate analyses to test the effects of childhood and adult adversity on three outcomes: depression, anxiety, and posttraumatic stress disorder (PTSD). We then fit a structural equation model to test whether the effects of childhood adversity on mental health are mediated by adult adversity. Over 80% of participants endorsed at least one adverse adult experience. Adult adversities correlated with each other and with the mental health outcomes. Controlling for ACEs and model covariates, adult adversity scores were positively associated with depression, anxiety, and PTSD scores. Path analyses revealed that the ACE-mental health connection was mediated by adult adversity. Our findings indicate that mental health problems may be better understood by accounting for processes through which early adversity leads to later adversity. Pending replication, this line of research has the potential to improve the identification of populations that are at risk of poor health outcomes. Copyright © 2018 Elsevier Ltd. All rights reserved.

Childhood adversities and post-traumatic stress disorder: evidence for stress sensitisation in the World Mental Health Surveys.

PubMed

McLaughlin, Katie A; Koenen, Karestan C; Bromet, Evelyn J; Karam, Elie G; Liu, Howard; Petukhova, Maria; Ruscio, Ayelet Meron; Sampson, Nancy A; Stein, Dan J; Aguilar-Gaxiola, Sergio; Alonso, Jordi; Borges, Guilherme; Demyttenaere, Koen; Dinolova, Rumyana V; Ferry, Finola; Florescu, Silvia; de Girolamo, Giovanni; Gureje, Oye; Kawakami, Norito; Lee, Sing; Navarro-Mateu, Fernando; Piazza, Marina; Pennell, Beth-Ellen; Posada-Villa, José; Ten Have, Margreet; Viana, Maria Carmen; Kessler, Ronald C

2017-11-01

Background Although childhood adversities are known to predict increased risk of post-traumatic stress disorder (PTSD) after traumatic experiences, it is unclear whether this association varies by childhood adversity or traumatic experience types or by age. Aims To examine variation in associations of childhood adversities with PTSD according to childhood adversity types, traumatic experience types and life-course stage. Method Epidemiological data were analysed from the World Mental Health Surveys ( n = 27 017). Results Four childhood adversities (physical and sexual abuse, neglect, parent psychopathology) were associated with similarly increased odds of PTSD following traumatic experiences (odds ratio (OR) = 1.8), whereas the other eight childhood adversities assessed did not predict PTSD. Childhood adversity-PTSD associations did not vary across traumatic experience types, but were stronger in childhood-adolescence and early-middle adulthood than later adulthood. Conclusions Childhood adversities are differentially associated with PTSD, with the strongest associations in childhood-adolescence and early-middle adulthood. Consistency of associations across traumatic experience types suggests that childhood adversities are associated with generalised vulnerability to PTSD following traumatic experiences. © The Royal College of Psychiatrists 2017.

An assessment of predictive value of the biophysical profile in women with preeclampsia using data from the fullPIERS database.

PubMed

Payne, Beth A; Kyle, Phillipa M; Lim, Kenneth; Lisonkova, Sarka; Magee, Laura A; Pullar, Barbra; Qu, Ziguang; von Dadelszen, Peter

2013-07-01

Pre-eclampsia is associated with increased risk to both the mother and fetus. Effective monitoring of the fetal condition is essential to the management of women with pre-eclampsia. The biophysical profile (BPP) is one monitoring tool available to clinicians. To compare the BPP test with cardiotocography/non-stress test (CTG/NST) alone for their ability to predict fetal acidemia at birth or a composite adverse perinatal outcome among women with preeclampsia and to estimate the effect of BPP assessment on mode of delivery and birth outcome. Secondary analysis of a prospective cohort of women with preeclampsia. The predictive ability of the tests was assessed based on sensitivity, specificity, positive and negative likelihood ratios (LR+, LR-). Women assessed with the BPP were compared with matched controls not assessed with the BPP to determine the odds of Cesarean delivery or adverse perinatal outcomes after adjustment for potential confounders. Five out of 89 women (5.6%) had an abnormal BPP; 18 out of 89 (20.2%) had an abnormal CTG/NST. Fetal acidemia was diagnosed in 13 fetuses (14.6%); composite adverse perinatal outcome in 68 fetuses/infants (76.4%). Both tests had relatively poor predictive performance for both outcomes (LR+ between 2.50 and 3.90 and LR- between 0.64 and 0.93). Assessment with the BPP was positively associated with fetal acidemia (adjusted OR 4.84; 95% CI 1.33-17.66). The BPP and CTG/NST alone were poor predictors of perinatal outcome in this cohort; multiple tests should be considered when assessing fetal risk in women with preeclampsia. Crown Copyright © 2013. Published by Elsevier B.V. All rights reserved.

Building predictive gene signatures through simultaneous assessment of transcription factor activation and gene expression.

EPA Science Inventory

Building predictive gene signatures through simultaneous assessment of transcription factor activation and gene expression Exposure to many drugs and environmentally-relevant chemicals can cause adverse outcomes. These adverse outcomes, such as cancer, have been linked to mol...

Prenatal stress effects in a wild, long-lived primate: predictive adaptive responses in an unpredictable environment.

PubMed

Berghänel, Andreas; Heistermann, Michael; Schülke, Oliver; Ostner, Julia

2016-09-28

Prenatal maternal stress affects offspring phenotype in numerous species including humans, but it is debated whether these effects are evolutionarily adaptive. Relating stress to adverse conditions, current explanations invoke either short-term developmental constraints on offspring phenotype resulting in decelerated growth to avoid starvation, or long-term predictive adaptive responses (PARs) resulting in accelerated growth and reproduction in response to reduced life expectancies. Two PAR subtypes were proposed, acting either on predicted internal somatic states or predicted external environmental conditions, but because both affect phenotypes similarly, they are largely indistinguishable. Only external (not internal) PARs rely on high environmental stability particularly in long-lived species. We report on a crucial test case in a wild long-lived mammal, the Assamese macaque (Macaca assamensis), which evolved and lives in an unpredictable environment where external PARs are probably not advantageous. We quantified food availability, growth, motor skills, maternal caretaking style and maternal physiological stress from faecal glucocorticoid measures. Prenatal maternal stress was negatively correlated to prenatal food availability and led to accelerated offspring growth accompanied by decelerated motor skill acquisition and reduced immune function. These results support the 'internal PAR' theory, which stresses the role of stable adverse internal somatic states rather than stable external environments. © 2016 The Author(s).

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.

Ecological Forecasting: Microbial Contamination and Atmospheric Loadings of Nutrients to Land and Water

EPA Science Inventory

The development of ecological forecasts, namely, methodologies to predict the chemical, biological, and physical changes in terrestrial and aquatic ecosystems is desirable so that effective strategies for reducing the adverse impacts of human activities and extreme natural events...

Do Childhood Adversities Predict Suicidality? Findings from the General Population of the Metropolitan Area of São Paulo, Brazil.

PubMed

Coêlho, Bruno Mendonça; Andrade, Laura Helena; Borges, Guilherme; Santana, Geilson Lima; Viana, Maria Carmen; Wang, Yuan-Pang

2016-01-01

Childhood adversities have been associated with a number of medical and psychiatric outcomes. However, the reported effects that specific childhood adversities have on suicidality vary across studies. This was a cross-sectional, stratified, multistage area probability investigation of a general population in Brazil, designated the São Paulo Megacity Mental Health Survey. The World Mental Health Composite International Diagnostic Interview was applied in 5037 individuals ≥ 18 years of age, in order to assess 12 different adversities occurring during childhood and/or adolescence, as well as to look for associations between those adversities and subsequent suicidality in different age strata. Over half of the respondents reported at least one childhood adversity. Only physical abuse was consistently associated with suicide attempts in all subsequent life stages (OR = 2.1). Among adults 20-29 years of age, the likelihood of a suicide attempt was correlated with parental divorce, whereas suicidal ideation was associated with prior sexual abuse. Among adults over 30 years of age, physical illness and economic adversity emerged as relevant childhood adversities associated with suicide attempts, whereas sexual abuse, family violence, and economic adversity were associated with suicidal ideation. Childhood adversities, especially physical abuse, are likely associated with unfavorable consequences in subsequent years. For suicidality across a lifespan, the role of different childhood adversities must be examined independently.

Do Childhood Adversities Predict Suicidality? Findings from the General Population of the Metropolitan Area of São Paulo, Brazil

PubMed Central

Andrade, Laura Helena; Borges, Guilherme; Santana, Geilson Lima; Viana, Maria Carmen; Wang, Yuan-Pang

2016-01-01

Background Childhood adversities have been associated with a number of medical and psychiatric outcomes. However, the reported effects that specific childhood adversities have on suicidality vary across studies. Method This was a cross-sectional, stratified, multistage area probability investigation of a general population in Brazil, designated the São Paulo Megacity Mental Health Survey. The World Mental Health Composite International Diagnostic Interview was applied in 5037 individuals ≥ 18 years of age, in order to assess 12 different adversities occurring during childhood and/or adolescence, as well as to look for associations between those adversities and subsequent suicidality in different age strata. Results Over half of the respondents reported at least one childhood adversity. Only physical abuse was consistently associated with suicide attempts in all subsequent life stages (OR = 2.1). Among adults 20–29 years of age, the likelihood of a suicide attempt was correlated with parental divorce, whereas suicidal ideation was associated with prior sexual abuse. Among adults over 30 years of age, physical illness and economic adversity emerged as relevant childhood adversities associated with suicide attempts, whereas sexual abuse, family violence, and economic adversity were associated with suicidal ideation. Conclusion Childhood adversities, especially physical abuse, are likely associated with unfavorable consequences in subsequent years. For suicidality across a lifespan, the role of different childhood adversities must be examined independently. PMID:27192171

Deviation from a preoperative surgical and anaesthetic care plan is associated with increased risk of adverse intraoperative events in major abdominal surgery.

PubMed

Gauss, T; Merckx, P; Brasher, C; Kavafyan, J; Le Bihan, E; Aussilhou, B; Belghiti, J; Mantz, J

2013-02-01

Perioperative coordination facilitates team communication and planning. The aim of this study was to determine how often deviation from predicted surgical conditions and a pre-established anaesthetic care plan in major abdominal surgery occurred, and whether this was associated with an increase in adverse clinical events. In this prospective observational study, weekly preoperative interdisciplinary team meetings were conducted according to a joint care plan checklist in a tertiary care centre in France. Any discordance with preoperative predictions and deviation from the care plan were noted. A link to the incidence of predetermined adverse intraoperative events was investigated. Intraoperative adverse clinical events (ACEs) occurred in 15 % of all cases and were associated with postoperative complications [relative risk (RR) = 1.5; 95 % confidence interval (1.1; 2.2)]. Quality of prediction of surgical procedural items was modest, with one in five to six items not correctly predicted. Discordant surgical prediction was associated with an increased incidence of ACE. Deviation from the anaesthetic care plan occurred in around 13 %, which was more frequent when surgical prediction was inaccurate (RR > 3) and independently associated with ACE (odds ratio 6). Surgery was more difficult than expected in up to one out of five cases. In a similar proportion, disagreement between preoperative care plans and observed clinical management was independently associated with an increased risk of adverse clinical events.

Data-driven prediction of adverse drug reactions induced by drug drug interactions

DTIC Science & Technology

2017-06-08

currently on the market and for which drug-protein interaction information is available . These predictions are publicly accessible at http://avoid...associated with these ADRs via DDIs. We made the predictions publicly available via internet access. Keywords: Drug-drug interactions, Adverse drug reactions...ˆDeceased Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research

Systematic drug safety evaluation based on public genomic expression (Connectivity Map) data: Myocardial and infectious adverse reactions as application cases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Kejian, E-mail: kejian.wang.bio@gmail.com; Weng, Zuquan; Sun, Liya

Adverse drug reaction (ADR) is of great importance to both regulatory agencies and the pharmaceutical industry. Various techniques, such as quantitative structure–activity relationship (QSAR) and animal toxicology, are widely used to identify potential risks during the preclinical stage of drug development. Despite these efforts, drugs with safety liabilities can still pass through safety checkpoints and enter the market. This situation raises the concern that conventional chemical structure analysis and phenotypic screening are not sufficient to avoid all clinical adverse events. Genomic expression data following in vitro drug treatments characterize drug actions and thus have become widely used in drug repositioning. Inmore » the present study, we explored prediction of ADRs based on the drug-induced gene-expression profiles from cultured human cells in the Connectivity Map (CMap) database. The results showed that drugs inducing comparable ADRs generally lead to similar CMap expression profiles. Based on such ADR-gene expression association, we established prediction models for various ADRs, including severe myocardial and infectious events. Drugs with FDA boxed warnings of safety liability were effectively identified. We therefore suggest that drug-induced gene expression change, in combination with effective computational methods, may provide a new dimension of information to facilitate systematic drug safety evaluation. - Highlights: • Drugs causing common toxicity lead to similar in vitro gene expression changes. • We built a model to predict drug toxicity with drug-specific expression profiles. • Drugs with FDA black box warnings were effectively identified by our model. • In vitro assay can detect severe toxicity in the early stage of drug development.« less

Risk factors for polyuria in a cross-section of community psychiatric lithium-treated patients.

PubMed

Kinahan, James Conor; NiChorcorain, Aoife; Cunningham, Sean; Freyne, Aideen; Cooney, Colm; Barry, Siobhan; Kelly, Brendan D

2015-02-01

Polyuria increases the risk of dehydration and lithium toxicity in lithium-treated patients. Risk factors have been inconsistently described and the variance of this adverse effect remains poorly understood. This study aimed to establish independent risk factors for polyuria in a community, secondary-level lithium-treated sample of patients. This was a cross-sectional study of the lithium-treated patients attending a general adult and an old age psychiatry service. Participants completed a 24-hour urine collection. Urine volume and the presence of polyuria were the outcomes of interest. The relationship between outcome and the participant's demographic and clinical characteristics was explored with univariable and multivariable analysis. A total of 122 participants were included in the analysis, with 38% being diagnosed with polyuria. Female gender and increased body weight independently predicted the presence of polyuria (standardized regression coefficient 1.01 and 0.94, respectively; p = 0.002 and p = 0.003, respectively). Female gender and increased body weight, lithium dose, and duration of lithium treatment independently predicted higher 24-hour urine volumes (standardized regression coefficients 0.693, p < 0.0005; 0.791, p < 0.0005; 0.276, p = 0.043; 0.181, p = 0.034, respectively). Of three different weight metrics, lean body weight was the most predictive. Female gender and increased body weight explain part of the variance of this adverse effect. Both risk factors offer fresh insights into the pathophysiology of this potentially reversible and dangerous adverse effect of lithium treatment. Future research should focus on understanding the differences between the genders and between different body compositions in terms of lithium pharmacokinetics and pharmacodynamics. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Aerosolized intranasal midazolam for safe and effective sedation for quality computed tomography imaging in infants and children.

PubMed

Mekitarian Filho, Eduardo; de Carvalho, Werther Brunow; Gilio, Alfredo Elias; Robinson, Fay; Mason, Keira P

2013-10-01

This pilot study introduces the aerosolized route for midazolam as an option for infant and pediatric sedation for computed tomography imaging. This technique produced predictable and effective sedation for quality computed tomography imaging studies with minimal artifact and no significant adverse events. Copyright © 2013 Mosby, Inc. All rights reserved.

Moderating the Effects of Childhood Exposure to Intimate Partner Violence: The Roles of Parenting Characteristics and Adolescent Peer Support

ERIC Educational Resources Information Center

Tajima, Emiko A.; Herrenkohl, Todd I.; Moylan, Carrie A.; Derr, Amelia S.

2011-01-01

We investigate parenting characteristics and adolescent peer support as potential moderators of the effects of childhood exposure to intimate partner violence (IPV) on adolescent outcomes. Lehigh Longitudinal Study (N = 416) data include parent and adolescent reports of childhood IPV exposure. Exposure to IPV predicted nearly all adverse outcomes…

A growth curve analysis of the course of dysthymic disorder: the effects of chronic stress and moderation by adverse parent-child relationships and family history.

PubMed

Dougherty, Lea R; Klein, Daniel N; Davila, Joanne

2004-12-01

Using mixed effects models, the authors examined the effects of chronic stress, adverse parent-child relationships, and family history on the 7.5-year course of dysthymic disorder. Participants included 97 outpatients with early-onset dysthymia who were assessed with semistructured interviews at baseline and 3 additional times at 30-month intervals for 7.5 years. Results indicated that higher levels of chronic stress 6 months prior to each follow-up predicted greater depression severity at follow-up, controlling for depression severity at the start of the chronic stress assessment. In addition, adverse parent-child relationships and family history of dysthymic disorder moderated this association. For patients with poorer parent-child relationships, chronic stress was associated with increased depression severity at follow-up, whereas patients with a higher familial loading for dysthymic disorder were less responsive to chronic stress over time. Copyright 2004 APA.

Adverse health effects of high-effort/low-reward conditions.

PubMed

Siegrist, J

1996-01-01

In addition to the person-environment fit model (J. R. French, R. D. Caplan, & R. V. Harrison, 1982) and the demand-control model (R. A. Karasek & T. Theorell, 1990), a third theoretical concept is proposed to assess adverse health effects of stressful experience at work: the effort-reward imbalance model. The focus of this model is on reciprocity of exchange in occupational life where high-cost/low-gain conditions are considered particularly stressful. Variables measuring low reward in terms of low status control (e.g., lack of promotion prospects, job insecurity) in association with high extrinsic (e.g., work pressure) or intrinsic (personal coping pattern, e.g., high need for control) effort independently predict new cardiovascular events in a prospective study on blue-collar men. Furthermore, these variables partly explain prevalence of cardiovascular risk factors (hypertension, atherogenic lipids) in 2 independent studies. Studying adverse health effects of high-effort/low-reward conditions seems well justified, especially in view of recent developments of the labor market.

Testing quantitative adverse outcome pathway predictions using aromatase inhibitors in female fathead minnows

EPA Science Inventory

To become more efficient and cost effective regulatory toxicology is increasingly averting from whole animal testing toward collecting data at lower levels of biological organization, through such means as in vitro high throughput screening (HTS) assays. When anchored to relevant...

PHOTOCHEMICAL PRODUCTS IN URBAN MIXTURES ENHANCE INFLAMMATORY RESPONSES IN LUNG CELLS

EPA Science Inventory

Complex urban air mixtures that realistically mimic urban smog can be generated for investigating adverse health effects. "Smog chambers" have been used for over 30 yr to conduct experiments for developing and testing photochemical models that predict ambient ozone (O(3)) concent...

Material scientific approach to predict nano materials risk of adverse health effects

NASA Astrophysics Data System (ADS)

Matsui, Yasuto; Miyaoi, Kenichi; Hayashi, Takeshi; Yamaguchi, Yukio

2009-05-01

To estimate the potential risk of nano materials, correlations were investigated between material properties and various biomarkers indicating adverse effects on humans. Nano materials have a variety of properties such as solubility, iso-electric point, crystal shape, BET specific surface area and so on. The purpose of our work was to predict relationships between material properties and hazard data by undertaking statistical survey of eleven papers arguing cell viability assays. The reviewed papers associate cytotoxicity (i) mainly with particle volume and (ii) a certain degree with particle solubility, with relatively large variability of toxicological responses. At present nanomaterials are often very broadly named, defined and categorized based upon only their chief chemical composition or product shape - e.g., "titanium," "carbon black," "nano tubes," etc. Such rough, imprecise categorization serves little or no useful purpose when attempting risk assessments for every nano material produced differently, since even materials with the same name can possess different properties and consequently different degrees of hazards.

Predictors of immune function in space flight

NASA Astrophysics Data System (ADS)

Shearer, William T.; Zhang, Shaojie; Reuben, James M.; Lee, Bang-Ning; Butel, Janet S.

2007-02-01

Of all of the environmental conditions of space flight that might have an adverse effect upon human immunity and the incidence of infection, space radiation stands out as the single-most important threat. As important as this would be on humans engaged in long and deep space flight, it obviously is not possible to plan Earth-bound radiation and infection studies in humans. Therefore, we propose to develop a murine model that could predict the adverse effects of space flight radiation and reactivation of latent virus infection for humans. Recent observations on the effects of gamma and latent virus infection demonstrate latent virus reactivation and loss of T cell mediated immune responses in a murine model. We conclude that using this small animal method of quantitating the amounts of radiation and latent virus infection and resulting alterations in immune responses, it may be possible to predict the degree of immunosuppression in interplanetary space travel for humans. Moreover, this model could be extended to include other space flight conditions, such as microgravity, sleep deprivation, and isolation, to obtain a more complete assessment of space flight risks for humans.

The impact of childhood adversity on suicidality and clinical course in treatment-resistant depression.

PubMed

Tunnard, Catherine; Rane, Lena J; Wooderson, Sarah C; Markopoulou, Kalypso; Poon, Lucia; Fekadu, Abebaw; Juruena, Mario; Cleare, Anthony J

2014-01-01

Childhood adversity is a risk factor for the development of depression and can also affect clinical course. We investigated this specifically in treatment-resistant depression (TRD). One hundred and thirty-seven patients with TRD previously admitted to an inpatient affective disorders unit were included. Clinical, demographic and childhood adversity (physical, sexual, emotional abuse; bullying victimization, traumatic events) data were obtained during admission. Associations between childhood adversity, depressive symptoms and clinical course were investigated. Most patients had experienced childhood adversity (62%), with traumatic events (35%) and bullying victimization (29%) most commonly reported. Childhood adversity was associated with poorer clinical course, including earlier age of onset, episode persistence and recurrence. Logistic regression analyses revealed childhood adversity predicted lifetime suicide attempts (OR 2.79; 95% CI 1.14, 6.84) and childhood physical abuse predicted lifetime psychosis (OR 3.42; 95% CI 1.00, 11.70). The cross-sectional design and retrospective measurement of childhood adversity are limitations of the study. Childhood adversity was common amongst these TRD patients and was associated with poor clinical course, psychosis and suicide attempts. Routine assessment of early adversity may help identify at risk individuals and inform clinical intervention. Copyright © 2013 Elsevier B.V. All rights reserved.

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...

Otorhinolaryngological Toxicities of New Drugs in Oncology.

PubMed

Hartl, Dana M; Morel, Daphné; Saavedra, Erika; Massard, Christophe; Rinaldo, Alessandra; Saba, Nabil F; Ferlito, Alfio; Soria, Jean-Charles

2017-04-01

Many new or relatively new cancer drugs-personalized anticancer agents-have been approved for use in various clinical settings in oncology or are still under evaluation in clinical trials. Targeted therapies as well as new immune checkpoint blockers have toxicity profiles that differ from conventional cytotoxic chemotherapy, and many can cause adverse effects that affect the mouth and pharynx, the nasal cavities, and the larynx. This review aims to provide an overview of current knowledge concerning these side effects and contemporary management. Adverse effects of the mouth/pharynx, nasal cavities, larynx, and cochlear-vestibular system are generally low grade (according to the Common Terminology Criteria for Adverse Events) and generally present non-life-threatening symptoms. However, the impact on patients' quality of life could be important. The incidence and severity vary according to the drug, its target(s), and dose, but there are currently no known predictive factors, and each patient has an individual toxicity profile. Management guidelines are based on expert opinion. These ear, nose, and throat adverse effects are not frequently mentioned in the literature because of the often non-specific nature of the symptoms and their mildness, but also the absence of specific treatment. These symptoms can contribute to decreased quality of life and lead to drug compliance issues if not diagnosed and managed appropriately.

Development of a Screening Tool for Predicting Adverse Outcomes of Gestational Diabetes Mellitus

PubMed Central

Park, Jee Soo; Kim, Deok Won; Kwon, Ja-Young; Park, Yong Won; Kim, Young Han; Cho, Hee Young

2016-01-01

Abstract Gestational diabetes mellitus (GDM) is a common disease in pregnancy causing maternal and fetal complications. To prevent these adverse outcomes, optimal screening and diagnostic criteria must be adequate, timely, and efficient. This study suggests a novel approach that is practical, efficient, and patient- and clinician-friendly in predicting adverse outcomes of GDM. The authors conducted a retrospective cohort study via medical record review of patients admitted between March 2001 and April 2013 at the Severance Hospital, Seoul, South Korea. Patients diagnosed by a conventional 2-step method were evaluated according to the presence of adverse outcomes (neonatal hypoglycemia, hyperbilirubinemia, and hyperinsulinemia; admission to the neonatal intensive care unit; large for gestational age; gestational insulin therapy; and gestational hypertension). Of 802 women who had an abnormal 50-g, 1-hour glucose challenge test, 306 were diagnosed with GDM and 496 did not have GDM (false-positive group). In the GDM group, 218 women (71.2%) had adverse outcomes. In contrast, 240 women (48.4%) in the false-positive group had adverse outcomes. Women with adverse outcomes had a significantly higher body mass index (BMI) at entry (P = 0.03) and fasting blood glucose (FBG) (P = 0.03). Our logistic regression model derived from 2 variables, BMI at entry and FBG, predicted GDM adverse outcome with an area under the curve of 0.642, accuracy of 61.3%, sensitivity of 57.2%, and specificity of 66.9% compared with the conventional 2-step method with an area under the curve of 0.610, accuracy of 59.1%, sensitivity of 47.6%, and specificity of 74.4%. Our model performed better in predicting GDM adverse outcomes than the conventional 2-step method using only BMI at entry and FBG. Moreover, our model represents a practical, inexpensive, efficient, reproducible, easy, and patient- and clinician-friendly approach. PMID:26735528

Development of a Screening Tool for Predicting Adverse Outcomes of Gestational Diabetes Mellitus: A Retrospective Cohort Study.

PubMed

Park, Jee Soo; Kim, Deok Won; Kwon, Ja-Young; Park, Yong Won; Kim, Young Han; Cho, Hee Young

2016-01-01

Gestational diabetes mellitus (GDM) is a common disease in pregnancy causing maternal and fetal complications. To prevent these adverse outcomes, optimal screening and diagnostic criteria must be adequate, timely, and efficient. This study suggests a novel approach that is practical, efficient, and patient- and clinician-friendly in predicting adverse outcomes of GDM. The authors conducted a retrospective cohort study via medical record review of patients admitted between March 2001 and April 2013 at the Severance Hospital, Seoul, South Korea. Patients diagnosed by a conventional 2-step method were evaluated according to the presence of adverse outcomes (neonatal hypoglycemia, hyperbilirubinemia, and hyperinsulinemia; admission to the neonatal intensive care unit; large for gestational age; gestational insulin therapy; and gestational hypertension). Of 802 women who had an abnormal 50-g, 1-hour glucose challenge test, 306 were diagnosed with GDM and 496 did not have GDM (false-positive group). In the GDM group, 218 women (71.2%) had adverse outcomes. In contrast, 240 women (48.4%) in the false-positive group had adverse outcomes. Women with adverse outcomes had a significantly higher body mass index (BMI) at entry (P = 0.03) and fasting blood glucose (FBG) (P = 0.03). Our logistic regression model derived from 2 variables, BMI at entry and FBG, predicted GDM adverse outcome with an area under the curve of 0.642, accuracy of 61.3%, sensitivity of 57.2%, and specificity of 66.9% compared with the conventional 2-step method with an area under the curve of 0.610, accuracy of 59.1%, sensitivity of 47.6%, and specificity of 74.4%. Our model performed better in predicting GDM adverse outcomes than the conventional 2-step method using only BMI at entry and FBG. Moreover, our model represents a practical, inexpensive, efficient, reproducible, easy, and patient- and clinician-friendly approach.

Prediction of human population responses to toxic compounds by a collaborative competition.

PubMed

Eduati, Federica; Mangravite, Lara M; Wang, Tao; Tang, Hao; Bare, J Christopher; Huang, Ruili; Norman, Thea; Kellen, Mike; Menden, Michael P; Yang, Jichen; Zhan, Xiaowei; Zhong, Rui; Xiao, Guanghua; Xia, Menghang; Abdo, Nour; Kosyk, Oksana; Friend, Stephen; Dearry, Allen; Simeonov, Anton; Tice, Raymond R; Rusyn, Ivan; Wright, Fred A; Stolovitzky, Gustavo; Xie, Yang; Saez-Rodriguez, Julio

2015-09-01

The ability to computationally predict the effects of toxic compounds on humans could help address the deficiencies of current chemical safety testing. Here, we report the results from a community-based DREAM challenge to predict toxicities of environmental compounds with potential adverse health effects for human populations. We measured the cytotoxicity of 156 compounds in 884 lymphoblastoid cell lines for which genotype and transcriptional data are available as part of the Tox21 1000 Genomes Project. The challenge participants developed algorithms to predict interindividual variability of toxic response from genomic profiles and population-level cytotoxicity data from structural attributes of the compounds. 179 submitted predictions were evaluated against an experimental data set to which participants were blinded. Individual cytotoxicity predictions were better than random, with modest correlations (Pearson's r < 0.28), consistent with complex trait genomic prediction. In contrast, predictions of population-level response to different compounds were higher (r < 0.66). The results highlight the possibility of predicting health risks associated with unknown compounds, although risk estimation accuracy remains suboptimal.

Separate and cumulative effects of adverse childhood experiences in predicting adult health and health care utilization.

PubMed

Chartier, Mariette J; Walker, John R; Naimark, Barbara

2010-06-01

Objectives of this population-based study were: (1) to examine the relative contribution of childhood abuse and other adverse childhood experiences to poor adult health and increased health care utilization and (2) to examine the cumulative effects of adverse childhood experiences on adult health and health care utilization. Data from the Ontario Health Survey, a representative population sample (n=9,953) of respondents aged 15 years and older, were analyzed using logistic regression. Adverse childhood experiences examined were childhood physical and sexual abuse, parental marital conflict, poor parent-child relationship, low parental education and parental psychopathology. Most (72%) respondents reported at least one adverse childhood experience and a considerable proportion of respondents (37%) reported two or more of these experiences. In examining the bivariate models, childhood physical and sexual abuse had a stronger influence than other types of adverse childhood experiences. With the addition of other adverse childhood experiences in the model, the odds ratios for childhood abuse were attenuated but remained statistically significant for most health outcomes. This suggests that childhood abuse may have a unique adverse influence on the development of poor adult health. When an aggregate variable was created to explore the cumulative effects of adverse childhood experience, the odds were increased, with each additional experience, for reporting multiple health problems [odds ratio (OR): 1.22], poor self-rated health (OR: 1.18), pain (OR: 1.24), disability (OR: 1.24), general practitioner use (OR: 1.12), emergency room use (OR: 1.29) and health professional use (OR: 1.19). This study suggests that childhood abuse and other adverse childhood experiences are overlapping risk factors for long-term adult health problems and that the accumulation of these adverse experiences increases the risk of poor adult health. This study highlights the importance of the many adverse childhood experiences influencing long-term health. In practice, childhood abuse is often difficult to identify as families tend to keep it hidden and reported cases represent only a small percentage of the actual cases. Assessments and interventions which focus on improving socio-economic status, strengthening marital and parent-child relationships, and supporting parents with mental health issues are less threatening for families than assessing their experiences with abuse and neglect and are more likely to be effective in identifying and supporting at-risk families. Copyright 2010 Elsevier Ltd. All rights reserved.

Three years of biomedical FEL use in medicine and surgery How far have we come?

NASA Astrophysics Data System (ADS)

Jean, Benedikt

1997-02-01

Since the FEL has been made available for biophysical research in the IR, it has revolutionized the optimization strategies of laser-tissue interaction and the minimizing of adverse effects, in particular for photoablative use in surgery. Its tunability together with the free combination of wavelength and energy made it an efficient research tool, allowing the reduction of risks and costs of preclinical biomedical research. New computer-assisted surgical techniques evolved and the broader data basis of IR photothermal ablation allows more accurate predictive modelling of the efficiency and the adverse effects of photoablation. New applications for diagnostic imaging as well as the first clinical applications in neurosurgery lay ahead.

Causal beliefs of the public and social acceptance of persons with mental illness: a comparative analysis of schizophrenia, depression and alcohol dependence.

PubMed

Schomerus, G; Matschinger, H; Angermeyer, M C

2014-01-01

There is an ongoing debate whether biological illness explanations improve tolerance towards persons with mental illness or not. Several theoretical models have been proposed to predict the relationship between causal beliefs and social acceptance. This study uses path models to compare different theoretical predictions regarding attitudes towards persons with schizophrenia, depression and alcohol dependence. In a representative population survey in Germany (n = 3642), we elicited agreement with belief in biogenetic causes, current stress and childhood adversities as causes of either disorder as described in an unlabelled case vignette. We further elicited potentially mediating attitudes related to different theories about the consequences of biogenetic causal beliefs (attribution theory: onset responsibility, offset responsibility; genetic essentialism: differentness, dangerousness; genetic optimism: treatability) and social acceptance. For each vignette condition, we calculated a multiple mediator path model containing all variables. Biogenetic beliefs were associated with lower social acceptance in schizophrenia and depression, and with higher acceptance in alcohol dependence. In schizophrenia and depression, perceived differentness and dangerousness mediated the largest indirect effects, the consequences of biogenetic causal explanations thus being in accordance with the predictions of genetic essentialism. Psychosocial causal beliefs had differential effects: belief in current stress as a cause was associated with higher acceptance in schizophrenia, while belief in childhood adversities resulted in lower acceptance of a person with depression. Biological causal explanations seem beneficial in alcohol dependence, but harmful in schizophrenia and depression. The negative correlates of believing in childhood adversities as a cause of depression merit further exploration.

Early cumulative risk predicts externalizing behavior at age 10: The mediating role of adverse parenting.

PubMed

Gach, Emily J; Ip, Ka I; Sameroff, Arnold J; Olson, Sheryl L

2018-02-01

Multiple environmental risk factors in early childhood predict a broad range of adverse developmental outcomes. However, most prior longitudinal research has not illuminated explanatory mechanisms. Our main goals were to examine predictive associations between cumulative ecological risk factors in early childhood and children's later externalizing problems and to determine whether these associations were explained by variations in parenting quality. Participants were 241 children (118 girls) at risk for school-age conduct problems and their parents and teachers. Children were approximately 3 years old at Time 1 (T1) and 10 years old at Time 2 (T2). Reports of contextual risk at T1 were used to develop a cumulative risk index consisting of 6 singular risk variables from 3 ecological levels: social resources (low income; social isolation), family resources (marital aggression; poor total family functioning), and maternal resources (single parent status; poor maternal mental health). At T1, parenting variables were measured (corporal punishment, warm responsiveness, maternal efficacy, and negative perceptions of child behavior). At T2, mothers, fathers, and teachers reported child externalizing problems. Johnson's relative weight analysis revealed that the cumulative risk index was a more powerful predictor of age 10 years externalizing behavior than any of the singular contextual risk variables. Adverse parenting mediated the effects of cumulative risk on later child externalizing problems. Our findings have significant implications for understanding long-term effects of multiple contextual risk factors present in early childhood and for the implementation of positive parenting interventions early on. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Maternal prenatal felt security and infant health at birth interact to predict infant fussing and crying at 12 months postpartum.

PubMed

Sawada, Natsumi; Gagné, Faby M; Séguin, Louise; Kramer, Michael S; McNamara, Helen; Platt, Robert W; Goulet, Lise; Meaney, Michael J; Lydon, John E

2015-08-01

Infants born with medical problems are at risk for less optimal developmental outcomes. This may be, in part, because neonatal medical problems are associated with maternal distress, which may adversely impact infants. However, the reserve capacity model suggests that an individual's bank of psychosocial resources buffers the adverse effects of later-encountered stressors. This prospective longitudinal study examined whether preexisting maternal psychosocial resources, conceptualized as felt security in close relationships, moderate the association between neonatal medical problems and infant fussing and crying 12 months postpartum. Maternal felt security was measured by assessing its indicators in 5,092 pregnant women. At birth, infants were classified as healthy or having a medical problem. At 12 months, experience sampling was used to assess daily maternal reports of fussing and crying in 135 mothers of infants who were healthy or had medical problems at birth. Confirmatory factor analyses revealed that attachment, relationship quality, self-esteem, and social support can be conceptualized as indicators of a single felt security factor. Multiple regression analyses revealed that prenatal maternal felt security interacts with infant health at birth to predict fussing and crying at 12 months. Among infants born with medical problems, higher felt security predicted decreased fussing and crying. Maternal felt security assessed before birth dampens the association between neonatal medical problems and subsequent infant behavior. This supports the hypothesis that psychosocial resources in reserve can be called upon in the face of a stressor to reduce its adverse effects on the self or others. (c) 2015 APA, all rights reserved).

Identifying crash-prone traffic conditions under different weather on freeways.

PubMed

Xu, Chengcheng; Wang, Wei; Liu, Pan

2013-09-01

Understanding the relationships between traffic flow characteristics and crash risk under adverse weather conditions will help highway agencies develop proactive safety management strategies to improve traffic safety in adverse weather conditions. The primary objective is to develop separate crash risk prediction models for different weather conditions. The crash data, weather data, and traffic data used in this study were collected on the I-880N freeway in California in 2008 and 2010. This study considered three different weather conditions: clear weather, rainy weather, and reduced visibility weather. The preliminary analysis showed that there was some heterogeneity in the risk estimates for traffic flow characteristics by weather conditions, and that the crash risk prediction model for all weather conditions cannot capture the impacts of the traffic flow variables on crash risk under adverse weather conditions. The Bayesian random intercept logistic regression models were applied to link the likelihood of crash occurrence with various traffic flow characteristics under different weather conditions. The crash risk prediction models were compared to their corresponding logistic regression model. It was found that the random intercept model improved the goodness-of-fit of the crash risk prediction models. The model estimation results showed that the traffic flow characteristics contributing to crash risk were different across different weather conditions. The speed difference between upstream and downstream stations was found to be significant in each crash risk prediction model. Speed difference between upstream and downstream stations had the largest impact on crash risk in reduced visibility weather, followed by that in rainy weather. The ROC curves were further developed to evaluate the predictive performance of the crash risk prediction models under different weather conditions. The predictive performance of the crash risk model for clear weather was better than those of the crash risk models for adverse weather conditions. The research results could promote a better understanding of the impacts of traffic flow characteristics on crash risk under adverse weather conditions, which will help transportation professionals to develop better crash prevention strategies in adverse weather. Copyright © 2013 National Safety Council and Elsevier Ltd. All rights reserved.

Immune-mediated Adverse Effects of Anti-CTLA-4 Antibody Therapy in Metastatic Melanoma

PubMed Central

Quirk, Shannon K.; Shure, Anna K.; Agrawal, Devendra K.

2015-01-01

Ipilimumab, an antibody that blocks cytotoxic T lymphocyte-associated antigen-4 (CTLA-4; CD152), was approved by the Food and Drug Administration (FDA) in 2011 for the treatment of unresectable stage III or IV malignant melanoma. Although the addition of this particular immunotherapy has broadened treatment options, immune-related adverse events (irAEs) are associated with ipilimumab therapy, including dermatologic effects, colitis and diarrhea, endocrine effects, hepatotoxicity, ocular effects, renal effects, neurologic effects, and others. In this article, a critical evaluation of the underlying mechanisms of irAEs associated with anti-CTLA-4 therapy is presented. Additionally, potentially beneficial effects of combinational therapies to alleviate ipilimumab-induced irAEs in malignant melanoma are discussed. Future research is warranted to elucidate the efficacy of such combination therapies as well as specific biomarkers that would help to predict a clinical response to ipilimumab in patients with malignant melanoma. PMID:26118951

Growing up with adversity: From juvenile justice involvement to criminal persistence and psychosocial problems in young adulthood.

PubMed

Basto-Pereira, Miguel; Miranda, Ana; Ribeiro, Sofia; Maia, Ângela

2016-12-01

Several studies have been carried out to investigate the effect of child maltreatment on juvenile justice involvement and future criminal life. However, little is known about the impact of other forms of adversity, beyond abuse and neglect, on juvenile delinquency and criminal persistence. The effect of early adversity on psychosocial problems is underexplored, particularly in juvenile delinquents. This study, using the Childhood Adverse Experiences (ACE) questionnaire, a tool accessing the exposure to different types of abuse, neglect and serious household dysfunction, explored the role of each adverse experience on juvenile justice involvement, persistence in crime and psychosocial problems during young adulthood. A Portuguese sample of 75 young adults with official records of juvenile delinquency in 2010/2011, and 240 young adults from a community sample completed ACE questionnaire and measures of psychosocial adjustment. Seven out of ten adverse experiences were significantly more prevalent in young adults with juvenile justice involvement than in the community sample, after matching the main demographic variables. The strongest predictor of juvenile justice involvement and criminal persistence during early adulthood was sexual abuse. Dimensions of child/adolescent emotional maltreatment and a mental illness in the household predicted a set of psychosocial problems in young adulthood. This study indicates that early adversity is significantly related to juvenile justice involvement, criminal persistence and psychosocial problems. This study also suggests that each experience has a different role in this process. There is an urgent need to screen, prevent and stop serious adversity. Future scientific directions and recommendations for policies are provided. Copyright © 2016 Elsevier Ltd. All rights reserved.

Prior adversities predict posttraumatic stress reactions in adolescents following the Oslo Terror events 2011

PubMed Central

Nordanger, Dag Ø.; Breivik, Kyrre; Haugland, Bente Storm; Lehmann, Stine; Mæhle, Magne; Braarud, Hanne Cecilie; Hysing, Mari

2014-01-01

Background Former studies suggest that prior exposure to adverse experiences such as violence or sexual abuse increases vulnerability to posttraumatic stress reactions in victims of subsequent trauma. However, little is known about how such a history affects responses to terror in the general adolescent population. Objective To explore the role of prior exposure to adverse experiences as risk factors for posttraumatic stress reactions to the Oslo Terror events. Method We used data from 10,220 high school students in a large cross-sectional survey of adolescents in Norway that took place seven months after the Oslo Terror events. Prior exposure assessed was: direct exposure to violence, witnessing of violence, and unwanted sexual acts. We explored how these prior adversities interact with well-established risk factors such as proximity to the events, perceived life threat during the terror events, and gender. Results All types of prior exposure as well as the other risk factors were associated with terror-related posttraumatic stress reactions. The effects of prior adversities were, although small, independent of adolescents’ proximity to the terror events. Among prior adversities, only the effect of direct exposure to violence was moderated by perceived life threat. Exposure to prior adversities increased the risk of posttraumatic stress reactions equally for both genders, but proximity to the terror events and perceived life threat increased the risk more in females. Conclusions Terror events can have a more destabilizing impact on victims of prior adversities, independent of their level of exposure. The findings may be relevant to mental health workers and others providing post-trauma health care. PMID:24872862

Prior adversities predict posttraumatic stress reactions in adolescents following the Oslo Terror events 2011.

PubMed

Nordanger, Dag Ø; Breivik, Kyrre; Haugland, Bente Storm; Lehmann, Stine; Mæhle, Magne; Braarud, Hanne Cecilie; Hysing, Mari

2014-01-01

Former studies suggest that prior exposure to adverse experiences such as violence or sexual abuse increases vulnerability to posttraumatic stress reactions in victims of subsequent trauma. However, little is known about how such a history affects responses to terror in the general adolescent population. To explore the role of prior exposure to adverse experiences as risk factors for posttraumatic stress reactions to the Oslo Terror events. We used data from 10,220 high school students in a large cross-sectional survey of adolescents in Norway that took place seven months after the Oslo Terror events. Prior exposure assessed was: direct exposure to violence, witnessing of violence, and unwanted sexual acts. We explored how these prior adversities interact with well-established risk factors such as proximity to the events, perceived life threat during the terror events, and gender. All types of prior exposure as well as the other risk factors were associated with terror-related posttraumatic stress reactions. The effects of prior adversities were, although small, independent of adolescents' proximity to the terror events. Among prior adversities, only the effect of direct exposure to violence was moderated by perceived life threat. Exposure to prior adversities increased the risk of posttraumatic stress reactions equally for both genders, but proximity to the terror events and perceived life threat increased the risk more in females. Terror events can have a more destabilizing impact on victims of prior adversities, independent of their level of exposure. The findings may be relevant to mental health workers and others providing post-trauma health care.

20171015 - Integrating Toxicity, Toxicokinetic, and Exposure Data for Risk-based Chemical Alternatives Assessment (ISES)

EPA Science Inventory

In order to predict the margin between the dose needed for adverse chemical effects and actual human exposure rates, data on hazard, exposure, and toxicokinetics are needed. In vitro methods, biomonitoring, and mathematical modeling have provided initial estimates for many extant...

INTERPRETING SPONTANEOUS RENAL LESIONS IN SAFETY AND RISK ASSESSMENT

EPA Science Inventory

Interpreting Spontaneous Renal Lesions in Safety and Risk Assessment
Douglas C. Wolf, D.V.M., Ph.D.

Introduction

Risk assessment is a process whereby the potential adverse health effects from exposure to a xenobiotic are predicted after evaluation of the availab...

Molecular Target Homology as a Basis for Species Extrapolation to Assess the Ecological Risk of Veterinary Drugs

EPA Science Inventory

Increased identification of veterinary pharmaceutical contaminants in aquatic environments has raised concerns regarding potential adverse effects of these chemicals on non-target organisms. The purpose of this work was to develop a method for predictive species extrapolation ut...

A 21st Century Roadmap for Human Health Risk Assessment

EPA Science Inventory

For decades human health risk assessment has depended primarily on animal testing to predict adverse effects in humans, but that paradigm has come under question because of calls for more accurate information, less use of animals, and more efficient use of resources. Moreover, t...

The Analysis of Genomic Dose-Response Data in the EPA ToxCast™ Program

EPA Science Inventory

The U.S. EPA must assess the potential adverse effects of thousands of chemicals, often with limited toxicity information. Accurate toxicity predictions will help prioritize chemicals for further testing, focusing resources on the greater potential hazards or risks. In vitro geno...

The Use of Graphs as Decision Aids in Relation to Information Overload and Managerial Decision Quality.

ERIC Educational Resources Information Center

Chan, Siu Y.

2001-01-01

Discussion of information overload focuses on a study of masters degree students at a Hong Kong university that investigated the effectiveness of graphs as decision aids to reduce adverse effects of information overload on decision quality. Results of a simulation of a business prediction task with a sample of business managers are presented.…

Computational Approaches for Identifying Adverse Outcome Pathways

EPA Science Inventory

Adverse Outcome Pathways (AOPs) provide a framework for organizing toxicity information to improve predictions of the potential adverse impact of environment stressors on humans or wildlife populations, but these benefits are currently limited by the small number of AOPs currentl...

The zone of comfort: Predicting visual discomfort with stereo displays

PubMed Central

Shibata, Takashi; Kim, Joohwan; Hoffman, David M.; Banks, Martin S.

2012-01-01

Recent increased usage of stereo displays has been accompanied by public concern about potential adverse effects associated with prolonged viewing of stereo imagery. There are numerous potential sources of adverse effects, but we focused on how vergence–accommodation conflicts in stereo displays affect visual discomfort and fatigue. In one experiment, we examined the effect of viewing distance on discomfort and fatigue. We found that conflicts of a given dioptric value were slightly less comfortable at far than at near distance. In a second experiment, we examined the effect of the sign of the vergence–accommodation conflict on discomfort and fatigue. We found that negative conflicts (stereo content behind the screen) are less comfortable at far distances and that positive conflicts (content in front of screen) are less comfortable at near distances. In a third experiment, we measured phoria and the zone of clear single binocular vision, which are clinical measurements commonly associated with correcting refractive error. Those measurements predicted susceptibility to discomfort in the first two experiments. We discuss the relevance of these findings for a wide variety of situations including the viewing of mobile devices, desktop displays, television, and cinema. PMID:21778252

The zone of comfort: Predicting visual discomfort with stereo displays.

PubMed

Shibata, Takashi; Kim, Joohwan; Hoffman, David M; Banks, Martin S

2011-07-21

Recent increased usage of stereo displays has been accompanied by public concern about potential adverse effects associated with prolonged viewing of stereo imagery. There are numerous potential sources of adverse effects, but we focused on how vergence-accommodation conflicts in stereo displays affect visual discomfort and fatigue. In one experiment, we examined the effect of viewing distance on discomfort and fatigue. We found that conflicts of a given dioptric value were slightly less comfortable at far than at near distance. In a second experiment, we examined the effect of the sign of the vergence-accommodation conflict on discomfort and fatigue. We found that negative conflicts (stereo content behind the screen) are less comfortable at far distances and that positive conflicts (content in front of screen) are less comfortable at near distances. In a third experiment, we measured phoria and the zone of clear single binocular vision, which are clinical measurements commonly associated with correcting refractive error. Those measurements predicted susceptibility to discomfort in the first two experiments. We discuss the relevance of these findings for a wide variety of situations including the viewing of mobile devices, desktop displays, television, and cinema.

Near Real-Time Optimal Prediction of Adverse Events in Aviation Data

NASA Technical Reports Server (NTRS)

Martin, Rodney Alexander; Das, Santanu

2010-01-01

The prediction of anomalies or adverse events is a challenging task, and there are a variety of methods which can be used to address the problem. In this paper, we demonstrate how to recast the anomaly prediction problem into a form whose solution is accessible as a level-crossing prediction problem. The level-crossing prediction problem has an elegant, optimal, yet untested solution under certain technical constraints, and only when the appropriate modeling assumptions are made. As such, we will thoroughly investigate the resilience of these modeling assumptions, and show how they affect final performance. Finally, the predictive capability of this method will be assessed by quantitative means, using both validation and test data containing anomalies or adverse events from real aviation data sets that have previously been identified as operationally significant by domain experts. It will be shown that the formulation proposed yields a lower false alarm rate on average than competing methods based on similarly advanced concepts, and a higher correct detection rate than a standard method based upon exceedances that is commonly used for prediction.

Efficacy of N-Acetylcysteine in Idiopathic Pulmonary Fibrosis

PubMed Central

Sun, Tong; Liu, Jing; Zhao, De Wei

2016-01-01

Abstract There are a number of conflicting reports describing the clinical outcomes of using N-acetylcysteine for the treatment of idiopathic pulmonary fibrosis. We have, therefore, performed a meta-analysis to evaluate the efficacy of N-acetylcysteine, compared with control, for the treatment of idiopathic pulmonary fibrosis. Original controlled clinical trials evaluating the efficacy of N-acetylcysteine for the treatment of idiopathic pulmonary fibrosis were included in the analysis. Searches for relevant articles were carried out in July 2014 by 2 independent researchers using PubMed, Embase, Cochrane Central, and Google Scholar. Change in forced vital capacity, change in percentage of predicted vital capacity, change in percentage of predicted carbon monoxide diffusing capacity, changes in 6 minutes walking test distance, rate of adverse events, and rate of death were expressed as outcomes using RevMan 5.0.1. Five trials, with a total of 564 patients, were included in this meta-analysis. The meta-analysis showed that the control group had significant decreases in percentage of predicted vital capacity (standardized mean difference [SMD] = 0.37; 95% confidence interval [CI]: 0.13 to −0.62; P = 0.003) and 6 minutes walking test distance (SMD = 0.25; 95% CI: 0.02–0.48; P = 0.04). There were no statistically significant differences in forced vital capacity (SMD = 0.07; 95% CI: −0.13–0.27; P = 0.52), percentage of predicted carbon monoxide diffusing capacity (SMD = 0.12; 95% CI: −0.06–0.30; P = 0.18), rates of adverse events (odd ratio = 4.50; 95% CI: 0.19–106.41; P = 0.35), or death rates (odd ratio = 1.79; 95% CI: 0.3–5.12; P = 0.28) between the N-acetylcysteine group and the control group. N-Acetylcysteine was found to have a significant effect only on decreases in percentage of predicted vital capacity and 6 minutes walking test distance. N-acetylcysteine showed no beneficial effect on changes in forced vital capacity, changes in predicted carbon monoxide diffusing capacity, rates of adverse events, or death rates. PMID:27175674

Efficacy of N-Acetylcysteine in Idiopathic Pulmonary Fibrosis: A Systematic Review and Meta-Analysis.

PubMed

Sun, Tong; Liu, Jing; Zhao, De Wei

2016-05-01

There are a number of conflicting reports describing the clinical outcomes of using N-acetylcysteine for the treatment of idiopathic pulmonary fibrosis. We have, therefore, performed a meta-analysis to evaluate the efficacy of N-acetylcysteine, compared with control, for the treatment of idiopathic pulmonary fibrosis.Original controlled clinical trials evaluating the efficacy of N-acetylcysteine for the treatment of idiopathic pulmonary fibrosis were included in the analysis. Searches for relevant articles were carried out in July 2014 by 2 independent researchers using PubMed, Embase, Cochrane Central, and Google Scholar. Change in forced vital capacity, change in percentage of predicted vital capacity, change in percentage of predicted carbon monoxide diffusing capacity, changes in 6 minutes walking test distance, rate of adverse events, and rate of death were expressed as outcomes using RevMan 5.0.1.Five trials, with a total of 564 patients, were included in this meta-analysis. The meta-analysis showed that the control group had significant decreases in percentage of predicted vital capacity (standardized mean difference [SMD] = 0.37; 95% confidence interval [CI]: 0.13 to -0.62; P = 0.003) and 6 minutes walking test distance (SMD = 0.25; 95% CI: 0.02-0.48; P = 0.04). There were no statistically significant differences in forced vital capacity (SMD = 0.07; 95% CI: -0.13-0.27; P = 0.52), percentage of predicted carbon monoxide diffusing capacity (SMD = 0.12; 95% CI: -0.06-0.30; P = 0.18), rates of adverse events (odd ratio = 4.50; 95% CI: 0.19-106.41; P = 0.35), or death rates (odd ratio = 1.79; 95% CI: 0.3-5.12; P = 0.28) between the N-acetylcysteine group and the control group.N-Acetylcysteine was found to have a significant effect only on decreases in percentage of predicted vital capacity and 6 minutes walking test distance. N-acetylcysteine showed no beneficial effect on changes in forced vital capacity, changes in predicted carbon monoxide diffusing capacity, rates of adverse events, or death rates.

An antenatal prediction model for adverse birth outcomes in an urban population: The contribution of medical and non-medical risks.

PubMed

Posthumus, A G; Birnie, E; van Veen, M J; Steegers, E A P; Bonsel, G J

2016-07-01

in the Netherlands the perinatal mortality rate is high compared to other European countries. Around eighty percent of perinatal mortality cases is preceded by being small for gestational age (SGA), preterm birth and/or having a low Apgar-score at 5 minutes after birth. Current risk detection in pregnancy focusses primarily on medical risks. However, non-medical risk factors may be relevant too. Both non-medical and medical risk factors are incorporated in the Rotterdam Reproductive Risk Reduction (R4U) scorecard. We investigated the associations between R4U risk factors and preterm birth, SGA and a low Apgar score. a prospective cohort study under routine practice conditions. six midwifery practices and two hospitals in Rotterdam, the Netherlands. 836 pregnant women. the R4U scorecard was filled out at the booking visit. after birth, the follow-up data on pregnancy outcomes were collected. Multivariate logistic regression was used to fit models for the prediction of any adverse outcome (preterm birth, SGA and/or a low Apgar score), stratified for ethnicity and socio-economic status (SES). factors predicting any adverse outcome for Western women were smoking during the first trimester and over-the-counter medication. For non-Western women risk factors were teenage pregnancy, advanced maternal age and an obstetric history of SGA. Risk factors for high SES women were low family income, no daily intake of vegetables and a history of preterm birth. For low SES women risk factors appeared to be low family income, non-Western ethnicity, smoking during the first trimester and a history of SGA. the presence of both medical and non-medical risk factors early in pregnancy predict the occurrence of adverse outcomes at birth. Furthermore the risk profiles for adverse outcomes differed according to SES and ethnicity. to optimise effective risk selection, both medical and non-medical risk factors should be taken into account in midwifery and obstetric care at the booking visit. Copyright © 2016. Published by Elsevier Ltd.

Effects of psychosocial work factors on lifestyle changes: a cohort study.

PubMed

Allard, Karin Olofsson; Thomsen, Jane Frølund; Mikkelsen, Sigurd; Rugulies, Reiner; Mors, Ole; Kærgaard, Anette; Kolstad, Henrik A; Kaerlev, Linda; Andersen, Johan Hviid; Hansen, Ase Marie; Bonde, Jens Peter

2011-12-01

To evaluate the effect of the demand-control-support model, the effort-reward imbalance model, and emotional demands on smoking, alcohol consumption, physical activity, and body mass index. This is a 2-year prospective cohort study of 3224 public sector employees. Measures were assessed with questionnaires. Multiple regression analyses were used to predict changes in lifestyle factors. Low reward predicted smoking, low-decision latitude predicted being inactive, and high demands predicted high-alcohol consumption but only for men at follow-up even after controlling for potential confounders. There were no other significant findings in the expected direction except for some of the confounders. We found only limited and inconsistent support for the hypothesis that a poor psychosocial work environment is associated with an adverse lifestyle.

Current nonclinical testing paradigm enables safe entry to First-In-Human clinical trials: The IQ consortium nonclinical to clinical translational database.

PubMed

Monticello, Thomas M; Jones, Thomas W; Dambach, Donna M; Potter, David M; Bolt, Michael W; Liu, Maggie; Keller, Douglas A; Hart, Timothy K; Kadambi, Vivek J

2017-11-01

The contribution of animal testing in drug development has been widely debated and challenged. An industry-wide nonclinical to clinical translational database was created to determine how safety assessments in animal models translate to First-In-Human clinical risk. The blinded database was composed of 182 molecules and contained animal toxicology data coupled with clinical observations from phase I human studies. Animal and clinical data were categorized by organ system and correlations determined. The 2×2 contingency table (true positive, false positive, true negative, false negative) was used for statistical analysis. Sensitivity was 48% with a 43% positive predictive value (PPV). The nonhuman primate had the strongest performance in predicting adverse effects, especially for gastrointestinal and nervous system categories. When the same target organ was identified in both the rodent and nonrodent, the PPV increased. Specificity was 84% with an 86% negative predictive value (NPV). The beagle dog had the strongest performance in predicting an absence of clinical adverse effects. If no target organ toxicity was observed in either test species, the NPV increased. While nonclinical studies can demonstrate great value in the PPV for certain species and organ categories, the NPV was the stronger predictive performance measure across test species and target organs indicating that an absence of toxicity in animal studies strongly predicts a similar outcome in the clinic. These results support the current regulatory paradigm of animal testing in supporting safe entry to clinical trials and provide context for emerging alternate models. Copyright © 2017 Elsevier Inc. All rights reserved.

By-product mutualism and the ambiguous effects of harsher environments - A game-theoretic model.

PubMed

De Jaegher, Kris; Hoyer, Britta

2016-03-21

We construct two-player two-strategy game-theoretic models of by-product mutualism, where our focus lies on the way in which the probability of cooperation among players is affected by the degree of adversity facing the players. In our first model, cooperation consists of the production of a public good, and adversity is linked to the degree of complementarity of the players׳ efforts in producing the public good. In our second model, cooperation consists of the defense of a public, and/or a private good with by-product benefits, and adversity is measured by the number of random attacks (e.g., by a predator) facing the players. In both of these models, our analysis confirms the existence of the so-called boomerang effect, which states that in a harsh environment, the individual player has few incentives to unilaterally defect in a situation of joint cooperation. Focusing on such an effect in isolation leads to the "common-enemy" hypothesis that a larger degree of adversity increases the probability of cooperation. Yet, we also find that a sucker effect may simultaneously exist, which says that in a harsh environment, the individual player has few incentives to unilaterally cooperate in a situation of joint defection. Looked at in isolation, the sucker effect leads to the competing hypothesis that a larger degree of adversity decreases the probability of cooperation. Our analysis predicts circumstances in which the "common enemy" hypothesis prevails, and circumstances in which the competing hypothesis prevails. Copyright © 2016 Elsevier Ltd. All rights reserved.

Associations of early childhood adversities with mental disorders, psychological functioning, and suitability for psychotherapy in adulthood.

PubMed

Heinonen, Erkki; Knekt, Paul; Härkänen, Tommi; Virtala, Esa; Lindfors, Olavi

2018-06-01

Childhood adversities frequently precede adulthood depression and anxiety. Yet, how they impact needed treatment duration, type or focus in these common disorders, is unclear. For developing more individualized and precise interventions, we investigated whether specific early adversities associate with patients' distinct psychiatric problems, psychological vulnerabilities, and suitability for psychotherapy. A total of 221 depressed and anxious adult outpatients (excluding psychotic, severe personality, bipolar, and substance abuse disorders) referred from community, student, occupational, and private healthcare services filled the Childhood Family Atmosphere Questionnaire (CFAQ). They also filled self-reports on interpersonal behavior and problems, perceived competence, dispositional optimism, sense of coherence, defenses, and psychiatric history. Clinicians assessed the patients' symptomatology, personality, object relations, cognitive performance, and psychotherapy suitability. Regression analyses were conducted. Childhood adversities predicted both worse current psychological functioning (e.g., interpersonal problems), and better clinician-rated capacities for benefiting from psychotherapy (e.g. self-reflection, capacity for interaction). Parental problems had the most numerous negative associations to psychological functioning. Best capacities for psychotherapy were predicted by recollected family unhappiness. Associations with psychiatric criteria were, however, largely non-significant. In conclusion, for psychosocial treatment planning, patients' early adversities may indicate both vulnerability and resources. As childhood adversities are frequent among treatment-seekers, further studies examining how early adversities predict psychotherapy outcome are needed. Copyright © 2018. Published by Elsevier B.V.

New developments and concepts related to biomarker application to vaccines

PubMed Central

Ahmed, S. Sohail; Black, Steve; Ulmer, Jeffrey

2012-01-01

Summary This minireview will provide a perspective on new developments and concepts related to biomarker applications for vaccines. In the context of preventive vaccines, biomarkers have the potential to predict adverse events in select subjects due to differences in genetic make‐up/underlying medical conditions or to predict effectiveness (good versus poor response). When expanding them to therapeutic vaccines, their utility in identification of patients most likely to respond favourably (or avoid potentially negative effects of treatment) becomes self‐explanatory. Despite the progress made so far on dissection of various pathways of biological significance in humans, there is still plenty to unravel about the mysteries related to the quantitative and qualitative aspects of the human host response. This review will provide a focused overview of new concepts and developments in the field of vaccine biomarkers including (i) vaccine‐dependent signatures predicting subject response and safety, (ii) predicting therapeutic vaccine efficacy in chronic diseases, (iii) exploring the genetic make‐up of the host that may modulate subject‐specific adverse events or affect the quality of immune responses, and (iv) the topic of volunteer stratification as a result of biomarker screening (e.g. for therapeutic vaccines but also potentially for preventive vaccines) or as a reflection of an effort to compare select groups (e.g. vaccinated subjects versus patients recovering from infection) to enable the discovery of clinically relevant biomarkers for preventive vaccines. PMID:21895991

Predicting DPP-IV inhibitors with machine learning approaches

NASA Astrophysics Data System (ADS)

Cai, Jie; Li, Chanjuan; Liu, Zhihong; Du, Jiewen; Ye, Jiming; Gu, Qiong; Xu, Jun

2017-04-01

Dipeptidyl peptidase IV (DPP-IV) is a promising Type 2 diabetes mellitus (T2DM) drug target. DPP-IV inhibitors prolong the action of glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP), improve glucose homeostasis without weight gain, edema, and hypoglycemia. However, the marketed DPP-IV inhibitors have adverse effects such as nasopharyngitis, headache, nausea, hypersensitivity, skin reactions and pancreatitis. Therefore, it is still expected for novel DPP-IV inhibitors with minimal adverse effects. The scaffolds of existing DPP-IV inhibitors are structurally diversified. This makes it difficult to build virtual screening models based upon the known DPP-IV inhibitor libraries using conventional QSAR approaches. In this paper, we report a new strategy to predict DPP-IV inhibitors with machine learning approaches involving naïve Bayesian (NB) and recursive partitioning (RP) methods. We built 247 machine learning models based on 1307 known DPP-IV inhibitors with optimized molecular properties and topological fingerprints as descriptors. The overall predictive accuracies of the optimized models were greater than 80%. An external test set, composed of 65 recently reported compounds, was employed to validate the optimized models. The results demonstrated that both NB and RP models have a good predictive ability based on different combinations of descriptors. Twenty "good" and twenty "bad" structural fragments for DPP-IV inhibitors can also be derived from these models for inspiring the new DPP-IV inhibitor scaffold design.

Food for thought ... A toxicology ontology roadmap.

PubMed

Hardy, Barry; Apic, Gordana; Carthew, Philip; Clark, Dominic; Cook, David; Dix, Ian; Escher, Sylvia; Hastings, Janna; Heard, David J; Jeliazkova, Nina; Judson, Philip; Matis-Mitchell, Sherri; Mitic, Dragana; Myatt, Glenn; Shah, Imran; Spjuth, Ola; Tcheremenskaia, Olga; Toldo, Luca; Watson, David; White, Andrew; Yang, Chihae

2012-01-01

Foreign substances can have a dramatic and unpredictable adverse effect on human health. In the development of new therapeutic agents, it is essential that the potential adverse effects of all candidates be identified as early as possible. The field of predictive toxicology strives to profile the potential for adverse effects of novel chemical substances before they occur, both with traditional in vivo experimental approaches and increasingly through the development of in vitro and computational methods which can supplement and reduce the need for animal testing. To be maximally effective, the field needs access to the largest possible knowledge base of previous toxicology findings, and such results need to be made available in such a fashion so as to be interoperable, comparable, and compatible with standard toolkits. This necessitates the development of open, public, computable, and standardized toxicology vocabularies and ontologies so as to support the applications required by in silico, in vitro, and in vivo toxicology methods and related analysis and reporting activities. Such ontology development will support data management, model building, integrated analysis, validation and reporting, including regulatory reporting and alternative testing submission requirements as required by guidelines such as the REACH legislation, leading to new scientific advances in a mechanistically-based predictive toxicology. Numerous existing ontology and standards initiatives can contribute to the creation of a toxicology ontology supporting the needs of predictive toxicology and risk assessment. Additionally, new ontologies are needed to satisfy practical use cases and scenarios where gaps currently exist. Developing and integrating these resources will require a well-coordinated and sustained effort across numerous stakeholders engaged in a public-private partnership. In this communication, we set out a roadmap for the development of an integrated toxicology ontology, harnessing existing resources where applicable. We describe the stakeholders' requirements analysis from the academic and industry perspectives, timelines, and expected benefits of this initiative, with a view to engagement with the wider community.

Does early second-trimester sonography predict adverse perinatal outcomes in monochorionic diamniotic twin pregnancies?

PubMed

Allaf, M Baraa; Campbell, Winston A; Vintzileos, Anthony M; Haeri, Sina; Javadian, Pouya; Shamshirsaz, Amir A; Ogburn, Paul; Figueroa, Reinaldo; Wax, Joseph; Markenson, Glenn; Chavez, Martin R; Ravangard, Samadh F; Ruano, Rodrigo; Sangi-Haghpeykar, Haleh; Salmanian, Bahram; Meyer, Marjorie; Johnson, Jeffery; Ozhand, Ali; Davis, Sarah; Borgida, Adam; Belfort, Michael A; Shamshirsaz, Alireza A

2014-09-01

To determine whether intertwin discordant abdominal circumference, femur length, head circumference, and estimated fetal weight sonographic measurements in early second-trimester monochorionic diamniotic twins predict adverse obstetric and neonatal outcomes. We conducted a multicenter retrospective cohort study involving 9 regional perinatal centers in the United States. We examined the records of all monochorionic diamniotic twin pregnancies with two live fetuses at the 16- to 18-week sonographic examination who had serial follow-up sonography until delivery. The intertwin discordance in abdominal circumference, femur length, head circumference, and estimated fetal weight was calculated as the difference between the two fetuses, expressed as a percentage of the larger using the 16- to 18-week sonographic measurements. An adverse composite obstetric outcome was defined as the occurrence of 1 or more of the following in either fetus: intrauterine growth restriction, twin-twin transfusion syndrome, intrauterine fetal death, abnormal growth discordance (≥20% difference), and very preterm birth at or before 28 weeks. An adverse composite neonatal outcome was defined as the occurrence of 1 or more of the following: respiratory distress syndrome, any stage of intraventricular hemorrhage, 5-minute Apgar score less than 7, necrotizing enterocolitis, culture-proven early-onset sepsis, and neonatal death. Receiver operating characteristic and logistic regression-with-generalized estimating equation analyses were constructed. Among the 177 monochorionic diamniotic twin pregnancies analyzed, intertwin abdominal circumference and estimated fetal weight discordances were only predictive of adverse composite obstetric outcomes (areas under the curve, 79% and 80%, respectively). Receiver operating characteristic curves showed that intertwin discordances in abdominal circumference, femur length, head circumference, and estimated fetal weight were not acceptable predictors of twin-twin transfusion syndrome or adverse neonatal outcomes. In our cohort, only second-trimester abdominal circumference and estimated fetal weight discordances in monochorionic diamniotic twin pregnancies were predictive of adverse composite obstetric outcomes. Twin-twin transfusion syndrome and adverse neonatal outcomes were not predicted by any of the intertwin discordances measured. © 2014 by the American Institute of Ultrasound in Medicine.

Systemic effects of intranasal steroids: an endocrinologist's perspective.

PubMed

Allen, D B

2000-10-01

Intranasal steroids (INSs) are established as first-line treatment for allergic rhinitis. Extensive use of INSs with few reported adverse events supports the safety of these medications. Nevertheless, the prescription of more potent INSs for consistent and more prolonged use to younger and older patients, often in combination with inhaled corticosteroids, justifies the careful examination of their potential adverse systemic effects. Systemic bioavailability of INSs, by way of nasal and intestinal absorption, can be substantial; but current INSs vary significantly in their degree of first-pass hepatic inactivation and clearance from the body of the swallowed drug. For safety studies of INSs, distinguishing detectable physiologic perturbations from important adverse events is aided by an understanding of normal endocrine physiology and the methods used to test these systems. A review of available information indicates that (1) sensitive tests can measure the effects of INSs on biologic feedback systems, but they do not accurately predict clinically relevant adverse effects; (2) the primary factors that influence the relationship between therapeutic and adverse systemic effects of INSs are dosing frequency and efficiency of hepatic inactivation of swallowed drug; (3) INS treatment in recommended doses does not cause clinically significant hypothalamic-pituitary-adrenal axis suppression; (4) growth suppression can occur with twice-daily administration of certain INSs but does not appear to occur with once-daily dosing or with agents with more complete first-pass hepatic inactivation; (5) harmful effects of INSs on bone metabolism have not yet been adequately studied but would not be expected with the use of an INS dose and dosing frequency that do not suppress basal hypothalamic-pituitary-adrenal axis function or growth; and (6) these conclusions apply to INS treatment alone and in recommended doses-the risk of adverse effects in individual patients who are treated with INSs is increased by excessive dosing or concomitant inhaled corticosteroid or other topical corticosteroid therapy.

Serum tryptase level is a better predictor of systemic side effects than prostaglandin D2 metabolites during venom immunotherapy in children.

PubMed

Cichocka-Jarosz, E; Sanak, M; Szczeklik, A; Brzyski, P; Gielicz, A; Pietrzyk, J J

2011-01-01

We performed a prospective study to analyze mast cell mediators as predictors of systemic adverse reactions during rush venom-specific immunotherapy (VIT) in children. Nineteen children aged 5-17 years received VIT with Venomenhal (HALAllergy). We analyzed serum tryptase (CAP, Phadia), plasma prostaglandin (PG) D2 metabolites (9alpha, 11beta-PGF2), and urine PGD2 metabolites (9alpha, 11beta-PGF2, tetranor-PGD-M) using gas chromatography mass spectrometry before and after the rush protocol. Three boys with high baseline serum tryptase values (>7.76 g/L) (P < .001) and low 9alpha, 11beta-PGF2 concentrations developed grade III systemic adverse reactions during VIT. Baseline serum tryptase was lowest in children who had a Mueller grade II reaction (1.93 [0.36]) before VIT and highest in children with a Mueller grade III reaction (6.31 [4.80]) (P = .029). Repeated measures analysis of variance confirmed that, in children who developed systemic adverse reactions during VIT, serum tryptase was higher both before and after desensitization and increased significantly following the procedure. Analysis of PGD2 metabolites in the prediction of systemic adverse reactions during VIT was inadequate (sensitivity 67% and specificity 0.53%), whilst prediction based on serum tryptase was accurate. In children with severe systemic adverse reactions to Hymenoptera sting, the evaluation of baseline tryptase levels should be a standard procedure. Children with Apis mellifera venom allergy and baseline tryptase levels higher than 7.75 g/L are at risk of anaphylaxis during buildup. Lower baseline values of plasma and urinary PGD2 metabolite concentration in patients with systemic adverse reaction during VIT suggest that prostaglandin catabolism is altered.

Benefit and harm of intensive blood pressure treatment: Derivation and validation of risk models using data from the SPRINT and ACCORD trials

PubMed Central

Denton, Brian T.; Hayward, Rodney A.

2017-01-01

Background Intensive blood pressure (BP) treatment can avert cardiovascular disease (CVD) events but can cause some serious adverse events. We sought to develop and validate risk models for predicting absolute risk difference (increased risk or decreased risk) for CVD events and serious adverse events from intensive BP therapy. A secondary aim was to test if the statistical method of elastic net regularization would improve the estimation of risk models for predicting absolute risk difference, as compared to a traditional backwards variable selection approach. Methods and findings Cox models were derived from SPRINT trial data and validated on ACCORD-BP trial data to estimate risk of CVD events and serious adverse events; the models included terms for intensive BP treatment and heterogeneous response to intensive treatment. The Cox models were then used to estimate the absolute reduction in probability of CVD events (benefit) and absolute increase in probability of serious adverse events (harm) for each individual from intensive treatment. We compared the method of elastic net regularization, which uses repeated internal cross-validation to select variables and estimate coefficients in the presence of collinearity, to a traditional backwards variable selection approach. Data from 9,069 SPRINT participants with complete data on covariates were utilized for model development, and data from 4,498 ACCORD-BP participants with complete data were utilized for model validation. Participants were exposed to intensive (goal systolic pressure < 120 mm Hg) versus standard (<140 mm Hg) treatment. Two composite primary outcome measures were evaluated: (i) CVD events/deaths (myocardial infarction, acute coronary syndrome, stroke, congestive heart failure, or CVD death), and (ii) serious adverse events (hypotension, syncope, electrolyte abnormalities, bradycardia, or acute kidney injury/failure). The model for CVD chosen through elastic net regularization included interaction terms suggesting that older age, black race, higher diastolic BP, and higher lipids were associated with greater CVD risk reduction benefits from intensive treatment, while current smoking was associated with fewer benefits. The model for serious adverse events chosen through elastic net regularization suggested that male sex, current smoking, statin use, elevated creatinine, and higher lipids were associated with greater risk of serious adverse events from intensive treatment. SPRINT participants in the highest predicted benefit subgroup had a number needed to treat (NNT) of 24 to prevent 1 CVD event/death over 5 years (absolute risk reduction [ARR] = 0.042, 95% CI: 0.018, 0.066; P = 0.001), those in the middle predicted benefit subgroup had a NNT of 76 (ARR = 0.013, 95% CI: −0.0001, 0.026; P = 0.053), and those in the lowest subgroup had no significant risk reduction (ARR = 0.006, 95% CI: −0.007, 0.018; P = 0.71). Those in the highest predicted harm subgroup had a number needed to harm (NNH) of 27 to induce 1 serious adverse event (absolute risk increase [ARI] = 0.038, 95% CI: 0.014, 0.061; P = 0.002), those in the middle predicted harm subgroup had a NNH of 41 (ARI = 0.025, 95% CI: 0.012, 0.038; P < 0.001), and those in the lowest subgroup had no significant risk increase (ARI = −0.007, 95% CI: −0.043, 0.030; P = 0.72). In ACCORD-BP, participants in the highest subgroup of predicted benefit had significant absolute CVD risk reduction, but the overall ACCORD-BP participant sample was skewed towards participants with less predicted benefit and more predicted risk than in SPRINT. The models chosen through traditional backwards selection had similar ability to identify absolute risk difference for CVD as the elastic net models, but poorer ability to correctly identify absolute risk difference for serious adverse events. A key limitation of the analysis is the limited sample size of the ACCORD-BP trial, which expanded confidence intervals for ARI among persons with type 2 diabetes. Additionally, it is not possible to mechanistically explain the physiological relationships explaining the heterogeneous treatment effects captured by the models, since the study was an observational secondary data analysis. Conclusions We found that predictive models could help identify subgroups of participants in both SPRINT and ACCORD-BP who had lower versus higher ARRs in CVD events/deaths with intensive BP treatment, and participants who had lower versus higher ARIs in serious adverse events. PMID:29040268

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...

Does the thyroid-stimulating hormone measured concurrently with first trimester biochemical screening tests predict adverse pregnancy outcomes occurring after 20 weeks gestation?

PubMed

Ong, Gregory S Y; Hadlow, Narelle C; Brown, Suzanne J; Lim, Ee Mun; Walsh, John P

2014-12-01

Maternal hypothyroidism in early pregnancy is associated with adverse outcomes, but not consistently across studies. First trimester screening for chromosomal anomalies is routine in many centers and provides an opportunity to test thyroid function. To determine if thyroid function tests performed with first trimester screening predicts adverse pregnancy outcomes. A cohort study of 2411 women in Western Australia with singleton pregnancies attending first trimester screening between 9 and 14 weeks gestation. We evaluated the association between TSH, free T4, free T3, thyroid antibodies, free beta human chorionic gonadotrophin (β-hCG) and pregnancy associated plasma protein A (PAPP-A) with a composite of adverse pregnancy events as the primary outcome. Secondary outcomes included placenta previa, placental abruption, pre-eclampsia, pregnancy loss after 20 weeks gestation, threatened preterm labor, preterm birth, small size for gestational age, neonatal death, and birth defects. TSH exceeded the 97.5th percentile for the first trimester (2.15 mU/L) in 133 (5.5%) women, including 22 (1%) with TSH above the nonpregnant reference range (4 mU/L) and 5 (0.2%) above 10 mU/L. Adverse outcomes occurred in 327 women (15%). TSH and free T4 did not differ significantly between women with or without adverse pregnancy events. On the multivariate analysis, neither maternal TSH >2.15 mU/L nor TSH as a continuous variable predicted primary or secondary outcomes. Testing maternal TSH as part of first trimester screening does not predict adverse pregnancy outcomes. This may be because in the community setting, mainly mild abnormalities in thyroid function are detected.

Simulating Microdosimetry of Environmental Chemicals for EPA’s Virtual Liver

EPA Science Inventory

US EPA Virtual Liver (v-Liver) is a cellular systems model of hepatic tissues aimed at predicting chemical-induced adverse effects through agent-based modeling. A primary objective of the project is to extrapolate in vitro data to in vivo outcomes. Agent-based approaches to tissu...

Computational Model of the Hypothalamic-pituitary-gonadal Axis to Predict Biochemical Adaptive Response to Endocrine Disrupting Fungicide Prochloraz

EPA Science Inventory

There is increasing evidence that exposure to endocrine disrupting chemicals can induce adverse effects on reproduction and development in both humans and wildlife. Recent studies report adaptive changes within exposed organisms in response to endocrine disrupting chemicals, and ...

Development of a Quantitative Model Incorporating Key Events in a Hepatoxic Mode of Action to Predict Tumor Incidence

EPA Science Inventory

Biologically-Based Dose Response (BBDR) modeling of environmental pollutants can be utilized to inform the mode of action (MOA) by which compounds elicit adverse health effects. Chemicals that produce tumors are typically described as either genotoxic or non-genotoxic. One common...

Fish population modeling approaches for assessing direct effects and recovery following mitigation of a pulp mill effluent in Jackfish Bay

EPA Science Inventory

We present an approach to link chemically-induced alterations in molecular and biochemical endpoints to adverse outcomes in whole organisms and populations. A predictive population model was developed to translate changes in fecundity measures of white sucker (Catostomus commers...

LSD Flashbacks: An Overview of the Literature for Counselors.

ERIC Educational Resources Information Center

Silling, S. Marc

1980-01-01

Surveyed the literature to delineate the etiology of LSD flashbacks. Concluded that adverse experiences while using LSD are predictive of flashbacks; physiological effects of LSD use may linger after the drug has been metabolized; and individuals who have flashbacks are highly suggestive and play a flashback "role."

AN OVERVIEW OF PARTITIONING AND BIOAVAILABILITY OF PAHS IN SEDIMENTS AND SOILS

EPA Science Inventory

Understanding and predicting any adverse effects of PAHs depends on generating a reliable measure or estimate of how much PAH is available for uptake. Simply knowing the total amount of PAH in soil, water or sediment is insufficient for determining whether or not these compounds ...

PREDICTING THE IMPACT OF TROPOSPHERIC OZONE ON PLANTS AND ECOSYSTEMS AS A BASIS FOR SETTING NATIONAL AIR QUALITY STANDARDS

EPA Science Inventory

The Clean Air Act provides for establishing National Ambient Air Quality Standards (NAAQS) to protect public welfare (including crops, forests, ecosystems, and soils) from adverse effects of air pollutants, including tropospheric ozone. The formulation of policies is science-base...

Integrated mineral-resource and mineral-environmental assessments of public lands: Applications for land management and resource planning

USGS Publications Warehouse

Plumlee, Geoffrey S.; Smith, Steven M.; Toth, Margo I.; Marsh, Sherman P.; Ludington, S.D.; Wallace, A.R.; Ficklin, W.H.; Smith, K.S.; Nash, J.T.; Foley, N.K.; Van Loenen, R. E.; Berger, B.R.; Green, G.

1993-01-01

This report presents prototype mineralenvironmental assessments of the State of Colorado and the San Juan National Forest. The following pages will show examples of how geologic information can be used to help predict and prevent adverse environmental effects of mineralresource development.

In vitro, ex vivo, and in vivo determination of thyroid hormone modulating activity of benzothiazoles

EPA Science Inventory

As in vitro assays are increasingly used to screen chemicals for their potential to produce endocrine disrupting adverse effects, it is important to understand their predictive capacity. The potential for a set of six benzothiazoles to affect endpoints related to thyroid hormone ...

Application of the WEPS and SWEEP models to non-agricultural disturbed lands

USDA-ARS?s Scientific Manuscript database

Wind erosion not only affects agricultural productivity but also soil, air, and water quality. Dust and specifically particulate matter = 10 µm (PM-10) has adverse effects on respiratory health and also reduces visibility along roadways, resulting in auto accidents. The Wind Erosion Prediction Syste...

In vitro function of the aryl hydrocarbon receptor predicts in vivo sensitivity of oviparous vertebrates to dioxin-like compounds

EPA Science Inventory

Differences in sensitivity to dioxin-like compounds (DLCs) among species and taxa presents a major challenge to ecological risk assessments. Activation of the aryl hydrocarbon receptor (AHR) regulates adverse effects associated with exposure to DLCs in vertebrates. Prior investig...

Functional correlates of the therapeutic and adverse effects evoked by thalamic stimulation for essential tremor

PubMed Central

Gibson, William S.; Jo, Hang Joon; Testini, Paola; Cho, Shinho; Felmlee, Joel P.; Welker, Kirk M.; Klassen, Bryan T.; Min, Hoon-Ki

2016-01-01

Deep brain stimulation is an established neurosurgical therapy for movement disorders including essential tremor and Parkinson’s disease. While typically highly effective, deep brain stimulation can sometimes yield suboptimal therapeutic benefit and can cause adverse effects. In this study, we tested the hypothesis that intraoperative functional magnetic resonance imaging could be used to detect deep brain stimulation-evoked changes in functional and effective connectivity that would correlate with the therapeutic and adverse effects of stimulation. Ten patients receiving deep brain stimulation of the ventralis intermedius thalamic nucleus for essential tremor underwent functional magnetic resonance imaging during stimulation applied at a series of stimulation localizations, followed by evaluation of deep brain stimulation-evoked therapeutic and adverse effects. Correlations between the therapeutic effectiveness of deep brain stimulation (3 months postoperatively) and deep brain stimulation-evoked changes in functional and effective connectivity were assessed using region of interest-based correlation analysis and dynamic causal modelling, respectively. Further, we investigated whether brain regions might exist in which activation resulting from deep brain stimulation might correlate with the presence of paraesthesias, the most common deep brain stimulation-evoked adverse effect. Thalamic deep brain stimulation resulted in activation within established nodes of the tremor circuit: sensorimotor cortex, thalamus, contralateral cerebellar cortex and deep cerebellar nuclei (FDR q < 0.05). Stimulation-evoked activation in all these regions of interest, as well as activation within the supplementary motor area, brainstem, and inferior frontal gyrus, exhibited significant correlations with the long-term therapeutic effectiveness of deep brain stimulation (P < 0.05), with the strongest correlation (P < 0.001) observed within the contralateral cerebellum. Dynamic causal modelling revealed a correlation between therapeutic effectiveness and attenuated within-region inhibitory connectivity in cerebellum. Finally, specific subregions of sensorimotor cortex were identified in which deep brain stimulation-evoked activation correlated with the presence of unwanted paraesthesias. These results suggest that thalamic deep brain stimulation in tremor likely exerts its effects through modulation of both olivocerebellar and thalamocortical circuits. In addition, our findings indicate that deep brain stimulation-evoked functional activation maps obtained intraoperatively may contain predictive information pertaining to the therapeutic and adverse effects induced by deep brain stimulation. PMID:27329768

Inequality in Landownership, the Emergence of Human-Capital Promoting Institutions, and the Great Divergence

PubMed Central

GALOR, ODED; MOAV, OMER; VOLLRATH, DIETRICH

2013-01-01

This paper suggests that inequality in the distribution of landownership adversely affected the emergence of human-capital promoting institutions (e.g. public schooling), and thus the pace and the nature of the transition from an agricultural to an industrial economy, contributing to the emergence of the great divergence in income per capita across countries. The prediction of the theory regarding the adverse effect of the concentration of landownership on education expenditure is established empirically based on evidence from the beginning of the 20th century in the U.S. PMID:23946551

Religiousness/Spirituality and anger management in community-dwelling older persons.

PubMed

Mefford, Linda; Thomas, Sandra P; Callen, Bonnie; Groer, Maureen

2014-04-01

Mismanaged anger is associated with adverse health outcomes. This study examined whether dimensions of religiousness/spirituality could predict healthy anger management in a sample of 82 community-dwelling older Americans. A correlational research design was employed using the Deffenbacher Anger Scale and the Brief Multidimensional Measure of Religiousness/Spirituality. Higher scores on Forgiveness, Daily Spiritual Experiences, Religiousness/Spirituality as Coping, and Self-Ranking of Religiousness/Spirituality were correlated with healthier anger management; however forgiveness was the only significant predictor in the regression analysis. Interventions to facilitate forgiveness may promote healthy anger management and minimize the adverse health effects of mismanaged anger.

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...

Quantitative Adverse Outcome Pathways and Their Application to Predictive Toxicology

EPA Science Inventory

A quantitative adverse outcome pathway (qAOP) consists of one or more biologically based, computational models describing key event relationships linking a molecular initiating event (MIE) to an adverse outcome. A qAOP provides quantitative, dose–response, and time-course p...

Using the Personal Background Preparation Survey to Identify Health Science Professions Students at Risk for Adverse Academic Events

ERIC Educational Resources Information Center

Johnson, Craig W.; Johnson, Ronald; McKee, John C.; Kim, Mira

2009-01-01

In the first predictive validity study of a diagnostic and prescriptive instrument for averting adverse academic status events (AASE) among multiple populations of diverse health science professions students, entering matriculates' personal background and preparation survey (PBPS) scores consistently significantly predicted 1st- or 2nd-year AASE.…

Childhood adversity and midlife suicidal ideation.

PubMed

Stansfeld, S A; Clark, C; Smuk, M; Power, C; Davidson, T; Rodgers, B

2017-01-01

Childhood adversity predicts adolescent suicidal ideation but there are few studies examining whether the risk of childhood adversity extends to suicidal ideation in midlife. We hypothesized that childhood adversity predicts midlife suicidal ideation and this is partially mediated by adolescent internalizing disorders, externalizing disorders and adult exposure to life events and interpersonal difficulties. At 45 years, 9377 women and men from the UK 1958 British Birth Cohort Study participated in a clinical survey. Childhood adversity was prospectively assessed at the ages of 7, 11 and 16 years. Suicidal ideation at midlife was assessed by the depressive ideas subscale of the Revised Clinical Interview Schedule. Internalizing and externalizing disorders were measured by the Rutter scales at 16 years. Life events, periods of unemployment, partnership separations and alcohol dependence were measured through adulthood. Illness in the household, paternal absence, institutional care, parental divorce and retrospective reports of parental physical and sexual abuse predicted suicidal ideation at 45 years. Three or more childhood adversities were associated with suicidal ideation at 45 years [odds ratio (OR) 4.31, 95% confidence interval (CI) 2.67-6.94]. Psychological distress at 16 years partially mediated the associations of physical abuse (OR 3.41, 95% CI 2.29-5.75), sexual abuse (OR 4.99, 95% CI 2.90-11.16) with suicidal ideation. Adult life events partially mediated the association of parental divorce (OR 6.34, 95% CI -7.16 to 36.75) and physical (OR 9.59, 95% CI 4.97-27.88) and sexual abuse (OR 6.59, 95% CI 2.40-38.36) with suicidal ideation at 45 years. Adversity in childhood predicts suicidal ideation in midlife, partially mediated by adolescent internalizing and externalizing disorders, adult life events and interpersonal difficulties. Understanding the pathways from adversity to suicidal ideation can inform suicide prevention and the targeting of preventive interventions.

Effects of cumulative stress and impulsivity on smoking status.

PubMed

Ansell, Emily B; Gu, Peihua; Tuit, Keri; Sinha, Rajita

2012-03-01

The stress-vulnerability model of addiction predicts that environmental factors, such as cumulative stress, will result in individual adaptations that decrease self-control, increase impulsivity, and increase risk for addiction. Impulsivity and cumulative stress are risk factors for tobacco smoking that are rarely examined simultaneously in research. We examined the indirect and direct effects of cumulative adversity in a community sample consisting of 291 men and women who participated in an assessment of cumulative stress, self-reported impulsivity, and smoking history. Data were analyzed using bootstrapping techniques to estimate indirect effects of stress on smoking via impulsivity. Cumulative adversity is associated with smoking status via direct effects and indirect effects through impulsivity scores. Additional models examining specific types of stress indicate contributions of traumatic stress and recent life events as well as chronic relationship stressors. Overall, cumulative stress is associated with increased risk of smoking via increased impulsivity and via pathways independent of impulsivity. These findings support the stress-vulnerability model and highlight the utility of mediation models in assessing how, and for whom, cumulative stress increases risk of current cigarette smoking. Increasing self-control is a target for interventions with individuals who have experienced cumulative adversity. Copyright © 2012 John Wiley & Sons, Ltd.

Effects of cumulative stress and impulsivity on smoking status

PubMed Central

Ansell, Emily B.; Gu, Peihua; Tuit, Keri; Sinha, Rajita

2013-01-01

Objective The stress-vulnerability model of addiction predicts that environmental factors, such as cumulative stress, will result in individual adaptations that decrease self-control, increase impulsivity, and increase risk for addiction. Impulsivity and cumulative stress are risk factors for tobacco smoking that are rarely examined simultaneously in research. Methods We examined the indirect and direct effects of cumulative adversity in a community sample consisting of 291 men and women who participated in an assessment of cumulative stress, self-reported impulsivity, and smoking history. Data were analyzed using bootstrapping techniques to estimate indirect effects of stress on smoking via impulsivity. Results Cumulative adversity is associated with smoking status via direct effects and indirect effects through impulsivity scores. Additional models examining specific types of stress indicate contributions of traumatic stress and recent life events as well as chronic relationship stressors. Conclusions Overall, cumulative stress is associated with increased risk of smoking via increased impulsivity and via pathways independent of impulsivity. These findings support the stress-vulnerability model and highlight the utility of mediation models in assessing how, and for whom, cumulative stress increases risk of current cigarette smoking. Increasing self-control is a target for interventions with individuals who have experienced cumulative adversity. PMID:22389084

The role of drug profiles as similarity metrics: applications to repurposing, adverse effects detection and drug-drug interactions.

PubMed

Vilar, Santiago; Hripcsak, George

2017-07-01

Explosion of the availability of big data sources along with the development in computational methods provides a useful framework to study drugs' actions, such as interactions with pharmacological targets and off-targets. Databases related to protein interactions, adverse effects and genomic profiles are available to be used for the construction of computational models. In this article, we focus on the description of biological profiles for drugs that can be used as a system to compare similarity and create methods to predict and analyze drugs' actions. We highlight profiles constructed with different biological data, such as target-protein interactions, gene expression measurements, adverse effects and disease profiles. We focus on the discovery of new targets or pathways for drugs already in the pharmaceutical market, also called drug repurposing, in the interaction with off-targets responsible for adverse reactions and in drug-drug interaction analysis. The current and future applications, strengths and challenges facing all these methods are also discussed. Biological profiles or signatures are an important source of data generation to deeply analyze biological actions with important implications in drug-related studies. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Close Friends' Psychopathology as a Pathway From Early Adversity to Young Adulthood Depressive Symptoms.

PubMed

Raposa, Elizabeth B; Hammen, Constance L; Brennan, Patricia A

2015-01-01

Past research has highlighted the negative impact of early adverse experiences on childhood social functioning, including friendship selection, and later mental health. The current study explored the long-term effects of early adversity on young adults' close friends' psychological symptoms and the impact of these close friendships on later depressive symptoms. A prospective longitudinal design was used to examine 816 youth from a large community-based sample, who were followed from birth through age 25. Participants' mothers provided contemporaneous information about adversity exposure up to age 5, and participants completed questionnaires about their own depressive symptoms at age 20 and in their early 20s. Youth also nominated a best friend to complete questionnaires about his or her own psychopathology at age 20. Individuals who experienced more early adversity by age 5 had best friends with higher rates of psychopathology at age 20. Moreover, best friends' psychopathology predicted target youth depressive symptoms 2 to 5 years later. Results indicate that early adversity continues to affect social functioning throughout young adulthood and that best friendships marked by elevated psychopathology in turn negatively affect mental health. Findings have implications for clinical interventions designed to prevent the development of depressive symptoms in youth who have been exposed to early adversity.

Differential associations of threat and deprivation with emotion regulation and cognitive control in adolescence

PubMed Central

Lambert, Hilary K; King, kevin M; Monahan, kathryn C; Mclaughlin, Katie A

2016-01-01

Research on childhood adversity has traditionally focused on single types of adversity, which is limited because of high co-occurrence, or on the total number of adverse experiences, which assumes that diverse experiences influence development similarly. Identifying dimensions of environmental experience that are common to multiple types of adversity may be a more effective strategy. We examined the unique associations of two such dimensions (threat and cognitive deprivation) with automatic emotion regulation and cognitive control using a multivariate approach that simultaneously examined both dimensions of adversity. Data were drawn from a community sample of adolescents (N = 287) with variability in exposure to violence, an indicator of threat, and poverty, which is associated with cognitive deprivation. Adolescents completed tasks measuring automatic emotion regulation and cognitive control in neutral and emotional contexts. Violence was associated with automatic emotion regulation deficits, but not cognitive control; poverty was associated with poor cognitive control, but not automatic emotion regulation. Both violence and poverty predicted poor inhibition in an emotional context. Utilizing an approach focused on either single types of adversity or cumulative risk obscured specificity in the associations of violence and poverty with emotional and cognitive outcomes. These findings suggest that different dimensions of childhood adversity have distinct influences on development and highlight the utility of a differentiated multivariate approach. PMID:27424571

Early adolescent adversity inflates threat estimation in females and promotes alcohol use initiation in both sexes.

PubMed

Walker, Rachel A; Andreansky, Christopher; Ray, Madelyn H; McDannald, Michael A

2018-06-01

Childhood adversity is associated with exaggerated threat processing and earlier alcohol use initiation. Conclusive links remain elusive, as childhood adversity typically co-occurs with detrimental socioeconomic factors, and its impact is likely moderated by biological sex. To unravel the complex relationships among childhood adversity, sex, threat estimation, and alcohol use initiation, we exposed female and male Long-Evans rats to early adolescent adversity (EAA). In adulthood, >50 days following the last adverse experience, threat estimation was assessed using a novel fear discrimination procedure in which cues predict a unique probability of footshock: danger (p = 1.00), uncertainty (p = .25), and safety (p = .00). Alcohol use initiation was assessed using voluntary access to 20% ethanol, >90 days following the last adverse experience. During development, EAA slowed body weight gain in both females and males. In adulthood, EAA selectively inflated female threat estimation, exaggerating fear to uncertainty and safety, but promoted alcohol use initiation across sexes. Meaningful relationships between threat estimation and alcohol use initiation were not observed, underscoring the independent effects of EAA. Results isolate the contribution of EAA to adult threat estimation, alcohol use initiation, and reveal moderation by biological sex. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Differential associations of threat and deprivation with emotion regulation and cognitive control in adolescence.

PubMed

Lambert, Hilary K; King, Kevin M; Monahan, Kathryn C; McLaughlin, Katie A

2017-08-01

Research on childhood adversity has traditionally focused on single types of adversity, which is limited because of high co-occurrence, or on the total number of adverse experiences, which assumes that diverse experiences influence development similarly. Identifying dimensions of environmental experience that are common to multiple types of adversity may be a more effective strategy. We examined the unique associations of two such dimensions (threat and cognitive deprivation) with automatic emotion regulation and cognitive control using a multivariate approach that simultaneously examined both dimensions of adversity. Data were drawn from a community sample of adolescents (N = 287) with variability in exposure to violence, an indicator of threat, and poverty, which is associated with cognitive deprivation. Adolescents completed tasks measuring automatic emotion regulation and cognitive control in neutral and emotional contexts. Violence was associated with automatic emotion regulation deficits, but not cognitive control; poverty was associated with poor cognitive control, but not automatic emotion regulation. Both violence and poverty predicted poor inhibition in an emotional context. Utilizing an approach focused on either single types of adversity or cumulative risk obscured specificity in the associations of violence and poverty with emotional and cognitive outcomes. These findings suggest that different dimensions of childhood adversity have distinct influences on development and highlight the utility of a differentiated multivariate approach.

Close Friends’ Psychopathology as a Pathway from Early Adversity to Young Adulthood Depressive Symptoms

PubMed Central

Raposa, Elizabeth; Hammen, Constance; Brennan, Patricia

2014-01-01

Objective Past research has highlighted the negative impact of early adverse experiences on childhood social functioning, including friendship selection, and later mental health. The current study explored the long-term effects of early adversity on young adults’ close friends’ psychological symptoms, and the impact of these close friendships on later depressive symptoms. Method A prospective longitudinal design was used to examine 816 youth from a large community-based sample, who were followed from birth through age 25. Participants’ mothers provided contemporaneous information about adversity exposure prior to age 5, and participants completed questionnaires about their own depressive symptoms at age 20 and in their early 20’s. Youth also nominated a best friend to complete questionnaires about their own psychopathology at age 20. Results Individuals who experienced more early adversity by age 5 had best friends with higher rates of psychopathology at age 20. Moreover, best friends’ psychopathology predicted target youth depressive symptoms two to five years later. Conclusions Results indicate that early adversity continues to affect social functioning throughout young adulthood, and that best friendships marked by elevated psychopathology in turn negatively affect mental health. Findings have implications for clinical interventions designed to prevent the development of depressive symptoms in youth who have been exposed to early adversity. PMID:24871609

Using clinical symptoms to predict adverse maternal and perinatal outcomes in women with preeclampsia: data from the PIERS (Pre-eclampsia Integrated Estimate of RiSk) study.

PubMed

Yen, Tin-Wing; Payne, Beth; Qu, Ziguang; Hutcheon, Jennifer A; Lee, Tang; Magee, Laura A; Walters, Barry N; von Dadelszen, Peter

2011-08-01

Preeclampsia is a leading cause of maternal morbidity. The clinical challenge lies in predicting which women with preeclampsia will suffer adverse outcomes and would benefit from treatment, while minimizing potentially harmful interventions. Our aim was to determine the ability of maternal symptoms (i.e., severe nausea or vomiting, headache, visual disturbance, right upper quadrant pain or epigastric pain, abdominal pain or vaginal bleeding, and chest pain or dyspnea) to predict adverse maternal or perinatal outcomes. We used data from the PIERS (Pre-eclampsia Integrated Estimate of RiSk) study, a multicentre, prospective cohort study designed to investigate the maternal risks associated with preeclampsia. Relative risks and receiver operating characteristic (ROC) curves were assessed for each preeclampsia symptom and outcome pair. Of 2023 women who underwent assessment, 52% experienced at least one preeclampsia symptom, with 5.2% and 5.3% respectively experiencing an adverse maternal or perinatal outcome. No symptom and outcome pair, in either of the maternal or perinatal groups, achieved an area under the ROC curve value > 0.7, which would be necessary to demonstrate a discriminatory predictive value. Maternal symptoms of preeclampsia are not independently valid predictors of maternal adverse outcome. Caution should be used when making clinical decisions on the basis of symptoms alone in the preeclamptic patient.

Biological Stress Systems, Adverse Life Events, and the Improvement of Chronic Multisite Musculoskeletal Pain Across a 6-Year Follow-Up.

PubMed

Generaal, Ellen; Vogelzangs, Nicole; Macfarlane, Gary J; Geenen, Rinie; Smit, Johannes H; de Geus, Eco J C N; Dekker, Joost; Penninx, Brenda W J H

2017-02-01

Dysfunction of biological stress systems and adverse life events, independently and in interaction, have been hypothesized to predict chronic pain persistence. Conversely, these factors may hamper the improvement of chronic pain. Longitudinal evidence is currently lacking. We examined whether: 1) function of biological stress systems, 2) adverse life events, and 3) their combination predict the improvement of chronic multisite musculoskeletal pain. Subjects of the Netherlands Study of Depression and Anxiety (NESDA) with chronic multisite musculoskeletal pain at baseline (N = 665) were followed-up 2, 4, and 6 years later. The Chronic Pain Grade Questionnaire was used to determine improvement (not meeting the criteria) of chronic multisite musculoskeletal pain at follow-up. Baseline assessment of biological stress systems included function of hypothalamic-pituitary-adrenal axis (1-hour cortisol awakening response, evening level, and post dexamethasone level), the immune system (basal and lipopolysaccharide-stimulated inflammatory markers), the autonomic nervous system (heart rate, pre-ejection period, SD of the normal-to-normal interval, and respiratory sinus arrhythmia). The number of adverse life events were assessed at baseline and 2-year follow-up using the List of Threatening Events Questionnaire. We showed that hypothalamic-pituitary-adrenal axis, immune system, and autonomic nervous system functioning and adverse life events were not associated with the improvement of chronic multisite musculoskeletal pain, either as a main effect or in interaction. This longitudinal study could not confirm that biological stress system dysfunction and adverse life events affect the course of chronic multisite musculoskeletal pain. Biological stress systems and adverse life events are not associated with the improvement of chronic multisite musculoskeletal pain over 6 years of follow-up. Other determinants should thus be considered in future research to identify in which persons pain symptoms will improve. Copyright © 2016 American Pain Society. Published by Elsevier Inc. All rights reserved.

Pneumococcal pneumonia - Are the new severity scores more accurate in predicting adverse outcomes?

PubMed

Ribeiro, C; Ladeira, I; Gaio, A R; Brito, M C

2013-01-01

The site-of-care decision is one of the most important factors in the management of patients with community-acquired pneumonia. The severity scores are validated prognostic tools for community-acquired pneumonia mortality and treatment site decision. The aim of this paper was to compare the discriminatory power of four scores - the classic PSI and CURB65 ant the most recent SCAP and SMART-COP - in predicting major adverse events: death, ICU admission, need for invasive mechanical ventilation or vasopressor support in patients admitted with pneumococcal pneumonia. A five year retrospective study of patients admitted for pneumococcal pneumonia. Patients were stratified based on admission data and assigned to low-, intermediate-, and high-risk classes for each score. Results were obtained comparing low versus non-low risk classes. We studied 142 episodes of hospitalization with 2 deaths and 10 patients needing mechanical ventilation and vasopressor support. The majority of patients were classified as low risk by all scores - we found high negative predictive values for all adverse events studied, the most negative value corresponding to the SCAP score. The more recent scores showed better accuracy for predicting ICU admission and need for ventilation or vasopressor support (mostly for the SCAP score with higher AUC values for all adverse events). The rate of all adverse outcomes increased directly with increasing risk class in all scores. The new gravity scores appear to have a higher discriminatory power in all adverse events in our study, particularly, the SCAP score. Copyright © 2012 Sociedade Portuguesa de Pneumologia. Published by Elsevier España. All rights reserved.

Telomere length and early severe social deprivation: linking early adversity and cellular aging

PubMed Central

Drury, SS; Theall, K; Gleason, MM; Smyke, AT; De Vivo, I; Wong, JYY; Fox, NA; Zeanah, CH; Nelson, CA

2012-01-01

Accelerated telomere length attrition has been associated with psychological stress and early adversity in adults; however, no studies have examined whether telomere length in childhood is associated with early experiences. The Bucharest Early Intervention Project is a unique randomized controlled trial of foster care placement compared with continued care in institutions. As a result of the study design, participants were exposed to a quantified range of time in institutional care, and represented an ideal population in which to examine the association between a specific early adversity, institutional care and telomere length. We examined the association between average relative telomere length, telomere repeat copy number to single gene copy number (T/S) ratio and exposure to institutional care quantified as the percent of time at baseline (mean age 22 months) and at 54 months of age that each child lived in the institution. A significant negative correlation between T/S ratio and percentage of time was observed. Children with greater exposure to institutional care had significantly shorter relative telomere length in middle childhood. Gender modified this main effect. The percentage of time in institutional care at baseline significantly predicted telomere length in females, whereas the percentage of institutional care at 54 months was strongly predictive of telomere length in males. This is the first study to demonstrate an association between telomere length and institutionalization, the first study to find an association between adversity and telomere length in children, and contributes to the growing literature linking telomere length and early adversity. PMID:21577215

The SEURAT-1 approach towards animal free human safety assessment.

PubMed

Gocht, Tilman; Berggren, Elisabet; Ahr, Hans Jürgen; Cotgreave, Ian; Cronin, Mark T D; Daston, George; Hardy, Barry; Heinzle, Elmar; Hescheler, Jürgen; Knight, Derek J; Mahony, Catherine; Peschanski, Marc; Schwarz, Michael; Thomas, Russell S; Verfaillie, Catherine; White, Andrew; Whelan, Maurice

2015-01-01

SEURAT-1 is a European public-private research consortium that is working towards animal-free testing of chemical compounds and the highest level of consumer protection. A research strategy was formulated based on the guiding principle to adopt a toxicological mode-of-action framework to describe how any substance may adversely affect human health.The proof of the initiative will be in demonstrating the applicability of the concepts on which SEURAT-1 is built on three levels:(i) Theoretical prototypes for adverse outcome pathways are formulated based on knowledge already available in the scientific literature on investigating the toxicological mode-of-actions leading to adverse outcomes (addressing mainly liver toxicity);(ii)adverse outcome pathway descriptions are used as a guide for the formulation of case studies to further elucidate the theoretical model and to develop integrated testing strategies for the prediction of certain toxicological effects (i.e., those related to the adverse outcome pathway descriptions);(iii) further case studies target the application of knowledge gained within SEURAT-1 in the context of safety assessment. The ultimate goal would be to perform ab initio predictions based on a complete understanding of toxicological mechanisms. In the near-term, it is more realistic that data from innovative testing methods will support read-across arguments. Both scenarios are addressed with case studies for improved safety assessment. A conceptual framework for a rational integrated assessment strategy emerged from designing the case studies and is discussed in the context of international developments focusing on alternative approaches for evaluating chemicals using the new 21st century tools for toxicity testing.

Use of the Biopharmaceutics Drug Disposition Classification System (BDDCS) to Help Predict the Occurrence of Idiosyncratic Cutaneous Adverse Drug Reactions Associated with Antiepileptic Drug Usage.

PubMed

Chan, Rosa; Wei, Chun-Yu; Chen, Yuan-Tsong; Benet, Leslie Z

2016-05-01

Cutaneous adverse reactions (CARs) from antiepileptic drugs (AEDs) are common, ranging from mild to life-threatening, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). The identification of subjects carrying the HLA-B*15:02, an inherited allelic variant of the HLA-B gene, and the avoidance of carbamazepine (CBZ) therapy in these subjects are strongly associated with a decrease in the incidence of carbamazepine-induced SJS/TEN. In spite of the strong genetic associations, the initiation of hypersensitivity for AEDs is still not very well characterized. Predicting the potential for other AEDs to cause adverse reactions will be undoubtedly beneficial to avoid CARs, which is the focus of this report. Here, we explore the use of the Biopharmaceutics Drug Disposition Classification System (BDDCS) to distinguish AEDs associated with and without CARs by examining the binding relationship of AEDs to HLA-B*15:02 and data from extensive reviews of medical records. We also evaluate the lack of benefit from a Hong Kong population policy on the effects of screening for HLA-B*15:02 and previous incorrect structure-activity hypotheses. Our analysis concludes that BDDCS class 2 AEDs are more prone to cause adverse cutaneous reactions than certain BDDCS class 1 AEDs and that BDDCS Class 3 drugs have the lowest levels of cutaneous adverse reactions. We propose that BDDCS Class 3 AEDs should be preferentially used for patients with Asian backgrounds (i.e., Han Chinese, Thai, and Malaysian populations) if possible and in patients predisposed to skin rashes.

The role of nonverbal cognitive ability in the association of adverse life events with dysfunctional attitudes and hopelessness in adolescence.

PubMed

Flouri, Eirini; Panourgia, Constantina

2012-10-01

The aim of this study was to test whether nonverbal cognitive ability buffers the effect of life stress (number of adverse life events in the last year) on diatheses for depression. It was expected that, as problem-solving aptitude, nonverbal cognitive ability would moderate the effect of life stress on those diatheses (such as dysfunctional attitudes) that are depressogenic because they represent deficits in information-processing or problem-solving skills, but not on diatheses (such as hopelessness) that are depressogenic because they represent deficits in motivation or effort to apply problem-solving skills. The sample included 558 10- to 19-year-olds from a state secondary school in London. Nonverbal cognitive ability was negatively associated with both dysfunctional attitudes and hopelessness. As expected, nonverbal cognitive ability moderated the association between life adversity and dysfunctional attitudes. However, hopelessness was not related to life stress, and therefore, there was no life stress effect for nonverbal cognitive ability to moderate. This study adds to knowledge about the association between problem-solving ability and depressogenic diatheses. By identifying life stress as a risk factor for dysfunctional attitudes but not hopelessness, it highlights the importance of considering outcome specificity in models predicting adolescent outcomes from adverse life events. Importantly for practice, it suggests that an emphasis on recent life adversity will likely underestimate the true level of hopelessness among adolescents. Copyright © 2012 Elsevier Inc. All rights reserved.

Gastroschisis: antenatal sonographic predictors of adverse neonatal outcome.

PubMed

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

2014-01-01

The aim of this review was to identify clinically significant ultrasound predictors of adverse neonatal outcome in fetal gastroschisis. A quasi-systematic review was conducted in PubMed and Ovid using the key terms "gastroschisis," "predictors," "outcome," and "ultrasound." 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). 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.

A PILOT PROJECT TO DETECT AND PREDICT HARMFUL ALGAL BLOOMS IN THE NORTHERN GULF OF MEXICO

EPA Science Inventory

More timely access to data and information on the initiation, evolution and effects of harmful algal blooms can reduce adverse impacts on valued natural resources and human health. To achieve this, a workshop was held to develop a user-driven, end-to-end (measurements to applicat...

Computational Model of the Fathead Minnow Hypothalamic-Pituitary-Gonadal Axis: Incorporating Protein Synthesis in Improving Predictability of Responses to Endocrine Active Chemicals

EPA Science Inventory

There is international concern about chemicals that alter endocrine system function in humans and/or wildlife and subsequently cause adverse effects. We previously developed a mechanistic computational model of the hypothalamic-pituitary-gonadal (HPG) axis in female fathead minno...

IN VITRO METABOLISM OF THE CHIRAL TRIAZOLE FUNGICIDE BROMUCONAZOLE 47 USING SUBSTRATE DEPLETION AND PRODUCT FORMATION KINETICS IN RAT HEPATIC MICROSOMES

EPA Science Inventory

Kinetic analysis of xenobiotic metabolism using in vitro hepatic microsomes are needed for predictive in vivo physiological modeling. Recently, much emphasis has been placed on the adverse effects of triazole fungicides in mammalian steroid metabolism. In vitro metabolism of the ...

Proteome Profiling Reveals Potential Toxicity and Detoxification Pathways Following Exposure of BEAS-2B Cells to Engineered Nanoparticle Titanium Dioxide

EPA Science Inventory

Identification of toxicity pathways linked to chemical -exposure is critical for a better understanding of biological effects of the exposure, toxic mechanisms, and for enhancement of the prediction of chemical toxicity and adverse health outcomes. To identify toxicity pathways a...

Cross-species extrapolation of toxicity information using the Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS) tool

EPA Science Inventory

In the United States, the Endocrine Disruptor Screening Program (EDSP) was established to identify chemicals that may lead to adverse effects via perturbation of the endocrine system (i.e., estrogen, androgen, and thyroid hormone systems). In the mid-1990s the EDSP adopted a two ...

Rodenticide incidents of exposure and adverse effects on non-raptor birds

USGS Publications Warehouse

Vyas, Nimish B.

2017-01-01

Interest in the adverse effects of rodenticides on birds has focused primarily on raptors. However, non-raptor birds are also poisoned (rodenticide exposure resulting in adverse effects including mortality) by rodenticides through consumption of the rodenticide bait and contaminated prey. A literature search for rodenticide incidents (evidence of exposure to a rodenticide, adverse effects, or exposure to placebo baits) involving non-raptor birds returned 641 records spanning the years 1931 to 2016. The incidents included 17 orders, 58 families, and 190 non-raptor bird species. Nineteen anticoagulant and non-anticoagulant rodenticide active ingredients were associated with the incidents. The number of incidents and species detected were compared by surveillance method. An incident was considered to have been reported through passive surveillance if it was voluntarily reported to the authorities whereas the report of an incident found through field work that was conducted with the objective of documenting adverse effects on birds was determined to be from active surveillance. More incidents were reported from passive surveillance than with active surveillance but a significantly greater number of species were detected in proportion to the number of incidents found through active surveillance than with passive surveillance (z = 7.61, p < 0.01). Results suggest that reliance on only one surveillance method can underestimate the number of incidents that have occurred and the number of species that are affected. Although rodenticides are used worldwide, incident records were found from only 15 countries. Therefore, awareness of the breadth of species diversity of non-raptor bird poisonings from rodenticides may increase incident reportings and can strengthen the predictions of harm characterized by risk assessments.

Evaluation of perampanel in patients with intellectual disability and epilepsy.

PubMed

Snoeijen-Schouwenaars, Francesca M; van Ool, Jans S; Tan, In Y; Schelhaas, Helenius J; Majoie, Marian H J M

2017-01-01

Initial registration studies of perampanel (PMP), an AMPA receptor antagonist, have now been followed up by 'clinical' studies that confirmed its efficacy and safety in patients with refractory epilepsy. Publications on the use of PMP among patients with intellectual disability (ID) are still limited. This study extends our knowledge with respect to the relevance of PMP for patients with both ID and epilepsy, and furthermore specifies the behavioral side effects of PMP in this specific population. Retrospective evaluation of medical records at 3, 6 and 12months of follow-up after the initial start of PMP. 62 patients were included. 21 patients (33.9%) were female. All patients had complete data of 6months follow-up and we were able to review 42 patients with a 1-year follow-up. Level of ID varied from borderline to profound, and mild ID was most common (43.5%). The mean maximum daily dosage of PMP was 5.6mg (range 1-12mg). Retention rates for PMP were 87.1% and 67.7% after three and six months. A trend indicated a longer mean retention time in patients with a more severe ID (borderline-mild-moderate ID: 205days, severe-profound ID: 275days). Seizure reduction was achieved in 53.2%. 36 patients (58.1%) experienced adverse effects, 80.6% of those within 3months. 45.2% of the patients experienced somatic adverse effects. Most common were fatigue & sleep problems, motor problems & unsteadiness, and gastrointestinal problems. Behavioral adverse effects were present in 40.3%. Most common were aggression, agitated behavior, disruptive behavior, and mood symptoms. Reasons for discontinuation of PMP were lack of efficacy in 14.8%, intolerable adverse effects in 44.4%, and a combination of both in 40.7%. Altogether, 24.2% (15/62) of the patients achieved seizure reduction without experiencing adverse effects, though none reached seizure freedom. The use of PMP might lead to an effective seizure reduction without adverse effects in a minority of patients with both epilepsy and ID. Pre-existing behavioral problems or polypharmacy do not predict the occurrence of additional behavioral adverse effects, implying that these patients need not be excluded from the introduction of PMP when clinically indicated. Patients should, ideally, be monitored at a multidisciplinary clinic. Copyright © 2016 Elsevier Inc. All rights reserved.

Predicting U.S. Army suicides after hospitalizations with psychiatric diagnoses in the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS)

PubMed Central

Kessler, Ronald C.; Warner, LTC Christopher H.; Ivany, LTC Christopher; Petukhova, Maria V.; Rose, Sherri; Bromet, Evelyn J.; Brown, LTC Millard; Cai, Tianxi; Colpe, Lisa J.; Cox, Kenneth L.; Fullerton, Carol S.; Gilman, Stephen E.; Gruber, Michael J.; Heeringa, Steven G.; Lewandowski-Romps, Lisa; Li, Junlong; Millikan-Bell, Amy M.; Naifeh, James A.; Nock, Matthew K.; Rosellini, Anthony J.; Sampson, Nancy A.; Schoenbaum, Michael; Stein, Murray B.; Wessely, Simon; Zaslavsky, Alan M.; Ursano, Robert J.

2014-01-01

IMPORTANCE The U.S. Army experienced a sharp rise in suicides beginning in 2004. Administrative data show that among those at highest risk are soldiers in the 12 months after inpatient treatment of a psychiatric disorder. OBJECTIVE To develop an actuarial risk algorithm predicting suicide in the 12 months after US Army soldier inpatient treatment of a psychiatric disorder to target expanded post-hospital care. DESIGN, SETTING, AND PARTICIPANTS There were 53,769 hospitalizations of active duty soldiers in 2004–2009 with ICD-9-CM psychiatric admission diagnoses. Administrative data available prior to hospital discharge abstracted from a wide range of data systems (socio81 demographic, Army career, criminal justice, medical/pharmacy) were used to predict suicides in the subsequent 12 months using machine learning methods (regression trees, penalized regressions) designed to evaluate cross-validated linear, nonlinear, and interactive predictive associations. MAIN OUTCOME Suicides of soldiers hospitalized with psychiatric disorders in the 12 months after hospital discharge. RESULTS 68 soldiers died by suicide within 12 months of hospital discharge (12.0% of all Army suicides), equivalent to 263.9 suicides/100,000 person-years compared to 18.5 suicides/100,000 person-years in the total Army. Strongest predictors included socio-demographics (male, late age of enlistment), criminal offenses (verbal violence, weapons possession), prior suicidality, aspects of prior psychiatric inpatient and outpatient treatment, and disorders diagnosed during the focal hospitalizations. 52.9% of post-hospital suicides occurred after the 5% of hospitalizations with highest predicted suicide risk (3,824.1 suicides/100,000 person years). These highest-risk hospitalizations also accounted for significantly elevated proportions of several other adverse post-hospital outcomes (unintentional injury deaths, suicide attempts, re-hospitalizations). CONCLUSIONS AND RELEVANCE The high concentration of risk of suicides and other adverse outcomes might justify targeting expanded post-hospital interventions to soldiers classified as having highest post-hospital suicide risk, although final determination requires careful consideration of intervention costs, comparative effectiveness, and possible adverse effects. PMID:25390793

Biological and behavioral factors modify urinary arsenic metabolic profiles in a U.S. population.

PubMed

Hudgens, Edward E; Drobna, Zuzana; He, Bin; Le, X C; Styblo, Miroslav; Rogers, John; Thomas, David J

2016-05-26

Because some adverse health effects associated with chronic arsenic exposure may be mediated by methylated arsenicals, interindividual variation in capacity to convert inorganic arsenic into mono- and di-methylated metabolites may be an important determinant of risk associated with exposure to this metalloid. Hence, identifying biological and behavioral factors that modify an individual's capacity to methylate inorganic arsenic could provide insights into critical dose-response relations underlying adverse health effects. A total of 904 older adults (≥45 years old) in Churchill County, Nevada, who chronically used home tap water supplies containing up to 1850 μg of arsenic per liter provided urine and toenail samples for determination of total and speciated arsenic levels. Effects of biological factors (gender, age, body mass index) and behavioral factors (smoking, recent fish or shellfish consumption) on patterns of arsenicals in urine were evaluated with bivariate analyses and multivariate regression models. Relative contributions of inorganic, mono-, and di-methylated arsenic to total speciated arsenic in urine were unchanged over the range of concentrations of arsenic in home tap water supplies used by study participants. Gender predicted both absolute and relative amounts of arsenicals in urine. Age predicted levels of inorganic arsenic in urine and body mass index predicted relative levels of mono- and di-methylated arsenic in urine. Smoking predicted both absolute and relative levels of arsenicals in urine. Multivariate regression models were developed for both absolute and relative levels of arsenicals in urine. Concentration of arsenic in home tap water and estimated water consumption were strongly predictive of levels of arsenicals in urine as were smoking, body mass index, and gender. Relative contributions of arsenicals to urinary arsenic were not consistently predicted by concentrations of arsenic in drinking water supplies but were more consistently predicted by gender, body mass index, age, and smoking. These findings suggest that analyses of dose-response relations in arsenic-exposed populations should account for biological and behavioral factors that modify levels of inorganic and methylated arsenicals in urine. Evidence of significant effects of these factors on arsenic metabolism may also support mode of action studies in appropriate experimental models.

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...

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...

A transcriptomics data-driven gene space accurately predicts liver cytopathology and drug-induced liver injury

PubMed Central

Kohonen, Pekka; Parkkinen, Juuso A.; Willighagen, Egon L.; Ceder, Rebecca; Wennerberg, Krister; Kaski, Samuel; Grafström, Roland C.

2017-01-01

Predicting unanticipated harmful effects of chemicals and drug molecules is a difficult and costly task. Here we utilize a ‘big data compacting and data fusion’—concept to capture diverse adverse outcomes on cellular and organismal levels. The approach generates from transcriptomics data set a ‘predictive toxicogenomics space’ (PTGS) tool composed of 1,331 genes distributed over 14 overlapping cytotoxicity-related gene space components. Involving ∼2.5 × 108 data points and 1,300 compounds to construct and validate the PTGS, the tool serves to: explain dose-dependent cytotoxicity effects, provide a virtual cytotoxicity probability estimate intrinsic to omics data, predict chemically-induced pathological states in liver resulting from repeated dosing of rats, and furthermore, predict human drug-induced liver injury (DILI) from hepatocyte experiments. Analysing 68 DILI-annotated drugs, the PTGS tool outperforms and complements existing tests, leading to a hereto-unseen level of DILI prediction accuracy. PMID:28671182

Childhood adversity predicts reduced physiological flexibility during the processing of negative affect among adolescents with major depression histories.

PubMed

Daches, Shimrit; Kovacs, Maria; George, Charles J; Yaroslavsky, Ilya; Kiss, Eniko; Vetró, Ágnes; Dochnal, Roberta; Benák, István; Baji, Ildikó; Halas, Kitti; Makai, Attila; Kapornai, Krisztina; Rottenberg, Jonathan

2017-11-01

Adversity during early development has been shown to have enduring negative physiological consequences. In turn, atypical physiological functioning has been associated with maladaptive processing of negative affect, including its regulation. The present study therefore explored whether exposure to adverse life events in childhood predicted maladaptive (less flexible) parasympathetic nervous system functioning during the processing of negative affect among adolescents with depression histories. An initially clinic-referred, pediatric sample (N=189) was assessed at two time points. At Time 1, when subjects were 10.17years old (SD=1.42), on average, and were depressed, parents reported on adverse life events the offspring experienced up to that point. At Time 2, when subjects were 17.18years old (SD=1.28), and were remitted from depression, parents again reported on adverse life events in their offspring's lives for the interim period. At time 2, subjects' parasympathetic nervous system functioning (quantified as respiratory sinus arrhythmia) also was assessed at rest, during sad mood induction, and during instructed mood repair. Extent of adverse life events experienced by T1 (but not events occurring between T1 and T2) predicted less flexible RSA functioning 7years later during the processing of negative affect. Adolescents with more extensive early life adversities exhibited less vagal withdrawal following negative mood induction and tended to show less physiological recovery following mood repair. Early adversities appear to be associated with less flexible physiological regulatory control during negative affect experience, when measured later in development. Stress-related autonomic dysfunction in vulnerable youths may contribute to the unfavorable clinical prognosis associated with juvenile-onset depression. Copyright © 2017 Elsevier B.V. All rights reserved.

Drug residues in urban water: A database for ecotoxicological risk management.

PubMed

Destrieux, Doriane; Laurent, François; Budzinski, Hélène; Pedelucq, Julie; Vervier, Philippe; Gerino, Magali

2017-12-31

Human-use drug residues (DR) are only partially eliminated by waste water treatment plants (WWTPs), so that residual amounts can reach natural waters and cause environmental hazards. In order to properly manage these hazards in the aquatic environment, a database is made available that integrates the concentration ranges for DR, which cause adverse effects for aquatic organisms, and the temporal variations of the ecotoxicological risks. To implement this database for the ecotoxicological risk assessment (ERA database), the required information for each DR is the predicted no effect concentrations (PNECs), along with the predicted environmental concentrations (PECs). The risk assessment is based on the ratio between the PNECs and the PECs. Adverse effect data or PNECs have been found in the publicly available literature for 45 substances. These ecotoxicity test data have been extracted from 125 different sources. This ERA database contains 1157 adverse effect data and 287 PNECs. The efficiency of this ERA database was tested with a data set coming from a simultaneous survey of WWTPs and the natural environment. In this data set, 26 DR were searched for in two WWTPs and in the river. On five sampling dates, concentrations measured in the river for 10 DR could pose environmental problems of which 7 were measured only downstream of WWTP outlets. From scientific literature and measurements, data implementation with unit homogenisation in a single database facilitates the actual ecotoxicological risk assessment, and may be useful for further risk coming from data arising from the future field survey. Moreover, the accumulation of a large ecotoxicity data set in a single database should not only improve knowledge of higher risk molecules but also supply an objective tool to help the rapid and efficient evaluation of the risk. Copyright © 2017 Elsevier B.V. All rights reserved.

Economics of Pharmacogenetic-Guided Treatments: Underwhelming or Overstated?

PubMed

Hughes, Dyfrig A

2018-05-01

Economic evaluations have dispelled a perception that precision medicine, achieved through pharmacogenetic testing, reduces healthcare costs. For many tests aimed at preventing adverse drug reactions, cost-effectiveness analyses predict modest improvements in health benefits and increases in total costs. While there are many uncertainties in estimating the value of testing, factors that influence cost-effectiveness include the rarity of the outcome, the effectiveness of alternative treatments, and the scope and perspective of analysis. © 2018 ASCPT.

Proceedings of the Conference on Low Reynolds Number Airfoil Aerodynamics

DTIC Science & Technology

1985-06-01

resulting in a simple bubble prediction method. The effect of tripping devices to decrease the adverse effect of the bubble on drag is discussed ...interacting flows. Of interest is a special form of the steady-state bifurcation , namely, symmetry breaking of an otherwise regular flow about a symmet- ric...Ratio Effects on the Aerodynamics of a Wortmann Airfoil at Low Reynolds Number J.F. Marchman, IIl, A.A. Abtahi and V. Sumantran . . . 183 Performance of

Application of Near Infrared Spectroscopy, Intravascular Ultrasound and the Coronary Calcium Score to Predict Adverse Coronary Events

DTIC Science & Technology

2015-10-01

planned. 15. SUBJECT TERMS coronary artery disease , near infrared spectroscopy, calcium scoring, intravascular ultrasound 16. SECURIY CLASSIFICATION OF...Award Number: W81XWH-11-1-0831 TITLE: Application of Near Infrared Spectroscopy, Intravascular Ultrasound and the Coronary Calcium Score to...Predict Adverse Coronary Events PRINCIPAL INVESTIGATOR: Dr. Charles Lambert CONTRACTING ORGANIZATION: University Community Hospital Tampa, FL 33613

A High-yield Fall Risk and Adverse Events Screening Questions From the Stopping Elderly Accidents, Death, and Injuries (STEADI) Guideline for Older Emergency Department Fall Patients.

PubMed

Sri-On, Jiraporn; Tirrell, Gregory Philip; Kamsom, Anucha; Marill, Keith A; Shankar, Kalpana Narayan; Liu, Shan W

2018-03-25

The objectives were to examine whether responses to the Stopping Elderly Accidents, Death, and Injuries (STEADI) questions responses predicted adverse events after an older adult emergency department (ED) fall visits and to identify factors associated with such recurrent fall. We conducted a prospective study at two urban, teaching hospitals. We included patients aged ≥ 65 years who presented to the ED for an accidental fall. Data were gathered for fall-relevant comorbidities, high-risk medications for falls, and the responses to 12 questions from the STEADI guideline recommendation. Our outcomes were the number of 6-month adverse events that were defined as mortality, ED revisit, subsequent hospitalization, recurrent falls, and a composite outcome. There were 548 (86.3%) patients who completed follow-up and 243 (44.3%) patients experienced an adverse event after a fall within 6 months. In multivariate analysis, seven questions from the STEADI guideline predicted various outcomes. The question "Had previous fall" predicted recurrent falls (odds ratio [OR] = 2.45, 95% confidence interval [CI] = 1.52 to 3.97), the question "Feels unsteady when walking sometimes" (OR = 2.34, 95% CI = 1.44 to 3.81), and "Lost some feeling in their feet" predicted recurrent falls. In addition to recurrent falls risk, the supplemental questions "Use or have been advised to use a cane or walker," "Take medication that sometimes makes them feel light-headed or more tired than usual," "Take medication to help sleep or improve mood," and "Have to rush to a toilet" predicted other outcomes. A STEADI score of ≥4 did not predict adverse outcomes although seven individual questions from the STEADI guidelines were associated with increased adverse outcomes within 6 months. These may be organized into three categories (previous falls, physical activity, and high-risk medications) and may assist emergency physicians to evaluate and refer high-risk fall patients for a comprehensive falls evaluation. © 2018 by the Society for Academic Emergency Medicine.

Metabolic Profiles Predict Adverse Events Following Coronary Artery Bypass Grafting

PubMed Central

Shah, Asad A.; Craig, Damian M.; Sebek, Jacqueline K.; Haynes, Carol; Stevens, Robert C.; Muehlbauer, Michael J.; Granger, Christopher B.; Hauser, Elizabeth R.; Newby, L. Kristin; Newgard, Christopher B.; Kraus, William E.; Hughes, G. Chad; Shah, Svati H.

2012-01-01

Objectives Clinical models incompletely predict outcomes following coronary artery bypass grafting. Novel molecular technologies may identify biomarkers to improve risk stratification. We examined whether metabolic profiles can predict adverse events in patients undergoing coronary artery bypass grafting. Methods The study population comprised 478 subjects from the CATHGEN biorepository of patients referred for cardiac catheterization who underwent coronary artery bypass grafting after enrollment. Targeted mass spectrometry-based profiling of 69 metabolites was performed in frozen, fasting plasma samples collected prior to surgery. Principal-components analysis and Cox proportional hazards regression modeling were used to assess the relation between metabolite factor levels and a composite outcome of post-coronary artery bypass grafting myocardial infarction, need for percutaneous coronary intervention, repeat coronary artery bypass grafting, or death. Results Over a mean follow-up of 4.3 ± 2.4 years, 126 subjects (26.4%) suffered an adverse event. Three principal-components analysis-derived factors were significantly associated with adverse outcome in univariable analysis: short-chain dicarboxylacylcarnitines (factor 2, P=0.001); ketone-related metabolites (factor 5, P=0.02); and short-chain acylcarnitines (factor 6, P=0.004). These three factors remained independently predictive of adverse outcome after multivariable adjustment: factor 2 (adjusted hazard ratio 1.23; 95% confidence interval [1.10-1.38]; P<0.001), factor 5 (1.17 [1.01-1.37], P=0.04), and factor 6 (1.14 [1.02-1.27], P=0.03). Conclusions Metabolic profiles are independently associated with adverse outcomes following coronary artery bypass grafting. These profiles may represent novel biomarkers of risk that augment existing tools for risk stratification of coronary artery bypass grafting patients and may elucidate novel biochemical pathways that mediate risk. PMID:22306227

Frailty and the prediction of dependence and mortality in low- and middle-income countries: a 10/66 population-based cohort study.

PubMed

At, Jotheeswaran; Bryce, Renata; Prina, Matthew; Acosta, Daisy; Ferri, Cleusa P; Guerra, Mariella; Huang, Yueqin; Rodriguez, Juan J Llibre; Salas, Aquiles; Sosa, Ana Luisa; Williams, Joseph D; Dewey, Michael E; Acosta, Isaac; Liu, Zhaorui; Beard, John; Prince, Martin

2015-06-10

In countries with high incomes, frailty indicators predict adverse outcomes in older people, despite a lack of consensus on definition or measurement. We tested the predictive validity of physical and multidimensional frailty phenotypes in settings in Latin America, India, and China. Population-based cohort studies were conducted in catchment area sites in Cuba, Dominican Republic, Venezuela, Mexico, Peru, India, and China. Seven frailty indicators, namely gait speed, self-reported exhaustion, weight loss, low energy expenditure, undernutrition, cognitive, and sensory impairment were assessed to estimate frailty phenotypes. Mortality and onset of dependence were ascertained after a median of 3.9 years. Overall, 13,924 older people were assessed at baseline, with 47,438 person-years follow-up for mortality and 30,689 for dependence. Both frailty phenotypes predicted the onset of dependence and mortality, even adjusting for chronic diseases and disability, with little heterogeneity of effect among sites. However, population attributable fractions (PAF) summarising etiologic force were highest for the aggregate effect of the individual indicators, as opposed to either the number of indicators or the dichotomised frailty phenotypes. The aggregate of all seven indicators provided the best overall prediction (weighted mean PAF 41.8 % for dependence and 38.3 % for mortality). While weight loss, underactivity, slow walking speed, and cognitive impairment predicted both outcomes, whereas undernutrition predicted only mortality and sensory impairment only dependence. Exhaustion predicted neither outcome. Simply assessed frailty indicators identify older people at risk of dependence and mortality, beyond information provided by chronic disease diagnoses and disability. Frailty is likely to be multidimensional. A better understanding of the construct and pathways to adverse outcomes could inform multidimensional assessment and intervention to prevent or manage dependence in frail older people, with potential to add life to years, and years to life.

Multivariate Prediction Equations for HbA1c Lowering, Weight Change, and Hypoglycemic Events Associated with Insulin Rescue Medication in Type 2 Diabetes Mellitus: Informing Economic Modeling.

PubMed

Willis, Michael; Asseburg, Christian; Nilsson, Andreas; Johnsson, Kristina; Kartman, Bernt

2017-03-01

Type 2 diabetes mellitus (T2DM) is chronic and progressive and the cost-effectiveness of new treatment interventions must be established over long time horizons. Given the limited durability of drugs, assumptions regarding downstream rescue medication can drive results. Especially for insulin, for which treatment effects and adverse events are known to depend on patient characteristics, this can be problematic for health economic evaluation involving modeling. To estimate parsimonious multivariate equations of treatment effects and hypoglycemic event risks for use in parameterizing insulin rescue therapy in model-based cost-effectiveness analysis. Clinical evidence for insulin use in T2DM was identified in PubMed and from published reviews and meta-analyses. Study and patient characteristics and treatment effects and adverse event rates were extracted and the data used to estimate parsimonious treatment effect and hypoglycemic event risk equations using multivariate regression analysis. Data from 91 studies featuring 171 usable study arms were identified, mostly for premix and basal insulin types. Multivariate prediction equations for glycated hemoglobin A 1c lowering and weight change were estimated separately for insulin-naive and insulin-experienced patients. Goodness of fit (R 2 ) for both outcomes were generally good, ranging from 0.44 to 0.84. Multivariate prediction equations for symptomatic, nocturnal, and severe hypoglycemic events were also estimated, though considerable heterogeneity in definitions limits their usefulness. Parsimonious and robust multivariate prediction equations were estimated for glycated hemoglobin A 1c and weight change, separately for insulin-naive and insulin-experienced patients. Using these in economic simulation modeling in T2DM can improve realism and flexibility in modeling insulin rescue medication. Copyright © 2017 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

The relationship between childhood adversity, attachment, and internalizing behaviors in a diversion program for child-to-mother violence.

PubMed

Nowakowski-Sims, Eva; Rowe, Amanda

2017-10-01

Very little research has been conducted on the role of childhood adversity in child-to-parent violence. Childhood adversity places youth at risk for internalizing behaviors (i.e. anxiety and depression) and externalizing behaviors (i.e. aggression). The purpose of this study was to explore the relationships between childhood adversity, child-mother attachment, and internalizing behaviors among a sample of 80 youth who have been arrested for domestic battery against a mother. This study reported high prevalence rates of childhood adversity (mean score of 10 out of 17 events). Multiple regression analysis indicated that insecure attachment predicted depression among females (F(6, 73)=4.87, p<0.001), and previous experience with child maltreatment and/or witness to parental violence predicted anxiety among females (F(6, 73)=3.08, p<0.01). This study is the first study to explore childhood adversity among a sample of perpetrators of child-to-mother violence and notably adds to our understanding of the multiple pathways connecting childhood adversity, child-mother attachment, and depression and anxiety among a difficult to treat youth population. Copyright © 2017 Elsevier Ltd. All rights reserved.

Developing confidence in adverse outcome pathway-based ...

EPA Pesticide Factsheets

An adverse outcome pathway (AOP) description linking inhibition of aromatase (cytochrome P450 [cyp] 19) to reproductive dysfunction was reviewed for scientific and technical quality and endorsed by the OECD. An intended application of the AOP framework is to support the use of mechanistic or pathway-based data to infer or predict chemical hazards and apical adverse outcomes. As part of this work, ToxCast high throughput screening data were used to identify a chemicals’ ability to inhibit aromatase activity in vitro. Twenty-four hour in vivo exposures, focused on effects on production and circulating concentrations of 17β-estradiol (E2), key events in the AOP, were conducted to verify in vivo activity. Based on these results, imazalil was selected as a case study chemical to test an AOP-based hazard prediction. A computational model of the fish hypothalamic-pituitary-gonadal-liver axis and a statistically-based model of oocyte growth dynamics were used to predict impacts of different concentrations of imazalil on multiple key events along the AOP, assuming continuous exposure for 21 d. Results of the model simulations were used to select test concentrations and design a fathead minnow reproduction study in which fish were exposed to 20, 60, or 200 µg imazalil/L for durations of 2.5, 10, or 21d. Within 60 h of exposure, female fathead minnows showed significant reductions in ex vivo production of E2, circulating E2 concentrations, and significant increases in

Tests of the Attachment and Developmental Dynamic Systems Theory of Crime (ADDSTOC): Toward a Differential RDoC Diagnostic and Treatment Approach.

PubMed

Lindberg, Marc A; Zeid, Dana

2018-01-01

The Attachment and Developmental Dynamic Systems Theory of Crime was tested on 206 male inmates. They completed measures tapping attachments, clinical issues, adverse childhood events, peer crime, and crime addictions. A significant path model was found, going from insecure parental attachments to adverse childhood events, and then on to the behavioral crime addiction and criminal peers scales. Peer crime was also predicted by insecure parent attachments and the crime addiction scale. Finally, the crime addiction, peer crime, and insecure parental attachment scales predicted frequencies of criminal behavior. The model also fit a sample of 239 female inmates. The notions of crime addiction, in this context of adverse events and insecure parental attachments, offered newer and more powerful explanations than previously offered by social learning theories on why some individuals are more likely to associate with peers engaging in criminal behavior, and also how these combine to predict degrees of criminal behavior. By moving beyond main effects models, it was found that a focus on systems of interactions was robust in theory and application. However, profile data from the Attachment and Clinical Issues Questionnaire showed that individual differences in Research Domain Criteria diagnoses are fundamental to treatment settings. Such approaches to reducing rates of recidivism and substance abuse should also enhance outcomes in many domains, including HIV prevention, costs to health care, and at the same time increase overall public safety.

Developing confidence in adverse outcome pathway-based ...

EPA Pesticide Factsheets

An adverse outcome pathway (AOP) description linking inhibition of aromatase (cytochrome P450 [cyp] 19) to reproductive dysfunction was reviewed for scientific and technical quality and endorsed by the OECD (https://aopwiki.org/wiki/index.php/Aop:25). An intended application of the AOP framework is to support the use of mechanistic or pathway-based data to infer or predict chemical hazards and apical adverse outcomes. As part of this work, ToxCast high throughput screening data were used to identify a chemicals’ ability to inhibit aromatase activity in vitro. Twenty-four hour in vivo exposures, focused on effects on production and circulating concentrations of 17â-estradiol (E2), key events in the AOP, were conducted to verify in vivo activity. Based on these results, imazalil was selected as a case study chemical to test an AOP-based hazard prediction. A computational model of the fish hypothalamic-pituitary-gonadal-liver axis and a statistically-based model of oocyte growth dynamics were used to predict impacts of different concentrations of imazalil on multiple key events along the AOP, assuming continuous exposure for 21 d. Results of the model simulations were used to select test concentrations and design a fathead minnow reproduction study in which fish were exposed to 20, 60, or 200 µg imazalil/L for durations of 2.5, 10, or 21d. Within 60 h of exposure, female fathead minnows showed significant reductions in ex vivo production of E2, circulating E2 c

What predictors matter: Risk factors for late adolescent outcomes.

PubMed

Wall-Wieler, Elizabeth; Roos, Leslie L; Chateau, Dan G; Rosella, Laura C

2016-06-27

A life course approach and linked Manitoba data from birth to age 18 were used to facilitate comparisons of two important outcomes: high school graduation and Attention-Deficit/Hyperactivity Disorder (ADHD). With a common set of variables, we sought to answer the following questions: Do the measures predicting high school graduation differ from those that predict ADHD? Which factors are most important? How well do the models fit each outcome? Administrative data from the Population Health Research Data Repository at the Manitoba Centre for Health Policy were used to conduct one of the strongest observational designs: multilevel modelling of large population (n = 62,739) and sibling (n = 29,444) samples. Variables included are neighbourhood characteristics, measures of family stability, and mental and physical health conditions in childhood and adolescence. The adverse childhood experiences important for each outcome differ. While family instability and economic adversity more strongly affect failing to graduate from high school, adverse health events in childhood and early adolescence have a greater effect on late adolescent ADHD. The variables included in the model provided excellent accuracy and discrimination. These results offer insights on the role of several family and social variables and can serve as the basis for reliable, valid prediction tools that can identify high-risk individuals. Applying such a tool at the population level would provide insight into the future burden of these outcomes in an entire region or nation and further quantify the burden of risk in the population.

Endocrine disrupting chemicals in fish: developing exposure indicators and predictive models of effects based on mechanism of action.

PubMed

Ankley, Gerald T; Bencic, David C; Breen, Michael S; Collette, Timothy W; Conolly, Rory B; Denslow, Nancy D; Edwards, Stephen W; Ekman, Drew R; Garcia-Reyero, Natalia; Jensen, Kathleen M; Lazorchak, James M; Martinović, Dalma; Miller, David H; Perkins, Edward J; Orlando, Edward F; Villeneuve, Daniel L; Wang, Rong-Lin; Watanabe, Karen H

2009-05-05

Knowledge of possible toxic mechanisms (or modes) of action (MOA) of chemicals can provide valuable insights as to appropriate methods for assessing exposure and effects, thereby reducing uncertainties related to extrapolation across species, endpoints and chemical structure. However, MOA-based testing seldom has been used for assessing the ecological risk of chemicals. This is in part because past regulatory mandates have focused more on adverse effects of chemicals (reductions in survival, growth or reproduction) than the pathways through which these effects are elicited. A recent departure from this involves endocrine-disrupting chemicals (EDCs), where there is a need to understand both MOA and adverse outcomes. To achieve this understanding, advances in predictive approaches are required whereby mechanistic changes caused by chemicals at the molecular level can be translated into apical responses meaningful to ecological risk assessment. In this paper we provide an overview and illustrative results from a large, integrated project that assesses the effects of EDCs on two small fish models, the fathead minnow (Pimephales promelas) and zebrafish (Danio rerio). For this work a systems-based approach is being used to delineate toxicity pathways for 12 model EDCs with different known or hypothesized toxic MOA. The studies employ a combination of state-of-the-art genomic (transcriptomic, proteomic, metabolomic), bioinformatic and modeling approaches, in conjunction with whole animal testing, to develop response linkages across biological levels of organization. This understanding forms the basis for predictive approaches for species, endpoint and chemical extrapolation. Although our project is focused specifically on EDCs in fish, we believe that the basic conceptual approach has utility for systematically assessing exposure and effects of chemicals with other MOA across a variety of biological systems.

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...

Relevance of risk predictions derived from a chronic species sensitivity distribution with cadmium to aquatic populations and ecosystems

USGS Publications Warehouse

Mebane, C.A.

2010-01-01

Criteria to protect aquatic life are intended to protect diverse ecosystems, but in practice are usually developed from compilations of single-species toxicity tests using standard test organisms that were tested in laboratory environments. Species sensitivity distributions (SSDs) developed from these compilations are extrapolated to set aquatic ecosystem criteria. The protectiveness of the approach was critically reviewed with a chronic SSD for cadmium comprising 27 species within 21 genera. Within the data set, one genus had lower cadmium effects concentrations than the SSD fifth percentile-based criterion, so in theory this genus, the amphipod Hyalella, could be lost or at least allowed some level of harm by this criteria approach. However, population matrix modeling projected only slightly increased extinction risks for a temperate Hyalella population under scenarios similar to the SSD fifth percentile criterion. The criterion value was further compared to cadmium effects concentrations in ecosystem experiments and field studies. Generally, few adverse effects were inferred from ecosystem experiments at concentrations less than the SSD fifth percentile criterion. Exceptions were behavioral impairments in simplified food web studies. No adverse effects were apparent in field studies under conditions that seldom exceeded the criterion. At concentrations greater than the SSD fifth percentile, the magnitudes of adverse effects in the field studies were roughly proportional to the laboratory-based fraction of species with adverse effects in the SSD. Overall, the modeling and field validation comparisons of the chronic criterion values generally supported the relevance and protectiveness of the SSD fifth percentile approach with cadmium. ?? 2009 Society for Risk Analysis.

Exploration of a Preflight Acuity Scale for Fixed Wing Air Ambulance Transport.

PubMed

Phipps, Marcy; Conley, Virginia; Constantine, William H

Despite the prevalence of fixed wing medical flights for specialized care and repatriation, few acuity rating scales exist aimed at the prediction of adverse in-flight medical events. An acuity scoring system can provide information to flight crews, allowing for staffing enhancements, protocol modifications, and flight planning, with the aim of improving patient care, outcomes, and preventing losses to providers because of costly diversions. Our medical crew developed an acuity scale, which was applied retrospectively to 296 patients transported between January 2016 and March 2017. Patients received scores based on conditions identified during the preflight medical report, the initial patient assessment, demographics, and flight factors. Five patients were identified as high-risk transports based on our scale. Three patients suffered adverse events according to our defined criteria, 2 of which occurred before transport and 1 during transport. The 3 patients suffering adverse events did not receive a score that indicated adverse events in flight. Our scale was not predictive of adverse events in flight. However, it did illuminate factors worthy of consideration. Consideration of these factors may have prevented adverse events. Published by Elsevier Inc.

Predictors of Response to Multiple Sclerosis Therapeutics in Individual Patients.

PubMed

Hegen, Harald; Auer, Michael; Deisenhammer, Florian

2016-10-01

Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system. Several disease-modifying therapies have been shown to ameliorate the disease course; however, the individual treatment response and the occurrence of adverse events remain highly unpredictable. In the last 2 decades, a multitude of studies have aimed to identify biomarkers that enable treatment allocation in the individual patient or subgroup of patients with regard to treatment efficacy and safety profile. Following a PubMed database search, we provide an overview on what is presently known about body fluid markers for the prediction of response to the currently approved MS therapeutics. We also discuss the potential use of biomarkers with regard to drug-induced adverse events. To date, only a few molecules have been introduced in clinical routine: anti-drug antibodies against interferon (IFN)-β and natalizumab that are associated with abolished drug levels and treatment failure; anti-JC virus (JCV) antibody index that allows risk stratification for the development of progressive multifocal leukoencephalopathy (PML), a rare but severe adverse event during natalizumab treatment; and serostatus of varicella zoster virus as screening examination prior to fingolimod therapy to prevent the infection. A few candidate biomarkers still need closer examination, such as type I IFN signature and T-helper cell (Th)-17 reactivity for prediction of IFN-β treatment response, L-selectin expression for prediction of natalizumab-associated PML, interleukin (IL)-21 levels for prediction of secondary autoimmunity after exposure to alemtuzumab, lymphocyte count with regard to PML risk while receiving dimethyl fumarate or N-terminal-pro-B-type natriuretic peptide (NT-proBNP) for monitoring of cardiac side effects during mitoxantrone therapy.

Variation in the Prediction of Cross-Cultural Adjustment by Asian-Indian Students in the United States

ERIC Educational Resources Information Center

Tochkov, Karin; Levine, Lisa; Sanaka, Amritha

2010-01-01

Homesickness is a major stressor for college students in general, and international students in particular, that has an adverse effect on their psychological health and academic performance. The present study examined the incidence and determinants of homesickness in a sample of international students from India attending a US university and…

PREDICTING THE TOXICITY OF MAJOR IONS IN SEAWATER TO MYSID SHRIMP (MYSIDOPSIS BAHIA), SHEEPSHEAD MINNOW (CYPRINODON VARIEGATUS), AND INLAND SILVERSIDE MINNOW (MENIDIA BERYLLINA)

EPA Science Inventory

Although marine organisms are naturally adapted to salinities well above those of freshwater, elevated concentrations of specific ions have been shown to cause adverse effects on some saltwater species. Because some ions are also physiologically essential, a deficiency of these i...

Inferring Toxicological Responses of HepG2 Cells from ToxCast High Content Imaging Data (SOT)

EPA Science Inventory

Understanding the dynamic perturbation of cell states by chemicals can aid in for predicting their adverse effects. High-content imaging (HCI) was used to measure the state of HepG2 cells over three time points (1, 24, and 72 h) in response to 976 ToxCast chemicals for 10 differe...

Interactive effects of deficit irrigation, elevated temperature, and elevated [CO2] on peanut growth in low irrigation production settings

USDA-ARS?s Scientific Manuscript database

Improving crop water use (both agronomic and biological) is critical to most cropping areas around the world. The persistance of adverse climate conditions and predicted decreased availability of fresh water for crop production are the largest challenges to agriculture in the coming decades. Our pri...

An Examination of the Relationship between Self-Control and Cyber Victimization in Adolescents

ERIC Educational Resources Information Center

Peker, Adem

2017-01-01

Purpose: Cyber bullying is a new phenomenon which adversely affects young people. Exposure to the cyber bullying can negatively affect the mental health. The aim of this study is to examine the predictive effect of self-control on cyber victimization in adolescents. Research Methods: The study group was composed of 353 Turkish secondary school…

Assessing cross species conservation of ToxCast Assay targets using Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS)

EPA Science Inventory

US EPA’s ToxCast program has screened thousands of chemicals in hundreds of mammalian-based HTS assays for biological activity suggestive of potential toxic effects. These data are being used to prioritize toxicity testing to focus on chemicals likely to lead to adverse health ef...

Developing Resilience in Children Who Are in Public Care: The Educational Psychology Perspective

ERIC Educational Resources Information Center

Dent, Renuka Jeyarajah; Cameron, R. J. Sean

2003-01-01

Significant adults who support and teach children are only too aware of the effects of adverse experiences on intellectual, social and personal development. Less easily predicted, however, is a small number of young people who, despite many negative experiences, seem to make a considerable success of their lives. In this paper, the intriguing…

76 FR 81437 - Proposed Significant New Use Rule for Phenol, 2,4-dimethyl-6-(1-methylpentadecyl)-

Federal Register 2010, 2011, 2012, 2013, 2014

2011-12-28

... Activity Relationships (EcoSAR) dataset for phenols has been significantly updated to include 203 chemicals... result, when the most recent version of EcoSAR was run for phenol, 2,4-dimethyl-6-(1-methylpentadecyl... the new EcoSAR prediction of no expected acute or chronic adverse ecological effects. Therefore, based...

[ANTHROPOMETRIC INDICATORS AND CARDIOMETABOLIC EVENTS AMONG SCHOOL-AGED CHILDREN FROM SONORA, MEXICO].

PubMed

Peralta Peña, Sandra Lidia; Reséndiz González, Eunice; Rubí Vargas, María; Terrazas Medina, Efraín Alonso; Cupul Uicab, Lea Aurora

2015-10-01

obesity in childhood is predictive of obesity in adulthood and it is associated with adverse health effect apparent since childhood; however, the joint assessment of obesity and adverse events among children in clinical settings is unusual. to assess the association of overweight and obesity, abdominal obesity, and excess body fat with systolic [SBP] and diastolic [DBP] blood pressure, lipid profile and glucose levels; and to identify the best anthropometric indicator of such events. we conducted a cross-sectional study in a sample of 412 schoolchildren. The presence of overweight and obesity, abdominal obesity and excess body fat was determined among all participants; levels of total cholesterol, triglycerides, high and low density lipoproteins, and glucose were measured in a subsample (n = 133). The associations of interest were assessed using adjusted linear and logistic regression models. 33% of the children were overweight or obese. Overall, overweight, obesity, abdominal obesity, and excess body fat were associated with elevated SBP and DBP and with a lipid profile and glucose levels that could indicate health risks among these children. Overweight and obesity were the best predictors of such events. among these school-aged children, we observed that obesity was associated with high odds of having adverse health outcomes such as high blood pressure, lipids and glucose. Such adverse events can be predicted by the presence of obesity measured by BMI, which is a noninvasive, inexpensive and easy to implement measure. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

Early life adversity influences stress response association with smoking relapse.

PubMed

al'Absi, Mustafa; Lemieux, Andrine; Westra, Ruth; Allen, Sharon

2017-11-01

We examined the hypothesis that stress-related blunting of cortisol in smokers is particularly pronounced in those with a history of severe life adversity. The two aims of this study were first to examine hormonal, craving, and withdrawal symptoms during ad libitum smoking and after the first 24 h of abstinence in smokers who experienced high or low levels of adversity. Second, we sought to examine the relationship between adversity and hypothalamic-pituitary-adrenal (HPA) hormones to predict relapse during the first month of a smoking cessation attempt. Hormonal and self-report measures were collected from 103 smokers (49 women) during ad libitum smoking and after the first 24 h of abstinence. HPA hormones were measured during baseline rest and in response to acute stress in both conditions. All smokers were interested in smoking cessation, and we prospectively used stress response measures to predict relapse during the first 4 weeks of the smoking cessation attempt. The results showed that high adversity was associated with higher distress and smoking withdrawal symptoms. High level of early life adversity was associated with elevated HPA activity, which was found in both salivary and plasma cortisol. Enhanced adrenocorticotropic hormone (ACTH) stress response was evident in high-adversity but not in low-adversity relapsers. This study demonstrated that early life adversity is associated with stress-related HPA responses. The study also demonstrated that, among smokers who experienced a high level of life adversity, heightened ACTH and cortisol responses were linked with increased risk for smoking relapse.

Metabolites as Biomarkers of Adverse Reactions Following Vaccination: A Pilot Study using Nuclear Magnetic Resonance Metabolomics

PubMed Central

McClenathan, Bruce M.; Stewart, Delisha A.; Spooner, Christina E.; Pathmasiri, Wimal W.; Burgess, Jason P.; McRitchie, Susan L.; Choi, Y. Sammy; Sumner, Susan C.J.

2017-01-01

An Adverse Event Following Immunization (AEFI) is an adverse reaction to a vaccination that goes above and beyond the usual side effects associated with vaccinations. One serious AEFI related to the smallpox vaccine is myopericarditis. Metabolomics involves the study of the low molecular weight metabolite profile of cells, tissues, and biological fluids, and provides a functional readout of the phenotype. Metabolomics may help identify a particular metabolic signature in serum of subjects who are predisposed to developing AEFIs. The goal of this study was to identify metabolic markers that may predict the development of adverse events following smallpox vaccination. Serum samples were collected from military personnel prior to and following receipt of smallpox vaccine. The study population included five subjects who were clinically diagnosed with myopericarditis, 30 subjects with asymptomatic elevation of troponins, and 31 subjects with systemic symptoms following immunization, and 34 subjects with no AEFI, serving as controls. Two-hundred pre- and post-smallpox vaccination sera were analyzed by untargeted metabolomics using 1H nuclear magnetic resonance (NMR) spectroscopy. Baseline (pre-) and post-vaccination samples from individuals who experienced clinically verified myocarditis or asymptomatic elevation of troponins were more metabolically distinguishable pre- and post-vaccination compared to individuals who only experienced systemic symptoms, or controls. Metabolomics profiles pre- and post-receipt of vaccine differed substantially when an AEFI resulted. This study is the first to describe pre- and post-vaccination metabolic profiles of subjects who developed an adverse event following immunization. The study demonstrates the promise of metabolites for determining mechanisms associated with subjects who develop AEFI and the potential to develop predictive biomarkers. PMID:28169076

Metabolites as biomarkers of adverse reactions following vaccination: A pilot study using nuclear magnetic resonance metabolomics.

PubMed

McClenathan, Bruce M; Stewart, Delisha A; Spooner, Christina E; Pathmasiri, Wimal W; Burgess, Jason P; McRitchie, Susan L; Choi, Y Sammy; Sumner, Susan C J

2017-03-01

An Adverse Event Following Immunization (AEFI) is an adverse reaction to a vaccination that goes above and beyond the usual side effects associated with vaccinations. One serious AEFI related to the smallpox vaccine is myopericarditis. Metabolomics involves the study of the low molecular weight metabolite profile of cells, tissues, and biological fluids, and provides a functional readout of the phenotype. Metabolomics may help identify a particular metabolic signature in serum of subjects who are predisposed to developing AEFIs. The goal of this study was to identify metabolic markers that may predict the development of adverse events following smallpox vaccination. Serum samples were collected from military personnel prior to and following receipt of smallpox vaccine. The study population included five subjects who were clinically diagnosed with myopericarditis, 30 subjects with asymptomatic elevation of troponins, and 31 subjects with systemic symptoms following immunization, and 34 subjects with no AEFI, serving as controls. Two-hundred pre- and post-smallpox vaccination sera were analyzed by untargeted metabolomics using 1 H nuclear magnetic resonance (NMR) spectroscopy. Baseline (pre-) and post-vaccination samples from individuals who experienced clinically verified myocarditis or asymptomatic elevation of troponins were more metabolically distinguishable pre- and post-vaccination compared to individuals who only experienced systemic symptoms, or controls. Metabolomics profiles pre- and post-receipt of vaccine differed substantially when an AEFI resulted. This study is the first to describe pre- and post-vaccination metabolic profiles of subjects who developed an adverse event following immunization. The study demonstrates the promise of metabolites for determining mechanisms associated with subjects who develop AEFI and the potential to develop predictive biomarkers. Published by Elsevier Ltd.

Admission hyperglycemia predicts inhospital mortality and major adverse cardiac events after primary percutaneous coronary intervention in patients without diabetes mellitus.

PubMed

Ekmekci, Ahmet; Cicek, Gokhan; Uluganyan, Mahmut; Gungor, Baris; Osman, Faizel; Ozcan, Kazim Serhan; Bozbay, Mehmet; Ertas, Gokhan; Zencirci, Aycan; Sayar, Nurten; Eren, Mehmet

2014-02-01

Admission hyperglycemia is associated with high inhospital and long-term adverse events in patients that undergo primary percutaneous coronary intervention (PCI). We aimed to evaluate whether hyperglycemia predicts inhospital mortality. We prospectively analyzed 503 consecutive patients. The patients were divided into tertiles according to the admission glucose levels. Tertile I: glucose <118 mg/dL (n = 166), tertile II: glucose 118 to 145 mg/dL (n = 168), and tertile III: glucose >145 mg/dL (n = 169). Inhospital mortality was 0 in tertile I, 2 in tertile II, and 9 in tertile III (P < .02). Cardiogenic shock occurred more frequently in tertile III compared to tertiles I and II (10% vs 4.1% and 0.6%, respectively, P = .01). Multivariate logistic regression analysis revealed that patients in tertile III had significantly higher risk of inhospital major adverse cardiac events compared to patients in tertile I (odds ratio: 9.55, P < .02). Admission hyperglycemia predicts inhospital adverse cardiac events in mortality and acute ST-segment elevation myocardial infarction in patients that underwent primary PCI.

Development and evaluation of sediment quality guidelines for Florida coastal waters

USGS Publications Warehouse

MacDonald, Donald D.; Carr, R. Scott; Calder, Fred D.; Long, Edward R.; Ingersoll, Christopher G.

1996-01-01

The weight-of-evidence approach to the development of sediment quality guidelines (SQGs) was modified to support the derivation of biological effects-based SQGs for Florida coastal waters. Numerical SQGs were derived for 34 substances, including nine trace metals, 13 individual polycyclic aromatic hydrocarbons (PAHs), three groups of PAHs, total polychlorinated biphenyls (PCBs), seven pesticides and one phthalate ester. For each substance, a threshold effects level (TEL) and a probable effects level (PEL) was calculated. These two values defined three ranges of chemical concentrations, including those that were (1) rarely, (2) occasionally or (3) frequently associated with adverse effects. The SQGs were then evaluated to determine their degree of agreement with other guidelines (an indicator of comparability) and the percent incidence of adverse effects within each concentration range (an indicator of reliability). The guidelines also were used to classify (using a dichotomous system: toxic, with one or more exceedances of the PELs or non-toxic, with no exceedances of the TELs) sediment samples collected from various locations in Florida and the Gulf of Mexico. The accuracy of these predictions was then evaluated using the results of the biological tests that were performed on the same sediment samples. The resultant SQGs were demonstrated to provide practical, reliable and predictive tools for assessing sediment quality in Florida and elsewhere in the southeastern portion of the United States.

Childhood adversities and adult psychopathology in the National Comorbidity Survey Replication (NCS-R) III: associations with functional impairment related to DSM-IV disorders.

PubMed

McLaughlin, K A; Green, J G; Gruber, M J; Sampson, N A; Zaslavsky, A M; Kessler, R C

2010-05-01

Despite evidence that childhood adversities (CAs) are associated with increased risk of mental disorders, little is known about their associations with disorder-related impairment. We report the associations between CAs and functional impairment associated with 12-month DSM-IV disorders in a national sample. We used data from the US National Comorbidity Survey Replication (NCS-R). Respondents completed diagnostic interviews that assessed 12-month DSM-IV disorder prevalence and impairment. Associations of 12 retrospectively reported CAs with impairment among cases (n=2242) were assessed using multiple regression analysis. Impairment measures included a dichotomous measure of classification in the severe range of impairment on the Sheehan Disability Scale (SDS) and a measure of self-reported number of days out of role due to emotional problems in the past 12 months. CAs were positively and significantly associated with impairment. Predictive effects of CAs on the SDS were particularly pronounced for anxiety disorders and were significant in predicting increased days out of role associated with mood, anxiety and disruptive behavior disorders. Predictive effects persisted throughout the life course and were not accounted for by disorder co-morbidity. CAs associated with maladaptive family functioning (MFF; parental mental illness, substance disorder, criminality, family violence, abuse, neglect) were more consistently associated with impairment than other CAs. The joint effects of co-morbid MFF CAs were significantly subadditive. Simulations suggest that CAs account for 19.6% of severely impairing disorders and 17.4% of days out of role. CAs predict greater disorder-related impairment, highlighting the ongoing clinical significance of CAs at every stage of the life course.

Early life stress, MAOA, and gene-environment interactions predict behavioral disinhibition in children.

PubMed

Enoch, M-A; Steer, C D; Newman, T K; Gibson, N; Goldman, D

2010-02-01

Several, but not all, studies have shown that the monoamine oxidase A functional promoter polymorphism (MAOA-LPR) interacts with childhood adversity to predict adolescent and adult antisocial behavior. However, it is not known whether MAOA-LPR interacts with early life (pre-birth-3 years) stressors to influence behavior in prepubertal children. The Avon Longitudinal Study of Parents and Children, UK, is a community-representative cohort study of children followed from pre-birth onwards. The impact of family adversity from pre-birth to age 3 years and stressful life events from 6 months to 7 years on behavioral disinhibition was determined in 7500 girls and boys. Behavioral disinhibition measures were: mother-reported hyperactivity and conduct disturbances (Strengths and Difficulties Questionnaire) at ages 4 and 7 years. In both sexes, exposure to family adversity and stressful life events in the first 3 years of life predicted behavioral disinhibition at age 4, persisting until age 7. In girls, MAOA-LPR interacted with stressful life events experienced from 6 months to 3.5 years to influence hyperactivity at ages 4 and 7. In boys, the interaction of MAOA-LPR with stressful life events between 1.5 and 2.5 years predicted hyperactivity at age 7 years. The low activity MAOA-LPR variant was associated with increased hyperactivity in girls and boys exposed to high stress. In contrast, there was no MAOA-LPR interaction with family adversity. In a general population sample of prepubertal children, exposure to common stressors from pre-birth to 3 years predicted behavioral disinhibition, and MAOA-LPR- stressful life event interactions specifically predicted hyperactivity.

Spacecraft external molecular contamination analysis

NASA Technical Reports Server (NTRS)

Ehlers, H. K. F.

1990-01-01

Control of contamination on and around spacecraft is required to avoid adverse effects on the performance of instruments and spacecraft systems. Recent work in this area is reviewed and discussed. Specific issues and limitations to be considered as part of the effort to predict contamination effects using modeling techniques are addressed. Significant results of Space Shuttle missions in the field of molecule/surface interactions as well as their implications for space station design and operation are reviewed.

Neighbourhood disadvantage and individual adversities in adolescence and total alcohol consumption up to mid-life-Results from the Northern Swedish Cohort.

PubMed

Johansson, Klara; San Sebastian, Miguel; Hammarström, Anne; Gustafsson, Per E

2015-05-01

This study tests if neighbourhood socioeconomic disadvantage and family social and material adversities during adolescence are independently related to total alcohol consumption from adolescence through to mid-life. Self-reports from the Northern Swedish Cohort (effective sample=950) at ages 16, 18, 21, 30 and 42 was combined with register data on the socioeconomic composition of neighbourhoods at age 16. Total volume of alcohol consumed between age 16-42 was estimated based on the five survey waves, and self-reported social and material adversities were computed as composite variables. Neighbourhood socioeconomic disadvantage at age 16 was associated with alcohol consumption age 16-42 for men but not for women. Social adversities at age 16 were associated with alcohol consumption age 16-42 for both women and men, but material adversity or parental class was not. In conclusion, neighbourhood socioeconomic disadvantage in adolescence has a significant relationship with later alcohol consumption among men, even independently from individual factors. On family level, social factors but not socioeconomic factors in adolescence independently predict later alcohol consumption. Copyright © 2015 Elsevier Ltd. All rights reserved.

Adverse adolescent relationship histories and young adult health: Cumulative effects of loneliness, low parental support, relationship instability, intimate partner violence and loss

PubMed Central

Adam, Emma K.; Chyu, Laura; Hoyt, Lindsay; Doane, Leah D.; Boisjoly, Johanne; Duncan, Greg; Chase-Lansdale, Lindsay; McDade, Thomas W.

2011-01-01

Purpose To examine the associations between adverse interpersonal relationship histories experienced during adolescence and health in young adulthood in a large, nationally representative sample. Methods Using data from Waves I, II and III of the National Longitudinal Study of Adolescent Health, multiple adverse relationship experiences are examined, including high loneliness, low perceived parental support, frequent transitions in romantic relationships (relationship instability), exposure to intimate partner violence, and loss by death of important relationship figures. These histories are assessed, both individually and in a relationship risk index, as predictors of self-reported general health and depressive symptoms at Wave III (ages 18 to 27), controlling for baseline (Wave I) health and for demographic and health behavior covariates. Results Net of baseline health and covariates, each type of relationship risk (experienced between Wave I and Wave III) was related to either depression or general health at Wave III, with the strongest effects seen for exposure to intimate partner violence. In addition, a cumulative relationship risk index examining the extent to which youth experienced high levels of multiple relationship risk factors revealed that each additional adverse relationship experience increased the odds of reporting poor mental and general health at Wave III, with increases occurring in an additive manner. Conclusions Multiple types of adverse relationship experiences predicted increases in poor general health and depressive symptoms from adolescence to early adulthood. Consistent with a cumulative risk hypothesis, the more types of adverse relationship experiences a youth experienced, the worse their young adult health outcomes. PMID:21856520

Safety pharmacology--current and emerging concepts.

PubMed

Hamdam, Junnat; Sethu, Swaminathan; Smith, Trevor; Alfirevic, Ana; Alhaidari, Mohammad; Atkinson, Jeffrey; Ayala, Mimieveshiofuo; Box, Helen; Cross, Michael; Delaunois, Annie; Dermody, Ailsa; Govindappa, Karthik; Guillon, Jean-Michel; Jenkins, Rosalind; Kenna, Gerry; Lemmer, Björn; Meecham, Ken; Olayanju, Adedamola; Pestel, Sabine; Rothfuss, Andreas; Sidaway, James; Sison-Young, Rowena; Smith, Emma; Stebbings, Richard; Tingle, Yulia; Valentin, Jean-Pierre; Williams, Awel; Williams, Dominic; Park, Kevin; Goldring, Christopher

2013-12-01

Safety pharmacology (SP) is an essential part of the drug development process that aims to identify and predict adverse effects prior to clinical trials. SP studies are described in the International Conference on Harmonisation (ICH) S7A and S7B guidelines. The core battery and supplemental SP studies evaluate effects of a new chemical entity (NCE) at both anticipated therapeutic and supra-therapeutic exposures on major organ systems, including cardiovascular, central nervous, respiratory, renal and gastrointestinal. This review outlines the current practices and emerging concepts in SP studies including frontloading, parallel assessment of core battery studies, use of non-standard species, biomarkers, and combining toxicology and SP assessments. Integration of the newer approaches to routine SP studies may significantly enhance the scope of SP by refining and providing mechanistic insight to potential adverse effects associated with test compounds. Copyright © 2013 Elsevier Inc. All rights reserved.

Combined exposure to low doses of pesticides causes decreased birth weights in rats.

PubMed

Hass, Ulla; Christiansen, Sofie; Axelstad, Marta; Scholze, Martin; Boberg, Julie

2017-09-01

Decreased birth weight is a common effect of many pesticides in reproductive toxicity studies, but there are no empirical data on how pesticides act in combination on this endpoint. We hypothesized that a mixture of six pesticides (cyromazine, MCPB, pirimicarb, quinoclamine, thiram, and ziram) would decrease birth weight, and that these mixture effects could be predicted by the Dose Addition model. Data for the predictions were obtained from the Draft Assessment Reports of the individual pesticides. A mixture of equi-effective doses of these pesticides was tested in two studies in Wistar rats, showing mixture effects in good agreement with the additivity predictions. Significantly lower birth weights were observed when compounds were present at individual doses below their no-observed adverse effect levels (NOAELs). These results emphasize the need for cumulative risk assessment of pesticides to avoid potentially serious impact of mixed exposure on prenatal development and pregnancy in humans. Copyright © 2017 Elsevier Inc. All rights reserved.

Local weather conditions have complex effects on the growth of blue tit nestlings.

PubMed

Mainwaring, Mark C; Hartley, Ian R

2016-08-01

Adverse weather conditions are expected to result in impaired nestling development in birds, but empirical studies have provided equivocal support for such a relationship. This may be because the negative effects of adverse weather conditions are masked by parental effects. Globally, ambient temperatures, rainfall levels and wind speeds are all expected to increase in a changing climate and so there is a need for a better understanding of the relationship between weather conditions and nestling growth. Here, we describe a correlative study that examined the relationships between local temperatures, rainfall levels and wind speeds and the growth of individual blue tit (Cyanistes caeruleus) nestlings in relation to their hatching order and sex. We found that changes in a range of morphological characters were negatively related to both temperature and wind speed, but positively related to rainfall. These patterns were further influenced by the hatching order of the nestlings but not by nestling sex. This suggests that the predicted changes in local weather conditions may have complex effects on nestling growth, but that parents may be able to mitigate the adverse effects via adaptive parental effects. We therefore conclude that local weather conditions have complex effects on avian growth and the implications for patterns of avian growth in a changing climate are discussed. Copyright © 2016 Elsevier Ltd. All rights reserved.

Predicting drug side-effect profiles: a chemical fragment-based approach

PubMed Central

2011-01-01

Background Drug side-effects, or adverse drug reactions, have become a major public health concern. It is one of the main causes of failure in the process of drug development, and of drug withdrawal once they have reached the market. Therefore, in silico prediction of potential side-effects early in the drug discovery process, before reaching the clinical stages, is of great interest to improve this long and expensive process and to provide new efficient and safe therapies for patients. Results In the present work, we propose a new method to predict potential side-effects of drug candidate molecules based on their chemical structures, applicable on large molecular databanks. A unique feature of the proposed method is its ability to extract correlated sets of chemical substructures (or chemical fragments) and side-effects. This is made possible using sparse canonical correlation analysis (SCCA). In the results, we show the usefulness of the proposed method by predicting 1385 side-effects in the SIDER database from the chemical structures of 888 approved drugs. These predictions are performed with simultaneous extraction of correlated ensembles formed by a set of chemical substructures shared by drugs that are likely to have a set of side-effects. We also conduct a comprehensive side-effect prediction for many uncharacterized drug molecules stored in DrugBank, and were able to confirm interesting predictions using independent source of information. Conclusions The proposed method is expected to be useful in various stages of the drug development process. PMID:21586169

Integration of different data gap filling techniques to facilitate ...

EPA Pesticide Factsheets

Data gap filling techniques are commonly used to predict hazard in the absence of empirical data. The most established techniques are read-across, trend analysis and quantitative structure-activity relationships (QSARs). Toxic equivalency factors (TEFs) are less frequently used data gap filling techniques which are applied to estimate relative potencies for mixtures of chemicals that contribute to an adverse outcome through a common biological target. For example, The TEF approach has been used for dioxin-like effects comparing individual chemical activity to that of the most toxic dioxin: 2,3,7,8-tetrachlorodibenzo-p-dioxin. The aim of this case study was to determine whether integration of two data gap filling techniques: QSARs and TEFs improved the predictive outcome for the assessment of a set of polychlorinated biphenyl (PCB) congeners and their mixtures. PCBs are associated with many different adverse effects, including their potential for neurotoxicity, which is the endpoint of interest in this study. The dataset comprised 209 PCB congeners, out of which 87 altered in vitro Ca(2+) homeostasis from which neurotoxic equivalency values (NEQs) were derived. The preliminary objective of this case study was to develop a QSAR model to predict NEQ values for the 122 untested PCB congeners. A decision tree model was developed using the number of position specific chlorine substitutions on the biphenyl scaffold as a fingerprint descriptor. Three different positiona

SSAIS: A Program to Assess Adverse Impact in Multistage Selection Decisions

ERIC Educational Resources Information Center

De Corte, Wilfried

2004-01-01

The article describes a Windows program to estimate the expected value and sampling distribution function of the adverse impact ratio for general multistage selections. The results of the program can also be used to predict the risk that a future selection decision will result in an outcome that reflects the presence of adverse impact. The method…

Quantitative Adverse Outcome Pathways and Their ...

EPA Pesticide Factsheets

A quantitative adverse outcome pathway (qAOP) consists of one or more biologically based, computational models describing key event relationships linking a molecular initiating event (MIE) to an adverse outcome. A qAOP provides quantitative, dose–response, and time-course predictions that can support regulatory decision-making. Herein we describe several facets of qAOPs, including (a) motivation for development, (b) technical considerations, (c) evaluation of confidence, and (d) potential applications. The qAOP used as an illustrative example for these points describes the linkage between inhibition of cytochrome P450 19A aromatase (the MIE) and population-level decreases in the fathead minnow (FHM; Pimephales promelas). The qAOP consists of three linked computational models for the following: (a) the hypothalamic-pitutitary-gonadal axis in female FHMs, where aromatase inhibition decreases the conversion of testosterone to 17β-estradiol (E2), thereby reducing E2-dependent vitellogenin (VTG; egg yolk protein precursor) synthesis, (b) VTG-dependent egg development and spawning (fecundity), and (c) fecundity-dependent population trajectory. While development of the example qAOP was based on experiments with FHMs exposed to the aromatase inhibitor fadrozole, we also show how a toxic equivalence (TEQ) calculation allows use of the qAOP to predict effects of another, untested aromatase inhibitor, iprodione. While qAOP development can be resource-intensive, the quan

[Suicidal behaviors among young adults: risk factors during development from early childhood to adolescence].

PubMed

Buchmann, Arlette F; Blomeyer, Dorothea; Laucht, Manfred

2012-01-01

Suicidal behaviors are prevalent among young people. Numerous risk factors have been implicated in their development. In the framework of the longitudinal Mannheim Study of Children at Risk, 311 young adults (143 males, 168 females) aged 19-23 years were investigated in order 1) to determine the significance of different risk factors during development in predicting suicidal behaviors in young adulthood, 2) to identify potential risk factors discriminating between suicidal ideation and suicide attempts, and 3) to examine whether the effect of early risk factors was mediated by later occurring predictors. Young adults with suicidal behaviors displayed a number of abnormalities during development, including high load of early family adversity, suicidal ideation and psychiatric problems in childhood and adolescence, as well as low self esteem, poor school functioning, higher levels of novelty seeking, and enhanced affiliations with deviant peers in adolescence. Independent contributions to predicting suicidal behaviors in young adults were provided by early family adversity, suicidal ideation during childhood and adolescence, and low self esteem (with regard to suicidal ideation) and novelty seeking (with regard to suicide attempt), respectively. The impact of early adversity was mediated by child and adolescent externalizing disorders and low self esteem in adolescence. Possible implications of these findings for the prevention and treatment of suicidal behaviors are discussed.

Building gene expression signatures indicative of transcription factor activation to predict AOP modulation

EPA Science Inventory

Building gene expression signatures indicative of transcription factor activation to predict AOP modulation Adverse outcome pathways (AOPs) are a framework for predicting quantitative relationships between molecular initiatin...

The Identification of Seniors at Risk (ISAR) score to predict clinical outcomes and health service costs in older people discharged from UK acute medical units.

PubMed

Edmans, Judi; Bradshaw, Lucy; Gladman, John R F; Franklin, Matthew; Berdunov, Vladislav; Elliott, Rachel; Conroy, Simon P

2013-11-01

tools are required to identify high-risk older people in acute emergency settings so that appropriate services can be directed towards them. to evaluate whether the Identification of Seniors At Risk (ISAR) predicts the clinical outcomes and health and social services costs of older people discharged from acute medical units. an observational cohort study using receiver-operator curve analysis to compare baseline ISAR to an adverse clinical outcome at 90 days (where an adverse outcome was any of death, institutionalisation, hospital readmission, increased dependency in activities of daily living (decrease of 2 or more points on the Barthel ADL Index), reduced mental well-being (increase of 2 or more points on the 12-point General Health Questionnaire) or reduced quality of life (reduction in the EuroQol-5D) and high health and social services costs over 90 days estimated from routine electronic service records. two acute medical units in the East Midlands, UK. a total of 667 patients aged ≥70 discharged from acute medical units. an adverse outcome at 90 days was observed in 76% of participants. The ISAR was poor at predicting adverse outcomes (AUC: 0.60, 95% CI: 0.54-0.65) and fair for health and social care costs (AUC: 0.70, 95% CI: 0.59-0.81). adverse outcomes are common in older people discharged from acute medical units in the UK; the poor predictive ability of the ISAR in older people discharged from acute medical units makes it unsuitable as a sole tool in clinical decision-making.

A novel differential susceptibility gene: CHRNA4 and moderation of the effect of maltreatment on child personality.

PubMed

Grazioplene, Rachael G; Deyoung, Colin G; Rogosch, Fred A; Cicchetti, Dante

2013-08-01

The differential susceptibility hypothesis states that some genetic variants that confer risk in adverse environments are beneficial in normal or nurturing environments. The cholinergic system is promising as a source of susceptibility genes because of its involvement in learning and neural plasticity. The cholinergic receptor gene CHRNA4 has been linked to characteristics related to the personality traits Neuroticism and Openness/Intellect. The effects of interaction between CHRNA4 genotype and maltreatment status on child personality were examined in a well matched sample of 339 maltreated and 275 non-maltreated children (aged 8-13 years). Variation in CHRNA4 interacted with childhood maltreatment to predict personality in a manner indicating differential susceptibility. The interaction of CHRNA4 and maltreatment status predicted Neuroticism and Openness/Intellect. Maltreated children with the rs1044396 T/T genotype scored highest on Neuroticism and showed no effect of genotype on Openness/Intellect. Non-maltreated children with this genotype scored lowest on Neuroticism and highest on Openness/Intellect. Variation in CHRNA4 appears to contribute to personality by affecting degree of developmental sensitivity to both normal and adverse environments. © 2012 The Authors. Journal of Child Psychology and Psychiatry © 2012 Association for Child and Adolescent Mental Health.

The inter- and intra- generational transmission of family poverty and hardship (adversity): A prospective 30 year study

PubMed Central

Bor, William; Ahmadabadi, Zohre; Williams, Gail M.; Alati, Rosa; Mamun, Abdullah A.; Scott, James G.; Clavarino, Alexandra M.

2018-01-01

Background Children exposed to family poverty have been found to have higher morbidity and mortality rates, poorer mental health and cognitive outcomes and reduced life chances across a wide range of life domains. There is, however, very little known about the extent to which poverty is experienced by children over their early life course, particularly in community samples. This study tracks changes in family poverty and the main factors that predict family poverty (adverse life experiences) over a 30-year period since the birth of the study child. Methods Data are from a prospective, longitudinal, birth cohort study conducted in Brisbane, Australia. Consecutive families were recruited at the mothers’ first obstetrical visit at one of two major obstetrical hospitals in Brisbane. Data are available for 2087 families with complete data at the 30-year follow-up. Poverty was measured using family income at each time point (adjusted for inflation). Findings Poverty affects about 20% of families at any time point. It is common for families to move in and out of poverty, as their circumstances are affected by such adversities as unemployment and marital breakdown. Over the period of the study about half the families in the study experienced poverty on at least one occasion. Only a very small minority of families experienced persistent poverty over the 30-year duration of the study. Logistic regressions with time lag show that family poverty predicts subsequent adversities and adverse events predict subsequent poverty. Conclusions Experiences of poverty and adversity are common and may vary greatly over the child’s early life course. In assessing the health consequences of poverty, it is important to distinguish the timing and chronicity of early life course experiences of poverty and adversity. PMID:29360828

The inter- and intra- generational transmission of family poverty and hardship (adversity): A prospective 30 year study.

PubMed

Najman, Jake M; Bor, William; Ahmadabadi, Zohre; Williams, Gail M; Alati, Rosa; Mamun, Abdullah A; Scott, James G; Clavarino, Alexandra M

2018-01-01

Children exposed to family poverty have been found to have higher morbidity and mortality rates, poorer mental health and cognitive outcomes and reduced life chances across a wide range of life domains. There is, however, very little known about the extent to which poverty is experienced by children over their early life course, particularly in community samples. This study tracks changes in family poverty and the main factors that predict family poverty (adverse life experiences) over a 30-year period since the birth of the study child. Data are from a prospective, longitudinal, birth cohort study conducted in Brisbane, Australia. Consecutive families were recruited at the mothers' first obstetrical visit at one of two major obstetrical hospitals in Brisbane. Data are available for 2087 families with complete data at the 30-year follow-up. Poverty was measured using family income at each time point (adjusted for inflation). Poverty affects about 20% of families at any time point. It is common for families to move in and out of poverty, as their circumstances are affected by such adversities as unemployment and marital breakdown. Over the period of the study about half the families in the study experienced poverty on at least one occasion. Only a very small minority of families experienced persistent poverty over the 30-year duration of the study. Logistic regressions with time lag show that family poverty predicts subsequent adversities and adverse events predict subsequent poverty. Experiences of poverty and adversity are common and may vary greatly over the child's early life course. In assessing the health consequences of poverty, it is important to distinguish the timing and chronicity of early life course experiences of poverty and adversity.

Plasma bilirubin values on admission and ventricular remodeling after a first anterior ST-segment elevation acute myocardial infarction.

PubMed

Miranda, Berta; Barrabés, José A; Figueras, Jaume; Pineda, Victor; Rodríguez-Palomares, José; Lidón, Rosa-Maria; Sambola, Antonia; Bañeras, Jordi; Otaegui, Imanol; García-Dorado, David

2016-01-01

Bilirubin may elicit cardiovascular protection and heme oxygenase-1 overexpression attenuated post-infarction ventricular remodeling in experimental animals, but the association between bilirubin levels and post-infarction remodeling is unknown. In 145 patients with a first anterior ST-segment elevation acute myocardial infarction (STEMI), we assessed whether plasma bilirubin on admission predicted adverse remodeling (left ventricular end-diastolic volume [LVEDV] increase ≥20% between discharge and 6 months, estimated by magnetic resonance imaging). Patients' baseline characteristics and management were comparable among bilirubin tertiles. LVEDV increased at 6 months (P < 0.001) with respect to the initial exam, but the magnitude of this increase was similar across increasing bilirubin tertiles (10.8 [30.2], 10.1 [22.9], and 12.7 [24.3]%, P = 0.500). Median (25-75 percentile) bilirubin values in patients with and without adverse remodeling were 0.75 (0.60-0.93) and 0.73 (0.60-0.92) mg/dL (P = 0.693). Absence of final TIMI flow grade 3 (odds ratio 3.92, 95% CI 1.12-13.66) and a history of hypertension (2.04, 0.93-4.50), but not admission bilirubin, were independently associated with adverse remodeling. Bilirubin also did not predict the increase in ejection fraction at 6 months. Admission bilirubin values are not related to LVEDV or ejection fraction progression after a first anterior STEMI and do not predict adverse ventricular remodeling. Key messages Bilirubin levels are inversely related to cardiovascular disease, and overexpression of heme oxygenase-1 (the enzyme that determines bilirubin production) has prevented post-infarction ventricular remodeling in experimental animals, but the association between bilirubin levels and the progression of ventricular volumes and function in patients with acute myocardial infarction remained unexplored. In this cohort of patients with a first acute anterior ST-segment elevation myocardial infarction receiving contemporary management, bilirubin levels on admission were not predictive of the changes in left ventricular volumes or ejection fraction at 6 months measured by serial cardiac magnetic resonance imaging. The data are contrary to a significant protective effect of bilirubin against post-infarction ventricular remodeling.

Using the Personality Assessment Inventory Antisocial and Borderline Features Scales to Predict Behavior Change.

PubMed

Penson, Brittany N; Ruchensky, Jared R; Morey, Leslie C; Edens, John F

2016-11-01

A substantial amount of research has examined the developmental trajectory of antisocial behavior and, in particular, the relationship between antisocial behavior and maladaptive personality traits. However, research typically has not controlled for previous behavior (e.g., past violence) when examining the utility of personality measures, such as self-report scales of antisocial and borderline traits, in predicting future behavior (e.g., subsequent violence). Examination of the potential interactive effects of measures of both antisocial and borderline traits also is relatively rare in longitudinal research predicting adverse outcomes. The current study utilizes a large sample of youthful offenders ( N = 1,354) from the Pathways to Desistance project to examine the separate effects of the Personality Assessment Inventory Antisocial Features (ANT) and Borderline Features (BOR) scales in predicting future offending behavior as well as trends in other negative outcomes (e.g., substance abuse, violence, employment difficulties) over a 1-year follow-up period. In addition, an ANT × BOR interaction term was created to explore the predictive effects of secondary psychopathy. ANT and BOR both explained unique variance in the prediction of various negative outcomes even after controlling for past indicators of those same behaviors during the preceding year.

Exploring the associations between drug side-effects and therapeutic indications.

PubMed

Wang, Fei; Zhang, Ping; Cao, Nan; Hu, Jianying; Sorrentino, Robert

2014-10-01

Drug therapeutic indications and side-effects are both measurable patient phenotype changes in response to the treatment. Inferring potential drug therapeutic indications and identifying clinically interesting drug side-effects are both important and challenging tasks. Previous studies have utilized either chemical structures or protein targets to predict indications and side-effects. In this study, we compared drug therapeutic indication prediction using various information including chemical structures, protein targets and side-effects. We also compared drug side-effect prediction with various information sources including chemical structures, protein targets and therapeutic indication. Prediction performance based on 10-fold cross-validation demonstrates that drug side-effects and therapeutic indications are the most predictive information source for each other. In addition, we extracted 6706 statistically significant indication-side-effect associations from all known drug-disease and drug-side-effect relationships. We further developed a novel user interface that allows the user to interactively explore these associations in the form of a dynamic bipartitie graph. Many relationship pairs provide explicit repositioning hypotheses (e.g., drugs causing postural hypotension are potential candidates for hypertension) and clear adverse-reaction watch lists (e.g., drugs for heart failure possibly cause impotence). All data sets and highly correlated disease-side-effect relationships are available at http://astro.temple.edu/∼tua87106/druganalysis.html. Copyright © 2014 Elsevier Inc. All rights reserved.

Kindergarten stressors and cumulative adrenocortical activation: the "first straws" of allostatic load?

PubMed

Bush, Nicole R; Obradović, Jelena; Adler, Nancy; Boyce, W Thomas

2011-11-01

Using an ethnically diverse longitudinal sample of 338 kindergarten children, this study examined the effects of cumulative contextual stressors on children's developing hypothalamic-pituitary-adrenocortical (HPA) axis regulation as an early life indicator of allostatic load. Chronic HPA axis regulation was assessed using cumulative, multiday measures of cortisol in both the fall and spring seasons of the kindergarten year. Hierarchical linear regression analyses revealed that contextual stressors related to ethnic minority status, socioeconomic status, and family adversity each uniquely predicted children's daily HPA activity and that some of those associations were curvilinear in conformation. Results showed that the quadratic, U-shaped influences of family socioeconomic status and family adversity operate in different directions to predict children's HPA axis regulation. Results further suggested that these associations differ for White and ethnic minority children. In total, this study revealed that early childhood experiences contribute to shifts in one of the principal neurobiological systems thought to generate allostatic load, confirming the importance of early prevention and intervention efforts. Moreover, findings suggested that analyses of allostatic load and developmental theories accounting for its accrual would benefit from an inclusion of curvilinear associations in tested predictive models.

Like Father, like Child: Early Life Family Adversity and Children's Bullying Behaviors in Elementary School.

PubMed

de Vries, Else E; Verlinden, Marina; Rijlaarsdam, Jolien; Jaddoe, Vincent W V; Verhulst, Frank C; Arseneault, Louise; Tiemeier, Henning

2017-12-19

Family adversity has been associated with children's bullying behaviors. The evidence is, however, dominated by mothers' perceptions of the family environment and a focus on mothers' behaviors. This prospective population-based study examined whether children's bullying behaviors were associated with mother- and father-reported family adversity, assessed before and after child birth. Peer-nominations were used to assess bullying behaviors of 1298 children in elementary school (mean age 7.5 years). The following paternal risk factors were prospectively associated with children's bullying behaviors: (1) father-reported prenatal family distress, (2) fathers' hostility at preschool age, and (3) fathers' harsh disciplinary practices at preschool age, but effect sizes were relatively small. The effect of maternal risk factors was less consistent, only mother-reported family distress in childhood was associated with children's bullying behaviors. The associations were independent of background family risk factors (i.e., life stress, contextual factors, and other background factors such as parental education and risk taking record) and early childhood externalizing problems. Moreover, our results indicated that father-reported family adversity predicted children's bullying behaviors over and above the background family risk factors, early childhood externalizing problems and mother-reported family adversity. We also demonstrated that the association of fathers' prenatal hostility and family distress with subsequent bullying behavior of their child at school was partly mediated by fathers' harsh disciplinary practices at preschool age. Our findings highlight the importance of fathers' behaviors in the development of children's bullying behaviors.

Predicting Long-Term Outcomes for Women Physically Abused in Childhood: Contribution of Abuse Severity versus Family Environment

ERIC Educational Resources Information Center

Griffin, Margaret L.; Amodeo, Maryann

2010-01-01

Objective: Child physical abuse (CPA) has been associated with adverse adult psychosocial outcomes, although some reports describe minimal long-term effects. The search for the explanation for heterogeneous outcomes in women with CPA has led to an examination of a range of CPA-related factors, from the severity of CPA incidents to the childhood…

Evaluation of two high through-put (HTP) androgen receptor based assays: Utility of data for prioritization for further testing versus prediction of adverse effects.

EPA Science Inventory

The androgen signaling pathway plays a critical role in sexual differentiation during development in mammals and is one of the better understood pathways in human development. Thus it was chosen as a model pathway to evaluate the potential of HTP in vitro assays as risk assessmen...

The Duty to Prevent Emotional Harm at Work: Arguments from Science and Law, Implications for Policy and Practice

ERIC Educational Resources Information Center

Shain, Martin

2004-01-01

Although science and law employ different methods to gather and weigh evidence, their conclusions are remarkably convergent with regard to the effect that workplace stress has on the health of employees. Science, using the language of probability, affirms that certain stressors predict adverse health outcomes such as disabling anxiety and…

Predicting Long-Term Outcomes for Women Sexually Abused in Childhood: Contribution of Abuse Severity Versus Family Environment

ERIC Educational Resources Information Center

Fassler, I.R.; Amodeo, M.; Griffin, M.L.; Clay, C.M.; Ellis, M.A.

2005-01-01

Objective:: Child sexual abuse (CSA) has been associated with adverse adult psychosocial outcomes, although some reports describe minimal long-term effects. The search for explanations for the heterogeneous outcomes in women with CSA has led to an examination of a range of CSA-related factors, from the severity of individual CSA incidents to the…

Adverse Pregnancy Outcomes after Abnormal First Trimester Screening for Aneuploidy

PubMed Central

Goetzl, Laura

2010-01-01

Women with abnormal first trimester screening but with a normal karyotype are at risk for adverse pregnancy outcomes. A nuchal translucency >3.5mm is associated with an increased risk of subsequent pregnancy loss, fetal infection, fetal heart abnormalities and other structural abnormalities. Abnormal first trimester analytes are also associated with adverse pregnancy outcomes but the predictive value is less impressive. As a single marker, PAPP-A <1st%ile has a good predictive value for subsequent fetal growth restriction. Women with PAPP-A<5th%ile should undergo subsequent risk assessment with routine MSAFP screening with the possible addition of uterine artery PI assessment in the midtrimester. PMID:20638576

The effect of customization and use of a fetal growth standard on the association between birthweight percentile and adverse perinatal outcome.

PubMed

Sovio, Ulla; Smith, Gordon C S

2018-02-01

It has been proposed that correction of offspring weight percentiles (customization) might improve the prediction of adverse pregnancy outcome; however, the approach is not accepted universally. A complication in the interpretation of the data is that the main method for calculation of customized percentiles uses a fetal growth standard, and multiple analyses have compared the results with birthweight-based standards. First, we aimed to determine whether women who deliver small-for-gestational-age infants using a customized standard differed from other women. Second, we aimed to compare the association between birthweight percentile and adverse outcome using 3 different methods for percentile calculation: (1) a noncustomized actual birthweight standard, (2) a noncustomized fetal growth standard, and (3) a fully customized fetal growth standard. We analyzed data from the Pregnancy Outcome Prediction study, a prospective cohort study of nulliparous women who delivered in Cambridge, UK, between 2008 and 2013. We used a composite adverse outcome, namely, perinatal morbidity or preeclampsia. Receiver operating characteristic curve analysis was used to compare the 3 methods of calculating birthweight percentiles in relation to the composite adverse outcome. We confirmed previous observations that delivering an infant who was small for gestational age (<10th percentile) with the use of a fully customized fetal growth standard but who was appropriate for gestational age with the use of a noncustomized actual birthweight standard was associated with higher rates of adverse outcomes. However, we also observed that the mothers of these infants were 3-4 times more likely to be obese and to deliver preterm. When we compared the risk of adverse outcome from logistic regression models that were fitted to the birthweight percentiles that were derived by each of the 3 predefined methods, the areas under the receiver operating characteristic curves were similar for all 3 methods: 0.56 (95% confidence interval, 0.54-0.59) fully customized, 0.56 (95% confidence interval, 0.53-0.59) noncustomized fetal weight standard, and 0.55 (95% confidence interval, 0.53-0.58) noncustomized actual birthweight standard. When we classified the top 5% of predicted risk as high risk, the methods that used a fetal growth standard showed attenuation after adjustment for gestational age, whereas the birthweight standard did not. Further adjustment for the maternal characteristics, which included weight, attenuated the association with the customized standard, but not the other 2 methods. The associations after full adjustment were similar when we compared the 3 approaches. The independent association between birthweight percentile and adverse outcome was similar when we compared actual birthweight standards and fetal growth standards and compared customized and noncustomized standards. Use of fetal weight standards and customized percentiles for maternal characteristics could lead to stronger associations with adverse outcome through confounding by preterm birth and maternal obesity. Copyright © 2017 Elsevier Inc. All rights reserved.

Comparison between Frailty Index of Deficit Accumulation and Phenotypic Model to Predict Risk of Falls: Data from the Global Longitudinal Study of Osteoporosis in Women (GLOW) Hamilton Cohort

PubMed Central

Thabane, Lehana; Ioannidis, George; Kennedy, Courtney; Papaioannou, Alexandra

2015-01-01

Objectives To compare the predictive accuracy of the frailty index (FI) of deficit accumulation and the phenotypic frailty (PF) model in predicting risks of future falls, fractures and death in women aged ≥55 years. Methods Based on the data from the Global Longitudinal Study of Osteoporosis in Women (GLOW) 3-year Hamilton cohort (n = 3,985), we compared the predictive accuracy of the FI and PF in risks of falls, fractures and death using three strategies: (1) investigated the relationship with adverse health outcomes by increasing per one-fifth (i.e., 20%) of the FI and PF; (2) trichotomized the FI based on the overlap in the density distribution of the FI by the three groups (robust, pre-frail and frail) which were defined by the PF; (3) categorized the women according to a predicted probability function of falls during the third year of follow-up predicted by the FI. Logistic regression models were used for falls and death, while survival analyses were conducted for fractures. Results The FI and PF agreed with each other at a good level of consensus (correlation coefficients ≥ 0.56) in all the three strategies. Both the FI and PF approaches predicted adverse health outcomes significantly. The FI quantified the risks of future falls, fractures and death more precisely than the PF. Both the FI and PF discriminated risks of adverse outcomes in multivariable models with acceptable and comparable area under the curve (AUCs) for falls (AUCs ≥ 0.68) and death (AUCs ≥ 0.79), and c-indices for fractures (c-indices ≥ 0.69) respectively. Conclusions The FI is comparable with the PF in predicting risks of adverse health outcomes. These findings may indicate the flexibility in the choice of frailty model for the elderly in the population-based settings. PMID:25764521

Comparison between frailty index of deficit accumulation and phenotypic model to predict risk of falls: data from the global longitudinal study of osteoporosis in women (GLOW) Hamilton cohort.

PubMed

Li, Guowei; Thabane, Lehana; Ioannidis, George; Kennedy, Courtney; Papaioannou, Alexandra; Adachi, Jonathan D

2015-01-01

To compare the predictive accuracy of the frailty index (FI) of deficit accumulation and the phenotypic frailty (PF) model in predicting risks of future falls, fractures and death in women aged ≥55 years. Based on the data from the Global Longitudinal Study of Osteoporosis in Women (GLOW) 3-year Hamilton cohort (n = 3,985), we compared the predictive accuracy of the FI and PF in risks of falls, fractures and death using three strategies: (1) investigated the relationship with adverse health outcomes by increasing per one-fifth (i.e., 20%) of the FI and PF; (2) trichotomized the FI based on the overlap in the density distribution of the FI by the three groups (robust, pre-frail and frail) which were defined by the PF; (3) categorized the women according to a predicted probability function of falls during the third year of follow-up predicted by the FI. Logistic regression models were used for falls and death, while survival analyses were conducted for fractures. The FI and PF agreed with each other at a good level of consensus (correlation coefficients ≥ 0.56) in all the three strategies. Both the FI and PF approaches predicted adverse health outcomes significantly. The FI quantified the risks of future falls, fractures and death more precisely than the PF. Both the FI and PF discriminated risks of adverse outcomes in multivariable models with acceptable and comparable area under the curve (AUCs) for falls (AUCs ≥ 0.68) and death (AUCs ≥ 0.79), and c-indices for fractures (c-indices ≥ 0.69) respectively. The FI is comparable with the PF in predicting risks of adverse health outcomes. These findings may indicate the flexibility in the choice of frailty model for the elderly in the population-based settings.

Differential relationships between social adversity and depressive symptoms by HIV-status and racial/ethnic identity

PubMed Central

Williamson, Timothy J.; Mahmood, Zanjbeel; Kuhn, Taylor P.; Thames, April D.

2016-01-01

Objective Historically marginalized groups are likely to be exposed to social adversity, which predicts important mental health outcomes (e.g., depression). Despite the well-established relationship between adversity and poor health, few studies have examined how adversity differentially predicts mental health among people living with multiple, co-occurring marginalized identities or statuses. The current study fills this gap by examining whether relationships between social adversity and depressive symptoms differed between those living with or without a stigmatized disease (i.e., HIV) and/or marginalized racial/ethnic identity (i.e., African American). Method A community sample of men and women (n = 149) completed questionnaires assessing demographics and depressive symptoms. Additionally, a composite index of social adversity was derived from measures of perceived discrimination, socioeconomic status, financial restriction to receiving medical care, and perceived neighborhood characteristics. Multiple regression was used to test whether relationships between adversity and depressive symptoms differed as a function of HIV-status and racial/ethnic identity. Results A significant three-way interaction between social adversity, HIV-status, and racial/ethnic identity indicated that there was a direct relationship between adversity and depressive symptoms for HIV-positive (HIV+) African Americans but not for HIV-negative (HIV-) African Americans, HIV+ Caucasians, or HIV- Caucasians. Further, HIV+ African Americans evidenced a significantly greater relationship between adversity and depressive symptoms, as compared to HIV- African Americans but not as compared to other groups. Conclusions The findings suggest that HIV+ African Americans may be at risk for higher depressive symptoms amidst adversity, highlighting the importance of evaluating intersectional identities/statuses in the context of mental health. PMID:27929330

Differential relationships between social adversity and depressive symptoms by HIV status and racial/ethnic identity.

PubMed

Williamson, Timothy J; Mahmood, Zanjbeel; Kuhn, Taylor P; Thames, April D

2017-02-01

Historically marginalized groups are likely to be exposed to social adversity, which predicts important mental health outcomes (e.g., depression). Despite the well-established relationship between adversity and poor health, few studies have examined how adversity differentially predicts mental health among people living with multiple, co-occurring marginalized identities or statuses. The current study fills this gap by examining whether relationships between social adversity and depressive symptoms differed between those living with or without a stigmatized disease (i.e., HIV) and/or marginalized racial/ethnic identity (i.e., African American). A community sample of men and women (N = 149) completed questionnaires assessing demographics and depressive symptoms. Additionally, a composite index of social adversity was derived from measures of perceived discrimination, socioeconomic status, financial restriction to receiving medical care, and perceived neighborhood characteristics. Multiple regression was used to test whether relationships between adversity and depressive symptoms differed as a function of HIV status and racial/ethnic identity. A significant 3-way interaction between social adversity, HIV status, and racial/ethnic identity indicated that there was a direct relationship between adversity and depressive symptoms for HIV-positive (HIV+) African Americans but not for HIV-negative (HIV-) African Americans, HIV+ Caucasians, or HIV- Caucasians. Further, HIV+ African Americans evidenced a significantly greater relationship between adversity and depressive symptoms compared with HIV- African Americans, but not compared with other groups. The findings suggest that HIV+ African Americans may be at risk for higher depressive symptoms amid adversity, highlighting the importance of evaluating intersectional identities/statuses in the context of mental health. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Adverse Drug Reactions in Dental Practice

PubMed Central

Becker, Daniel E.

2014-01-01

Adverse reactions may occur with any of the medications prescribed or administered in dental practice. Most of these reactions are somewhat predictable based on the pharmacodynamic properties of the drug. Others, such as allergic and pseudoallergic reactions, are less common and unrelated to normal drug action. This article will review the most common adverse reactions that are unrelated to drug allergy. PMID:24697823

Predictive modeling of structured electronic health records for adverse drug event detection.

PubMed

Zhao, Jing; Henriksson, Aron; Asker, Lars; Boström, Henrik

2015-01-01

The digitization of healthcare data, resulting from the increasingly widespread adoption of electronic health records, has greatly facilitated its analysis by computational methods and thereby enabled large-scale secondary use thereof. This can be exploited to support public health activities such as pharmacovigilance, wherein the safety of drugs is monitored to inform regulatory decisions about sustained use. To that end, electronic health records have emerged as a potentially valuable data source, providing access to longitudinal observations of patient treatment and drug use. A nascent line of research concerns predictive modeling of healthcare data for the automatic detection of adverse drug events, which presents its own set of challenges: it is not yet clear how to represent the heterogeneous data types in a manner conducive to learning high-performing machine learning models. Datasets from an electronic health record database are used for learning predictive models with the purpose of detecting adverse drug events. The use and representation of two data types, as well as their combination, are studied: clinical codes, describing prescribed drugs and assigned diagnoses, and measurements. Feature selection is conducted on the various types of data to reduce dimensionality and sparsity, while allowing for an in-depth feature analysis of the usefulness of each data type and representation. Within each data type, combining multiple representations yields better predictive performance compared to using any single representation. The use of clinical codes for adverse drug event detection significantly outperforms the use of measurements; however, there is no significant difference over datasets between using only clinical codes and their combination with measurements. For certain adverse drug events, the combination does, however, outperform using only clinical codes. Feature selection leads to increased predictive performance for both data types, in isolation and combined. We have demonstrated how machine learning can be applied to electronic health records for the purpose of detecting adverse drug events and proposed solutions to some of the challenges this presents, including how to represent the various data types. Overall, clinical codes are more useful than measurements and, in specific cases, it is beneficial to combine the two.

Predictive modeling of structured electronic health records for adverse drug event detection

PubMed Central

2015-01-01

Background The digitization of healthcare data, resulting from the increasingly widespread adoption of electronic health records, has greatly facilitated its analysis by computational methods and thereby enabled large-scale secondary use thereof. This can be exploited to support public health activities such as pharmacovigilance, wherein the safety of drugs is monitored to inform regulatory decisions about sustained use. To that end, electronic health records have emerged as a potentially valuable data source, providing access to longitudinal observations of patient treatment and drug use. A nascent line of research concerns predictive modeling of healthcare data for the automatic detection of adverse drug events, which presents its own set of challenges: it is not yet clear how to represent the heterogeneous data types in a manner conducive to learning high-performing machine learning models. Methods Datasets from an electronic health record database are used for learning predictive models with the purpose of detecting adverse drug events. The use and representation of two data types, as well as their combination, are studied: clinical codes, describing prescribed drugs and assigned diagnoses, and measurements. Feature selection is conducted on the various types of data to reduce dimensionality and sparsity, while allowing for an in-depth feature analysis of the usefulness of each data type and representation. Results Within each data type, combining multiple representations yields better predictive performance compared to using any single representation. The use of clinical codes for adverse drug event detection significantly outperforms the use of measurements; however, there is no significant difference over datasets between using only clinical codes and their combination with measurements. For certain adverse drug events, the combination does, however, outperform using only clinical codes. Feature selection leads to increased predictive performance for both data types, in isolation and combined. Conclusions We have demonstrated how machine learning can be applied to electronic health records for the purpose of detecting adverse drug events and proposed solutions to some of the challenges this presents, including how to represent the various data types. Overall, clinical codes are more useful than measurements and, in specific cases, it is beneficial to combine the two. PMID:26606038

Exploring the Potential of Direct-To-Consumer Genomic Test Data for Predicting Adverse Drug Events.

PubMed

Zhang, Patrick M; Sarkar, Indra Neil

2018-01-01

Recent technological advancements in genetic testing and the growing accessibility of public genomic data provide researchers with a unique avenue to approach personalized medicine. This feasibility study examined the potential of direct-to-consumer (DTC) genomic tests (focusing on 23andMe) in research and clinical applications. In particular, we combined population genetics information from the Personal Genome Project with adverse event reports from AEOLUS and pharmacogenetic information from PharmGKB. Primarily, associations between drugs based on co-occurring genetic variations and associations between variants and adverse events were used to assess the potential for leveraging single nucleotide polymorphism information from 23andMe. The results of this study suggest potential clinical uses of DTC tests in light of potential drug interactions. Furthermore, the results suggest great potential for analyzing associations at a population level to facilitate knowledge discovery in the realm of predicting adverse drug events.

Current status of predictive biomarkers for neoadjuvant therapy in esophageal cancer

PubMed Central

Uemura, Norihisa; Kondo, Tadashi

2014-01-01

Neoadjuvant therapy has been proven to be extremely valuable and is widely used for advanced esophageal cancer. However, a significant proportion of treated patients (60%-70%) does not respond well to neoadjuvant treatments and develop severe adverse effects. Therefore, predictive markers for individualization of multimodality treatments are urgently needed in esophageal cancer. Recently, molecular biomarkers that predict the response to neoadjuvant therapy have been explored in multimodal approaches in esophageal cancer and successful examples of biomarker identification have been reported. In this review, promising candidates for predictive molecular biomarkers developed by using multiple molecular approaches are reviewed. Moreover, treatment strategies based on the status of predicted biomarkers are discussed, while considering the international differences in the clinical background. However, in the absence of adequate treatment options related to the results of the biomarker test, the usefulness of these diagnostic tools is limited and new effective therapies for biomarker-identified nonresponders to cancer treatment should be concurrent with the progress of predictive technologies. Further improvement in the prognosis of esophageal cancer patients can be achieved through the introduction of novel therapeutic approaches in clinical practice. PMID:25133032

Clinicopathological Features to Predict Progression of IgA Nephropathy with Mild Proteinuria.

PubMed

Chen, Ding; Liu, Jian; Duan, Shuwei; Chen, Pu; Tang, Li; Zhang, Li; Feng, Zhe; Cai, Guangyan; Wu, Jie; Chen, Xiangmei

2018-03-06

In the past, little attention has been paid to patients with IgA nephropathy (IgAN) who had minimal proteinuria upon the onset. The aim of this study was to analyze the clinicopathological features and the prognostic factors in patients with IgA nephropathy. Data of patients that had their first renal biopsy in our hospital and were diagnosed with primary IgAN with proteinuria <1 g/d from January 1995 to December 2014 were retrospectively examined. Clinical records of the clinicopathological features, renal function, and proteinuria were collected and investigated. The factors affecting the renal function and proteinuria were analyzed by Cox regression. The predictive efficiencies of clinical and pathological models were evaluated by Harrell concordance index (C-index). A total of 506 patients with IgA nephropathy were included in this study. (1) Baseline proteinuria greater than 0.5 g/d was positively associated with Oxford M, S, and T lesions. eGFR less than 90 mL/min/1.73 m2 were positively associated with Oxford T. (2) In the follow-up with a median of 50 months, 82 patients (16.2%) achieved complete clinical remission (CCR), whereas 54 patients (10.6%) showed an increase in creatinine by more than 50% (not progressing to end-stage renal disease). The cumulative proportion of creatinine increased >50%, and the values obtained by life-table analysis in 10, 15, and 20 years were 15%, 21%, and 22%, respectively. Significant differences were found in baseline age, proteinuria, and Oxford T between the group of creatinine increase >50% and the CCR group. (4) Multivariate COX regression showed that baseline age and proteinuria > 0.5 g/d were independent risk factors of adverse outcome. C-index suggested that the clinical model was more effective than the pathological models in predicting endpoint events. (5) Effect of the mean value during the follow-up on adverse endpoint events: Multivariate COX regression found that the mean proteinuria during follow-up was an independent influencing factor for the increase of creatinine by more than 50%. (1) Proteinuria > 0.5g/d and eGFR < 90 mL/min/1.73 m2 may predict more severe pathological changes; (2) With the increase in age and baseline proteinuria, the risks of adverse endpoint events would increase significantly; (3) Pathology could roughly predict the adverse endpoint events but is less efficient than the clinical indicators; (4) Data during follow-up suggested that the patients should regularly test their renal function and proactively control their proteinuria. © 2018 The Author(s). Published by S. Karger AG, Basel.

Predicting outcome of acute non-variceal upper gastrointestinal haemorrhage without endoscopy using the clinical Rockall Score.

PubMed

Tham, T C K; James, C; Kelly, M

2006-11-01

The Rockall risk scoring system uses clinical criteria and endoscopy to identify patients at risk of adverse outcomes after acute upper gastrointestinal haemorrhage. A clinical Rockall score obtained using only the clinical criteria may be able to predict outcome without endoscopy. To validate the clinical Rockall Score in predicting outcome after acute non-variceal upper gastrointestinal haemorrhage. A retrospective observational study of consecutive patients who were admitted with non-variceal acute upper gastrointestinal haemorrhage was undertaken. Medical records were abstracted using a standardised form. 102 cases were identified (51 men and 51 women; mean age 59 years). 38 (37%) patients considered to be at low risk of adverse outcomes (clinical Rockall Score 0) had no adverse outcomes and did not require transfusion. Patients with a clinical Rockall Score of 1-3 had no adverse outcomes, although 13 of 45 (29%) patients required blood transfusions. Clinical Rockall Scores >3 (n = 19) were associated with adverse outcomes (rebleeding in 4 (21%), surgery in 1 (5%) and death in 2 (10%)). The clinical Rockall Score without endoscopy may be a useful prognostic indicator in this cohort of patients with acute non-variceal upper gastrointestinal haemorrhage. This score may reduce the need for urgent endoscopy in low-risk patients, which can instead be carried out on a more elective outpatient basis.

Early Life Stress, MAOA, and Gene-Environment Interactions Predict Behavioral Disinhibition in Children

PubMed Central

Enoch, Mary-Anne; Steer, Colin D.; Newman, Timothy K.; Gibson, Nerea; Goldman, David

2009-01-01

Several, but not all, studies have shown that the monoamine oxidase A functional promoter polymorphism (MAOA-LPR) interacts with childhood adversity to predict adolescent and adult antisocial behavior. However, it is not known whether MAOA-LPR interacts with early life (pre-birth – 3 years) stressors to influence behavior in pre-pubertal children. The Avon Longitudinal Study of Parents and Children, U.K., is a community-representative cohort study of children followed from pre-birth onwards. The impact of family adversity from pre-birth to age 3 years and stressful life events from 6 months to 7 years on behavioral disinhibition was determined in 7500 girls and boys. Behavioral disinhibition measures were: mother-reported hyperactivity and conduct disturbances (Strengths and Difficulties Questionnaire) at ages 4 and 7 years. In both sexes, exposure to family adversity and stressful life events in the first three years of life predicted behavioral disinhibition at age 4, persisting until age 7. In girls, MAOA-LPR interacted with stressful life events experienced from 6 months to 3 ½ years to influence hyperactivity at ages 4 and 7. In boys, the interaction of MAOA-LPR with stressful life events between 1 ½ and 2 ½ years predicted hyperactivity at age 7 years. The low activity MAOA-LPR variant was associated with increased hyperactivity in girls and boys exposed to high stress. In contrast, there was no MAOA-LPR interaction with family adversity. In a general population sample of pre-pubertal children, exposure to common stressors from pre-birth to 3 years predicted behavioral disinhibition, and MAOA-LPR - stressful life event interactions specifically predicted hyperactivity. PMID:19804559

[Spanish versions of the Simplified Motor Score and the Glasgow Coma Scale in out-of-hospital treatment of head injury in adults: a preliminary study of each scale's ability to predict adverse events].

PubMed

Roca, Guillem; Mayol, Sergi; García, Esteban; Casajuana, Edgar; Quintana, Salvador

2015-06-01

To determine the ability of the modified (Spanish) version of the Simplified Motor Score (mSMS) to predict adverse events during hospitalization and to compare its predictive ability to that of the Glasgow Coma Scale (GCS) in adults with head injuries treated outside the hospital. Observational study of retrospective cohorts including all patients over the age of 14 years attended for head injuries occurring within 24 hours of treatment by an advanced life-support unit staffed by nurses between May 1, 2013, and May 1, 2014. The mSMS was a translation of the English original, created through a process of discussions of direct and back translations to arrive at consensus. Out-of-hospital patient records were searched to find GCS and mSMS scores. To predict the ability of each scale to predict brain injuries, neurosurgery, intubation, and/or inhospital death, we calculated the area under the receiving operator characteristic curves (AUCs). Of the total of 115 head-injury patients attended, 64 met the inclusion criteria. The mean (SD) age was 47 (24) years. Twelve (18.8%) patients developed some form of adverse event during hospitalization; 91.6% had brain damage, 58.3% required intubation, 8.3% required surgery, and 41.6% died. The AUC for the GCS was 0.907 (95% CI, 0.81-1.00; P<.001); the AUC for the mSMS was 0.796 (95% CI, 0.64-0.95; P=.001). Although the ability of the mSMS to predict in-hospital adverse outcomes is good, it is inferior to the GCS in adults with head injuries attended outside the hospital.

Negative Emotionality and Disconstraint Influence PTSD Symptom Course via Exposure to New Major Adverse Life Events

PubMed Central

Sadeh, Naomi; Miller, Mark W.; Wolf, Erika J.; Harkness, Kate L.

2015-01-01

Identifying the factors that influence stability and change in chronic posttraumatic stress disorder (PTSD) is important for improving clinical outcomes. Using a cross-lagged design, we analyzed the reciprocal effects of personality and PTSD symptoms over time and their effects on stress exposure in a sample of 222 trauma-exposed veterans (ages 23 – 68; 90.5% male). Personality functioning and PTSD were measured approximately 4 years apart, and self-reported exposure to major adverse life events during the interim was also assessed. Negative emotionality positively predicted future PTSD symptoms, and this effect was partially mediated by exposure to new events. Constraint (negatively) indirectly affected PTSD via its association with exposure to new events. There were no significant effects of positive emotionality nor did PTSD symptom severity exert influences on personality over time. Results indicate that high negative affect and disconstraint influence the course of PTSD symptoms by increasing exposure to stressful life events. PMID:25659969

Negative emotionality and disconstraint influence PTSD symptom course via exposure to new major adverse life events.

PubMed

Sadeh, Naomi; Miller, Mark W; Wolf, Erika J; Harkness, Kate L

2015-04-01

Identifying the factors that influence stability and change in chronic posttraumatic stress disorder (PTSD) is important for improving clinical outcomes. Using a cross-lagged design, we analyzed the reciprocal effects of personality and PTSD symptoms over time and their effects on stress exposure in a sample of 222 trauma-exposed veterans (ages 23-68; 90.5% male). Personality functioning and PTSD were measured approximately 4 years apart, and self-reported exposure to major adverse life events during the interim was also assessed. Negative emotionality positively predicted future PTSD symptoms, and this effect was partially mediated by exposure to new events. Constraint (negatively) indirectly affected PTSD via its association with exposure to new events. There were no significant effects of positive emotionality nor did PTSD symptom severity exert influences on personality over time. Results indicate that high negative affect and disconstraint influence the course of PTSD symptoms by increasing exposure to stressful life events. Published by Elsevier Ltd.

Novel surgical performance evaluation approximates Standardized Incidence Ratio with high accuracy at simple means.

PubMed

Gabbay, Itay E; Gabbay, Uri

2013-01-01

Excess adverse events may be attributable to poor surgical performance but also to case-mix, which is controlled through the Standardized Incidence Ratio (SIR). SIR calculations can be complicated, resource consuming, and unfeasible in some settings. This article suggests a novel method for SIR approximation. In order to evaluate a potential SIR surrogate measure we predefined acceptance criteria. We developed a new measure - Approximate Risk Index (ARI). "Number Needed for Event" (NNE) is the theoretical number of patients needed "to produce" one adverse event. ARI is defined as the quotient of the group of patients needed for no observed events Ge by total patients treated Ga. Our evaluation compared 2500 surgical units and over 3 million heterogeneous risk surgical patients that were induced through a computerized simulation. Surgical unit's data were computed for SIR and ARI to evaluate compliance with the predefined criteria. Approximation was evaluated by correlation analysis and performance prediction capability by Receiver Operating Characteristics (ROC) analysis. ARI strongly correlates with SIR (r(2) = 0.87, p < 0.05). ARI prediction of excessive risk revealed excellent ROC (Area Under the Curve > 0.9) 87% sensitivity and 91% specificity. ARI provides good approximation of SIR and excellent prediction capability. ARI is simple and cost-effective as it requires thorough risk evaluation of only the adverse events patients. ARI can provide a crucial screening and performance evaluation quality control tool. The ARI method may suit other clinical and epidemiological settings where relatively small fraction of the entire population is affected. Copyright © 2013 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.

The added predictive value of biphasic events in ST analysis of the fetal electrocardiogram for intrapartum fetal monitoring.

PubMed

Becker, Jeroen H; Krikhaar, Anniek; Schuit, Ewoud; Mårtendal, Annika; Maršál, Karel; Kwee, Anneke; Visser, Gerard H A; Amer-Wåhlin, Isis

2015-02-01

To study the predictive value of biphasic ST-events for interventions for suspected fetal distress and adverse neonatal outcome, when using ST-analysis of the fetal electrocardiogram (FECG) for intrapartum fetal monitoring. Prospective cohort study. Three academic hospitals in Sweden. Women in labor with a high-risk singleton fetus in cephalic position beyond 36 weeks of gestation. In women in labor who were monitored with conventional cardiotocography, ST-waveform analysis was recorded and concealed. Traces with biphasic ST-events of the FECG (index) were compared with traces without biphasic events of the FECG. The ability of biphasic events to predict interventions for suspected fetal distress and adverse outcome was assessed using univariable and multivariable logistic regression analyses. Interventions for suspected fetal distress and adverse outcome (defined as presence of metabolic acidosis (i.e. umbilical cord pH <7.05 and base deficit in extracellular fluid >12 mmol), umbilical cord pH <7.00, 5-min Apgar score <7, admittance to neonatal intensive care unit or perinatal death). Although the presence of biphasic events of the FECG was associated with more interventions for fetal distress and an increased risk of adverse outcome compared with cases with no biphasic events, the presence of significant (i.e. intervention advised according to cardiotocography interpretation) biphasic events showed no independent association with interventions for fetal distress [odds ratio (OR) 1.71, 95% confidence interval (CI) 0.65-4.50] or adverse outcome (OR 1.96, 95% CI 0.74-5.24). The presence of significant biphasic events did not discriminate in the prediction of interventions for fetal distress or adverse outcome. Therefore, biphasic events in relation to ST-analysis monitoring during birth should be omitted if future studies confirm our findings. © 2014 Nordic Federation of Societies of Obstetrics and Gynecology.

Framework for computationally-predicted AOPs

EPA Science Inventory

Framework for computationally-predicted AOPs Given that there are a vast number of existing and new chemicals in the commercial pipeline, emphasis is placed on developing high throughput screening (HTS) methods for hazard prediction. Adverse Outcome Pathways (AOPs) represent a...

Predicting Nonauditory Adverse Radiation Effects Following Radiosurgery for Vestibular Schwannoma: A Volume and Dosimetric Analysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hayhurst, Caroline; Monsalves, Eric; Bernstein, Mark

2012-04-01

Purpose: To define clinical and dosimetric predictors of nonauditory adverse radiation effects after radiosurgery for vestibular schwannoma treated with a 12 Gy prescription dose. Methods: We retrospectively reviewed our experience of vestibular schwannoma patients treated between September 2005 and December 2009. Two hundred patients were treated at a 12 Gy prescription dose; 80 had complete clinical and radiological follow-up for at least 24 months (median, 28.5 months). All treatment plans were reviewed for target volume and dosimetry characteristics; gradient index; homogeneity index, defined as the maximum dose in the treatment volume divided by the prescription dose; conformity index; brainstem; andmore » trigeminal nerve dose. All adverse radiation effects (ARE) were recorded. Because the intent of our study was to focus on the nonauditory adverse effects, hearing outcome was not evaluated in this study. Results: Twenty-seven (33.8%) patients developed ARE, 5 (6%) developed hydrocephalus, 10 (12.5%) reported new ataxia, 17 (21%) developed trigeminal dysfunction, 3 (3.75%) had facial weakness, and 1 patient developed hemifacial spasm. The development of edema within the pons was significantly associated with ARE (p = 0.001). On multivariate analysis, only target volume is a significant predictor of ARE (p = 0.001). There is a target volume threshold of 5 cm3, above which ARE are more likely. The treatment plan dosimetric characteristics are not associated with ARE, although the maximum dose to the 5th nerve is a significant predictor of trigeminal dysfunction, with a threshold of 9 Gy. The overall 2-year tumor control rate was 96%. Conclusions: Target volume is the most important predictor of adverse radiation effects, and we identified the significant treatment volume threshold to be 5 cm3. We also established through our series that the maximum tolerable dose to the 5th nerve is 9 Gy.« less

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...

Parenting begets parenting: A neurobiological perspective on early adversity and the transmission of parenting styles across generations.

PubMed

Lomanowska, A M; Boivin, M; Hertzman, C; Fleming, A S

2017-02-07

The developing brains of young children are highly sensitive to input from their social environment. Nurturing social experience during this time promotes the acquisition of social and cognitive skills and emotional competencies. However, many young children are confronted with obstacles to healthy development, including poverty, inappropriate care, and violence, and their enhanced sensitivity to the social environment means that they are highly susceptible to these adverse childhood experiences. One source of social adversity in early life can stem from parenting that is harsh, inconsistent, non-sensitive or hostile. Parenting is considered to be the cornerstone of early socio-emotional development and an adverse parenting style is associated with adjustment problems and a higher risk of developing mood and behavioral disorders. Importantly, there is a growing literature showing that an important predictor of parenting behavior is how parents, especially mothers, were parented themselves. In this review, we examine how adversity in early-life affects mothering behavior in later-life and how these effects may be perpetuated inter-generationally. Relying on studies in humans and animal models, we consider evidence for the intergenerational transmission of mothering styles. We then describe the psychological underpinnings of mothering, including responsiveness to young, executive function and affect, as well as the physiological mediators of mothering behavior, including hormones, brain regions and neurotransmitters, and we consider how development in these relevant domains may be affected by adversity experienced in early life. Finally, we explore how genes and early experience interact to predict mothering behavior, including the involvement of epigenetic mechanisms. Understanding how adverse parenting begets adverse parenting in the next generation is critical for designing interventions aimed at preventing this intergenerational cycle of early adversity. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

Sensitivity to psychosocial chronic stressors and adolescents' externalizing problems: Combined moderator effects of resting heart rate and parental psychiatric history.

PubMed

Zandstra, Anna Roos E; Ormel, Johan; Dietrich, Andrea; van den Heuvel, Edwin R; Hoekstra, Pieter J; Hartman, Catharina A

2018-04-01

From the literature it is not clear whether low resting heart rate (HR) reflects low or high sensitivity to the detrimental effects of adverse environments on externalizing problems. We studied parental psychiatric history (PH), reflecting general vulnerability, as possible moderator explaining these inconsistencies. Using Linear Mixed Models, we analyzed data from 1914 subjects, obtained in three measurement waves (mean age 11, 13.5, and 16 years) from the TRacking Adolescents' Individual Lives Survey population-based cohort and the parallel clinic-referred cohort. As hypothesized, more chronic stressors predicted more externalizing problems in vulnerable individuals with high resting HR but not in those with low resting HR, suggesting high vs. low sensitivity, respectively, to adverse environmental influences. Low sensitivity to adverse environmental influences in vulnerable individuals exposed to high stressor levels was additionally confirmed by high heart rate variability (Root Mean Squared Successive Difference; RMSSD). In adolescents with low vulnerability, in contrast, the association between chronic stressors and externalizing problems did not substantially differ by resting HR and RMSSD. Future research may demonstrate whether our findings extend to other adverse, or beneficial, influences. Notwithstanding their theoretical interest, the effects were small, only pertained to parent-reported externalizing problems, refer to a small subset of respondents in our sample, and are in need of replication. We conclude that HR and RMSSD are unlikely to be strong moderators of the association between stressors and externalizing problems. Copyright © 2018 Elsevier B.V. All rights reserved.

The perfect storm: obesity, adipocyte dysfunction, and metabolic consequences.

PubMed

de Ferranti, Sarah; Mozaffarian, Dariush

2008-06-01

As the prevalence of adiposity soars in both developed and developing nations, appreciation of the close links between obesity and disease increases. The strong relationships between excess adipose tissue and poor health outcomes, including cardiovascular disease, diabetes, and cancer, mandate elucidation of the complex cellular, hormonal, and molecular pathophysiology whereby adiposity initiates and maintains adverse health effects. In this report we review adipocyte metabolism and function in the context of energy imbalance and postprandial nutrient excess, including adipocyte hypertrophy and hyperplasia, adipocyte dysfunction, and other systemic consequences. We also discuss implications for laboratory evaluation and clinical care, including the role of lifestyle modifications. Chronic energy imbalance produces adipocyte hypertrophy and hyperplasia, endoplasmic reticulum stress, and mitochondrial dysfunction. These processes lead to increased intracellular and systemic release of adipokines, free fatty acids, and inflammatory mediators that cause adipocyte dysfunction and induce adverse effects in the liver, pancreatic beta-cells, and skeletal muscle as well as the heart and vascular beds. Several specialized laboratory tests can quantify these processes and predict clinical risk, but translation to the clinical setting is premature. Current and future pharmacologic interventions may target these pathways; modest changes in diet, physical activity, weight, and smoking are likely to have the greatest impact. Adipocyte endoplasmic reticulum and mitochondrial stress, and associated changes in circulating adipokines, free fatty acids, and inflammatory mediators, are central to adverse health effects of adiposity. Future investigation should focus on these pathways and on reversing the adverse lifestyle behaviors that are the fundamental causes of adiposity.

Controlling costs without compromising quality: paying hospitals for total knee replacement.

PubMed

Pine, Michael; Fry, Donald E; Jones, Barbara L; Meimban, Roger J; Pine, Gregory J

2010-10-01

Unit costs of health services are substantially higher in the United States than in any other developed country in the world, without a correspondingly healthier population. An alternative payment structure, especially for high volume, high cost episodes of care (eg, total knee replacement), is needed to reward high quality care and reduce costs. The National Inpatient Sample of administrative claims data was used to measure risk-adjusted mortality, postoperative length-of-stay, costs of routine care, adverse outcome rates, and excess costs of adverse outcomes for total knee replacements performed between 2002 and 2005. Empirically identified inefficient and ineffective hospitals were then removed to create a reference group of high-performance hospitals. Predictive models for outcomes and costs were recalibrated to the reference hospitals and used to compute risk-adjusted outcomes and costs for all hospitals. Per case predicted costs were computed and compared with observed costs. Of the 688 hospitals with acceptable data, 62 failed to meet effectiveness criteria and 210 were identified as inefficient. The remaining 416 high-performance hospitals had 13.4% fewer risk-adjusted adverse outcomes (4.56%-3.95%; P < 0.001; χ) and 9.9% lower risk-adjusted total costs ($12,773-$11,512; P < 0.001; t test) than all study hospitals. Inefficiency accounted for 96% of excess costs. A payment system based on the demonstrated performance of effective, efficient hospitals can produce sizable cost savings without jeopardizing quality. In this study, 96% of total excess hospital costs resulted from higher routine costs at inefficient hospitals, whereas only 4% was associated with ineffective care.

Small-for-gestational age and large-for-gestational age thresholds to predict infants at risk of adverse delivery and neonatal outcomes: are current charts adequate? An observational study from the Born in Bradford cohort

PubMed Central

Norris, T; Johnson, W; Farrar, D; Tuffnell, D; Wright, J; Cameron, N

2015-01-01

Objectives Construct an ethnic-specific chart and compare the prediction of adverse outcomes using this chart with the clinically recommended UK-WHO and customised birth weight charts using cut-offs for small-for-gestational age (SGA: birth weight <10th centile) and large-for-gestational age (LGA: birth weight >90th centile). Design Prospective cohort study. Setting Born in Bradford (BiB) study, UK. Participants 3980 White British and 4448 Pakistani infants with complete data for gestational age, birth weight, ethnicity, maternal height, weight and parity. Main outcome measures Prevalence of SGA and LGA, using the three charts and indicators of diagnostic utility (sensitivity, specificity and area under the receiver operating characteristic (AUROC)) of these chart-specific cut-offs to predict delivery and neonatal outcomes and a composite outcome. Results In White British and Pakistani infants, the prevalence of SGA and LGA differed depending on the chart used. Increased risk of SGA was observed when using the UK-WHO and customised charts as opposed to the ethnic-specific chart, while the opposite was apparent when classifying LGA infants. However, the predictive utility of all three charts to identify adverse clinical outcomes was poor, with only the prediction of shoulder dystocia achieving an AUROC>0.62 on all three charts. Conclusions Despite being recommended in national clinical guidelines, the UK-WHO and customised birth weight charts perform poorly at identifying infants at risk of adverse neonatal outcomes. Being small or large may increase the risk of an adverse outcome; however, size alone is not sensitive or specific enough with current detection to be useful. However, a significant amount of missing data for some of the outcomes may have limited the power needed to determine true associations. PMID:25783424

The interaction between temperament and the family environment in adolescent substance use and externalizing behaviors: Support for diathesis–stress or differential susceptibility?

PubMed Central

Rioux, Charlie; Castellanos-Ryan, Natalie; Parent, Sophie; Séguin, Jean R.

2016-01-01

Both individual and environmental factors predict externalizing behaviors and substance use (EB-SU); however, different patterns of interaction among these factors may have different implications. This review first examines how temperament and the family environment interact in the prediction of adolescent EB-SU. Second, studies are reviewed according to two theoretical models: (1) diathesis–stress, i.e., certain individual characteristics are linked to vulnerability and later problems in adverse environments; (2) differential susceptibility, i.e., these characteristics are linked to susceptibility, predicting problems in adverse environments, but also better than average outcomes in good environments. Fourteen studies focusing on the prediction of EB-SU at ages 12–18 were selected through a literature search. Results showed that certain temperament traits (high levels of impulsivity and disinhibition; low levels of effortful control, negative affect, fearfulness and shyness), hereby designated as “adventurous” disposition, were associated with higher levels of EB-SU in adverse family environments. Some studies also showed that children with “adventurous” temperament traits in positive environments had the lowest levels of EB-SU. This suggests that prevention of EB-SU might target family factors such as parenting and focus on children with “adventurous” temperament traits. Further, studies that supported the differential susceptibility model were those assessing temperament and the family environment in childhood and studies that supported the diathesis–stress model assessed these variables in adolescence. It is thus possible that some of these “adventurous” temperament traits, with regard to EB-SU, would be indicators of susceptibility to both enriched and adverse environments in childhood but no longer in adolescence, when they would only be indicators of vulnerability to adverse environments. PMID:27413247

The long reach of early adversity: Parenting, stress, and neural pathways to antisocial behavior in adulthood.

PubMed

Gard, Arianna M; Waller, Rebecca; Shaw, Daniel S; Forbes, Erika E; Hariri, Ahmad R; Hyde, Luke W

2017-10-01

Early life adversities including harsh parenting, maternal depression, neighborhood deprivation, and low family economic resources are more prevalent in low-income urban environments and are potent predictors of psychopathology, including, for boys, antisocial behavior (AB). However, little research has examined how these stressful experiences alter later neural function. Moreover, identifying genetic markers of greater susceptibility to adversity is critical to understanding biopsychosocial pathways from early adversity to later psychopathology. Within a sample of 310 low-income boys followed from age 1.5 to 20, multimethod assessments of adversities were examined at age 2 and age 12. At age 20, amygdala reactivity to emotional facial expressions was assessed using fMRI, and symptoms of Antisocial Personality Disorder were assessed via structured clinical interview. Genetic variability in cortisol signaling ( CRHR1 ) was examined as a moderator of pathways to amygdala reactivity. Observed parenting and neighborhood deprivation at age 2 each uniquely predicted amygdala reactivity to emotional faces at age 20 over and above other adversities measured at multiple developmental periods. Harsher parenting and greater neighborhood deprivation in toddlerhood predicted clinically-significant symptoms of AB via less amygdala reactivity to fearful facial expressions and this pathway was moderated by genetic variation in CRHR1 . These results elucidate a pathway linking early adversity to less amygdala reactivity to social signals of interpersonal distress 18 years later, which in turn increased risk for serious AB. Moreover, these findings suggest a genetic marker of youth more susceptible to adversity.

Pharmacodynamics and effectiveness of topical nitroglycerin at lowering blood pressure during autonomic dysreflexia.

PubMed

Solinsky, R; Bunnell, A E; Linsenmeyer, T A; Svircev, J N; Engle, A; Burns, S P

2017-10-01

Secondary analysis of prospectively collected observational data assessing the safety of an autonomic dysreflexia (AD) management protocol. To estimate the time to onset of action, time to full clinical effect (sustained systolic blood pressure (SBP) <160 mm Hg) and effectiveness of nitroglycerin ointment at lowering blood pressure for patients with spinal cord injuries experiencing AD. US Veterans Affairs inpatient spinal cord injury (SCI) unit. Episodes of AD recalcitrant to nonpharmacologic interventions that were given one to two inches of 2% topical nitroglycerin ointment were recorded. Pharmacodynamics as above and predictive characteristics (through a mixed multivariate logistic regression model) were calculated. A total of 260 episodes of pharmacologically managed AD were recorded in 56 individuals. Time to onset of action for nitroglycerin ointment was 9-11 min. Time to full clinical effect was 14-20 min. Topical nitroglycerin controlled SBP <160 mm Hg in 77.3% of pharmacologically treated AD episodes with the remainder requiring additional antihypertensive medications. A multivariate logistic regression model was unable to identify statistically significant factors to predict which patients would respond to nitroglycerin ointment (odds ratios 95% confidence intervals 0.29-4.93). The adverse event rate, entirely attributed to hypotension, was 3.6% with seven of the eight events resolving with close observation alone and one episode requiring normal saline. Nitroglycerin ointment has a rapid onset of action and time to full clinical effect with high efficacy and relatively low adverse event rate for patients with SCI experiencing AD.

The Mediating and Moderating Effects of Workplace Social Capital on the Associations between Adverse Work Characteristics and Psychological Distress among Japanese Workers

PubMed Central

OSHIO, Takashi; INOUE, Akiomi; TSUTSUMI, Akizumi

2014-01-01

Our current study investigated how workplace social capital (WSC) mediates and moderates the associations between adverse work characteristics and psychological distress among Japanese workers. We collected cross-sectional data (N=9,350) from a baseline survey of an occupational Japanese cohort study. We focused on individual WSC and considered job demands/control, effort/reward, and two types (i.e., procedural and interactional) of organizational justice as work-characteristic variables. We defined psychological distress as a score of ≥5 on the Kessler Psychological Distress Scale (K6 scale). Multivariate logistic regression analyses predicted a binary variable of psychological distress by individual WSC and adverse work characteristics, adjusting for individual-level covariates. Individual WSC mediated the associations between adverse work characteristics and psychological distress in almost all model specifications. Additionally, individual WSC moderated the associations of psychological distress with high job demands, high effort, and low interactional justice when we used a high WSC cutoff point. In contrast, individual WSC did not moderate such interactions with low job control, reward, or procedural justice. We concluded that individual WSC mediated the associations between adverse work characteristics and psychological distress among Japanese workers while selectively moderating their associations at high levels of WSC. PMID:24705803

Clinical Decision Support to Implement CYP2D6 Drug-Gene Interaction.

PubMed

Caraballo, Pedro J; Parkulo, Mark; Blair, David; Elliott, Michelle; Schultz, Cloann; Sutton, Joseph; Rao, Padma; Bruflat, Jamie; Bleimeyer, Robert; Crooks, John; Gabrielson, Donald; Nicholson, Wayne; Rohrer Vitek, Carolyn; Wix, Kelly; Bielinski, Suzette J; Pathak, Jyotishman; Kullo, Iftikhar

2015-01-01

The level of CYP2D6 metabolic activity can be predicted by pharmacogenomic testing, and concomitant use of clinical decision support has the potential to prevent adverse effects from those drugs metabolized by this enzyme. Our initial findings after implementation of clinical decision support alerts integrated in the electronic health records suggest high feasibility, but also identify important challenges.

Modeling sediment transport from an off-road vehicle trail stream crossing using WEPP model

Treesearch

Renee' D. Ayala; Puneet Srivastava; Christian J. Brodbeck; Emily A. Carter; Timothy P. McDonald

2005-01-01

There is a limited information available pertaining to the adverse effects of Off-Road-Vehicle (ORV) use and trail impacts. As a result, this study was initiated in 2003 to (a) quantify water quality impacts of an ORV trail stream crossing through monitoring of total suspended solids, and (b) conduct WEPP (Water Erosion Prediction Project) simulations to determine long...

Controlling for Frailty in Pharmacoepidemiologic Studies of Older Adults: Validation of an Existing Medicare Claims-based Algorithm.

PubMed

Cuthbertson, Carmen C; Kucharska-Newton, Anna; Faurot, Keturah R; Stürmer, Til; Jonsson Funk, Michele; Palta, Priya; Windham, B Gwen; Thai, Sydney; Lund, Jennifer L

2018-07-01

Frailty is a geriatric syndrome characterized by weakness and weight loss and is associated with adverse health outcomes. It is often an unmeasured confounder in pharmacoepidemiologic and comparative effectiveness studies using administrative claims data. Among the Atherosclerosis Risk in Communities (ARIC) Study Visit 5 participants (2011-2013; n = 3,146), we conducted a validation study to compare a Medicare claims-based algorithm of dependency in activities of daily living (or dependency) developed as a proxy for frailty with a reference standard measure of phenotypic frailty. We applied the algorithm to the ARIC participants' claims data to generate a predicted probability of dependency. Using the claims-based algorithm, we estimated the C-statistic for predicting phenotypic frailty. We further categorized participants by their predicted probability of dependency (<5%, 5% to <20%, and ≥20%) and estimated associations with difficulties in physical abilities, falls, and mortality. The claims-based algorithm showed good discrimination of phenotypic frailty (C-statistic = 0.71; 95% confidence interval [CI] = 0.67, 0.74). Participants classified with a high predicted probability of dependency (≥20%) had higher prevalence of falls and difficulty in physical ability, and a greater risk of 1-year all-cause mortality (hazard ratio = 5.7 [95% CI = 2.5, 13]) than participants classified with a low predicted probability (<5%). Sensitivity and specificity varied across predicted probability of dependency thresholds. The Medicare claims-based algorithm showed good discrimination of phenotypic frailty and high predictive ability with adverse health outcomes. This algorithm can be used in future Medicare claims analyses to reduce confounding by frailty and improve study validity.

Atmospheric Effects on Signal Propagation in Adverse Environmental Conditions: A Validation of the Advanced Refractive Effects Prediction System

DTIC Science & Technology

2008-09-01

65 Figure 30. Chiang Mai , Thailand March Climatology AREPS M-unit graphic. ..............66 Figure 31. Standard Atmosphere AREPS M-unit...experiment as a precursor to the annual capstone field experiment (May and June) at the Mae Ngat Dam north of Chiang Mai , Thailand. COASTS R&D...Motorola 802.16 network components as discussed in Chapter II. Testing occurred approximately 40 km north of Chiang Mai , Thailand, at the Mae Ngat Dam

Numerical Simulations of Vortex Shedding in Hydraulic Turbines

NASA Technical Reports Server (NTRS)

Dorney, Daniel; Marcu, Bogdan

2004-01-01

Turbomachines for rocket propulsion applications operate with many different working fluids and flow conditions. Oxidizer boost turbines often operate in liquid oxygen, resulting in an incompressible flow field. Vortex shedding from airfoils in this flow environment can have adverse effects on both turbine performance and durability. In this study the effects of vortex shedding in a low-pressure oxidizer turbine are investigated. Benchmark results are also presented for vortex shedding behind a circular cylinder. The predicted results are compared with available experimental data.

Impact of the HLA-B(*)58:01 Allele and Renal Impairment on Allopurinol-Induced Cutaneous Adverse Reactions.

PubMed

Ng, Chau Yee; Yeh, Yu-Ting; Wang, Chuang-Wei; Hung, Shuen-Iu; Yang, Chih-Hsun; Chang, Ya-Ching; Chang, Wan-Chun; Lin, Yu-Jr; Chang, Chee-Jen; Su, Shih-Chi; Fan, Wen-Lang; Chen, Der-Yuan; Wu, Yeong-Jian Jan; Tian, Ya-Chung; Hui, Rosaline Chung-Yee; Chung, Wen-Hung

2016-07-01

Allopurinol, a common drug for treating hyperuricemia, is associated with cutaneous adverse drug reactions ranging from mild maculopapular exanthema to life-threatening severe cutaneous adverse reactions, including drug reaction with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, and toxic epidermal necrolysis. We have previously reported that HLA-B*58:01 is strongly associated with allopurinol-induced severe cutaneous adverse reactions in Han Chinese, but the associations of the HLA-B*58:01 genotype in an allopurinol-induced hypersensitivity phenotype remain unclear. To investigate the comprehensive associations of HLA-B*58:01, we enrolled 146 patients with allopurinol-induced cutaneous adverse drug reactions (severe cutaneous adverse reactions, n = 106; maculopapular exanthema, n = 40) and 285 allopurinol-tolerant control subjects. Among these allopurinol-induced cutaneous adverse drug reactions, HLA-B*58:01 was strongly associated with severe cutaneous adverse reactions (odds ratio [OR] = 44.0; 95% confidence interval = 21.5-90.3; P = 2.6 × 10(-41)), and the association was correlated with disease severity (OR = 44.0 for severe cutaneous adverse reactions, OR = 8.5 for maculopapular exanthema). The gene dosage effect of HLA-B*58:01 also influenced the development of allopurinol-induced cutaneous adverse drug reactions (OR = 15.25 for HLA-B*58:01 heterozygotes and OR = 72.45 for homozygotes). Furthermore, coexistence of HLA-B*58:01 and renal impairment increased the risk and predictive accuracy of allopurinol-induced cutaneous adverse drug reactions (heterozygous HLA-B*58:01 and normal renal function: OR = 15.25, specificity = 82%; homozygous HLA-B*58:01 and severe renal impairment: OR = 1269.45, specificity = 100%). This HLA-B*58:01 correlation study suggests that patients with coexisting HLA-B*58:01 and renal impairment (especially estimated glomerular filtration rate < 30ml/minute/1.73 m(2)) should be cautious and avoid using allopurinol. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Hip fractures are risky business: an analysis of the NSQIP data.

PubMed

Sathiyakumar, Vasanth; Greenberg, Sarah E; Molina, Cesar S; Thakore, Rachel V; Obremskey, William T; Sethi, Manish K

2015-04-01

Hip fractures are one of the most common types of orthopaedic injury with high rates of morbidity. Currently, no study has compared risk factors and adverse events following the different types of hip fracture surgeries. The purpose of this paper is to investigate the major and minor adverse events and risk factors for complication development associated with five common surgeries for the treatment of hip fractures using the NSQIP database. Using the ACS-NSQIP database, complications for five forms of hip surgeries were selected and categorized into major and minor adverse events. Demographics and clinical variables were collected and an unadjusted bivariate logistic regression analyses was performed to determine significant risk factors for adverse events. Five multivariate regressions were run for each surgery as well as a combined regression analysis. A total of 9640 patients undergoing surgery for hip fracture were identified with an adverse events rate of 25.2% (n=2433). Open reduction and internal fixation of a femoral neck fracture had the greatest percentage of all major events (16.6%) and total adverse events (27.4%), whereas partial hip hemiarthroplasty had the greatest percentage of all minor events (11.6%). Mortality was the most common major adverse event (44.9-50.6%). For minor complications, urinary tract infections were the most common minor adverse event (52.7-62.6%). Significant risk factors for development of any adverse event included age, BMI, gender, race, active smoking status, history of COPD, history of CHF, ASA score, dyspnoea, and functional status, with various combinations of these factors significantly affecting complication development for the individual surgeries. Hip fractures are associated with significantly high numbers of adverse events. The type of surgery affects the type of complications developed and also has an effect on what risk factors significantly predict the development of a complication. Concerted efforts from orthopaedists should be made to identify higher risk patients and prevent the most common adverse events that occur postoperatively. Copyright © 2014 Elsevier Ltd. All rights reserved.

Development and validation of a physiology-based model for the prediction of pharmacokinetics/toxicokinetics in rabbits

PubMed Central

Hermes, Helen E.; Teutonico, Donato; Preuss, Thomas G.; Schneckener, Sebastian

2018-01-01

The environmental fates of pharmaceuticals and the effects of crop protection products on non-target species are subjects that are undergoing intense review. Since measuring the concentrations and effects of xenobiotics on all affected species under all conceivable scenarios is not feasible, standard laboratory animals such as rabbits are tested, and the observed adverse effects are translated to focal species for environmental risk assessments. In that respect, mathematical modelling is becoming increasingly important for evaluating the consequences of pesticides in untested scenarios. In particular, physiologically based pharmacokinetic/toxicokinetic (PBPK/TK) modelling is a well-established methodology used to predict tissue concentrations based on the absorption, distribution, metabolism and excretion of drugs and toxicants. In the present work, a rabbit PBPK/TK model is developed and evaluated with data available from the literature. The model predictions include scenarios of both intravenous (i.v.) and oral (p.o.) administration of small and large compounds. The presented rabbit PBPK/TK model predicts the pharmacokinetics (Cmax, AUC) of the tested compounds with an average 1.7-fold error. This result indicates a good predictive capacity of the model, which enables its use for risk assessment modelling and simulations. PMID:29561908

Flight evaluation of the transonic stability and control characteristics of an airplane incorporating a supercritical wing

NASA Technical Reports Server (NTRS)

Matheny, N. W.; Gatlin, D. H.

1978-01-01

A TF-8A airplane was equipped with a transport type supercritical wing and fuselage fairings to evaluate predicted performance improvements for cruise at transonic speeds. A comparison of aerodynamic derivatives extracted from flight and wind tunnel data showed that static longitudinal stability, effective dihedral, and aileron effectiveness, were higher than predicted. The static directional stability derivative was slower than predicted. The airplane's handling qualities were acceptable with the stability augmentation system on. The unaugmented airplane exhibited some adverse lateral directional characteristics that involved low Dutch roll damping and low roll control power at high angles of attack and roll control power that was greater than satisfactory for transport aircraft at cruise conditions. Longitudinally, the aircraft exhibited a mild pitchup tendency. Leading edge vortex generators delayed the onset of flow separation, moving the pitchup point to a higher lift coefficient and reducing its severity.

Thermal-structural modeling of polymer Bragg grating waveguides illuminated by a light emitting diode.

PubMed

Joon Kim, Kyoung; Bar-Cohen, Avram; Han, Bongtae

2012-02-20

This study reports both analytical and numerical thermal-structural models of polymer Bragg grating (PBG) waveguides illuminated by a light emitting diode (LED). A polymethyl methacrylate (PMMA) Bragg grating (BG) waveguide is chosen as an analysis vehicle to explore parametric effects of incident optical powers and substrate materials on the thermal-structural behavior of the BG. Analytical models are verified by comparing analytically predicted average excess temperatures, and thermally induced axial strains and stresses with numerical predictions. A parametric study demonstrates that the PMMA substrate induces more adverse effects, such as higher excess temperatures, complex axial temperature profiles, and greater and more complicated thermally induced strains in the BG compared with the Si substrate. © 2012 Optical Society of America

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)...

Ventral striatum and amygdala activity as convergence sites for early adversity and conduct disorder

PubMed Central

Boecker-Schlier, Regina; Buchmann, Arlette F.; Blomeyer, Dorothea; Jennen-Steinmetz, Christine; Baumeister, Sarah; Plichta, Michael M.; Cattrell, Anna; Schumann, Gunter; Esser, Günter; Schmidt, Martin; Buitelaar, Jan; Meyer-Lindenberg, Andreas; Banaschewski, Tobias; Brandeis, Daniel; Laucht, Manfred

2017-01-01

Abstract Childhood family adversity (CFA) increases the risk for conduct disorder (CD) and has been associated with alterations in regions of affective processing like ventral striatum (VS) and amygdala. However, no study so far has demonstrated neural converging effects of CFA and CD in the same sample. At age 25 years, functional MRI data during two affective tasks, i.e. a reward (N = 171) and a face-matching paradigm (N = 181) and anatomical scans (N = 181) were acquired in right-handed currently healthy participants of an epidemiological study followed since birth. CFA during childhood was determined using a standardized parent interview. Disruptive behaviors and CD diagnoses during childhood and adolescence were obtained by diagnostic interview (2–19 years), temperamental reward dependence was assessed by questionnaire (15 and 19 years). CFA predicted increased CD and amygdala volume. Both exposure to CFA and CD were associated with a decreased VS response during reward anticipation and blunted amygdala activity during face-matching. CD mediated the effect of CFA on brain activity. Temperamental reward dependence was negatively correlated with CFA and CD and positively with VS activity. These findings underline the detrimental effects of CFA on the offspring's affective processing and support the importance of early postnatal intervention programs aiming to reduce childhood adversity factors. PMID:27694318

Identifying Childhood Characteristics that Underlie Pre-Morbid Risk for Substance Use Disorders: Socialization and Boldness

PubMed Central

Hicks, Brian M.; Iacono, William G.; McGue, Matt

2013-01-01

Utilizing a longitudinal twin study (N = 2510), we identified the child characteristics present prior to initiation of substance use that best predicted later substance use disorders. Two independent traits accounted for the majority of pre-morbid risk: socialization (conformity to rules and conventional values) and boldness (sociability and social assurance, stress resilience, and thrill seeking). Low socialization was associated with disruptive behavior disorders, parental externalizing disorders, and environmental adversity, and exhibited moderate genetic (.45) and shared environmental influences (.30). Boldness was highly heritable (.71) and associated with less internalizing distress and environmental adversity. Together, these traits exhibited robust associations with adolescent and young adult substance use disorders (R = .48 and .50, respectively), and incremental prediction over disruptive behavior disorders, parental externalizing disorders, and environmental adversity. Results were replicated in an independent sample. Socialization and boldness offer a novel conceptualization of underlying risk for substance use disorders that has the potential to improve prediction and theory with implications for basic research, prevention, and intervention. PMID:24280373

Identifying childhood characteristics that underlie premorbid risk for substance use disorders: socialization and boldness.

PubMed

Hicks, Brian M; Iacono, William G; McGue, Matt

2014-02-01

We utilized a longitudinal twin study (N = 2,510) to identify the child characteristics present prior to initiation of substance use that best predicted later substance use disorders. Two independent traits accounted for the majority of premorbid risk: socialization (conformity to rules and conventional values) and boldness (sociability and social assurance, stress resilience, and thrill seeking). Low socialization was associated with disruptive behavior disorders, parental externalizing disorders, and environmental adversity and exhibited moderate genetic (0.45) and shared environmental influences (0.30). Boldness was highly heritable (0.71) and associated with less internalizing distress and environmental adversity. In combination, these traits exhibited robust associations with adolescent and young adult substance use disorders (R = .48 and .50, respectively) and incremental prediction over disruptive behavior disorders, parental externalizing disorders, and environmental adversity. The results were replicated in an independent sample. Socialization and boldness offer a novel conceptualization of underlying risk for substance use disorders that has the potential to improve prediction and theory with implications for basic research, prevention, and intervention.

Positive life events predict salivary cortisol in pregnant women.

PubMed

Pluess, Michael; Wurmser, Harald; Buske-Kirschbaum, Angelika; Papousek, Mechthild; Pirke, Karl-Martin; Hellhammer, Dirk; Bolten, Margarete

2012-08-01

Maternal stress during pregnancy has been repeatedly associated with problematic child development. According to the fetal programming hypothesis adverse experiences during pregnancy increase maternal cortisol, which is then assumed to exert a negative effect on fetal development. Recent studies in non-pregnant women report significant associations between positive emotionality and low cortisol levels. We tested in a sample of 60 pregnant women whether both negative and positive life events independently predicted third-trimester baseline awakening cortisol levels. While the effect of negative life events proved unrelated positive life events significantly predicted lower cortisol levels. These findings suggest that positive experiences are of relevance regarding maternal morning cortisol levels in pregnancy reflecting a resource with potentially beneficial effects for the mother and the developing fetus. It might be promising for psychological intervention programs to focus on increasing positive experiences of the expecting mother rather than exclusively trying to reduce maternal stress during pregnancy. Copyright © 2012 Elsevier Ltd. All rights reserved.

Possible biomarkers modulating haloperidol efficacy and/or tolerability.

PubMed

Porcelli, Stefano; Crisafulli, Concetta; Calabrò, Marco; Serretti, Alessandro; Rujescu, Dan

2016-04-01

Haloperidol (HP) is widely used in the treatment of several forms of psychosis. Despite of its efficacy, HP use is a cause of concern for the elevated risk of adverse drug reactions. adverse drug reactions risk and HP efficacy greatly vary across subjects, indicating the involvement of several factors in HP mechanism of action. The use of biomarkers that could monitor or even predict HP treatment impact would be of extreme importance. We reviewed the elements that could potentially be used as peripheral biomarkers of HP effectiveness. Although a validated biomarker still does not exist, we underlined the several potential findings (e.g., about cytokines, HP metabolites and genotypic biomarkers) which could pave the way for future research on HP biomarkers.

[Predictive value of qualitative assessment of general movements for adverse outcomes at 24 months of age in infants with asphyxia].

PubMed

Chen, Nan; Wen, Xiao-Hong; Huang, Jin-Hua; Wang, Shui-Yun; Zhu, Yue-E

2015-12-01

To investigate the predictive value of the qualitative assessment of general movements (GMs) for adverse outcomes at 24 months of age in full-term infants with asphyxia. A total of 114 full-term asphyxiated infants, who were admitted to the neonatal intensive care unit between 2009 and 2012 and took part in follow-ups after discharge were included in the study. All of them received the qualitative assessment of GMs within 3 months after birth. The development quotient was determined with the Bayley Scales of Infant Development at 24 months of age. The results of the qualitative assessment of GMs within 3 months after birth showed that among 114 infants, 20 (17.5%) had poor repertoire movements and 7 (6.1%) had cramped-synchronized movements during the writhing movements period; 8 infants (7.0%) had the absence of fidgety movements during the fidgety movements period. The results of development quotient at 24 months of age showed that 7 infants (6.1%) had adverse developmental outcomes: 6 cases of cerebral palsy and mental retardation and 1 case of mental retardation. There was a poor consistency between poor repertoire movements during the writhing movements period and the developmental outcomes at 24 months of age (Kappa=-0.019; P>0.05). There was a high consistency between cramped-synchronized movements during the writhing movements period and the developmental outcomes at 24 months of age (Kappa=0.848; P<0.05), and the results of predictive values of cramped-synchronized movements were shown as follows: predictive validity 98.2%, sensitivity 85.7%, specificity 99.1%, positive predictive value 85.7%, and negative predictive value 99.1%. There was a high consistency between the absence of fidgety movements during the fidgety movements period and the developmental outcomes at 24 months of age (Kappa=0.786; P<0.05), and its predictive values were expressed as follows: predictive validity 97.4%, sensitivity 85.7%, specificity 98.1%, positive predictive value 75.0%, and negative predictive value 99.1%. Cramped-synchronized movements and absence of fidgety movements can predict adverse developmental outcomes at 24 months of age in full-term infants with asphyxia.

Predicting long-term outcomes for children affected by HIV and AIDS: perspectives from the scientific study of children's development.

PubMed

Stein, Alan; Desmond, Christopher; Garbarino, James; Van IJzendoorn, Marinus H; Barbarin, Oscar; Black, Maureen M; Stein, Aryeh D; Hillis, Susan D; Kalichman, Seth C; Mercy, James A; Bakermans-Kranenburg, Marian J; Rapa, Elizabeth; Saul, Janet R; Dobrova-Krol, Natasha A; Richter, Linda M

2014-07-01

The immediate and short-term consequences of adult HIV for affected children are well documented. Little research has examined the long-term implications of childhood adversity stemming from caregiver HIV infection. Through overviews provided by experts in the field, together with an iterative process of consultation and refinement, we have extracted insights from the broader field of child development of relevance to predicting the long-term consequences to children affected by HIV and AIDS. We focus on what is known about the impact of adversities similar to those experienced by HIV-affected children, and for which there is longitudinal evidence. Cautioning that findings are not directly transferable across children or contexts, we examine findings from the study of parental death, divorce, poor parental mental health, institutionalization, undernutrition, and exposure to violence. Regardless of the type of adversity, the majority of children manifest resilience and do not experience any long-term negative consequences. However, a significant minority do and these children experience not one, but multiple problems, which frequently endure over time in the absence of support and opportunities for recovery. As a result, they are highly likely to suffer numerous and enduring impacts. These insights suggest a new strategic approach to interventions for children affected by HIV and AIDS, one that effectively combines a universal lattice of protection with intensive intervention targeted to selected children and families.

Activation of CAR and PXR by Dietary, Environmental and Occupational Chemicals Alters Drug Metabolism, Intermediary Metabolism, and Cell Proliferation

PubMed Central

Hernandez, J.P.; Mota, L.C.; Baldwin, W.S.

2010-01-01

The constitutive androstane receptor (CAR) and the pregnane × receptor (PXR) are activated by a variety of endogenous and exogenous ligands, such as steroid hormones, bile acids, pharmaceuticals, and environmental, dietary, and occupational chemicals. In turn, they induce phase I–III detoxification enzymes and transporters that help eliminate these chemicals. Because many of the chemicals that activate CAR and PXR are environmentally-relevant (dietary and anthropogenic), studies need to address whether these chemicals or mixtures of these chemicals may increase the susceptibility to adverse drug interactions. In addition, CAR and PXR are involved in hepatic proliferation, intermediary metabolism, and protection from cholestasis. Therefore, activation of CAR and PXR may have a wide variety of implications for personalized medicine through physiological effects on metabolism and cell proliferation; some beneficial and others adverse. Identifying the chemicals that activate these promiscuous nuclear receptors and understanding how these chemicals may act in concert will help us predict adverse drug reactions (ADRs), predict cholestasis and steatosis, and regulate intermediary metabolism. This review summarizes the available data on CAR and PXR, including the environmental chemicals that activate these receptors, the genes they control, and the physiological processes that are perturbed or depend on CAR and PXR action. This knowledge contributes to a foundation that will be necessary to discern interindividual differences in the downstream biological pathways regulated by these key nuclear receptors. PMID:20871735

Masculine norms, disclosure, and childhood adversities predict long-term mental distress among men with histories of child sexual abuse.

PubMed

Easton, Scott D

2014-02-01

Child sexual abuse (CSA) can have a profound effect on the long-term mental health of boys/men. However, not all men with histories of CSA experience psychopathology. To improve prevention and intervention services, more research is needed to understand why some male survivors experience mental health problems and others do not. The purpose of this study was to examine factors related to mental distress among a large, non-clinical sample of men with histories of CSA (N=487). Using a cross-sectional design with purposive sampling from three national survivor organizations, data were collected through an anonymous Internet-based survey. Multivariate analyses found that only one of the four CSA severity variables-use of physical force by the abuser-was related to mental distress. Additional factors that were related to mental distress included the number of other childhood adversities, years until disclosure, overall response to disclosure, and conformity to masculine norms. Overall, the final model predicted 36% of the variance in the number of mental health symptoms. Mental health practitioners should include masculine norms, disclosure history, and childhood adversities in assessments and intervention planning with male survivors. To more fully explicate risk factors for psychopathology in this population, future studies with probability samples of men that focus on mediational processes and use longitudinal designs are needed. Copyright © 2013 Elsevier Ltd. All rights reserved.

Circulating Endothelial Cells and Endothelial Function predict Major Adverse Cardiac Events and Early Adverse Left Ventricular Remodeling in Patients with ST-Segment Elevation Myocardial Infarction

PubMed Central

Magdy, Abdel Hamid; Bakhoum, Sameh; Sharaf, Yasser; Sabry, Dina; El-Gengehe, Ahmed T; Abdel-Latif, Ahmed

2016-01-01

Endothelial progenitor cells (EPCs) and circulating endothelial cells (CECs) are mobilized from the bone marrow and increase in the early phase after ST-elevation myocardial infarction (STEMI). The aim of this study was to assess the prognostic significance of CECs and indices of endothelial dysfunction in patients with STEMI. In 78 patients with acute STEMI, characterization of CD34+/VEGFR2+ CECs, and indices of endothelial damage/dysfunction such as brachial artery flow mediated dilatation (FMD) were determined. Blood samples for CECs assessment and quantification were obtained within 24 hours of admission and FMD was assessed during the index hospitalization. At 30 days follow up, the primary composite end point of major cardiac adverse events (MACE) consisting of all-cause mortality, recurrent non-fatal MI, or heart failure and the secondary endpoint of early adverse left ventricular (LV) remodeling were analyzed. The 17 patients (22%) who developed MACE had significantly higher CEC level (P = 0.004), vWF level (P =0.028), and significantly lower FMD (P = 0.006) compared to the remaining patients. Logistic regression analysis showed that CECs level and LV ejection fraction were independent predictors of MACE. The areas under the receiver operating characteristic curves (ROC) for CEC level, FMD, and the logistic model with both markers were 0.73, 0.75, and 0.82 respectively for prediction of the MACE. The 16 patients who developed the secondary endpoint had significantly higher CEC level compared to remaining patients (p =0.038). In conclusion, increased circulating endothelial cells and endothelial dysfunction predicted the occurrence of major adverse cardiac events and adverse cardiac remodeling in patients with STEMI. PMID:26864952

Pathways between childhood/adolescent adversity, adolescent socioeconomic status, and long-term cardiovascular disease risk in young adulthood.

PubMed

Doom, Jenalee R; Mason, Susan M; Suglia, Shakira F; Clark, Cari Jo

2017-09-01

The current study investigated mediators between childhood/adolescent adversities (e.g., dating violence, maltreatment, homelessness, and parental death), low socioeconomic status (SES) during adolescence, and cardiovascular disease (CVD) risk in young adulthood. The purpose of these analyses was to understand whether SES during adolescence and childhood/adolescent adversities affect CVD risk through similar pathways, including maternal relationship quality, health behaviors, financial stress, medical/dental care, educational attainment, sleep problems, and depressive symptoms. Using the National Longitudinal Study of Adolescent to Adult Health (N = 14,493), which has followed US adolescents (Wave 1; M = 15.9 years) through early adulthood (Wave 4; M = 28.9 years), associations were examined between childhood/adolescent adversity and SES to 30-year CVD risk in young adulthood. The outcome was a Framingham-based prediction model of CVD risk that included age, sex, body mass index, smoking, systolic blood pressure, diabetes, and antihypertensive medication use at Wave 4. Path analysis was used to examine paths through the adolescent maternal relationship to young adult mediators of CVD risk. Childhood/adolescent adversity significantly predicted greater adult CVD risk through the following pathways: maternal relationship, health behaviors, financial stress, lack of medical/dental care, and educational attainment; but not through depressive symptoms or sleep problems. Lower SES during adolescence significantly predicted greater adult CVD risk through the following pathways: health behaviors, financial stress, lack of medical/dental care, and educational attainment, but not maternal relationship, depressive symptoms, or sleep problems. Childhood/adolescent adversities and SES affected CVD risk in young adulthood through both similar and unique pathways that may inform interventions. Copyright © 2017 Elsevier Ltd. All rights reserved.

Early adversity, RSA, and inhibitory control: evidence of children's neurobiological sensitivity to social context.

PubMed

Skowron, Elizabeth A; Cipriano-Essel, Elizabeth; Gatzke-Kopp, Lisa M; Teti, Douglas M; Ammerman, Robert T

2014-07-01

This study examined parasympathetic physiology as a moderator of the effects of early adversity (i.e., child abuse and neglect) on children's inhibitory control. Children's respiratory sinus arrhythmia (RSA) was assessed during a resting baseline, two joint challenge tasks with mother, and an individual frustration task. RSA assessed during each of the joint parent-child challenge tasks moderated the effects of child maltreatment (CM) status on children's independently-assessed inhibitory control. No moderation effect was found for RSA assessed at baseline or in the child-alone challenge task. Among CM-exposed children, lower RSA levels during the joint task predicted the lowest inhibitory control, whereas higher joint task RSA was linked to higher inhibitory control scores that were indistinguishable from those of non-CM children. Results are discussed with regard to the importance of considering context specificity (i.e., individual and caregiver contexts) in how biomarkers inform our understanding of individual differences in vulnerability among at-risk children. © 2013 Wiley Periodicals, Inc.

Defense mechanisms against toxic phytochemicals in the diet of domestic animals.

PubMed

Fink-Gremmels, Johanna

2010-02-01

Plant secondary metabolites (PSMs) are non-nutritional components that occur in numerous feed materials and are able to exert toxic effects in animals. The current article aims to summarize innate defense strategies developed by different animal species to avoid excessive exposure to PSMs. These mechanisms include pre-systemic degradation of PSMs by rumen microbiota, the intestinal barrier including efflux transporters of monogastric species, as well as pre-hepatic and intra-hepatic biotransformation processes. These physiological barriers determine systemic exposure and ultimately the dose-dependent adverse effects in the target animal species. Considering the large number of potentially toxic PSMs, which makes an evaluation of all individual PSMs virtually impossible, such a mechanism-oriented approach could improve the predictability of adverse effects and support the interpretation of clinical field observations. Moreover, mechanistic data related to tissue disposition and excretion pathways of PSMs for example into milk, could substantially support the assessment of the risks for consumers of foods derived from PSM-exposed animals.

Early Adversity, RSA, and Inhibitory Control: Evidence of Children’s Neurobiological Sensitivity to Social Context

PubMed Central

Skowron, Elizabeth A.; Cipriano-Essel, Elizabeth; Gatzke-Kopp, Lisa M.; Teti, Douglas M.; Ammerman, Robert T.

2014-01-01

This study examined parasympathetic physiology as a moderator of the effects of early adversity (i.e., child abuse and neglect) on children’s inhibitory control. Children’s respiratory sinus arrhythmia (RSA) was assessed during a resting baseline, two joint challenge tasks with mother, and an individual frustration task. RSA assessed during each of the joint parent–child challenge tasks moderated the effects of child maltreatment (CM) status on children’s independently-assessed inhibitory control. No moderation effect was found for RSA assessed at baseline or in the child-alone challenge task. Among CM-exposed children, lower RSA levels during the joint task predicted the lowest inhibitory control, whereas higher joint task RSA was linked to higher inhibitory control scores that were indistinguishable from those of non-CM children. Results are discussed with regard to the importance of considering context specificity (i.e., individual and caregiver contexts) in how biomarkers inform our understanding of individual differences in vulnerability among at-risk children. PMID:24142832

Synthetic cannabinoids: the hidden side of Spice drugs.

PubMed

Pintori, Nicholas; Loi, Barbara; Mereu, Maddalena

2017-09-01

Spice drugs are herbal mixtures sprayed with synthetic cannabinoids designed to mimic the psychoactive ingredient in marijuana [Δ-tetrahydrocannabinol (Δ-THC)] and synthesized by introducing modifications to the chemical structure of parental compounds aiming to circumvent legal regulations. Synthetic cannabinoid use/abuse can be devastating as toxicological effects and adverse reactions cannot be entirely predicted and may vary with the dose, route of administration, individual vulnerability and concomitant intake with other drugs. The absence of validated testing procedures in the clinical field makes difficult the adoption of a therapeutic approach effective in coping with the synthetic cannabinoid phenomenon, posing a significant challenge for prevention, treatment and public health in general. The aim of this review is to gain insights into the epidemiological, pharmacological and toxicological properties of synthetic cannabinoids, aiming to provide a reliable background needed for the management of synthetic cannabinoid-related adverse effects. Consumers, competent authorities and medical care professionals should be aware of the risks associated with synthetic cannabinoid use.

Magnetic Resonance Imaging Parameters in Predicting the Treatment Outcome of High-intensity Focused Ultrasound Ablation of Uterine Fibroids With an Immediate Nonperfused Volume Ratio of at Least 90.

PubMed

Keserci, Bilgin; Duc, Nguyen Minh

2018-03-07

We aimed to investigate the role of magnetic resonance imaging parameters in predicting the treatment outcome of high-intensity focused ultrasound (HIFU) ablation of uterine fibroids with a nonperfused volume (NPV) ratio of at least 90%. A total of 120 women who underwent HIFU treatment were divided into groups 1 (n = 72) and 2 (n = 48), comprising patients with an NPV ratio of at least 90% and less than 90%, respectively. Multivariate logistic regression analyses were carried out to investigate the potential predictors of the NPV ratio of at least 90%. The NPV ratios immediately post-treatment, therapeutic efficacy at 6 months' follow-up, and safety in terms of adverse effects and changes in anti-Mullerian hormone level were assessed. By introducing multiple predictors obtained from multivariate analyses into a generalized estimating equation model, the results showed that the thickness of the subcutaneous fat layer in the anterior abdominal wall, peak enhancement of fibroid, time to peak of fibroid, and the ratio of area under the curve of fibroid to myometrium were statistically significant, except T2 signal intensity ratio of fibroid to myometrium, hence predicting an NPV ratio of at least 90%. No serious adverse effects and no significant difference between the anti-Mullerian hormone levels before or 6 months post-treatment were reported. The findings in this study suggest that the achievement of NPV ratio of at least 90% in magnetic resonance imaging-guided HIFU treatment of uterine fibroids based on prediction model appears clinically possible without compromising the safety of patients. Copyright © 2018 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.

Health implications of engineered nanomaterials

NASA Astrophysics Data System (ADS)

Pietroiusti, Antonio

2012-02-01

With the development of nanotechnology, a growing number of people are expected to be exposed to its products, the engineered nanomaterials (ENMs). Some physico-chemical properties of ENMs, linked to their size in the nanoscale (1-100 nm), make them potentially more reactive, and therefore raise concern about possible adverse effects in humans. In this article, I discuss human diseases which may be predicted after exposure to ENMs, and how their pathogenetic mechanisms may be linked to exposure; in this regard, special emphasis has been given to the triad of oxidative stress/inflammation/genotoxicity and to the interaction of ENMs/proteins in different biological compartments. The analysis of possible adverse effects has been made on an organ-by-organ basis, starting from the skin, respiratory system and gastrointestinal tract. These sites are in fact not only those exposed to the highest amounts of ENMs, but are also the portals of entry to internal organs for possible systemic effects. Although the list and the relevance of possible human disorders linked to ENM exposure are at least as impressive as that of their direct or indirect beneficial effects for human health, we must be clear that ENM-linked diseases belong to the realm of possible risk (i.e. cannot be excluded, but are unlikely), whereas ENMs with proven beneficial effects are on the market. Therefore, the mandatory awareness about possible adverse effects of ENMs should in no way be interpreted as a motivation to disregard the great opportunity represented by nanotechnology.

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

Clinical Errors and Medical Negligence

PubMed Central

Oyebode, Femi

2013-01-01

This paper discusses the definition, nature and origins of clinical errors including their prevention. The relationship between clinical errors and medical negligence is examined as are the characteristics of litigants and events that are the source of litigation. The pattern of malpractice claims in different specialties and settings is examined. Among hospitalized patients worldwide, 3–16s% suffer injury as a result of medical intervention, the most common being the adverse effects of drugs. The frequency of adverse drug effects appears superficially to be higher in intensive care units and emergency departments but once rates have been corrected for volume of patients, comorbidity of conditions and number of drugs prescribed, the difference is not significant. It is concluded that probably no more than 1 in 7 adverse events in medicine result in a malpractice claim and the factors that predict that a patient will resort to litigation include a prior poor relationship with the clinician and the feeling that the patient is not being kept informed. Methods for preventing clinical errors are still in their infancy. The most promising include new technologies such as electronic prescribing systems, diagnostic and clinical decision-making aids and error-resistant systems. PMID:23343656

Clinical errors and medical negligence.

PubMed

Oyebode, Femi

2013-01-01

This paper discusses the definition, nature and origins of clinical errors including their prevention. The relationship between clinical errors and medical negligence is examined as are the characteristics of litigants and events that are the source of litigation. The pattern of malpractice claims in different specialties and settings is examined. Among hospitalized patients worldwide, 3-16% suffer injury as a result of medical intervention, the most common being the adverse effects of drugs. The frequency of adverse drug effects appears superficially to be higher in intensive care units and emergency departments but once rates have been corrected for volume of patients, comorbidity of conditions and number of drugs prescribed, the difference is not significant. It is concluded that probably no more than 1 in 7 adverse events in medicine result in a malpractice claim and the factors that predict that a patient will resort to litigation include a prior poor relationship with the clinician and the feeling that the patient is not being kept informed. Methods for preventing clinical errors are still in their infancy. The most promising include new technologies such as electronic prescribing systems, diagnostic and clinical decision-making aids and error-resistant systems. Copyright © 2013 S. Karger AG, Basel.

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.

Childhood adversities predict strongly the use of psychotropic drugs in adulthood: a population-based cohort study of 24,284 Finns.

PubMed

Koskenvuo, Karoliina; Koskenvuo, Markku

2015-04-01

Exposure to adverse childhood experiences has been shown to be associated with negative health outcomes including mental health problems, but only a few studies with register-based data have used psychotropic drugs as an outcome variable. The purpose of this study is to examine whether adverse emotional childhood experiences, such as serious conflicts in the family and frequent fear of a family member, predict the use of psychotropic drugs in adulthood. In addition, the association of a child-parent relationship during childhood with the use of psychotropic drugs is studied. The participants of the population-based Health and Social Support Study (24,284 working aged Finns) were followed up for 9 years. The information on childhood experiences and child-parent relationships was obtained from the questionnaires in 1998 and 2003. The number of psychotropic purchases (antipsychotics, drugs for bipolar disorder, antidepressants, anxiolytics, hypnotics and sedatives) was obtained from the National-Drug-Prescription-Register. Logistic and multinomial regression models were used. A graded association between childhood adversities and the use of psychotropic drugs was found, even after adjustments for occupational training, work status, recent life events and health behaviour. Frequent fear of a family member showed the strongest association: the OR for multiple use of antidepressants was 3.08 (95% CI 2.72 to 3.49) and 2.69 (2.27 to 3.20) for multiple use of anxiolytics. Use of psychotropic drugs was clearly increased among those with poor child-parent relationship and multiple childhood adversities. The results highlight the effect of environmental factors during childhood on mental health and the need for early recognition of families at risk. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Fish early life stage: Developing AOPs to support targeted reduction and replacement

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 chronic toxicity outcomes (e.g., impacts on growth and survival). Development and characterization of adverse outcome pathways (AOPs) related...

Development of a Novel Quantitative Adverse Outcome Pathway Predictive Model for Lung Cancer

EPA Science Inventory

Traditional methods for carcinogenicity testing are resource-intensive, retrospective, and time consuming. An increasing testing burden has generated interest in the adverse outcome pathway (AOP) concept as a tool to evaluate chemical safety in a more efficient, rapid and effecti...

Integrating publicly-available data to generate computationally-predicted adverse outcome pathways for hepatic steatosis

EPA Science Inventory

The adverse outcome pathway (AOP) framework provides a way of organizing knowledge related to the key biological events that result in a particular health outcome. For the majority of environmental chemicals, the availability of curated pathways characterizing potential toxicity ...

The 5-Item Modified Frailty Index Is Predictive of 30-Day Postoperative Complications in Patients Undergoing Kyphoplasty Vertebral Augmentation.

PubMed

Segal, Dale N; Wilson, Jacob M; Staley, Christopher; Michael, Keith W

2018-05-03

Vertebral compression fractures are the most common spine injury seen in elderly patients. Vertebral augmentation is considered a safe and effective treatment. The ability to predict outcomes based on comorbidities is lacking. The modified frailty index has been used to predict complications after orthopedic and surgical procedures. We hypothesized that despite a low rate of adverse outcomes, postoperative complications after kyphoplasty would be greater in patients who are frail. The National Surgical Quality Improvement Program database was queried for patients who underwent kyphoplasty between 2006 and 2015. Complication data including 30-day complications, life-threatening complications, reoperation and readmission rate, and length of stay data was recorded, and 5-item modified frailty index (5i-mFI) scores were calculated. Univariate and multivariate logistic regression analyses were then conducted to analyze frailty as a predictor of postoperative complications after kyphoplasty. In total, 2465 patients were identified (mean age = 73.98). As 5i-mFI increased from 0 to ≥2, the rate of overall complications increased nearly 3-fold from 3.7% to 10.4% (P < 0.001) and the rate of life-threatening complications increased from 0.8% to 2.4% (P = 0.042). In addition, 30-day readmission increased from 8.9% to 12.9% (P = 0.005), adverse hospital discharge increased from 7.6% to 25.6% (P < 0.001), and length of stay increased from 1.66 days to 3.75 days (P < 0.001). Frailty was associated with increased total complications, Clavien-Dindo IV complications, length of stay, and 30-day readmission rates. The 5i-mFI is a straightforward assessment tool that correlates with outcomes after kyphoplasty. It can be used to help clinicians predict adverse events and facilitate informed discussions with their patients. Copyright © 2018 Elsevier Inc. All rights reserved.

Identifying the independent effect of HbA1c variability on adverse health outcomes in patients with Type 2 diabetes.

PubMed

Prentice, J C; Pizer, S D; Conlin, P R

2016-12-01

To characterize the relationship between HbA 1c variability and adverse health outcomes among US military veterans with Type 2 diabetes. This retrospective cohort study used Veterans Affairs and Medicare claims for veterans with Type 2 diabetes taking metformin who initiated a second diabetes medication (n = 50 861). The main exposure of interest was HbA 1c variability during a 3-year baseline period. HbA 1c variability, categorized into quartiles, was defined as standard deviation, coefficient of variation and adjusted standard deviation, which accounted for the number and mean number of days between HbA 1c tests. Cox proportional hazard models predicted mortality, hospitalization for ambulatory care-sensitive conditions, and myocardial infarction or stroke and were controlled for mean HbA 1c levels and the direction of change in HbA 1c levels during the baseline period. Over a mean 3.3 years of follow-up, all HbA 1c variability measures significantly predicted each outcome. Using the adjusted standard deviation measure for HbA 1c variability, the hazard ratios for the third and fourth quartile predicting mortality were 1.14 (95% CI 1.04, 1.25) and 1.42 (95% CI 1.28, 1.58), for myocardial infarction and stroke they were 1.25 (95% CI 1.10, 1.41) and 1.23 (95% CI 1.07, 1.42) and for ambulatory-care sensitive condition hospitalization they were 1.10 (95% CI 1.03, 1.18) and 1.11 (95% CI 1.03, 1.20). Higher baseline HbA 1c levels independently predicted the likelihood of each outcome. In veterans with Type 2 diabetes, greater HbA 1c variability was associated with an increased risk of adverse long-term outcomes, independently of HbA 1c levels and direction of change. Limiting HbA 1c fluctuations over time may reduce complications. © 2016 Diabetes UK.

Selection of nontarget arthropod taxa for field research on transgenic insecticidal crops: using empirical data and statistical power.

PubMed

Prasifka, J R; Hellmich, R L; Dively, G P; Higgins, L S; Dixon, P M; Duan, J J

2008-02-01

One of the possible adverse effects of transgenic insecticidal crops is the unintended decline in the abundance of nontarget arthropods. Field trials designed to evaluate potential nontarget effects can be more complex than expected because decisions to conduct field trials and the selection of taxa to include are not always guided by the results of laboratory tests. Also, recent studies emphasize the potential for indirect effects (adverse impacts to nontarget arthropods without feeding directly on plant tissues), which are difficult to predict because of interactions among nontarget arthropods, target pests, and transgenic crops. As a consequence, field studies may attempt to monitor expansive lists of arthropod taxa, making the design of such broad studies more difficult and reducing the likelihood of detecting any negative effects that might be present. To improve the taxonomic focus and statistical rigor of future studies, existing field data and corresponding power analysis may provide useful guidance. Analysis of control data from several nontarget field trials using repeated-measures designs suggests that while detection of small effects may require considerable increases in replication, there are taxa from different ecological roles that are sampled effectively using standard methods. The use of statistical power to guide selection of taxa for nontarget trials reflects scientists' inability to predict the complex interactions among arthropod taxa, particularly when laboratory trials fail to provide guidance on which groups are more likely to be affected. However, scientists still may exercise judgment, including taxa that are not included in or supported by power analyses.

Mediators and Moderators of the Relation Between Parental ADHD Symptomatology and the Early Development of Child ADHD and ODD Symptoms

PubMed Central

Breaux, Rosanna P.; Brown, Hallie R.; Harvey, Elizabeth A.

2016-01-01

The present study examined mediators and moderators of the relation between parental ADHD symptomatology and the development of child attention deficit/hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD) symptoms across the preschool years. Participants included 258 (138 boys) 3-year-old children (M = 44.13 months, SD = 3.39) with and without behavior problems and their parents who took part in a 3-year longitudinal study. Maternal ADHD symptoms predicted later ADHD symptoms in children, controlling for early child symptomatology. Both family history of ADHD and paternal comorbid psychopathology predicted later child ADHD and ODD symptoms, but they did not account for the association between maternal and child ADHD symptoms. Although paternal ADHD symptoms were associated with age 3 child ADHD symptoms, they did not significantly predict later child ADHD symptoms controlling for early symptomatology. Family adversity moderated the relation between maternal ADHD and child ADHD symptoms, such that the relation between maternal and child ADHD symptoms was stronger for families with less adversity. Maternal overreactive parenting mediated the relation between maternal ADHD symptoms and later child ADHD and ODD symptoms. Our findings suggest that targeting paternal comorbid psychopathology and maternal parenting holds promise for attenuating the effects of parental ADHD on children’s ADHD. PMID:27752934

Increased titres of anti-human heat shock protein 60 predict an adverse one year prognosis in patients with acute cardiac chest pain

PubMed Central

Birnie, D H; Vickers, L E; Hillis, W S; Norrie, J; Cobbe, S M

2005-01-01

Objective: To assess whether antibodies to human heat shock protein 60 (anti-huhsp60) or to mycobacterial heat shock protein 65 (anti-mhsp65) predict an adverse one year prognosis in patients admitted with acute cardiac chest pain. Design: Prospective observational study. Setting: Teaching hospital. Patients: 588 consecutive emergency admissions of patients with acute chest pain of suspected cardiac origin. Main outcome measures: Anti-huhsp60 and anti-mhsp65 titres were assayed on samples drawn on the morning after admission. The end points after discharge were coronary heart disease death, non-fatal myocardial infarction, coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, angiogram, or readmission with further cardiac ischaemic chest pain. Results: During follow up after discharge (mean of 304 days, range 1–788 days), 277 patients had at least one of the study outcomes. Patients with increased titres of anti-huhsp60 had an adverse prognosis (hazard ratio 1.56 (95% confidence interval 1.09 to 2.23) comparing highest versus lowest quartiles, p  =  0.015). Anti-mhsp65 titres were not predictive. Conclusions: Patients admitted with acute cardiac chest pain and increased titres of anti-huhsp60 had an adverse one year prognosis. PMID:16103543

Do adverse childhood experiences predict adult interpersonal difficulties? The role of emotion dysregulation.

PubMed

Poole, Julia C; Dobson, Keith S; Pusch, Dennis

2018-06-01

Adverse childhood experiences (ACEs) are risk factors for interpersonal difficulties in adulthood, however the mechanism that underlies this association is unknown. The current study investigated the association of a wide range of ACEs with interpersonal difficulties in adulthood, and tested whether emotion dysregulation mediated the relationship between ACEs and interpersonal difficulties. Patients over the age of 18 were recruited from primary care clinics (N = 4006). Participants completed self-report questionnaires that assessed ACEs, emotion dysregulation, and interpersonal difficulties. Results indicated that, after controlling for a range of demographic variables, each type of ACE significantly predicted increased interpersonal difficulties and that cumulative ACEs predicted increased interpersonal difficulties, F(8, 3137) = 39.68, p < .001, R 2  = 0.09. Further, emotion dysregulation mediated the association between ACEs and interpersonal difficulties, B = 0.79, SE = 0.09, 95% CI [0.64, 0.97]. These findings emphasize the role of childhood adversity on interpersonal functioning in adulthood, and highlight emotion dysregulation as a mechanism by which this association occurs. Results have the potential to inform preventative and treatment efforts to improve adaptive outcomes among individuals with a history of childhood adversity. Copyright © 2018 Elsevier Ltd. All rights reserved.

Sex Differences in the Contribution of Respiratory Sinus Arrhythmia and Trauma to Children's Psychopathology.

PubMed

Gray, Sarah A O; Theall, Katherine; Lipschutz, Rebecca; Drury, Stacy

2017-03-01

Respiratory sinus arrhythmia (RSA), a marker of parasympathetic activity, has been shown to moderate the relation between adversity and child behavioral outcomes; however, this work has been conducted in primarily Caucasian samples and limited in focus to family-level adversity. The current analysis extends the previous literature to examine the co-contribution of exposure to potentially traumatic events (PTEs), baseline RSA, and RSA withdrawal to internalizing and externalizing behavior in a sample of primarily African American youth ( n = 92) recruited using neighborhood mapping techniques from communities high in epidemiological indicators of adversity. Exposure to PTEs was associated with lower baseline RSA. Complex interactions were observed between sex of the child, baseline RSA and RSA withdrawal, and PTE exposure predicting to internalizing behaviors. Among girls with high (4+) levels of PTEs, high baseline RSA and RSA withdrawal predicted higher internalizing; for RSA withdrawal only, the inverse was observed for girls with low PTE exposure, for whom high RSA withdrawal predicted lower internalizing. No associations were observed from RSA to externalizing, or among boys to internalizing. Findings are consistent with distinct patterns among primarily African American samples and suggest the need for sex-specific conceptualizations of the link between environmental adversity, physiological reactivity, and internalizing behaviors.

Sex Differences in the Contribution of Respiratory Sinus Arrhythmia and Trauma to Children’s Psychopathology

PubMed Central

Gray, Sarah A. O.; Theall, Katherine; Lipschutz, Rebecca; Drury, Stacy

2016-01-01

Respiratory sinus arrhythmia (RSA), a marker of parasympathetic activity, has been shown to moderate the relation between adversity and child behavioral outcomes; however, this work has been conducted in primarily Caucasian samples and limited in focus to family-level adversity. The current analysis extends the previous literature to examine the co-contribution of exposure to potentially traumatic events (PTEs), baseline RSA, and RSA withdrawal to internalizing and externalizing behavior in a sample of primarily African American youth (n = 92) recruited using neighborhood mapping techniques from communities high in epidemiological indicators of adversity. Exposure to PTEs was associated with lower baseline RSA. Complex interactions were observed between sex of the child, baseline RSA and RSA withdrawal, and PTE exposure predicting to internalizing behaviors. Among girls with high (4+) levels of PTEs, high baseline RSA and RSA withdrawal predicted higher internalizing; for RSA withdrawal only, the inverse was observed for girls with low PTE exposure, for whom high RSA withdrawal predicted lower internalizing. No associations were observed from RSA to externalizing, or among boys to internalizing. Findings are consistent with distinct patterns among primarily African American samples and suggest the need for sex-specific conceptualizations of the link between environmental adversity, physiological reactivity, and internalizing behaviors. PMID:28479668

Early Elevations of the Complement Activation Fragment C3a and Adverse Pregnancy Outcomes

PubMed Central

Lynch, Anne M.; Gibbs, Ronald S.; Murphy, James R.; Giclas, Patricia C.; Salmon, Jane E.; Holers, V. Michael

2016-01-01

OBJECTIVE To estimate whether elevations of complement C3a early in pregnancy are predictive of the subsequent development of adverse pregnancy outcomes. METHODS A plasma sample was obtained from each enrolled pregnant woman before 20 weeks of gestation. The cohort (n=1,002) was evaluated for the development of adverse pregnancy outcomes defined as hypertensive diseases of pregnancy (gestational hypertension or preeclampsia), preterm birth (before 37 weeks of gestation), premature rupture of the membranes, pregnancy loss (during the embryonic and fetal period), intrauterine growth restriction, and the composite outcome of any adverse outcome. RESULTS One or more adverse pregnancy outcomes occurred in 211 (21%) of the cohort. The mean levels (ng/mL) of C3a in early pregnancy were significantly (P=<.001) higher among women with one or more adverse outcomes (858±435) compared with women with an uncomplicated pregnancy (741±407). Adjusted for parity and prepregnancy body mass index, women with levels of C3a in the upper quartile in early pregnancy were three times more likely to have an adverse outcome later in pregnancy compared with women in the lowest quartile (95% confidence interval, 1.8–4.8; P<.001). The link between early elevated C3a levels and adverse pregnancy outcomes was driven primarily by individual significant (P<.05) associations of C3a with hypertensive diseases of pregnancy, preterm birth, and premature rupture of the membranes. CONCLUSION Elevated C3a as early as the first trimester of pregnancy is an independent predictive factor for adverse pregnancy outcomes, suggesting that complement-related inflammatory events in pregnancy contribute to the subsequent development of poor outcomes at later stages of pregnancy. PMID:21173647

Adverse trajectories of mental health problems predict subsequent burnout and work-family conflict - a longitudinal study of employed women with children followed over 18 years.

PubMed

Nilsen, Wendy; Skipstein, Anni; Demerouti, Evangelia

2016-11-08

The long-term consequence of experiencing mental health problems may lead to several adverse outcomes. The current study aims to validate previous identified trajectories of mental health problems from 1993 to 2006 in women by examining their implications on subsequent work and family-related outcomes in 2011. Employed women (n = 439) with children were drawn from the Tracking Opportunities and Problems-Study (TOPP), a community-based longitudinal study following Norwegian families across 18 years. Previous identified latent profiles of mental health trajectories (i.e., High; Moderate; Low-rising and Low levels of mental health problems over time) measured at six time points between 1993 and 2006 were examined as predictors of burnout (e.g., exhaustion and disengagement from work) and work-family conflict in 2011 in univariate and multivariate analyses of variance adjusted for potential confounders (age, job demands, and negative emotionality). We found that having consistently High and Moderate symptoms as well as Low-Rising symptoms from 1993 to 2006 predicted higher levels of exhaustion, disengagement from work and work-family conflict in 2011. Findings remained unchanged when adjusting for several potential confounders, but when adjusting for current mental health problems only levels of exhaustion were predicted by the mental health trajectories. The study expands upon previous studies on the field by using a longer time span and by focusing on employed women with children who experience different patterns of mental health trajectories. The long-term effect of these trajectories highlight and validate the importance of early identification and prevention in women experiencing adverse patterns of mental health problems with regards to subsequent work and family-related outcomes.

Stem cell-derived models to improve mechanistic understanding and prediction of human drug-induced liver injury.

PubMed

Goldring, Christopher; Antoine, Daniel J; Bonner, Frank; Crozier, Jonathan; Denning, Chris; Fontana, Robert J; Hanley, Neil A; Hay, David C; Ingelman-Sundberg, Magnus; Juhila, Satu; Kitteringham, Neil; Silva-Lima, Beatriz; Norris, Alan; Pridgeon, Chris; Ross, James A; Young, Rowena Sison; Tagle, Danilo; Tornesi, Belen; van de Water, Bob; Weaver, Richard J; Zhang, Fang; Park, B Kevin

2017-02-01

Current preclinical drug testing does not predict some forms of adverse drug reactions in humans. Efforts at improving predictability of drug-induced tissue injury in humans include using stem cell technology to generate human cells for screening for adverse effects of drugs in humans. The advent of induced pluripotent stem cells means that it may ultimately be possible to develop personalized toxicology to determine interindividual susceptibility to adverse drug reactions. However, the complexity of idiosyncratic drug-induced liver injury means that no current single-cell model, whether of primary liver tissue origin, from liver cell lines, or derived from stem cells, adequately emulates what is believed to occur during human drug-induced liver injury. Nevertheless, a single-cell model of a human hepatocyte which emulates key features of a hepatocyte is likely to be valuable in assessing potential chemical risk; furthermore, understanding how to generate a relevant hepatocyte will also be critical to efforts to build complex multicellular models of the liver. Currently, hepatocyte-like cells differentiated from stem cells still fall short of recapitulating the full mature hepatocellular phenotype. Therefore, we convened a number of experts from the areas of preclinical and clinical hepatotoxicity and safety assessment, from industry, academia, and regulatory bodies, to specifically explore the application of stem cells in hepatotoxicity safety assessment and to make recommendations for the way forward. In this short review, we particularly discuss the importance of benchmarking stem cell-derived hepatocyte-like cells to their terminally differentiated human counterparts using defined phenotyping, to make sure the cells are relevant and comparable between labs, and outline why this process is essential before the cells are introduced into chemical safety assessment. (Hepatology 2017;65:710-721). © 2016 by the American Association for the Study of Liver Diseases.

Monoacylglycerol lipase (MGLL) polymorphism rs604300 interacts with childhood adversity to predict cannabis dependence symptoms and amygdala habituation: Evidence from an endocannabinoid system-level analysis

PubMed Central

Carey, Caitlin E.; Agrawal, Arpana; Zhang, Bo; Conley, Emily D.; Degenhardt, Louisa; Heath, Andrew C.; Li, Daofeng; Lynskey, Michael T.; Martin, Nicholas G.; Montgomery, Grant W.; Wang, Ting; Bierut, Laura J.; Hariri, Ahmad R.; Nelson, Elliot C.; Bogdan, Ryan

2015-01-01

Despite evidence for heritable variation in cannabis involvement and the discovery of cannabinoid receptors and their endogenous ligands, no consistent patterns have emerged from candidate endocannabinoid (eCB) genetic association studies of cannabis involvement. Given interactions between eCB and stress systems and associations between childhood stress and cannabis involvement, it may be important to consider childhood adversity in the context of eCB-related genetic variation. We employed a system-level gene-based analysis of data from the Comorbidity and Trauma Study (N = 1,558) to examine whether genetic variation in 6 eCB genes (anabolism: DAGLA, DAGLB, NAPEPLD, catabolism: MGLL, FAAH, binding: CNR1; SNPs N = 65) and childhood sexual abuse (CSA) predicts cannabis dependence symptoms. Significant interactions with CSA emerged for MGLL at the gene-level (p = .009), and for rs604300 within MGLL (ΔR2 = .007, p < .001), the latter of which survived SNP-level Bonferroni correction and was significant in an additional sample with similar directional effects (N = 859; ΔR2 = .005, p = .026). Furthermore, in a third sample (N = 312), there was evidence that rs604300 genotype interacts with early life adversity to predict threat-related basolateral amygdala habituation, a neural phenotype linked to the eCB system and addiction (ΔR2 = .013, p = .047). Rs604300 may be related to epigenetic modulation of MGLL expression. These results are consistent with rodent models implicating 2-arachidonoylglycerol (2-AG), an endogenous cannabinoid metabolized by the enzyme encoded by MGLL, in the etiology of stress adaptation related to cannabis dependence, but require further replication. PMID:26595473

Adverse childhood experiences predict earlier age of drinking onset: results from a representative US sample of current or former drinkers.

PubMed

Rothman, Emily F; Edwards, Erika M; Heeren, Timothy; Hingson, Ralph W

2008-08-01

Our goal was to determine whether adverse childhood experiences predicted the age at which drinking was initiated and drinking motives in a representative sample of current or former drinkers in the United States. In 2006, a probability sample of 3592 US current or former drinkers aged 18 to 39 were surveyed. Multinomial logistic regression examined whether each of 10 adverse childhood experiences was associated with earlier ages of drinking onset, controlling for demographics, parental alcohol use, parental attitudes toward drinking, and peers' drinking in adolescence. We also examined whether there was a graded relationship between the number of adverse childhood experiences and age of drinking onset and whether adverse childhood experiences were related to self-reported motives for drinking during the first year that respondents drank. Sixty-six percent of respondents reported >or=1 adverse childhood experiences, and 19% reported experiencing >or=4. The most commonly reported adverse childhood experiences were parental separation/divorce (41.3%), living with a household member who was a problem drinker (28.7%), mental illness of a household member (24.8%), and sexual abuse (19.1%). Of the 10 specific adverse childhood experiences assessed, 5 were significantly associated with initiating drinking at or=21 years of age) after adjustment for confounders, including physical abuse, sexual abuse, having a mentally ill household member, substance abuse in the home, and parental discord or divorce. Compared with those without adverse childhood experiences, respondents with adverse childhood experiences were substantially more likely to report that they drank to cope during the first year that they used alcohol. Results suggest that children with particular adverse childhood experiences may initiate drinking earlier than their peers and that they may be more likely to drink to cope with problems (rather than for pleasure or to be social).

Choosing the appropriate forecasting model for predictive parameter control.

PubMed

Aleti, Aldeida; Moser, Irene; Meedeniya, Indika; Grunske, Lars

2014-01-01

All commonly used stochastic optimisation algorithms have to be parameterised to perform effectively. Adaptive parameter control (APC) is an effective method used for this purpose. APC repeatedly adjusts parameter values during the optimisation process for optimal algorithm performance. The assignment of parameter values for a given iteration is based on previously measured performance. In recent research, time series prediction has been proposed as a method of projecting the probabilities to use for parameter value selection. In this work, we examine the suitability of a variety of prediction methods for the projection of future parameter performance based on previous data. All considered prediction methods have assumptions the time series data has to conform to for the prediction method to provide accurate projections. Looking specifically at parameters of evolutionary algorithms (EAs), we find that all standard EA parameters with the exception of population size conform largely to the assumptions made by the considered prediction methods. Evaluating the performance of these prediction methods, we find that linear regression provides the best results by a very small and statistically insignificant margin. Regardless of the prediction method, predictive parameter control outperforms state of the art parameter control methods when the performance data adheres to the assumptions made by the prediction method. When a parameter's performance data does not adhere to the assumptions made by the forecasting method, the use of prediction does not have a notable adverse impact on the algorithm's performance.

Understanding the inter-relationship between improved glycaemic control, hypoglycaemia and weight change within a long-term economic model.

PubMed

McEwan, P; Evans, M; Kan, H; Bergenheim, K

2010-05-01

Current guidelines for the management of type 2 diabetes advocate the attainment of sustained near normal glycaemia levels. Metformin is widely accepted as the treatment of choice for the initiation of pharmacotherapy; however, secondary failure of oral monotherapy occurs in 60% of patients resulting in the need for multiple pharmacotherapies. Therapy-related consequences of treatment, such as weight gain and hypoglycaemia impact on the cost-effectiveness profile of various agents. We therefore sought to ascertain the respective contribution of hypoglycaemia, weight change and improved blood glucose control on second-line therapy options added to metformin. This study uses a simulation model designed to evaluate the cost utility of new therapies in a population of patients with type 2 diabetes mellitus. Standard model outputs include incidence of micro- and macrovascular complications and diabetes-specific and all-cause mortality. The mean discounted quality-adjusted life year (QALY) predicted by the model was 12.31 years. Reducing Glycosylated haemoglobin (HbA1c) by 1% gave a predicted gain of 0.413 QALYs per patient. A 3-kg weight loss and 30% reduction in hypoglycaemia frequency produced a combined QALY gain of 0.355, whereas the reverse gave a QALY decrement of 0.356. The results of this analysis quantify the QALY decrement that may result from adverse therapy effects. The beneficial effects of improved glycaemic control on QALYs may be offset by characteristic treatment-specific adverse effects, such as weight gain and hypoglycaemia frequency.

Pathways Linking Adverse Childhood Experiences to Cigarette Smoking Among Young Black Men: a Prospective Analysis of the Role of Sleep Problems and Delayed Reward Discounting.

PubMed

Oshri, Assaf; Kogan, Steven; Liu, Sihong; Sweet, Lawrence; Mackillop, James

2017-12-01

African American men experience increases in smoking during the young adult transition. Exposure to childhood adversity, a risk factor which disproportionately affects African American men, has been identified as a robust precursor to health risk behavior in general and cigarette smoking in particular. The intermediate mechanisms that transmit the influence of early adversity to smoking behavior are not well understood. We tested a model of the escalation of smoking behaviors among young adult African American men, investigating sleep disturbance and delayed reward discounting as intermediate factors linking adverse childhood experiences with smoking. Hypotheses were tested with three waves of data (M age-T1  = 20.34, M age-T2  = 21.92, M age-T3  = 23.02) from 505 African American men living in rural counties in South Georgia. Men provided self-report data on their adverse childhood experiences, sleep problems, and smoking behavior using audio-assisted computer self-interviews. Men also completed a computer-based delayed reward discounting task. Structural equation modeling analyses supported our hypotheses: Adverse childhood experiences predicted poor sleep adequacy, which forecast increases in delayed reward discounting; discounting, in turn, predicted increased smoking. Significant indirect pathways were detected linking adversity to discounting via sleep adequacy and linking sleep adequacy to smoking via discounting. Prevention and intervention researchers can draw on these findings to develop programs that focus on sleep adequacy to reduce smoking in African American men exposed to childhood adversity.

The Influence of Childhood Adversity on Rural Black Men's Sexual Risk Behavior.

PubMed

Kogan, Steven M; Cho, Junhan; Oshri, Assaf

2016-12-01

Young Black men living in resource-poor rural environments are disproportionately affected by both adverse childhood experiences and HIV/STIs. The influence of childhood adversity on sexual risk behavior remains to be examined among this vulnerable population. In this study, we investigated the influence of overall adversity as well as three subcomponents, abusive parenting, parental neglect, and witnessing family violence, on men's engagement in sexual risk behavior. We hypothesized that adverse experiences would predict engagement in sexual risk behaviors including multiple sexual partnerships, inconsistent condom use, frequent sexual activity, and concurrent substance abuse and sexual activity. We tested formally the extent to which defensive relational schemas mediated these associations. Hypotheses were tested with data from 505 rural Black men (M age = 20.29, SD = 1.10) participating in the African American Men's Health Project. Participants were recruited using respondent-driven sampling. Self-report data were gathered from participants via audio computer-assisted self-interviews. Bi-factor analyses revealed that, in addition to a common adversity factor, neglect independently predicted sexual risk behavior. Men's defensive relational schemas partially mediated the influence of the common adversity factor as well as the neglect subcomponent on sexual risk behavior. The present research identified a potential risk factor for sexual risk behavior in an understudied and vulnerable population. Adverse childhood experiences in general, and neglect in particular, may place many young Black men at risk for engaging in sexual risk behavior due in part to the influence of these experiences on men's development of relational schemas characterized by defensiveness and mistrust.

Resistance Predictions for a High-Speed Sealift Trimaran

DTIC Science & Technology

2007-10-01

layout and operability, rather than de- sults for both the absolute value and the relative tails of resistance and structural strength. The pre- change...interferences between the circumstances, the sidehulls may be referred to as sidehulls and the centerhull, which can create an outriggers , adverse effect (that...uration 4 and Configuration 5; as a result, an exces- .. sive amount of spray impacted on the bridging cross structure connecting the three subhulls

Quantitative systems toxicology

PubMed Central

Bloomingdale, Peter; Housand, Conrad; Apgar, Joshua F.; Millard, Bjorn L.; Mager, Donald E.; Burke, John M.; Shah, Dhaval K.

2017-01-01

The overarching goal of modern drug development is to optimize therapeutic benefits while minimizing adverse effects. However, inadequate efficacy and safety concerns remain to be the major causes of drug attrition in clinical development. For the past 80 years, toxicity testing has consisted of evaluating the adverse effects of drugs in animals to predict human health risks. The U.S. Environmental Protection Agency recognized the need to develop innovative toxicity testing strategies and asked the National Research Council to develop a long-range vision and strategy for toxicity testing in the 21st century. The vision aims to reduce the use of animals and drug development costs through the integration of computational modeling and in vitro experimental methods that evaluates the perturbation of toxicity-related pathways. Towards this vision, collaborative quantitative systems pharmacology and toxicology modeling endeavors (QSP/QST) have been initiated amongst numerous organizations worldwide. In this article, we discuss how quantitative structure-activity relationship (QSAR), network-based, and pharmacokinetic/pharmacodynamic modeling approaches can be integrated into the framework of QST models. Additionally, we review the application of QST models to predict cardiotoxicity and hepatotoxicity of drugs throughout their development. Cell and organ specific QST models are likely to become an essential component of modern toxicity testing, and provides a solid foundation towards determining individualized therapeutic windows to improve patient safety. PMID:29308440

Surgical Adverse Events, Risk Management, and Malpractice Outcome: Morbidity and Mortality Review Is Not Enough

PubMed Central

Morris, John A.; Carrillo, Ysela; Jenkins, Judith M.; Smith, Philip W.; Bledsoe, Sandy; Pichert, James; White, Andrew

2003-01-01

Objective To review all admissions (age > 13) to three surgical patient care centers at a single academic medical center between January 1, 1995, and December 6, 1999, for significant surgical adverse events. Summary Background Data Little data exist on the interrelationships between surgical adverse events, risk management, malpractice claims, and resulting indemnity payments to plaintiffs. The authors hypothesized that examination of this process would identify performance improvement opportunities overlooked by standard medical peer review; the risk of litigation would be constant across the three homogeneous patient care centers; and the risk management process would exceed the performance improvement process. Methods Data collected included patient demographics (age, gender, and employment status), hospital financials (hospital charges, costs, and financial class), and outcome. Outcome categories were medical (disability: <1 month, 1–6 months, permanent/death), legal (no legal action, settlement, summary judgment), financial (indemnity payments, legal fees, write-offs), and cause and effect analysis. Cause and effect analysis attempts to identify system failures contributing to adverse outcomes. This was determined by two independent analysts using the 17 Harvard criteria and subdividing these into subsystem causative factors. Results The study group consisted of 130 patients with surgical adverse events resulting in total liabilities of $8.2 million. The incidence of adverse events per 1,000 admissions across the three patient care centers was similar, but indemnity payments per 1,000 admissions varied (cardiothoracic = $30, women’s health = $90, trauma = $520). Patient demographics were not predictive of high-risk subgroups for adverse events or litigation. In terms of medical outcome, 51 patients had permanent disability or death, accounting for 98% of the indemnity payments. In terms of legal outcome, 103 patients received no indemnity payments, 15 patients received indemnity payments, four suits remain open, and in eight cases charges were written off ($0.121 million). To date, no cases have been adjudicated in court. Cause and effect analysis identified 390 system failures contributing to the adverse events (mean 3.0 failures per adverse event); there were 4.7 failures per adverse event in the 15 indemnity cases. Five categories of causes accounted for 75% of the failures (patient management, n = 104; communication, n = 89; administration, n = 33; documentation, n = 32; behavior, n = 23). The current medical review process would have identified 104 of 390 systems failures (37%). Conclusions This study demonstrates no rational link between the tort system and the reduction of adverse events. Sixty-three percent of contributing causes to adverse events were undetected by current medical review processes. Adverse events occur at the interface between different systems or disciplines and result from multiple failures. Indemnity costs per hospital day vary dramatically by patient care center (range $3.60–97.60 a day). The regionalization of healthcare is in jeopardy from the burden of high indemnity payments. PMID:12796581

Practices to identify and preclude adverse Aircraft-and-Rotorcraft-Pilot Couplings - A design perspective

NASA Astrophysics Data System (ADS)

Pavel, Marilena D.; Masarati, Pierangelo; Gennaretti, Massimo; Jump, Michael; Zaichik, Larisa; Dang-Vu, Binh; Lu, Linghai; Yilmaz, Deniz; Quaranta, Giuseppe; Ionita, Achim; Serafini, Jacopo

2015-07-01

Understanding, predicting and supressing the inadvertent aircraft oscillations caused by Aircraft/Rotorcraft Pilot Couplings (A/RPC) is a challenging problem for designers. These are potential instabilities that arise from the effort of controlling aircraft with high response actuation systems. The present paper reviews, updates and discusses desirable practices to be used during the design process for unmasking A/RPC phenomena. These practices are stemming from the European Commission project ARISTOTEL Aircraft and Rotorcraft Pilot Couplings - Tools and Techniques for Alleviation and Detection (2010-2013) and are mainly related to aerodynamic and structural modelling of the aircraft/rotorcraft, pilot modelling and A/RPC prediction criteria. The paper proposes new methodologies for precluding adverse A/RPCs events taking into account the aeroelasticity of the structure and pilot biodynamic interaction. It is demonstrated that high-frequency accelerations due to structural elasticity cause negative effects on pilot control, since they lead to involuntary body and limb-manipulator system displacements and interfere with pilot's deliberate control activity (biodynamic interaction) and, finally, worsen handling quality ratings.

Significance of the DNA-Histone Complex Level as a Predictor of Major Adverse Cardiovascular Events in Hemodialysis Patients: The Effect of Uremic Toxin on DNA-Histone Complex Formation.

PubMed

Jeong, Jong Cheol; Kim, Ji-Eun; Gu, Ja-Yoon; Yoo, Hyun Ju; Ryu, Ji Won; Kim, Dong Ki; Joo, Kwon Wook; Kim, Hyun Kyung

2016-01-01

Neutrophils can release the DNA-histone complex into circulation following exposure to inflammatory stimuli. This prospective study investigated whether the DNA-histone complex and other biomarkers could predict major cardiovascular adverse events (MACEs) in hemodialysis (HD) patients. The levels of circulating DNA-histone complexes, cell-free DNA, interleukin (IL)-6, and neutrophil elastase were measured in 60 HD patients and 28 healthy controls. MACE was assessed at 24 months. Uremic toxin-induced neutrophil released contents were measured in vitro. Compared with controls, HD patients showed higher levels of DNA-histone complexes and IL-6. The DNA-histone complex level was inversely associated with the Kt/V. In a multivariable Cox analysis, the high level of DNA-histone complexes was a significant independent predictor of MACE. The uremic toxins induced DNA-histone complex formation in normal neutrophils in vitro. The DNA-histone complex is a potentially useful marker to predict MACE in HD patients. Uremic toxins induced DNA-histone complex formation in vitro. © 2015 S. Karger AG, Basel.

Effects of spray drift of glyphosate on nontarget terrestrial plants-A critical review.

PubMed

Cederlund, Harald

2017-11-01

Glyphosate is a widely used broad-spectrum postemergent herbicide used for weed control in both agricultural and nonagricultural settings. Spray drift of glyphosate can pose a risk to nontarget terrestrial plants and plant communities outside the intended area of application, but the lack of a well-established predicted-no-effect drift rate makes properly assessing such risk difficult. For this reason, a literature review and meta-analysis was carried out with the aim to determine the level of drift that is likely to cause harm to plants and to explore what spray-reducing targets would be sufficiently protective. No-observed-adverse effect rates, lowest-observed-adverse effect rates, and effect rates giving 10, 25, and 50% effects were extracted from a total of 39 different publications. The data were combined per species, and species sensitivity distributions were constructed and fitted with a log-logistic model to assess protectiveness. No systematic differences were detected between the responses of monocotyledons or dicotyledons, but wild plants were found to be generally less sensitive to glyphosate drift than domesticated plants. The results indicate that restricting spray drift to a level below 5 g a.e./ha would protect approximately 95% of all higher plant species against minor adverse effects of glyphosate drift and that rates below 1 to 2 g a.e./ha would be almost completely protective. No studies were encountered that evaluated effects of spray drift against nonvascular plants, and therefore, the conclusions are only valid for vascular plants. Environ Toxicol Chem 2017;36:2879-2886. © 2017 SETAC. © 2017 SETAC.

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...

Evaluation of safety in clinical use of generic paclitaxel [NK] for injection.

PubMed

Tsukiyama, Ikuto; Hotta, Kazuo; Takeuchi, Masayuki; Onishi, Masahumi; Toyama, Yukio; Saito, Hiroko; Sai, Yoshimichi; Miyamoto, Ken-Ichi; Hasegawa, Takaaki

2012-04-01

The introduction of generic drugs is a favored strategy in reducing medical costs, but some clinicians are often reluctant to use them because of lack of information with regard to their side effects. Generic paclitaxel [NK] differs from the proprietary version, Taxol®, in containing added citric acid and a more pure form of castor oil. However, little information exists regarding the effects of these additives on adverse events such as vascular pain, phlebitis, hypersensitivity and hepatic dysfunction. To compensate for this lack of information and to validate the safety of using generic paclitaxel, we investigated adverse events in response to generic paclitaxel [NK]. Our investigation focused on patients treated with both the proprietary formulation (Taxol® for injection) and the generic version(paclitaxel [NK] for injection)sequentially from April 2008 to March 2009. Adverse events were investigated retrospectively. Incidence of vascular pain, phlebitis and hypersensitivity was similar to that with the original product. Although the expression of some liver enzymes was slightly increased and some gastrointestinal events were reduced following generic paclitaxel [NK] treatment there was no statistically significant difference. The profiles of other adverse events were not significantly different. Increased vascular pain and phlebitis, predicted due to low pH conditions caused by citric acid, were not observed. Similarly, the pure castor oil included in generic paclitaxel [NK] did not influence hypersensitivity and hepatic function. We found no significant differences in our study of proprietary and generic paclitaxel [NK]. Thus, clinicians have no reason for prejudice against using generic paclitaxel [NK] on the basis of increased risk of side effects.

Setting the stage for chronic health problems: cumulative childhood adversity among homeless adults with mental illness in Vancouver, British Columbia.

PubMed

Patterson, Michelle L; Moniruzzaman, Akm; Somers, Julian M

2014-04-12

It is well documented that childhood abuse, neglect and household dysfunction are disproportionately present in the backgrounds of homeless adults, and that these experiences adversely impact child development and a wide range of adult outcomes. However, few studies have examined the cumulative impact of adverse childhood experiences on homeless adults with mental illness. This study examines adverse events in childhood as predictors of duration of homelessness, psychiatric and substance use disorders, and physical health in a sample of homeless adults with mental illness. This study was conducted using baseline data from a randomized controlled trial in Vancouver, British Columbia for participants who completed the Adverse Childhood Experiences (ACE) scale at 18 months follow-up (n=364). Primary outcomes included current mental disorders; substance use including type, frequency and severity; physical health; duration of homelessness; and vocational functioning. In multivariable regression models, ACE total score independently predicted a range of mental health, physical health, and substance use problems, and marginally predicted duration of homelessness. Adverse childhood experiences are overrepresented among homeless adults with complex comorbidities and chronic homelessness. Our findings are consistent with a growing body of literature indicating that childhood traumas are potent risk factors for a number of adult health and psychiatric problems, particularly substance use problems. Results are discussed in the context of cumulative adversity and self-trauma theory. This trial has been registered with the International Standard Randomized Control Trial Number Register and assigned ISRCTN42520374.

Cumulative contextual risk at birth in relation to adolescent substance use, conduct problems, and risky sex: General and specific predictive associations in a Finnish birth cohort.

PubMed

Mason, W Alex; January, Stacy-Ann A; Chmelka, Mary B; Parra, Gilbert R; Savolainen, Jukka; Miettunen, Jouko; Järvelin, Marjo-Riitta; Taanila, Anja; Moilanen, Irma

2016-07-01

Research indicates that risk factors cluster in the most vulnerable youth, increasing their susceptibility for adverse developmental outcomes. However, most studies of cumulative risk are cross-sectional or short-term longitudinal, and have been based on data from the United States or the United Kingdom. Using data from the Northern Finland Birth Cohort 1986 Study (NFBC1986), we examined cumulative contextual risk (CCR) at birth as a predictor of adolescent substance use and co-occurring conduct problems and risky sex to determine the degree to which CCR predicts specific outcomes over-and-above its effect on general problem behavior, while testing for moderation of associations by gender. Analyses of survey data from 6963 participants of the NFBC1986 followed from the prenatal/birth period into adolescence were conducted using structural equation modeling. CCR had long-term positive associations with first-order substance use, conduct problems, and risky sex factors, and, in a separate analysis, with a second-order general problem behavior factor. Further analyses showed that there was a positive specific effect of CCR on risky sex, over-and-above general problem behavior, for girls only. This study, conducted within the Finnish context, showed that CCR at birth had long-term general and specific predictive associations with substance use and co-occurring problem behaviors in adolescence; effects on risky sex were stronger for girls. Results are consistent with the hypothesis that early exposure to CCR can have lasting adverse consequences, suggesting the need for early identification and intervention efforts for vulnerable children. Copyright © 2016 Elsevier Ltd. All rights reserved.

Enhancing the fathead minnow fish embryo toxicity test: Optimizing embryo production and assessing the utility of additional test endpoints.

PubMed

Roush, Kyle S; Krzykwa, Julie C; Malmquist, Jacob A; Stephens, Dane A; Sellin Jeffries, Marlo K

2018-05-30

The fathead minnow fish embryo toxicity (FET) test has been identified as a potential alternative to toxicity test methods that utilize older fish. However, several challenges have been identified with the fathead minnow FET test, including: 1) difficulties in obtaining appropriately-staged embryos for FET test initiation, 2) a paucity of data comparing fathead minnow FET test performance to the fathead minnow larval growth and survival (LGS) test and 3) a lack of sublethal endpoints that could be used to estimate chronic toxicity and/or predict adverse effects. These challenges were addressed through three study objectives. The first objective was to optimize embryo production by assessing the effect of breeding group composition (number of males and females) on egg production. Results showed that groups containing one male and four females produced the largest clutches, enhancing the likelihood of procuring sufficient numbers of embryos for FET test initiation. The second study objective was to compare the performance of the FET test to that of the fathead minnow LGS test using three reference toxicants. The FET and LGS tests were similar in their ability to predict the acute toxicity of sodium chloride and ethanol, but the FET test was found to be more sensitive than the LGS test for sodium dodecyl sulfate. The last objective of the study was to evaluate the utility and practicality of several sublethal metrics (i.e., growth, developmental abnormalities and growth- and stress-related gene expression) as FET test endpoints. Developmental abnormalities, including pericardial edema and hatch success, were found to offer the most promise as additional FET test endpoints, given their responsiveness, potential for predicting adverse effects, ease of assessment and low cost of measurement. Copyright © 2018 Elsevier Inc. All rights reserved.

Predicting sugar consumption: Application of an integrated dual-process, dual-phase model.

PubMed

Hagger, Martin S; Trost, Nadine; Keech, Jacob J; Chan, Derwin K C; Hamilton, Kyra

2017-09-01

Excess consumption of added dietary sugars is related to multiple metabolic problems and adverse health conditions. Identifying the modifiable social cognitive and motivational constructs that predict sugar consumption is important to inform behavioral interventions aimed at reducing sugar intake. We tested the efficacy of an integrated dual-process, dual-phase model derived from multiple theories to predict sugar consumption. Using a prospective design, university students (N = 90) completed initial measures of the reflective (autonomous and controlled motivation, intentions, attitudes, subjective norm, perceived behavioral control), impulsive (implicit attitudes), volitional (action and coping planning), and behavioral (past sugar consumption) components of the proposed model. Self-reported sugar consumption was measured two weeks later. A structural equation model revealed that intentions, implicit attitudes, and, indirectly, autonomous motivation to reduce sugar consumption had small, significant effects on sugar consumption. Attitudes, subjective norm, and, indirectly, autonomous motivation to reduce sugar consumption predicted intentions. There were no effects of the planning constructs. Model effects were independent of the effects of past sugar consumption. The model identified the relative contribution of reflective and impulsive components in predicting sugar consumption. Given the prominent role of the impulsive component, interventions that assist individuals in managing cues-to-action and behavioral monitoring are likely to be effective in regulating sugar consumption. Copyright © 2017 Elsevier Ltd. All rights reserved.

Simultaneous measurement of cerebral hemoglobin oxygen saturation and blood volume in asphyxiated neonates by near-infrared time-resolved spectroscopy.

PubMed

Nakamura, Shinji; Koyano, Kosuke; Jinnai, Wataru; Hamano, Satoshi; Yasuda, Saneyuki; Konishi, Yukihiko; Kuboi, Toru; Kanenishi, Kenji; Nishida, Tomoko; Kusaka, Takashi

2015-11-01

Hypoxic-ischemic encephalopathy (HIE) usually results in a poor clinical outcome even when treated with hypothermic therapy (HT). Early postnatal changes in cerebral blood oxygenation and hemodynamics may be critical determinants of brain injury and the efficacy of HT. We measured cerebral hemoglobin oxygen saturation (ScO2) and cerebral blood volume (CBV) by near-infrared time-resolved spectroscopy (TRS) in HT-treated and non-HT-treated neonatal HIE patients to assess the influence of these parameters on clinical outcome. We retrospectively compared ScO2, CBV, and clinical outcomes of 11 neonates with HIE: 5 were treated by HT (HT-treated; 33.5°C±0.5°C for 72h starting approximately 6h after delivery) and 6 were not (non-HT-treated). Both CBV and ScO2 were measured by TRS at 6, 24, 48, and 72h after birth. Magnetic resonance imaging (MRI) was performed 1-2weeks after birth to assess brain injury. Five neonates had adverse outcomes (3 HT-treated, 2 non-HT-treated). Of these, 1 died within 3days of birth and 4 had abnormal MRI findings, including basal ganglia, white matter, and/or thalamic lesions. The other 6 neonates had normal MRI findings (favorable outcome). At 6h after birth, CBV was significantly higher in neonates with adverse outcomes compared with those with a favorable outcome. At 24h after birth, ScO2 was significantly higher in neonates with adverse outcomes. Furthermore, we found that combined CBV at 24h after birth plus ScO2 had the best predictive ability for neurological outcome: sensitivity, specificity, positive predictive value, and negative predictive value were all 100%. Early postnatal CBV and ScO2 elevations were predictive of a poor outcome in HIE. Therefore, measuring combined CBV plus ScO2 at 24h after birth can allow more precise prediction of neurological outcome. Control of postnatal CBV and ScO2 is critical for effective HIE treatment. Copyright © 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Randomized, controlled trial of TNF-α antagonist in CTL-mediated severe cutaneous adverse reactions.

PubMed

Wang, Chuang-Wei; Yang, Lan-Yan; Chen, Chun-Bing; Ho, Hsin-Chun; Hung, Shuen-Iu; Yang, Chih-Hsun; Chang, Chee-Jen; Su, Shih-Chi; Hui, Rosaline Chung-Yee; Chin, See-Wen; Huang, Li-Fang; Lin, Yang Yu-Wei; Chang, Wei-Yang; Fan, Wen-Lang; Yang, Chin-Yi; Ho, Ji-Chen; Chang, Ya-Ching; Lu, Chun-Wei; Chung, Wen-Hung

2018-03-01

Cytotoxic T lymphocyte-mediated (CTL-mediated) severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), are rare but life-threatening adverse reactions commonly induced by drugs. Although high levels of CTL-associated cytokines, chemokines, or cytotoxic proteins, including TNF-α and granulysin, were observed in SJS-TEN patients in recent studies, the optimal treatment for these diseases remains controversial. We aimed to evaluate the efficacy, safety, and therapeutic mechanism of a TNF-α antagonist in CTL-mediated SCARs. We enrolled 96 patients with SJS-TEN in a randomized trial to compare the effects of the TNF-α antagonist etanercept versus traditional corticosteroids. Etanercept improved clinical outcomes in patients with SJS-TEN. Etanercept decreased the SCORTEN-based predicted mortality rate (predicted and observed rates, 17.7% and 8.3%, respectively). Compared with corticosteroids, etanercept further reduced the skin-healing time in moderate-to-severe SJS-TEN patients (median time for skin healing was 14 and 19 days for etanercept and corticosteroids, respectively; P = 0.010), with a lower incidence of gastrointestinal hemorrhage in all SJS-TEN patients (2.6% for etanercept and 18.2% for corticosteroids; P = 0.03). In the therapeutic mechanism study, etanercept decreased the TNF-α and granulysin secretions in blister fluids and plasma (45.7%-62.5% decrease after treatment; all P < 0.05) and increased the Treg population (2-fold percentage increase after treatment; P = 0.002), which was related to mortality in severe SJS-TEN. The anti-TNF-α biologic agent etanercept serves as an effective alternative for the treatment of CTL-mediated SCARs. ClinicalTrials.gov NCT01276314. Ministry of Science and Technology of Taiwan.

Randomized, controlled trial of TNF-α antagonist in CTL-mediated severe cutaneous adverse reactions

PubMed Central

Wang, Chuang-Wei; Yang, Lan-Yan; Ho, Hsin-Chun; Hung, Shuen-Iu; Yang, Chih-Hsun; Chang, Chee-Jen; Su, Shih-Chi; Hui, Rosaline Chung-Yee; Chin, See-Wen; Huang, Li-Fang; Lin, Yang Yu-Wei; Chang, Wei-Yang; Fan, Wen-Lang; Yang, Chin-Yi; Ho, Ji-Chen; Chung, Wen-Hung

2018-01-01

BACKGROUND. Cytotoxic T lymphocyte–mediated (CTL-mediated) severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), are rare but life-threatening adverse reactions commonly induced by drugs. Although high levels of CTL-associated cytokines, chemokines, or cytotoxic proteins, including TNF-α and granulysin, were observed in SJS-TEN patients in recent studies, the optimal treatment for these diseases remains controversial. We aimed to evaluate the efficacy, safety, and therapeutic mechanism of a TNF-α antagonist in CTL-mediated SCARs. METHODS. We enrolled 96 patients with SJS-TEN in a randomized trial to compare the effects of the TNF-α antagonist etanercept versus traditional corticosteroids. RESULTS. Etanercept improved clinical outcomes in patients with SJS-TEN. Etanercept decreased the SCORTEN-based predicted mortality rate (predicted and observed rates, 17.7% and 8.3%, respectively). Compared with corticosteroids, etanercept further reduced the skin-healing time in moderate-to-severe SJS-TEN patients (median time for skin healing was 14 and 19 days for etanercept and corticosteroids, respectively; P = 0.010), with a lower incidence of gastrointestinal hemorrhage in all SJS-TEN patients (2.6% for etanercept and 18.2% for corticosteroids; P = 0.03). In the therapeutic mechanism study, etanercept decreased the TNF-α and granulysin secretions in blister fluids and plasma (45.7%–62.5% decrease after treatment; all P < 0.05) and increased the Treg population (2-fold percentage increase after treatment; P = 0.002), which was related to mortality in severe SJS-TEN. CONCLUSIONS. The anti–TNF-α biologic agent etanercept serves as an effective alternative for the treatment of CTL-mediated SCARs. TRIAL REGISTRATION. ClinicalTrials.gov NCT01276314. FUNDING. Ministry of Science and Technology of Taiwan. PMID:29400697

Adverse morphological development in embryonic zebrafish exposed to environmental concentrations of contaminants individually and in mixture.

PubMed

Kinch, Cassandra D; Kurrasch, Deborah M; Habibi, Hamid R

2016-06-01

Exposure to environmental contaminants has been linked to developmental and reproductive abnormalities leading to infertility, spontaneous abortion, reduced number of offspring, and metabolic disorders. In addition, there is evidence linking environmental contaminants and endocrine disruption to abnormal developmental rate, defects in heart and eye morphology, and alterations in behavior. Notably, these effects could not be explained by interaction with a single hormone receptor. Here, using a whole-organism approach, we investigated morphological changes to developing zebrafish caused by exposure to a number of environmental contaminants, including bisphenol A (BPA), di(2-ethylhexyl)phthalate (DEHP), nonylphenol, and fucosterol at concentrations measured in a local water body (Oldman River, AB), individually and in mixture. Exposure to nanomolar contaminant concentrations resulted in abnormal morphological development, including changes to body length, pericardia (heart), and the head. We also characterize the spatiotemporal expression profiles of estrogen, androgen, and thyroid hormone receptors to demonstrate that localization of these receptors might be mediating contaminant effects on development. Finally, we examined the effects of contaminants singly and in mixture. Combined, our results support the hypothesis that adverse effects of contaminants are not mediated by single hormone receptor signaling, and adversity of contaminants in mixture could not be predicted by simple additive effect of contaminants. The findings provide a framework for better understanding of developmental toxicity of environmental contaminants in zebrafish and other vertebrate species. Copyright © 2016 Elsevier B.V. All rights reserved.

Failure or success of search strategies to identify adverse effects of medical devices: a feasibility study using a systematic review.

PubMed

Golder, Su; Wright, Kath; Rodgers, Mark

2014-10-13

Research has indicated that adverse effects terms are increasingly prevalent in the title, abstract or indexing terms of articles that contain adverse drug effects data in MEDLINE and Embase. However, it is unknown whether adverse effects terms are present in the database records of articles that contain adverse effects data of medical devices, and thus, to what extent the development of an adverse effects search filter for medical devices may be feasible. A case study systematic review of a medical device was selected. The included studies from a systematic review of the safety of recombinant human bone morphogenetic protein-2 (rhBMP-2) for spinal fusion were used in the analysis. For each included study, the corresponding database record on MEDLINE and Embase was assessed to measure the presence or absence of adverse effects terms in the title, abstract or indexing. The performance of each potential adverse effects search term was also measured and compared. There were 82 publications (49 studies) included in the systematic review with 51 of these indexed on MEDLINE and 55 on Embase. Ninety-four percent (48/51) of the records on MEDLINE and 95% (52/55) of the records on Embase contained at least one adverse effects related search term. The wide variety of adverse effects terms included in the title, abstract or indexing of bibliographic records, and the lack of any individual high-performing search terms suggests that a combination of terms in different fields is required to identify adverse effects of medical devices. In addition, the most successful search terms differed from the most successful terms for identifying adverse drug effects. The search filters currently available for adverse drug effects are not necessarily useful for searching adverse effects data of medical devices. The presence of adverse effects terms in the bibliographic records of articles on medical devices, however, indicates that combinations of adverse effects search terms may be useful in search strategies in MEDLINE and Embase. The results, therefore, suggest that not only a search filter for the adverse effects of medical devices is feasible, but also that it should be a research priority.

Are adverse effects incorporated in economic models? An initial review of current practice.

PubMed

Craig, D; McDaid, C; Fonseca, T; Stock, C; Duffy, S; Woolacott, N

2009-12-01

To identify methodological research on the incorporation of adverse effects in economic models and to review current practice. Major electronic databases (Cochrane Methodology Register, Health Economic Evaluations Database, NHS Economic Evaluation Database, EconLit, EMBASE, Health Management Information Consortium, IDEAS, MEDLINE and Science Citation Index) were searched from inception to September 2007. Health technology assessment (HTA) reports commissioned by the National Institute for Health Research (NIHR) HTA programme and published between 2004 and 2007 were also reviewed. The reviews of methodological research on the inclusion of adverse effects in decision models and of current practice were carried out according to standard methods. Data were summarised in a narrative synthesis. Of the 719 potentially relevant references in the methodological research review, five met the inclusion criteria; however, they contained little information of direct relevance to the incorporation of adverse effects in models. Of the 194 HTA monographs published from 2004 to 2007, 80 were reviewed, covering a range of research and therapeutic areas. In total, 85% of the reports included adverse effects in the clinical effectiveness review and 54% of the decision models included adverse effects in the model; 49% included adverse effects in the clinical review and model. The link between adverse effects in the clinical review and model was generally weak; only 3/80 (< 4%) used the results of a meta-analysis from the systematic review of clinical effectiveness and none used only data from the review without further manipulation. Of the models including adverse effects, 67% used a clinical adverse effects parameter, 79% used a cost of adverse effects parameter, 86% used one of these and 60% used both. Most models (83%) used utilities, but only two (2.5%) used solely utilities to incorporate adverse effects and were explicit that the utility captured relevant adverse effects; 53% of those models that included utilities derived them from patients on treatment and could therefore be interpreted as capturing adverse effects. In total, 30% of the models that included adverse effects used withdrawals related to drug toxicity and therefore might be interpreted as using withdrawals to capture adverse effects, but this was explicitly stated in only three reports. Of the 37 models that did not include adverse effects, 18 provided justification for this omission, most commonly lack of data; 19 appeared to make no explicit consideration of adverse effects in the model. There is an implicit assumption within modelling guidance that adverse effects are very important but there is a lack of clarity regarding how they should be dealt with and considered in modelling. In many cases a lack of clear reporting in the HTAs made it extremely difficult to ascertain what had actually been carried out in consideration of adverse effects. The main recommendation is for much clearer and explicit reporting of adverse effects, or their exclusion, in decision models and for explicit recognition in future guidelines that 'all relevant outcomes' should include some consideration of adverse events.

Hazards of Hospitalization: Residence Prior to Admission Predicts Outcomes

ERIC Educational Resources Information Center

Friedman, Susan M.; Mendelson, Daniel A.; Bingham, Karilee W.; McCann, Robert M.

2008-01-01

Purpose: Previous studies investigating adverse outcomes of hospitalized elders have focused on community-dwelling patients. Given the rapid growth of populations living in other settings, such as assisted living facilities, it is important to understand whether these patients are at higher risk of experiencing specific adverse outcomes during…

Initial investigation of a hypothesized link between thyroid peroxidase inhibition and 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...

Early Adversity, Elevated Stress Physiology, Accelerated Sexual Maturation, and Poor Health in Females

ERIC Educational Resources Information Center

Belsky, Jay; Ruttle, Paula L.; Boyce, W. Thomas; Armstrong, Jeffrey M.; Essex, Marilyn J.

2015-01-01

Evolutionary-minded developmentalists studying predictive-adaptive-response processes linking childhood adversity with accelerated female reproductive development and health scientists investigating the developmental origins of health and disease (DOoHaD) may be tapping the same process, whereby longer-term health costs are traded off for…

Developing and applying the adverse outcome pathway concept for understanding and predicting neurotoxicity

EPA Science Inventory

To support a paradigm shift in regulatory toxicology testing and risk assessment, the Adverse Outcome Pathway (AOP) concept has recently been proposed. This concept is similar to that for Mode of Action (MOA), describing a sequence of measurable key events triggered by a molecula...

Adverse effects of aromatherapy: a systematic review of case reports and case series.

PubMed

Posadzki, Paul; Alotaibi, Amani; Ernst, Edzard

2012-01-01

This systematic review was aimed at critically evaluating the evidence regarding the adverse effects associated with aromatherapy. Five electronic databases were searched to identify all relevant case reports and case series. Forty two primary reports met our inclusion criteria. In total, 71 patients experienced adverse effects of aromatherapy. Adverse effects ranged from mild to severe and included one fatality. The most common adverse effect was dermatitis. Lavender, peppermint, tea tree oil and ylang-ylang were the most common essential oils responsible for adverse effects. Aromatherapy has the potential to cause adverse effects some of which are serious. Their frequency remains unknown. Lack of sufficiently convincing evidence regarding the effectiveness of aromatherapy combined with its potential to cause adverse effects questions the usefulness of this modality in any condition.

Which daily experiences can foster well-being at work? A diary study on the interplay between flow experiences, affective commitment, and self-control demands.

PubMed

Rivkin, Wladislaw; Diestel, Stefan; Schmidt, Klaus-Helmut

2018-01-01

Previous research has provided strong evidence for affective commitment as a direct predictor of employees' psychological well-being and as a resource that buffers the adverse effects of self-control demands as a stressor. However, the mechanisms that underlie the beneficial effects of affective commitment have not been examined yet. Drawing on the self-determination theory, we propose day-specific flow experiences as the mechanism that underlies the beneficial effects of affective commitment, because flow experiences as peaks of intrinsic motivation constitute manifestations of autonomous regulation. In a diary study covering 10 working days with N = 90 employees, we examine day-specific flow experiences as a mediator of the beneficial effects of interindividual affective commitment and a buffering moderator of the adverse day-specific effects of self-control demands on indicators of well-being (ego depletion, need for recovery, work engagement, and subjective vitality). Our results provide strong support for our predictions that day-specific flow experiences a) mediate the beneficial effects of affective commitment on employees' day-specific well-being and b) moderate (buffer) the adverse day-specific effects of self-control demands on well-being. That is, on days with high levels of flow experiences, employees were better able to cope with self-control demands whereas self-control demands translated into impaired well-being when employees experienced lower levels of day-specific flow experiences. We then discuss our findings and suggest practical implications. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Debris flow runup on vertical barriers and adverse slopes

USGS Publications Warehouse

Iverson, Richard M.; George, David L.; Logan, Matthew

2016-01-01

Runup of debris flows against obstacles in their paths is a complex process that involves profound flow deceleration and redirection. We investigate the dynamics and predictability of runup by comparing results from large-scale laboratory experiments, four simple analytical models, and a depth-integrated numerical model (D-Claw). The experiments and numerical simulations reveal the important influence of unsteady, multidimensional flow on runup, and the analytical models highlight key aspects of the underlying physics. Runup against a vertical barrier normal to the flow path is dominated by rapid development of a shock, or jump in flow height, associated with abrupt deceleration of the flow front. By contrast, runup on sloping obstacles is initially dominated by a smooth flux of mass and momentum from the flow body to the flow front, which precedes shock development and commonly increases the runup height. D-Claw simulations that account for the emergence of shocks show that predicted runup heights vary systematically with the adverse slope angle and also with the Froude number and degree of liquefaction (or effective basal friction) of incoming flows. They additionally clarify the strengths and limitations of simplified analytical models. Numerical simulations based on a priori knowledge of the evolving dynamics of incoming flows yield quite accurate runup predictions. Less predictive accuracy is attained in ab initio simulations that compute runup based solely on knowledge of static debris properties in a distant debris flow source area. Nevertheless, the paucity of inputs required in ab initio simulations enhances their prospective value in runup forecasting.

The Role of Agonistic Striving in the Association Between Cortisol and High Blood Pressure.

PubMed

Ewart, Craig K; Elder, Gavin J; Jorgensen, Randall S; Fitzgerald, Sheila T

2017-05-01

A social action theory of chronic stress proposes that agonistic striving (seeking to influence or control others) impairs cardiovascular health by magnifying the impact of high adversity-induced cortisol levels on blood pressure. We tested three predictions of social action theory: (1) the social action theory taxonomy of regulatory strivings characterizes young adults from high-adversity neighborhoods; (2) high cortisol levels predict high blood pressure more reliably in the subgroup with the agonistic striving profile than in subgroups with other profiles; (3) the association of higher cortisol and higher blood pressure with agonistic striving is not explained by negative affect (depressive symptoms/dysphoria, anger, hostility). Participants were young adults (N = 198, mean [SD] age = 32 [3.4] years); 71% female; 65% black) from disadvantaged urban neighborhoods. Motive profiles (including agonistic strivings) were assessed using the Social Competence Interview. Cortisol levels were derived from saliva samples; blood pressure level was obtained during two days of ambulatory monitoring. Psychological measures of negative affect were assessed using questionnaires. The predicted taxonomy of regulatory strivings was replicated in this sample; the interaction between cortisol and motive profile was significant (F(2, 91) = 6.72, p = .002); analyses of simple effects disclosed that higher cortisol levels predicted higher ambulatory blood pressure only in individuals who exhibited agonistic striving. Depressive symptoms/dysphoria, trait anger, and hostility were not correlated with agonistic striving, cortisol, or blood pressure. Agonistic striving may represent a distinctive (and novel) social-cognitive mechanism of toxic stress and cardiovascular risk.

Social inhibition modulates the effect of negative emotions on cardiac prognosis following percutaneous coronary intervention in the drug-eluting stent era.

PubMed

Denollet, Johan; Pedersen, Susanne S; Ong, Andrew T L; Erdman, Ruud A M; Serruys, Patrick W; van Domburg, Ron T

2006-01-01

Negative emotions have an adverse effect on cardiac prognosis. We investigated whether social inhibition (inhibited self-expression in social interaction) modulates the effect of negative emotions on clinical outcome following percutaneous coronary intervention (PCI). Eight hundred and seventy-five consecutive patients from the RESEARCH registry (Erasmus Medical Centre, Rotterdam) completed depression, anxiety, negativity (negative emotions in general), and social inhibition scales 6 months following PCI. The endpoint was major adverse cardiac event (MACE-death, myocardial infarction, coronary artery bypass graft (CABG), or PCI) at 9 months following assessment. There were 100 MACE; patients who were high in both negativity and inhibition were at increased risk of MACE (38/254=15%) when compared with high negativity/low inhibition patients (13/136=10%; P=0.018). Depression (P=0.23) or anxiety (P=0.63) did not explain away this moderating effect of inhibition. High negativity/high inhibition (HR=1.92, 95%CI 1.22-3.01, P=0.005) and previous CABG (HR=1.90, 95%CI 1.04-3.47, P=0.038) were independent predictors of MACE. Patients with high negativity but low inhibition were not at increased risk (P=0.76). High negativity/high inhibition also independently predicted death/MI (n=20) as a more specific endpoint (HR=5.85, P=0.001). The interaction effect of social inhibition and negative emotions, rather than negative emotions per se, predicted poor clinical outcome following PCI. Social inhibition should not be overlooked as a modulating factor.

Acute Kidney Injury Predicts Major Adverse Outcomes in Diabetes: Synergic Impact With Low Glomerular Filtration Rate and Albuminuria.

PubMed

Monseu, Mathilde; Gand, Elise; Saulnier, Pierre-Jean; Ragot, Stéphanie; Piguel, Xavier; Zaoui, Philippe; Rigalleau, Vincent; Marechaud, Richard; Roussel, Ronan; Hadjadj, Samy; Halimi, Jean-Michel

2015-12-01

Subjects with diabetes are prone to the development of cardiovascular and noncardiovascular complications. In separate studies, acute kidney injury (AKI), albuminuria, and low estimated glomerular filtration rate (eGFR) were shown to predict adverse outcomes, but, when considered together, their respective prognostic value is unknown. Patients with type 2 diabetes consecutively recruited in the SURDIAGENE cohort were prospectively followed up for major diabetes-related events, as adjudicated by an independent committee: death (with cause), major cardiovascular events (myocardial infarction, stroke, congestive heart failure, amputation, and arterial revascularization), and renal failure (i.e., sustained doubling of serum creatinine level or end-stage renal disease). Intrahospital AKI occurred in 411 of 1,371 patients during the median follow-up period of 69 months. In multivariate analyses, AKI was significantly associated with cardiovascular and noncardiovascular death, including cancer-related death. In multivariate analyses, AKI was a powerful predictor of major adverse cardiovascular events, heart failure requiring hospitalization, myocardial infarction, stroke, lower-limb amputation or revascularization, and carotid artery revascularization. AKI, eGFR, and albuminuria, even when simultaneously considered in multivariate models, predicted all-cause and cardiovascular deaths. All three renal biomarkers were also prognostic of most adverse outcomes and of the risk of renal failure. AKI, low eGFR, and elevated albuminuria, separately or together, are compelling biomarkers of major adverse outcomes and death in diabetes. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Child Maltreatment and Children's Developmental Trajectories in Early- to Middle-Childhood

PubMed Central

Font, Sarah A.; Berger, Lawrence M.

2014-01-01

Associations between experiencing child maltreatment and adverse developmental outcomes are widely studied, yet conclusions regarding the extent to which effects are bidirectional, and whether they are likely causal, remain elusive. This study uses the Fragile Families and Child Well-Being study, a birth cohort of 4,898 children followed from birth through age 9. Hierarchical linear modeling and structural equation modeling are employed to estimate associations of maltreatment with cognitive and social-emotional well-being. Results suggest that effects of early childhood maltreatment emerge immediately, though developmental outcomes are also affected by newly occurring maltreatment over time. Additionally, findings indicate that children's early developmental scores predict their subsequent probability of experiencing maltreatment, though to a lesser extent than early maltreatment predicts subsequent developmental outcomes. PMID:25521556

In silico prediction of drug-induced myelotoxicity by using Naïve Bayes method.

PubMed

Zhang, Hui; Yu, Peng; Zhang, Teng-Guo; Kang, Yan-Li; Zhao, Xiao; Li, Yuan-Yuan; He, Jia-Hui; Zhang, Ji

2015-11-01

Drug-induced myelotoxicity usually leads to decrease the production of platelets, red cells, and white cells. Thus, early identification and characterization of myelotoxicity hazard in drug development is very necessary. The purpose of this investigation was to develop a prediction model of drug-induced myelotoxicity by using a Naïve Bayes classifier. For comparison, other prediction models based on support vector machine and single-hidden-layer feed-forward neural network  methods were also established. Among all the prediction models, the Naïve Bayes classification model showed the best prediction performance, which offered an average overall prediction accuracy of [Formula: see text] for the training set and [Formula: see text] for the external test set. The significant contributions of this study are that we first developed a Naïve Bayes classification model of drug-induced myelotoxicity adverse effect using a larger scale dataset, which could be employed for the prediction of drug-induced myelotoxicity. In addition, several important molecular descriptors and substructures of myelotoxic compounds have been identified, which should be taken into consideration in the design of new candidate compounds to produce safer and more effective drugs, ultimately reducing the attrition rate in later stages of drug development.

Indoor Tanning within UK Young Adults: An Extended Theory of Planned Behaviour Approach.

PubMed

Dodd, Lorna J; Forshaw, Mark J; Williams, Stella

2013-01-01

The indoor tanning industry poses a long-term public health risk. Despite the adverse health effects, indoor tanning seems to be gaining considerable popularity. The study examined indoor tanning intentions and behaviour within UK young adults using an extended theory of planned behaviour model, which included variables on "appearance reasons to tan," "perceived susceptibility to damaging appearance," "perceived susceptibility to health consequences," and "tanning knowledge." The model was successful in predicting indoor tanning intentions and behaviour (explained 17% and 71%, resp.). An interesting outcome was the magnitude of the variable "appearance reasons to tan." A current tanned appearance therefore seemed to outweigh any adverse future appearance or health consequences caused by indoor tanning. Appearance-focused interventions to reduce such behaviour may now prove to be efficacious within a UK sample.

Drug-Target Interactions: Prediction Methods and Applications.

PubMed

Anusuya, Shanmugam; Kesherwani, Manish; Priya, K Vishnu; Vimala, Antonydhason; Shanmugam, Gnanendra; Velmurugan, Devadasan; Gromiha, M Michael

2018-01-01

Identifying the interactions between drugs and target proteins is a key step in drug discovery. This not only aids to understand the disease mechanism, but also helps to identify unexpected therapeutic activity or adverse side effects of drugs. Hence, drug-target interaction prediction becomes an essential tool in the field of drug repurposing. The availability of heterogeneous biological data on known drug-target interactions enabled many researchers to develop various computational methods to decipher unknown drug-target interactions. This review provides an overview on these computational methods for predicting drug-target interactions along with available webservers and databases for drug-target interactions. Further, the applicability of drug-target interactions in various diseases for identifying lead compounds has been outlined. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Does Problem Behavior Elicit Poor Parenting?: A Prospective Study of Adolescent Girls

PubMed Central

Huh, David; Tristan, Jennifer; Wade, Emily; Stice, Eric

2006-01-01

This study tested the hypothesis that perceived parenting would show reciprocal relations with adolescents' problem behavior using longitudinal data from 496 adolescent girls. Results provided support for the assertion that female problem behavior has an adverse effect on parenting; elevated externalizing symptoms and substance abuse symptoms predicted future decreases in perceived parental support and control. There was less support for the assertion that parenting deficits foster adolescent problem behaviors; initially low parental control predicted future increases in substance abuse, but not externalizing symptoms, and low parental support did not predict future increases in externalizing or substance abuse symptoms. Results suggest that problem behavior is a more consistent predictor of parenting than parenting is of problem behavior, at least for girls during middle adolescence. PMID:16528407

Revolutionizing Toxicity Testing For Predicting Developmental Outcomes (DNT4)

EPA Science Inventory

Characterizing risk from environmental chemical exposure currently requires extensive animal testing; however, alternative approaches are being researched to increase throughput of chemicals screened, decrease reliance on animal testing, and improve accuracy in predicting adverse...

Predictive Models and Computational Embryology

EPA Science Inventory

EPA’s ‘virtual embryo’ project is building an integrative systems biology framework for predictive models of developmental toxicity. One schema involves a knowledge-driven adverse outcome pathway (AOP) framework utilizing information from public databases, standardized ontologies...

A single microfocus (5% or less) of Gleason 6 prostate cancer at biopsy--can we predict adverse pathological outcomes?

PubMed

Thong, Alan E; Shikanov, Sergey; Katz, Mark H; Gofrit, Ofer N; Eggener, Scott; Zagaja, Gregory P; Shalhav, Arieh L; Zorn, Kevin C

2008-12-01

Patients with Gleason score 6 microfocal prostate cancer, defined as 5% or less in 1 biopsy core, are often considered to have favorable disease. Few studies have addressed clinical parameters that predict pathological upgrading or up staging at radical prostatectomy. From a prospective database of 1,271 consecutive robot assisted laparoscopic prostatectomies performed from 2003 to 2008 patients with Gleason score 6 microfocal prostate cancer were identified. Adverse pathological outcome was defined as any upgrading and/or up staging on prostatectomy pathological findings. Multivariate logistic regression was used to evaluate the ability of patient age, clinical stage, the total number of biopsy cores, preoperative prostate specific antigen, prostate volume and pathological prostate specific antigen density to predict adverse pathological outcomes. A total of 192 patients with a median age of 59 years (range 42 to 73) were identified with Gleason score 6 prostate cancer involving 5% or less of 1 biopsy core, including 177 (92%) with clinical T1c disease. Mean +/- SD preoperative prostate specific antigen was 6.0 +/- 3.9 ng/ml (range 0.8 to 35). Overall 42 patients (22%) had adverse pathological outcomes, including upgrading in 35 (18%) and up staging in 16 (8%). Multivariate logistic regression revealed that age more than 65 years and pathological prostate specific antigen density greater than 0.20 ng/ml/gm were predictive of an increased risk of adverse pathological results (p = 0.0081 and 0.0169, respectively). While a microfocus of Gleason score 6 prostate cancer on biopsy is commonly considered low risk disease, there was a greater than 1/5 risk of pathological upgrading and/or up staging. Patients with Gleason score 6 microfocal prostate cancer should be counseled that they may harbor more aggressive disease, especially when pretreatment clinical risk factors are present, such as advanced age or high clinical prostate specific antigen density.

Biomarkers of adverse drug reactions.

PubMed

Carr, Daniel F; Pirmohamed, Munir

2018-02-01

Adverse drug reactions can be caused by a wide range of therapeutics. Adverse drug reactions affect many bodily organ systems and vary widely in severity. Milder adverse drug reactions often resolve quickly following withdrawal of the casual drug or sometimes after dose reduction. Some adverse drug reactions are severe and lead to significant organ/tissue injury which can be fatal. Adverse drug reactions also represent a financial burden to both healthcare providers and the pharmaceutical industry. Thus, a number of stakeholders would benefit from development of new, robust biomarkers for the prediction, diagnosis, and prognostication of adverse drug reactions. There has been significant recent progress in identifying predictive genomic biomarkers with the potential to be used in clinical settings to reduce the burden of adverse drug reactions. These have included biomarkers that can be used to alter drug dose (for example, Thiopurine methyltransferase (TPMT) and azathioprine dose) and drug choice. The latter have in particular included human leukocyte antigen (HLA) biomarkers which identify susceptibility to immune-mediated injuries to major organs such as skin, liver, and bone marrow from a variety of drugs. This review covers both the current state of the art with regard to genomic adverse drug reaction biomarkers. We also review circulating biomarkers that have the potential to be used for both diagnosis and prognosis, and have the added advantage of providing mechanistic information. In the future, we will not be relying on single biomarkers (genomic/non-genomic), but on multiple biomarker panels, integrated through the application of different omics technologies, which will provide information on predisposition, early diagnosis, prognosis, and mechanisms. Impact statement • Genetic and circulating biomarkers present significant opportunities to personalize patient therapy to minimize the risk of adverse drug reactions. ADRs are a significant heath issue and represent a significant burden to patients, healthcare providers, and the pharmaceutical industry. • This review details the current state of the art in biomarkers of ADRs (both genetic and circulating). There is still significant variability in patient response which cannot be explained by current knowledge of genetic risk factors for ADRs; however, we discussed how specific advances in genomics have the potential to yield better and more predictive models. • Many current clinically utilized circulating biomarkers of tissue injury are valid biomarkers for a number of ADRs. However, they often give little insight into the specific cell or tissue subtype which may be affected. Emerging circulating biomarkers with potential to provide greater information on the etiology/pathophysiology of ADRs are described.

[The outcomes of Adoption in the Case of the "British Chinese Adoption Study"].

PubMed

Rushton, Alan

2015-01-01

Practitioners can over-estimate the incidence of problems in adopted children and adults because they do not see those who make good psychological and social adjustments. Research into adoption outcomes can be hard to interpret without information about differing pre-adoption histories. Examples are given of research into three types of adoption: domestic infant adoption, adoptions from public care of maltreated children and international adoption of ex-orphanage children. Although negative outcomes are indisputably evident for some, recovery from adversity is more common than many would predict. It is important to recognize that subsequent nurturing in consistent and stimulating environments can build a platform for effective adaptations to challenges in the future. However, a proper understanding of the consequences of adoption has been limited by the fact that follow-up studies have rarely extended beyond adolescence and early adulthood. The British Chinese Adoption Study is a 50 year follow-up of orphanage girls internationally adopted into the United Kingdom, and is given as an example of good outcomes despite early years of adversity. Scores on mental health assessments were equivalent to the non-adopted, age-matched comparison group of UK women. Most of the women were rated as "good functioning" and educational achievements were many times higher than the comparison women. Life-long adverse effects are not inevitable following early adversity. Improved circumstances can promote recovery and good adult adjustment. Practice and research implications are discussed.

Intermittent blood pressure control: potential consequences for outcome.

PubMed

Leenen, F H

1999-05-01

Although both blood pressure (BP) and left ventricular (LV) mass at initial evaluation predict future cardiovascular risk, the actual BP and LV mass achieved over years of treatment more clearly relate to cardiovascular event rates. Intermittent compliance or noncompliance is the major reason for uncontrolled hypertension and presumably persistent LV hypertrophy. In general, drugs with rapid onset and short duration of action are not desirable because this profile may lead to large variations in BP lowering effect during actual drug intake and rapid disappearance of the antihypertensive effect with missed doses. In addition, intermittent compliance per se introduces the potential for adverse events. For drugs requiring several dose-titrations (e.g., alpha1-blockers), restarting at full doses may lead to excessive drug action and symptomatic hypotension. For other drugs (e.g., short acting beta-blockers or clonidine-like drugs), sudden discontinuation with intermittent compliance may lead to rebound-enhanced sympathetic responsiveness after one to two days, resulting not only in side effects, but also in adverse events, particularly in patients with (silent) coronary artery disease. The rapid onset, short acting dihydropyridines cause intermittent BP control at each dosing, particularly at higher doses. This intermittent control of BP is even more apparent at dosing intervals that are long relative to the duration of action. Thus, sympathetic activation and potential for adverse events can be anticipated at each dosing unless these drugs are being taken frequently at relatively low doses. For diuretics, angiotensin-converting enzyme inhibitors and angiotensin I receptor blockers, no adverse effects have been identified with intermittent compliance. Intermittent BP control is, in general, not an appropriate approach to the management of hypertension and introduces additional risks depending on the type of antihypertensive drug. In contrast, drugs with slow onset and long duration of action provide a more consistent effect during actual drug intake and a more persistent effect during short periods of noncompliance.

Assessing the impact of race, social factors and air pollution on birth outcomes: a population-based study.

PubMed

Gray, Simone C; Edwards, Sharon E; Schultz, Bradley D; Miranda, Marie Lynn

2014-01-29

Both air pollution exposure and socioeconomic status (SES) are important indicators of children's health. Using highly resolved modeled predictive surfaces, we examine the joint effects of air pollution exposure and measures of SES in a population level analysis of pregnancy outcomes in North Carolina (NC). Daily measurements of particulate matter <2.5 μm in aerodynamic diameter (PM2.5) and ozone (O3) were calculated through a spatial hierarchical Bayesian model which produces census-tract level point predictions. Using multilevel models and NC birth data from 2002-2006, we examine the association between pregnancy averaged PM2.5 and O3, individual and area-based SES indicators, and birth outcomes. Maternal race and education, and neighborhood household income were associated with adverse birth outcomes. Predicted concentrations of PM2.5 and O3 were also associated with an additional effect on reductions in birth weight and increased risks of being born low birth weight and small for gestational age. This paper builds on and complements previous work on the relationship between pregnancy outcomes and air pollution exposure by using 1) highly resolved air pollution exposure data; 2) a five-year population level sample of pregnancies; and 3) including personal and areal level measures of social determinants of pregnancy outcomes. Results show a stable and negative association between air pollution exposure and adverse birth outcomes. Additionally, the more socially disadvantaged populations are at a greater risk; controlling for both SES and environmental stressors provides a better understanding of the contributing factors to poor children's health outcomes.

Understanding the risks associated with the use of new psychoactive substances (NPS): high variability of active ingredients concentration, mislabelled preparations, multiple psychoactive substances in single products.

PubMed

Zamengo, Luca; Frison, Giampietro; Bettin, Chiara; Sciarrone, Rocco

2014-08-17

New psychoactive substances (NPS), are now a large group of substances of abuse not yet completely controlled by international drug conventions, which may pose a public health threat. Anxiety, paranoia, hallucinations, seizures, hyperthermia and cardiotoxicity are some of the common adverse effects associated with these compounds. In this paper, three case reports taken from the archive of processed cases of the authors' laboratory are presented and discussed to stress the risks of possible adverse consequences for NPS users: in particular, (i) the risk deriving from the difficulty of predicting the actual consumed dose, due to variability of active ingredients concentration in consumed products, (ii) the risk deriving from the difficulty of predicting the actual active ingredients present in consumed products, as opposed to those claimed by the manufacturer, and (iii) the risk deriving from the difficulty of predicting the actual pharmacological and toxicological effects related to the simultaneous consumption of different psychoactive ingredients contained in single products, whose interactions are mostly unknown. Each of them individually provide a source of concern for possible serious health related consequences. However, they should be considered in conjunction with each others, with the worldwide availability of NPS through the web and also with the incessantly growing business derived from the manipulation and synthesis of new substances. The resulting scenario is that of a cultural challenge which demands a global approach from different fields of knowledge. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Modeling Liver-Related Adverse Effects of Drugs Using kNN QSAR Method

PubMed Central

Rodgers, Amie D.; Zhu, Hao; Fourches, Dennis; Rusyn, Ivan; Tropsha, Alexander

2010-01-01

Adverse effects of drugs (AEDs) continue to be a major cause of drug withdrawals both in development and post-marketing. While liver-related AEDs are a major concern for drug safety, there are few in silico models for predicting human liver toxicity for drug candidates. We have applied the Quantitative Structure Activity Relationship (QSAR) approach to model liver AEDs. In this study, we aimed to construct a QSAR model capable of binary classification (active vs. inactive) of drugs for liver AEDs based on chemical structure. To build QSAR models, we have employed an FDA spontaneous reporting database of human liver AEDs (elevations in activity of serum liver enzymes), which contains data on approximately 500 approved drugs. Approximately 200 compounds with wide clinical data coverage, structural similarity and balanced (40/60) active/inactive ratio were selected for modeling and divided into multiple training/test and external validation sets. QSAR models were developed using the k nearest neighbor method and validated using external datasets. Models with high sensitivity (>73%) and specificity (>94%) for prediction of liver AEDs in external validation sets were developed. To test applicability of the models, three chemical databases (World Drug Index, Prestwick Chemical Library, and Biowisdom Liver Intelligence Module) were screened in silico and the validity of predictions was determined, where possible, by comparing model-based classification with assertions in publicly available literature. Validated QSAR models of liver AEDs based on the data from the FDA spontaneous reporting system can be employed as sensitive and specific predictors of AEDs in pre-clinical screening of drug candidates for potential hepatotoxicity in humans. PMID:20192250

Application of gene expression programming and neural networks to predict adverse events of radical hysterectomy in cervical cancer patients.

PubMed

Kusy, Maciej; Obrzut, Bogdan; Kluska, Jacek

2013-12-01

The aim of this article was to compare gene expression programming (GEP) method with three types of neural networks in the prediction of adverse events of radical hysterectomy in cervical cancer patients. One-hundred and seven patients treated by radical hysterectomy were analyzed. Each record representing a single patient consisted of 10 parameters. The occurrence and lack of perioperative complications imposed a two-class classification problem. In the simulations, GEP algorithm was compared to a multilayer perceptron (MLP), a radial basis function network neural, and a probabilistic neural network. The generalization ability of the models was assessed on the basis of their accuracy, the sensitivity, the specificity, and the area under the receiver operating characteristic curve (AUROC). The GEP classifier provided best results in the prediction of the adverse events with the accuracy of 71.96 %. Comparable but slightly worse outcomes were obtained using MLP, i.e., 71.87 %. For each of measured indices: accuracy, sensitivity, specificity, and the AUROC, the standard deviation was the smallest for the models generated by GEP classifier.

Assessing the interplay of childhood adversities with more recent stressful life events and conditions in predicting panic pathology among adults from the general population.

PubMed

Asselmann, E; Stender, J; Grabe, H J; König, J; Schmidt, C O; Hamm, A O; Pané-Farré, C A

2018-01-01

Although research suggests that (a) childhood adversities and more recent stressful life events/conditions are risk factors for panic pathology and that (b) early life stress increases vulnerability to later psychopathology, it remains unclear whether childhood adversities amplify the association between more recent stressful life events/conditions and panic pathology. Data were derived from a general population sample (Study of Health in Pomerania, SHIP). Lifetime panic pathology was assessed with the Munich Composite International Diagnostic Interview (M-CIDI). Childhood adversities (emotional, physical and sexual abuse; emotional and physical neglect) were assessed with the Childhood Trauma Questionnaire (CTQ). More recent separation/loss events and long-lasting stressful conditions were assessed with the Stralsund Life Event List (SEL). Individuals with lifetime panic pathology (fearful spell, panic attack or panic disorder, N = 286) were compared to controls without any psychopathology (N = 286, matched for sex and age). Conditional logistic regressions revealed that childhood adversities as well as more recent separation/loss events and long-lasting stressful conditions were associated with panic pathology (OR 1.1-2.5). Moreover, more recent separation/loss events - but not long-lasting stressful conditions - interacted statistically with each of the examined childhood adversities except for sexual abuse in predicting panic pathology (OR 1.1-1.3). That is, separation/loss events were associated more strongly with panic pathology among individuals with higher childhood adversities. Data were assessed retrospectively and might be subject to recall biases. Findings suggest that early childhood adversities amplify the risk of developing panic pathology after experiencing separation or loss events. Copyright © 2017. Published by Elsevier B.V.

An elevated gap between admission and A1C-derived average glucose levels is associated with adverse outcomes in diabetic patients with pyogenic liver abscess.

PubMed

Liao, Wen-I; Sheu, Wayne Huey-Herng; Chang, Wei-Chou; Hsu, Chin-Wang; Chen, Yu-Long; Tsai, Shih-Hung

2013-01-01

To assess whether chronic glycemic control and stress-induced hyperglycemia, determined by the gap between admission glucose levels and A1C-derived average glucose (ADAG) levels adversely affects outcomes in diabetic patients with pyogenic liver abscess (PLA). Clinical, laboratory, and multi-detector computed tomography (MDCT) findings of 329 PLA patients (2004-2010) were retrospectively reviewed. HbA1C levels were used to determine long-term glycemic control status, which were then converted to estimated average glucose values. For the gap between admission glucose levels and ADAG levels, we used receiver operating characteristic (ROC) curve to determine the optimal cut-off values predicting adverse outcomes. Univariate and multivariate logistic regressions were used to identify predictors of adverse outcomes. Diabetic PLA patients with poorer glycemic control had significantly higher Klebsiella pneumoniae (KP) infection rates, lower albumin levels, and longer hospital stays than those with suboptimal and good glycemic control. The ROC curve showed that a glycemic gap of 72 mg/dL was the optimal cut-off value for predicting adverse outcomes and showed a 22.3% relative increase in adverse outcomes compared with a glycemic gap<72 mg/dL. Multivariate analysis revealed that an elevated glycemic gap≥72 mg/dL was important predictor of adverse outcomes. A glycemic gap≥72 mg/dL, rather than admission hyperglycemia or chronic glycemic control, was significantly correlated with adverse outcomes in diabetic PLA patients. Poorer chronic glycemic control in diabetic PLA patients is associated with high incidence of KP infection, hypoalbuminemia and longer hospital stay.

On the impact of adverse pressure gradient on the supersonic turbulent boundary layer

NASA Astrophysics Data System (ADS)

Wang, Qian-Cheng; Wang, Zhen-Guo; Zhao, Yu-Xin

2016-11-01

By employing the particle image velocimetry, the mean and turbulent characteristics of a Mach 2.95 turbulent boundary layer are experimentally investigated without the impact of curvature. The physical mechanism with which the streamwise adverse pressure gradient affects the supersonic boundary layer is revealed. The data are compared to that of the concave boundary layer with similar streamwise distributions of wall static pressure to clarify the separate impacts of the adverse pressure gradient and the concave curvature. The logarithmic law is observed to be well preserved for both of the cases. The dip below the logarithmic law is not observed in present investigation. Theoretical analysis indicates that it could be the result of compromise between the opposite impacts of the compression wave and the increased turbulent intensity. Compared to the zero pressure gradient boundary layer, the principal strain rate and the turbulent intensities are increased by the adverse pressure gradient. The shear layer formed due the hairpin packets could be sharpened by the compression wave, which leads to higher principal strain rate and the associated turbulent level. Due to the additional impact of the centrifugal instability brought by the concave wall, even higher turbulent intensities than that of the adverse pressure gradient case are introduced. The existence of velocity modes within the zero pressure gradient boundary layer suggests that the large scale motions are statistically well organized. The generation of new velocity modes due to the adverse pressure gradient indicates that the turbulent structure is changed by the adverse pressure gradient, through which more turbulence production that cannot be effectively predicted by the Reynolds-stress transport equations could be brought.

Pharmacogenetics of Antipsychotics

PubMed Central

Brandl, Eva J; Kennedy, James L; Müller, Daniel J

2014-01-01

Objective: During the past decades, increasing efforts have been invested in studies to unravel the influence of genetic factors on antipsychotic (AP) dosage, treatment response, and occurrence of adverse effects. These studies aimed to improve clinical care by predicting outcome of treatment with APs and thus allowing for individualized treatment strategies. We highlight most important findings obtained through both candidate gene and genome-wide association studies, including pharmacokinetic and pharmacodynamic factors. Methods: We reviewed studies on pharmacogenetics of AP response and adverse effects published on PubMed until early 2012. Owing to the high number of published studies, we focused our review on findings that have been replicated in independent studies or are supported by meta-analyses. Results: Most robust findings were reported for associations between polymorphisms of the cytochrome P450 system, the dopamine and the serotonin transmitter systems, and dosage, treatment response, and adverse effects, such as AP-induced weight gain or tardive dyskinesia. These associations were either detected for specific medications or for classes of APs. Conclusion: First promising and robust results show that pharmacogenetics bear promise for a widespread use in future clinical practice. This will likely be achieved by developing algorithms that will include many genetic variants. However, further investigation is warranted to replicate and validate previous findings, as well as to identify new genetic variants involved in AP response and for replication of existing findings. PMID:24881126

Adverse Housing Conditions and Early-Onset Delinquency.

PubMed

Jackson, Dylan B; Newsome, Jamie; Lynch, Kellie R

2017-09-01

Housing constitutes an important health resource for children. Research has revealed that, when housing conditions are unfavorable, they can interfere with child health, academic performance, and cognition. Little to no research, however, has considered whether adverse housing conditions and early-onset delinquency are significantly associated with one another. This study explores the associations between structural and non-structural housing conditions and delinquent involvement during childhood. Data from the Fragile Families and Child Wellbeing Study (FFCWS) were employed in this study. Each adverse housing condition was significantly associated with early-onset delinquency. Even so, disarray and deterioration were only significantly linked to early delinquent involvement in the presence of health/safety hazards. The predicted probability of early-onset delinquency among children exposed to housing risks in the presence of health/safety hazards was nearly three times as large as the predicted probability of early-onset delinquency among children exposed only to disarray and/or deterioration, and nearly four times as large as the predicted probability of early-onset delinquency among children exposed to none of the adverse housing conditions. The findings suggest that minimizing housing-related health/safety hazards among at-risk subsets of the population may help to alleviate other important public health concerns-particularly early-onset delinquency. Addressing household health/safety hazards may represent a fruitful avenue for public health programs aimed at the prevention of early-onset delinquency. © Society for Community Research and Action 2017.

Translational toxicology: a developmental focus for integrated research strategies.

PubMed

Hughes, Claude; Waters, Michael; Allen, David; Obasanjo, Iyabo

2013-09-30

Given that toxicology studies the potential adverse effects of environmental exposures on various forms of life and that clinical toxicology typically focuses on human health effects, what can and should the relatively new term of "translational toxicology" be taken to mean? Our assertion is that the core concept of translational toxicology must incorporate existing principles of toxicology and epidemiology, but be driven by the aim of developing safe and effective interventions beyond simple reduction or avoidance of exposure to prevent, mitigate or reverse adverse human health effects of exposures.The field of toxicology has now reached a point where advances in multiple areas of biomedical research and information technologies empower us to make fundamental transitions in directly impacting human health. Translational toxicology must encompass four action elements as follows: 1) Assessing human exposures in critical windows across the lifespan; 2) Defining modes of action and relevance of data from animal models; 3) Use of mathematical models to develop plausible predictions as the basis for: 4) Protective and restorative human health interventions. The discussion focuses on the critical window of in-utero development. Exposure assessment, basic toxicology and development of certain categories of mathematical models are not new areas of research; however overtly integrating these in order to conceive, assess and validate effective interventions to mitigate or reverse adverse effects of environmental exposures is our novel opportunity. This is what we should do in translational toxicology so that we have a portfolio of interventional options to improve human health that include both minimizing exposures and specific preventative/restorative/mitigative therapeutics.

Combinations of resting RSA and RSA reactivity impact maladaptive mood repair and depression symptoms

PubMed Central

Yaroslavsky, Ilya; Bylsma, Lauren M.; Rottenberg, Jonathan; Kovacs, Maria

2013-01-01

We examined whether the combined indices of respiratory sinus arrhythmia at rest (resting RSA) and in response to a sad film (RSA reactivity) predict effective and ineffective responses to reduce sadness (adaptive vs. maladaptive mood repair) in women with histories of juvenile-onset depression (n = 74) and no history of major mental disorders (n = 75). Structural equation models were used to estimate latent resting RSA, depression, and adaptive and maladaptive mood repair and to test the study hypotheses. Results indicated that combinations of resting RSA+RSA reactivity (RSA patterns) predicted maladaptive mood repair, which in turn, mediated the effects of RSA pattern on depression. Further, RSA patterns moderated the depressogenic effects of maladaptive mood repair. RSA patterns were unrelated to adaptive mood repair. Our findings suggest that mood repair is one mechanism through which physiological vulnerabilities adversely affect mental health. PMID:23827087

Combinations of resting RSA and RSA reactivity impact maladaptive mood repair and depression symptoms.

PubMed

Yaroslavsky, Ilya; Bylsma, Lauren M; Rottenberg, Jonathan; Kovacs, Maria

2013-10-01

We examined whether the combined indices of respiratory sinus arrhythmia at rest (resting RSA) and in response to a sad film (RSA reactivity) predict effective and ineffective responses to reduce sadness (adaptive vs. maladaptive mood repair) in women with histories of juvenile-onset depression (n=74) and no history of major mental disorders (n=75). Structural equation models were used to estimate latent resting RSA, depression, and adaptive and maladaptive mood repair and to test the study hypotheses. Results indicated that combinations of resting RSA+RSA reactivity (RSA patterns) predicted maladaptive mood repair, which in turn, mediated the effects of RSA pattern on depression. Further, RSA patterns moderated the depressogenic effects of maladaptive mood repair. RSA patterns were unrelated to adaptive mood repair. Our findings suggest that mood repair is one mechanism through which physiological vulnerabilities adversely affect mental health. Copyright © 2013 Elsevier B.V. All rights reserved.

Micro-Ramp Flow Control for Oblique Shock Interactions: Comparisons of Computational and Experimental Data

NASA Technical Reports Server (NTRS)

Hirt, Stefanie M.; Reich, David B.; O'Connor, Michael B.

2010-01-01

Computational fluid dynamics was used to study the effectiveness of micro-ramp vortex generators to control oblique shock boundary layer interactions. Simulations were based on experiments previously conducted in the 15 x 15 cm supersonic wind tunnel at NASA Glenn Research Center. Four micro-ramp geometries were tested at Mach 2.0 varying the height, chord length, and spanwise spacing between micro-ramps. The overall flow field was examined. Additionally, key parameters such as boundary-layer displacement thickness, momentum thickness and incompressible shape factor were also examined. The computational results predicted the effects of the micro-ramps well, including the trends for the impact that the devices had on the shock boundary layer interaction. However, computing the shock boundary layer interaction itself proved to be problematic since the calculations predicted more pronounced adverse effects on the boundary layer due to the shock than were seen in the experiment.

Micro-Ramp Flow Control for Oblique Shock Interactions: Comparisons of Computational and Experimental Data

NASA Technical Reports Server (NTRS)

Hirt, Stephanie M.; Reich, David B.; O'Connor, Michael B.

2012-01-01

Computational fluid dynamics was used to study the effectiveness of micro-ramp vortex generators to control oblique shock boundary layer interactions. Simulations were based on experiments previously conducted in the 15- by 15-cm supersonic wind tunnel at the NASA Glenn Research Center. Four micro-ramp geometries were tested at Mach 2.0 varying the height, chord length, and spanwise spacing between micro-ramps. The overall flow field was examined. Additionally, key parameters such as boundary-layer displacement thickness, momentum thickness and incompressible shape factor were also examined. The computational results predicted the effects of the microramps well, including the trends for the impact that the devices had on the shock boundary layer interaction. However, computing the shock boundary layer interaction itself proved to be problematic since the calculations predicted more pronounced adverse effects on the boundary layer due to the shock than were seen in the experiment.

How to acquire new biological activities in old compounds by computer prediction

NASA Astrophysics Data System (ADS)

Poroikov, V. V.; Filimonov, D. A.

2002-11-01

Due to the directed way of testing chemical compounds' in drug research and development many projects fail because serious adverse effects and toxicity are discovered too late, and many existing prospective activities remain unstudied. Evaluation of the general biological potential of molecules is possible using a computer program PASS that predicts more than 780 pharmacological effects, mechanisms of action, mutagenicity, carcinogenicity, etc. on the basis of structural formulae of compounds, with average accuracy ˜85%. PASS applications to both databases of available samples included hundreds of thousands compounds, and small collections of compounds synthesized by separate medicinal chemists are described. It is shown that 880 compounds from Prestwick chemical library represent a very diverse pharmacological space. New activities can be found in existing compounds by prediction. Therefore, on this basis, the selection of compounds with required and without unwanted properties is possible. Even when PASS cannot predict very new activities, it may recognize some unwanted actions at the early stage of R&D, providing the medicinal chemist with the means to increase the efficiency of projects.

Do race, neglect, and childhood poverty predict physical health in adulthood? A multilevel prospective analysis

PubMed Central

Nikulina, Valentina

2015-01-01

Childhood neglect and poverty often co-occur and both have been linked to poor physical health outcomes. In addition, Blacks have higher rates of childhood poverty and tend to have worse health than Whites. This paper examines the unique and interacting effects of childhood neglect, race, and family and neighborhood poverty on adult physical health outcomes. This prospective cohort design study uses a sample (N = 675) of court-substantiated cases of childhood neglect and matched controls followed into adulthood (Mage = 41). Health indicators (C-Reactive Protein [CRP], hypertension, and pulmonary functioning) were assessed through blood collection and measurements by a registered nurse. Data were analyzed using hierarchical linear models to control for clustering of participants in childhood neighborhoods. Main effects showed that growing up Black predicted CRP and hypertension elevations, despite controlling for neglect and childhood family and neighborhood poverty and their interactions. Multivariate results showed that race and childhood adversities interacted to predict adult health outcomes. Childhood family poverty predicted increased risk for hypertension for Blacks, not Whites. In contrast, among Whites, childhood neglect predicted elevated CRP. Childhood neighborhood poverty interacted with childhood family poverty to predict pulmonary functioning in adulthood. Gender differences in health indicators were also observed. The effects of childhood neglect, childhood poverty, and growing up Black in the United States are manifest in physical health outcomes assessed 30 years later. Implications are discussed. PMID:24189205

Diagnosis, monitoring and management of immune-related adverse drug reactions of anti-PD-1 antibody therapy.

PubMed

Eigentler, Thomas K; Hassel, Jessica C; Berking, Carola; Aberle, Jens; Bachmann, Oliver; Grünwald, Viktor; Kähler, Katharina C; Loquai, Carmen; Reinmuth, Niels; Steins, Martin; Zimmer, Lisa; Sendl, Anna; Gutzmer, Ralf

2016-04-01

PD-1 checkpoint inhibitors are associated with a specific spectrum of immune-related adverse events. This spectrum is different from toxicities known for kinase inhibitors or cytotoxic drugs. Since PD-1 directed therapies show effectivity in an increasing number of malignant diseases, their clinical usage will increase rapidly. Therefore clinicians from different specialities such as medical oncology, internal medicine, family doctors and emergency unit staff should be aware of the adverse effects of PD-1 checkpoint inhibitors to avoid delays in diagnosis and treatment. Based on pooled data from pivotal trials as reported by the European Medicines Agency, the present paper reviews incidences and kinetics of onset and resolution of immune-mediated "adverse events of specific interest" (AEOSI) of both approved PD-1 inhibitors nivolumab and pembrolizumab. In general, the severity of AEOSI is mild to moderate (grade 1-2); the frequency of immune-mediated but also idiopathic grade 3-4 adverse drug reactions is ⩽2% for any event term. Recommendations for the diagnosis, monitoring and management of the relevant dermatological, gastrointestinal, pulmonary, endocrine, renal and hepatic toxicities are convened by an expert panel that consolidated and clarified treatment recommendations after the onset of AEOSI. Although the time of onset is not predictable - the medians range from 1 to 6months - the huge majority of events is reversible, with no impact of the time of onset. By the systemic use of glucocorticoids, notably methylprednisolone or equivalents, most AEOSI are well manageable. Non-steroidal immunosuppressants may be used in certain cases of refractory/recalcitrant, long-lasting immune toxicities. With regard to the outstanding clinical activity of the anti-PD-1 antibodies, therapy restart is the principal therapeutic option after recovery of grade 2 AEOSI, or diminution of higher grade skin or endocrine events to mild severity. Early diagnosis and close clinical monitoring are essential for successful management of immune-related adverse events. Copyright © 2016 Elsevier Ltd. All rights reserved.

Predictive Models and Computational Toxicology (II IBAMTOX)

EPA Science Inventory

EPA’s ‘virtual embryo’ project is building an integrative systems biology framework for predictive models of developmental toxicity. One schema involves a knowledge-driven adverse outcome pathway (AOP) framework utilizing information from public databases, standardized ontologies...

Predictive Models of Liver Cancer

EPA Science Inventory

Predictive models of chemical-induced liver cancer face the challenge of bridging causative molecular mechanisms to adverse clinical outcomes. The latent sequence of intervening events from chemical insult to toxicity are poorly understood because they span multiple levels of bio...

Stress, Behavior and Health: Developing a Model for Predicting Post-Deployment Morbidity, Mortality and Other Adverse Outcomes

DTIC Science & Technology

1999-07-01

related health outcomes and risk factors for adverse health events. A secondary effort is to link self-reports of stress and subsequent increases in...Gulf War era veterans, information critical to the interpretation of postwar differences between these two groups . We have identified potential

The Impact of Postnatal Depression and Associated Adversity on Early Mother-Infant Interactions and Later Infant Outcome.

ERIC Educational Resources Information Center

Murray, Lynne; And Others

1996-01-01

Examined the impact of maternal depression and adversity on mother-infant face-to-face interactions at 2 months, and on subsequent infant cognitive development and attachment. Disturbances in early mother-infant interactions were found to be predictive of poorer infant cognitive outcomes at 18 months. (MDM)

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

USDA-ARS?s Scientific Manuscript database

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...

Chemical-agnostic hazard prediction: statistical inference of in vitro toxicity pathways from proteomics responses to chemical mixtures

EPA Science Inventory

Toxicity pathways have been defined as normal cellular pathways that, when sufficiently perturbed as a consequence of chemical exposure, lead to an adverse outcome. If an exposure alters one or more normal biological pathways to an extent that leads to an adverse toxicity outcome...

Prenatal Family Adversity and Maternal Mental Health and Vulnerability to Peer Victimisation at School

ERIC Educational Resources Information Center

Lereya, Suzet Tanya; Wolke, Dieter

2013-01-01

Background: Prenatal stress has been shown to predict persistent behavioural abnormalities in offspring. Unknown is whether prenatal stress makes children more vulnerable to peer victimisation. Methods: The current study is based on the Avon Longitudinal Study of Parents and Children, a prospective community-based study. Family adversity, maternal…

Predictive Factors of Nivolumab-induced Hypothyroidism in Patients with Non-small Cell Lung Cancer.

PubMed

Maekura, Toshiya; Naito, Maiko; Tahara, Masahiro; Ikegami, Naoya; Kimura, Yohei; Sonobe, Shoko; Kobayashi, Takehiko; Tsuji, Taisuke; Minomo, Shojiro; Tamiya, Akihiro; Atagi, Shinji

2017-01-01

Although immune checkpoint inhibitors play an important role in the therapy of lung cancer, they are associated with various immune-related adverse events and predictive factors of them are unclear. In this study, we investigated predictive factors of nivolumab-induced hypothyroidism which is one of the adverse events in patients with lung cancer. Patients with non-small-cell lung cancer who were administered nivolumab at our hospital between December 2015 and May 2016 were retrospectively enrolled. The thyroid-stimulating hormone, free triiodothyronine, free thyroxine, thyroid peroxidase (TPO) antibody, and thyroglobulin antibody levels of each patient were analyzed. Of the 64 patients enrolled, 5 (7.8%) developed hypothyroidism after treatment with nivolumab. The TPO and thyroglobulin antibodies were significantly positive in patients who developed primary hypothyroidism. TPO and thyroglobulin antibody levels at baseline may be predictive of hypothyroidism. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Predictive modeling of nanomaterial exposure effects in biological systems

PubMed Central

Liu, Xiong; Tang, Kaizhi; Harper, Stacey; Harper, Bryan; Steevens, Jeffery A; Xu, Roger

2013-01-01

Background Predictive modeling of the biological effects of nanomaterials is critical for industry and policymakers to assess the potential hazards resulting from the application of engineered nanomaterials. Methods We generated an experimental dataset on the toxic effects experienced by embryonic zebrafish due to exposure to nanomaterials. Several nanomaterials were studied, such as metal nanoparticles, dendrimer, metal oxide, and polymeric materials. The embryonic zebrafish metric (EZ Metric) was used as a screening-level measurement representative of adverse effects. Using the dataset, we developed a data mining approach to model the toxic endpoints and the overall biological impact of nanomaterials. Data mining techniques, such as numerical prediction, can assist analysts in developing risk assessment models for nanomaterials. Results We found several important attributes that contribute to the 24 hours post-fertilization (hpf) mortality, such as dosage concentration, shell composition, and surface charge. These findings concur with previous studies on nanomaterial toxicity using embryonic zebrafish. We conducted case studies on modeling the overall effect/impact of nanomaterials and the specific toxic endpoints such as mortality, delayed development, and morphological malformations. The results show that we can achieve high prediction accuracy for certain biological effects, such as 24 hpf mortality, 120 hpf mortality, and 120 hpf heart malformation. The results also show that the weighting scheme for individual biological effects has a significant influence on modeling the overall impact of nanomaterials. Sample prediction models can be found at http://neiminer.i-a-i.com/nei_models. Conclusion The EZ Metric-based data mining approach has been shown to have predictive power. The results provide valuable insights into the modeling and understanding of nanomaterial exposure effects. PMID:24098077

Daily Associations Among Self-control, Heavy Episodic Drinking, and Relationship Functioning: An Examination of Actor and Partner Effects

PubMed Central

Crane, Cory A.; Testa, Maria; Derrick, Jaye L.; Leonard, Kenneth E.

2014-01-01

An emerging literature suggests that temporary deficits in the ability to inhibit impulsive urges may be proximally associated with intimate partner aggression. The current study examined the experience of alcohol use and the depletion of self-control in the prediction of relationship functioning. Daily diary data collected from 118 heterosexual couples were analyzed using parallel multi-level Actor Partner Interdependence Models to assess the effects of heavy episodic drinking and depletion of self-control across partners on outcomes of participant-reported daily arguing with and anger toward an intimate partner. Heavy episodic drinking among actors predicted greater arguing but failed to interact with either actor or partner depletion. We also found that greater arguing was reported on days of high congruent actor and partner depletion. Both actor and partner depletion, as well as their interaction, predicted greater partner-specific anger. Greater partner-specific anger was generally reported on days of congruent actor and partner depletion, particularly on days of high partner depletion. The current results highlight the importance of independently assessing partner effects (i.e., depletion of self-control), which interact dynamically with disinhibiting actor effects, in the prediction of daily adverse relationship functioning. Results offer further support for the development of prospective individualized and couples-based interventions for partner conflict. PMID:24700558

Fitness, but not physical activity, is related to functional integrity of brain networks associated with aging.

PubMed

Voss, Michelle W; Weng, Timothy B; Burzynska, Agnieszka Z; Wong, Chelsea N; Cooke, Gillian E; Clark, Rachel; Fanning, Jason; Awick, Elizabeth; Gothe, Neha P; Olson, Erin A; McAuley, Edward; Kramer, Arthur F

2016-05-01

Greater physical activity and cardiorespiratory fitness are associated with reduced age-related cognitive decline and lower risk for dementia. However, significant gaps remain in the understanding of how physical activity and fitness protect the brain from adverse effects of brain aging. The primary goal of the current study was to empirically evaluate the independent relationships between physical activity and fitness with functional brain health among healthy older adults, as measured by the functional connectivity of cognitively and clinically relevant resting state networks. To build context for fitness and physical activity associations in older adults, we first demonstrate that young adults have greater within-network functional connectivity across a broad range of cortical association networks. Based on these results and previous research, we predicted that individual differences in fitness and physical activity would be most strongly associated with functional integrity of the networks most sensitive to aging. Consistent with this prediction, and extending on previous research, we showed that cardiorespiratory fitness has a positive relationship with functional connectivity of several cortical networks associated with age-related decline, and effects were strongest in the default mode network (DMN). Furthermore, our results suggest that the positive association of fitness with brain function can occur independent of habitual physical activity. Overall, our findings provide further support that cardiorespiratory fitness is an important factor in moderating the adverse effects of aging on cognitively and clinically relevant functional brain networks. Copyright © 2015 Elsevier Inc. All rights reserved.

Fitness, but not physical activity, is related to functional integrity of brain networks associated with aging

PubMed Central

Voss, Michelle W.; Weng, Timothy B.; Burzynska, Agnieszka Z.; Wong, Chelsea N.; Cooke, Gillian E.; Clark, Rachel; Fanning, Jason; Awick, Elizabeth; Gothe, Neha P.; Olson, Erin A.; McAuley, Edward; Kramer, Arthur F.

2015-01-01

Greater physical activity and cardiorespiratory fitness are associated with reduced age-related cognitive decline and lower risk for dementia. However, significant gaps remain in the understanding of how physical activity and fitness protect the brain from adverse effects of brain aging. The primary goal of the current study was to empirically evaluate the independent relationships between physical activity and fitness with functional brain health among healthy older adults, as measured by the functional connectivity of cognitively and clinically relevant resting state networks. To build context for fitness and physical activity associations in older adults, we first demonstrate that young adults have greater within-network functional connectivity across a broad range of cortical association networks. Based on these results and previous research, we predicted that individual differences in fitness and physical activity would be most strongly associated with functional integrity of the networks most sensitive to aging. Consistent with this prediction, and extending on previous research, we showed that cardiorespiratory fitness has a positive relationship with functional connectivity of several cortical networks associated with age-related decline, and effects were strongest in the Default Mode Network (DMN). Furthermore, our results suggest that the positive association of fitness with brain function can occur independent of habitual physical activity. Overall, our findings provide further support that cardiorespiratory fitness is an important factor in moderating the adverse effects of aging on cognitively and clinically relevant functional brain networks. PMID:26493108

Music therapy-induced changes in salivary cortisol level are predictive of cardiovascular mortality in patients under maintenance hemodialysis.

PubMed

Hou, Yi-Chou; Lin, Yen-Ju; Lu, Kuo-Cheng; Chiang, Han-Sun; Chang, Chia-Chi; Yang, Li-King

2017-01-01

Music therapy has been applied in hemodialysis (HD) patients for relieving mental stress. Whether the stress-relieving effect by music therapy is predictive of clinical outcome in HD patients is still unclear. We recruited a convenience sample of 99 patients on maintenance HD and randomly assigned them to the experimental (n=49) or control (n=50) group. The experimental group received relaxing music therapy for 1 week, whereas the control group received no music therapy. In the experimental group, we compared cardiovascular mortality in the patients with and without cortisol changes. The salivary cortisol level was lowered after 1 week of music therapy in the experimental group (-2.41±3.08 vs 1.66±2.11 pg/mL, P <0.05), as well as the frequency of the adverse reaction score (-3.35±5.76 vs -0.81±4.59, P <0.05), the severity of adverse reactions score (-1.93±2.73 vs 0.33±2.71, P <0.05), and hemodialysis stressor scale (HSS) score (-6.00±4.68 vs -0.877±7.08, P <0.05). The difference in salivary cortisol correlated positively with HD stress score scales ( r =0.231, P <0.05), systolic blood pressure ( r =0.264, P <0.05), and respiratory rates ( r =0.369, P <0.05) and negatively with finger temperature ( r =-0.235, P <0.05) in the total study population. The 5-year cardiovascular survival in the experimental group was higher in patients whose salivary cortisol lowered by <0.6 pg/mL than that in patients whose salivary cortisol lowered by >0.6 pg/mL (83.8% vs 63.6%, P <0.05). Providing music during HD is an effective complementary therapy to relieve the frequency and severity of adverse reactions, as well as to lower salivary cortisol levels. Differences in salivary cortisol after music therapy may predict cardiovascular mortality in patients under maintenance HD.

Cumulative stress and autonomic dysregulation in a community sample.

PubMed

Lampert, Rachel; Tuit, Keri; Hong, Kwang-Ik; Donovan, Theresa; Lee, Forrester; Sinha, Rajita

2016-05-01

Whether cumulative stress, including both chronic stress and adverse life events, is associated with decreased heart rate variability (HRV), a non-invasive measure of autonomic status which predicts poor cardiovascular outcomes, is unknown. Healthy community dwelling volunteers (N = 157, mean age 29 years) participated in the Cumulative Stress/Adversity Interview (CAI), a 140-item event interview measuring cumulative adversity including major life events, life trauma, recent life events and chronic stressors, and underwent 24-h ambulatory ECG monitoring. HRV was analyzed in the frequency domain and standard deviation of NN intervals (SDNN) calculated. Initial simple regression analyses revealed that total cumulative stress score, chronic stressors and cumulative adverse life events (CALE) were all inversely associated with ultra low-frequency (ULF), very low-frequency (VLF) and low-frequency (LF) power and SDNN (all p < 0.05). In hierarchical regression analyses, total cumulative stress and chronic stress each was significantly associated with SDNN and ULF even after the highly significant contributions of age and sex, with no other covariates accounting for additional appreciable variance. For VLF and LF, both total cumulative stress and chronic stress significantly contributed to the variance alone but were not longer significant after adjusting for race and health behaviors. In summary, total cumulative stress, and its components of adverse life events and chronic stress were associated with decreased cardiac autonomic function as measured by HRV. Findings suggest one potential mechanism by which stress may exert adverse effects on mortality in healthy individuals. Primary preventive strategies including stress management may prove beneficial.

Cumulative stress and autonomic dysregulation in a community sample

PubMed Central

Lampert, Rachel; Tuit, Keri; Hong, Kwang-ik; Donovan, Theresa; Lee, Forrester; Sinha, Rajita

2016-01-01

Whether cumulative stress, including both chronic stress and adverse life events, is associated with decreased heart rate variability (HRV), a non-invasive measure of autonomic status which predicts poor cardiovascular outcomes, is unknown. Healthy community dwelling volunteers, (N= 157, mean age 29 years) participated in the Cumulative Stress/Adversity Interview, (CAI) a 140-item event interview measuring cumulative adversity including major life events, life trauma, recent life events and chronic stressors, and underwent 24 hour ambulatory ECG monitoring. HRV was analyzed in the frequency domain and standard deviation of NN intervals (SDNN) calculated. Initial simple regression analyses revealed that total cumulative stress score, chronic stressors, and cumulative adverse life events (CALE) were all inversely associated with ultra low frequency (ULF), very low frequency (VLF), and low frequency (LF) power and SDNN (all p<0.05). In hierarchical regression analyses, total cumulative stress and chronic stress each was significantly associated with SDNN and ULF even after the high significant contribution of age and sex, with no other covariates accounting for additional appreciable variance. For VLF and LF, both total cumulative stress and chronic stress significantly contributed to the variance were no longer significant after adjusting for race and health behaviors. (p’s<.05). In summary, total cumulative stress, and its components of adverse life events and chronic stress were associated with decreased cardiac autonomic function as measured by HRV. Findings suggest one potential mechanism by which stress may exert adverse effects on mortality in healthy individuals. Primary preventive strategies including stress management may prove beneficial. PMID:27112063

Guidance on health effects of toxic chemicals. Safety Analysis Report Update Program

DOE Office of Scientific and Technical Information (OSTI.GOV)

Foust, C.B.; Griffin, G.D.; Munro, N.B.

1994-02-01

Martin Marietta Energy Systems, Inc. (MMES), and Martin Marietta Utility Services, Inc. (MMUS), are engaged in phased programs to update the safety documentation for the existing US Department of Energy (DOE)-owned facilities. The safety analysis of potential toxic hazards requires a methodology for evaluating human health effects of predicted toxic exposures. This report provides a consistent set of health effects and documents toxicity estimates corresponding to these health effects for some of the more important chemicals found within MMES and MMUS. The estimates are based on published toxicity information and apply to acute exposures for an ``average`` individual. The healthmore » effects (toxicological endpoints) used in this report are (1) the detection threshold; (2) the no-observed adverse effect level; (3) the onset of irritation/reversible effects; (4) the onset of irreversible effects; and (5) a lethal exposure, defined to be the 50% lethal level. An irreversible effect is defined as a significant effect on a person`s quality of life, e.g., serious injury. Predicted consequences are evaluated on the basis of concentration and exposure time.« less

Value of α-fetoprotein as an early biomarker for treatment response to sorafenib therapy in advanced hepatocellular carcinoma.

PubMed

Sánchez, Ana Isabel Plano; Roces, Lucía Velasco; García, Isabel Zapico; López, Eva Lázaro; Hernandez, Miguel Angel Calleja; Parejo, Maria Isabel Baena; Peña-Díaz, Jaime

2018-06-01

Sorafenib is an oral multikinase inhibitor with antiangiogenic and antiproliferative properties, and is used as the first-line treatment for patients with advanced hepatocellular carcinoma (HCC). Previous studies have identified an improvement in overall survival and progression-free survival in patients with a manageable toxicity profile. α-fetoprotein (AFP) has been revealed to be of great diagnostic and predictive value for tumour staging in multiple studies; however, its role as a predictive factor of response to treatment with sorafenib is not entirely clear. The present study aimed to determine the effectiveness of sorafenib and investigate the value of AFP as a predictive factor of early response to sorafenib in patients with HCC. Effectiveness was analysed based on median overall survival (mOS) time, while to analyse the possible predictive value of AFP, patients were classified into two groups: Non-responders (≤20% AFP reduction) and responders (>20% AFP reduction) at 6-8 weeks of treatment when compared with basal AFP level. For assessment of toxicity, any adverse effects were recorded. A total of 167 patients were included, who collectively exhibited a mOS time of 11 months with a median treatment duration of 5 months. The mOS time was significantly higher for patients with better hepatic function (12 months in cases of Child-Pugh score A vs. 8 months in cases of Child-Pugh score B; P=0.03) and with basal AFP values ≤200 ng/ml (14 months vs. 8 months in patients with AFP levels >200 ng/ml; P=0.01). A >20% reduction of AFP at 6-8 weeks was determined to be a positive predictive factor upon multivariate analysis (P=0.002), obtaining, for the responder patients, an mOS of 18 months compared with 10 months (P=0.004) for the non-responders. The main adverse reactions were hand-foot syndrome (35/167; 21%), diarrhoea (39/167; 23.4%), anorexia (29/167; 17.4%) and arterial hypertension (30/167; 18%). In conclusion, a >20% drop in AFP at 6-8 weeks may be useful as a predictive factor of response to sorafenib, as indicated by its association with longer survival times in patients with advanced HCC following treatment with sorafenib in the present study.

Development and application of the adverse outcome pathway framework for understanding and predicting chronic toxicity: I. Challenges and research needs in ecotoxicology.

PubMed

Groh, Ksenia J; Carvalho, Raquel N; Chipman, James K; Denslow, Nancy D; Halder, Marlies; Murphy, Cheryl A; Roelofs, Dick; Rolaki, Alexandra; Schirmer, Kristin; Watanabe, Karen H

2015-02-01

To elucidate the effects of chemicals on populations of different species in the environment, efficient testing and modeling approaches are needed that consider multiple stressors and allow reliable extrapolation of responses across species. An adverse outcome pathway (AOP) is a concept that provides a framework for organizing knowledge about the progression of toxicity events across scales of biological organization that lead to adverse outcomes relevant for risk assessment. In this paper, we focus on exploring how the AOP concept can be used to guide research aimed at improving both our understanding of chronic toxicity, including delayed toxicity as well as epigenetic and transgenerational effects of chemicals, and our ability to predict adverse outcomes. A better understanding of the influence of subtle toxicity on individual and population fitness would support a broader integration of sublethal endpoints into risk assessment frameworks. Detailed mechanistic knowledge would facilitate the development of alternative testing methods as well as help prioritize higher tier toxicity testing. We argue that targeted development of AOPs supports both of these aspects by promoting the elucidation of molecular mechanisms and their contribution to relevant toxicity outcomes across biological scales. We further discuss information requirements and challenges in application of AOPs for chemical- and site-specific risk assessment and for extrapolation across species. We provide recommendations for potential extension of the AOP framework to incorporate information on exposure, toxicokinetics and situation-specific ecological contexts, and discuss common interfaces that can be employed to couple AOPs with computational modeling approaches and with evolutionary life history theory. The extended AOP framework can serve as a venue for integration of knowledge derived from various sources, including empirical data as well as molecular, quantitative and evolutionary-based models describing species responses to toxicants. This will allow a more efficient application of AOP knowledge for quantitative chemical- and site-specific risk assessment as well as for extrapolation across species in the future. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

Tolerability of High-dose Baclofen in the Treatment of Patients with Alcohol Disorders: A Retrospective Study.

PubMed

Rigal, Laurent; Legay Hoang, Léa; Alexandre-Dubroeucq, Constance; Pinot, Juliette; Le Jeunne, Claire; Jaury, Philippe

2015-09-01

The aim of this study was to describe the tolerability of high-dose baclofen taken by patients with alcohol disorders during their first year of treatment. The medical records of all patients prescribed baclofen by one general practitioner were examined and all patients who could be contacted were retrospectively interviewed about adverse effects. Of the 146 eligible patients, 116 (79%) could be interviewed. Ninety (78%) reported at least one adverse effect (mean number per patient: 2.8 ± 2.7). The mean dosage of baclofen at the onset of the first adverse effect was 83 ± 57 mg/day. The most frequent group of adverse effects involved disruption of the wake-sleep cycle and affected 73 patients (63%). Persistent adverse effects occurred in 62 patients (53%). Eight patients (7%) had adverse effects that led them to stop taking baclofen. Their dosages were <90 mg/day at that time. Alertness disorders and depression were the adverse effects that most frequently led to stopping baclofen. Bouts of somnolence and hypomanic episodes were the most potentially dangerous adverse effects. Women reported significantly more adverse effects than men. High-dose baclofen exposes patients with alcohol disorders to many adverse effects. Generally persistent, some adverse effects appear at low doses and may be dangerous. © The Author 2015. Medical Council on Alcohol and Oxford University Press. All rights reserved.

The sFlt-1/PlGF ratio associates with prolongation and adverse outcome of pregnancy in women with (suspected) preeclampsia: analysis of a high-risk cohort.

PubMed

Saleh, Langeza; Verdonk, Koen; Jan Danser, A H; Steegers, Eric A P; Russcher, Henk; van den Meiracker, Anton H; Visser, Willy

2016-04-01

To evaluate the additive value of the sFlt-1/PlGF ratio for diagnosing preeclampsia (PE) and predicting prolongation of pregnancy and adverse outcome in a cohort of women with PE or at high risk of PE. Patients with suspected or confirmed clinical PE were recruited. At time of inclusion blood for measurement of sFlt-1and PlGF was taken. Values were determined after delivery. A cut-off ratio of ≥85 was defined as a positive test. A total of 107 patients were included. Of the patients, 62 (58%) met the clinical criteria of PE at time of blood sampling. In 10% of these patients (n=6) the ratio was <85 (false negative), whereas in 7% (n=3) of patients without clinical PE the ratio was ≥85 (false positive), resulting in positive and negative predictive values of 95% and 88% respectively. One patient with false positive ratio developed superimposed PE and 2 developed gestational hypertension, and adverse outcome occurred in all three. An adverse pregnancy outcome was only encountered in 1 of the 6 patients with a false negative ratio. Using a binary regression model with adjustment for gestational age <34 weeks, the adverse outcome risk was 11 times increased on the basis of clinical PE, and 30 times on the basis of an elevated ratio (P=0.036). The additive value of an increased ratio for diagnosing PE is limited since most patients with clinical PE also have a positive ratio. However, an elevated ratio is superior to the clinical diagnosis of PE for predicting an adverse pregnancy outcome. Furthermore, irrespective of clinical PE, a low ratio is inversely correlated with prolongation of pregnancy. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Usefulness of fetal urine production measurement for prediction of perinatal outcomes in uteroplacental insufficiency.

PubMed

Lee, Seung Mi; Jun, Jong Kwan; Kim, Su Ah; Lee, Eun Ja; Kim, Byoung Jae; Park, Chan-Wook; Park, Joong Shin

2014-12-01

To evaluate whether fetal urine production measurement is useful for predicting adverse outcomes in patients with uteroplacental insufficiency. We enrolled patients with uteroplacental insufficiency at 24 to 40 weeks' gestation and normal pregnancies matched for gestational age and divided them into 3 groups according to perinatal outcomes: group 1 (n = 141), a control group of normal pregnancies; group 2 (n = 29), uteroplacental insufficiency without adverse outcomes; and group 3 (n = 18), uteroplacental insufficiency with adverse outcomes. An adverse outcome was defined as 1 or more of the following: (1) cesarean delivery because of fetal distress; (2) admission to the neonatal intensive care unit; (3) cord arterial pH less than 7.15 at birth; and (4) low 5-minute Apgar score (<7). The fetal urine production rate was obtained by serial bladder volume measurement using virtual organ computer-aided analysis. For bladder volume determination, we scanned the bladder in the 3-dimensional mode and defined the bladder surface contour in the reference plane, repeating the rotation of the reference plane with an angle of 30° and determining the surface contour on each plane. Statistical methods, including the Mann-Whitney U test, Fisher exact test, χ(2) test, and Kruskal-Wallis analysis of variance, were used. Group 3 had a lower mean fetal urine production rate than groups 1 and 2, whereas the urine production rate was not different between groups 1 and 2 (group 1, 49.0 mL/h; group 2, 59.4 mL/h; group 3, 20.7 mL/h; P < .001 between groups 1 and 3 and between groups 2 and 3). This difference between groups 2 and 3 remained significant after adjusting for the amniotic fluid index, umbilical artery Doppler pulsatility index, and presence of fetal growth restriction. Uteroplacental insufficiency cases with adverse perinatal outcomes had a lower fetal urine production rate than those without adverse outcomes. This difference might be used to predict adverse perinatal outcomes in uteroplacental insufficiency. © 2013 by the American Institute of Ultrasound in Medicine.

Predicting Adverse Outcomes After Myocardial Infarction Among Patients With Diabetes Mellitus.

PubMed

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

2016-07-01

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, whereas others are at high risk. We sought to develop prediction models to stratify risk after AMI in patients with diabetes mellitus. We developed prediction models for long-term mortality and angina among 1613 patients with diabetes mellitus discharged alive after AMI from 24 US hospitals and then validated the models in a separate, multicenter registry of 786 patients with diabetes mellitus. 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 before the AMI, younger age, history of prior coronary bypass graft surgery, and non-white race. The lowest and highest deciles of predicted risk ranged from 4% to 80% for mortality and 12% to 59% for angina. The models also performed well in external validation (c-indices=0.78 and 0.73, respectively). We found a wide range of risk for adverse outcomes after AMI in diabetic patients. Predictive models can identify patients with diabetes mellitus for whom closer follow-up and aggressive secondary prevention strategies should be considered. © 2016 American Heart Association, Inc.

Effects of early maternal distress and parenting on the development of children's self-regulation and externalizing behavior.

PubMed

Choe, Daniel Ewon; Olson, Sheryl L; Sameroff, Arnold J

2013-05-01

Emotional distress experienced by mothers increases young children's risk of externalizing problems through suboptimal parenting and child self-regulation. An integrative structural equation model tested hypotheses that mothers' parenting (i.e., low levels of inductive discipline and maternal warmth) would mediate adverse effects of early maternal distress on child effortful control, which in turn would mediate effects of maternal parenting on child externalizing behavior. This longitudinal study spanning ages 3, 6, and 10 included 241 children, mothers, and a subset of teachers. The hypothesized model was partially supported. Elevated maternal distress was associated with less inductive discipline and maternal warmth, which in turn were associated with less effortful control at age 3 but not at age 6. Inductive discipline and maternal warmth mediated adverse effects of maternal distress on children's effortful control. Less effortful control at ages 3 and 6 predicted smaller relative decreases in externalizing behavior at 6 and 10, respectively. Effortful control mediated effects of inductive discipline, but not maternal warmth, on externalizing behavior. Findings suggest elevated maternal distress increases children's risk of externalizing problems by compromising early parenting and child self-regulation.

The effect of pre-donation hypotension on whole blood donor adverse reactions: a systematic review.

PubMed

Pauwels, Nele S; Cusack, Leila; De Buck, Emmy; Compernolle, Veerle; Vandekerckhove, Philippe

2014-06-01

Blood services are reliant upon healthy blood donors to provide a safe and adequate supply of blood products. Inappropriate variables contained within blood donor exclusion criteria can defer potentially appropriate donors. The aim of this systematic review was to examine the effect of low pre-donation blood pressure, as compared with normal blood pressure, on adverse events in allogeneic whole blood donors. A systematic review was performed using highly sensitive search strategies within five databases (Cochrane Central Register of Controlled Trials, CINAHL, Embase, MEDLINE, and Web of Science) from inception date until April 12, 2013. Out of 8305 records, 10 observational studies were identified that addressed the question. Five of these studies (with a combined total of 1,482,020 donations and 2903 donors) included either a statistical analysis or an appropriate study design that controlled for possible confounding factors. Based on the currently available evidence, hypotension has not been shown to be an independent predictive factor for donor complications. However, the overall quality of evidence was rather limited and rated 'low,' using the GRADE approach. In conclusion there is currently no evidence that hypotensive blood donors have a greater risk for donor adverse events compared with their normotensive counterparts. Copyright © 2014 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.

Direct and indirect effects of child abuse and environmental stress: A lifecourse perspective on adversity and depressive symptoms.

PubMed

Sousa, Cindy; Mason, W Alex; Herrenkohl, Todd I; Prince, Dana; Herrenkohl, Roy C; Russo, M Jean

2018-01-01

There is a great deal of evidence about the mental health implications of physical child abuse and environmental stressors, or hardships that people experience at the household and neighborhood level (e.g., neighborhood violence; economic hardship, substance abuse, or conflict among family members). Yet, studies often focus on either abuse or environmental stress, not both, or examine abuse and environmental stressors as a combined set of experiences. Less is known, therefore, about how child abuse and environmental stress might work as either distinct or interrelated risks to diminish mental health over time. In this longitudinal study, we used path analyses to examine the cumulative effects of physical child abuse and environmental stressors on adult depressive symptoms among a sample of children followed into adulthood (N = 356). The goal was to assess whether chronic physical child abuse remains an independent predictor of adult outcomes once we accounted for the cumulative effects of household and neighborhood stressors across the lifecourse. Cumulative measures of physical child abuse and environmental stress each independently predicted a higher likelihood of adult depressive symptoms (ß = .122, p < .01 and ß = .283, p < .001, respectively). After accounting for adolescent depressive symptoms, only cumulative environmental stressors independently predicted depressive symptoms (ß = .202, p < .001). Tests of the indirect effect of cumulative environmental stress on the relationship between cumulative physical abuse and adult depressive symptoms were marginally statistically significant. Results add to literature that examines child abuse, adversity, and lifecourse perspectives on health. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Prenatal stress accelerates offspring growth to compensate for reduced maternal investment across mammals

PubMed Central

Berghänel, Andreas; Heistermann, Michael; Schülke, Oliver; Ostner, Julia

2017-01-01

Across mammals, prenatal maternal stress (PREMS) affects many aspects of offspring development, including offspring growth. However, how PREMS translates to offspring growth is inconsistent, even within species. To explain the full range of reported effects of prenatal adversity on offspring growth, we propose an integrative hypothesis: developmental constraints and a counteracting adaptive growth plasticity work in opposition to drive PREMS effects on growth. Mothers experiencing adversity reduce maternal investment leading to stunted growth (developmental constraints). Concomitantly, the pace of offspring life history is recalibrated to partly compensate for these developmental constraints (adaptive growth plasticity). Moreover, the relative importance of each process changes across ontogeny with increasing offspring independence. Thus, offspring exposed to PREMS may grow at the same rate as controls during gestation and lactation, but faster after weaning when direct maternal investment has ceased. We tested these predictions with a comparative analysis on the outcomes of 719 studies across 21 mammal species. First, the observed growth changes in response to PREMS varied across offspring developmental periods as predicted. We argue that the observed growth acceleration after weaning is not “catch-up growth,” because offspring that were small for age grew slower. Second, only PREMS exposure early during gestation produced adaptive growth plasticity. Our results suggest that PREMS effects benefit the mother’s future reproduction and at the same time accelerate offspring growth and possibly maturation and reproductive rate. In this sense, PREMS effects on offspring growth allow mother and offspring to make the best of a bad start. PMID:29180423

Dysthymic Disorder and Double Depression: Prediction of 10-Year Course Trajectories and Outcomes

PubMed Central

Klein, Daniel N.; Shankman, Stewart A.; Rose, Suzanne

2008-01-01

We sought to identify baseline predictors of 10-year course trajectories and outcomes in patients with dysthymic disorder and double depression. Eighty-seven outpatients with early-onset (< 21 years) dysthymic disorder, with or without superimposed major depression, were assessed five times at 30-month intervals for 10 years. Baseline evaluations included semi-structured diagnostic interviews for Axis I and II psychopathology and childhood adversity. Direct interview and family history data were collected on first-degree relatives. Follow-up assessments included the Longitudinal Follow-up Evaluation and Hamilton Depression Rating Scale. Using mixed effects growth curve models, univariate predictors of depression severity and functional impairment at 10-year outcome included older age, less education, concurrent anxiety disorder, greater familial loading for chronic depression, a history of a poorer maternal relationship in childhood, and a history of childhood sexual abuse. In addition, longer duration of dysthymic disorder also predicted greater impairment 10 years later. Predictors of a poorer trajectory of depressive symptoms over time included ethnicity and personality disorders; predictors of a poorer trajectory of social functioning included familial loading of chronic depression and quality of the childhood maternal relationship. Thus, demographic, clinical, family history, and early adversity variables all contribute to predicting the long term trajectory and outcome of DD. These variables should be routinely assessed in clinical evaluations and can provide clinicians with valuable prognostic information. PMID:17466334

Dysthymic disorder and double depression: prediction of 10-year course trajectories and outcomes.

PubMed

Klein, Daniel N; Shankman, Stewart A; Rose, Suzanne

2008-04-01

We sought to identify baseline predictors of 10-year course trajectories and outcomes in patients with dysthymic disorder and double depression. Eighty-seven outpatients with early-onset (<21 years) dysthymic disorder, with or without superimposed major depression, were assessed five times at 30-month intervals for 10 years. Baseline evaluations included semi-structured diagnostic interviews for Axis I and II psychopathology and childhood adversity. Direct interview and family history data were collected on first-degree relatives. Follow-up assessments included the Longitudinal Follow-up Evaluation and Hamilton Depression Rating Scale. Using mixed effects growth curve models, univariate predictors of depression severity and functional impairment at 10-year outcome included older age, less education, concurrent anxiety disorder, greater familial loading for chronic depression, a history of a poorer maternal relationship in childhood, and a history of childhood sexual abuse. In addition, longer duration of dysthymic disorder also predicted greater impairment 10 years later. Predictors of a poorer trajectory of depressive symptoms over time included ethnicity and personality disorders; predictors of a poorer trajectory of social functioning included familial loading of chronic depression and quality of the childhood maternal relationship. Thus, demographic, clinical, family history, and early adversity variables all contribute to predicting the long-term trajectory and outcome of DD. These variables should be routinely assessed in clinical evaluations and can provide clinicians with valuable prognostic information.

New approach to predict photoallergic potentials of chemicals based on murine local lymph node assay.

PubMed

Maeda, Yosuke; Hirosaki, Haruka; Yamanaka, Hidenori; Takeyoshi, Masahiro

2018-05-23

Photoallergic dermatitis, caused by pharmaceuticals and other consumer products, is a very important issue in human health. However, S10 guidelines of the International Conference on Harmonization do not recommend the existing prediction methods for photoallergy because of their low predictability in human cases. We applied local lymph node assay (LLNA), a reliable, quantitative skin sensitization prediction test, to develop a new photoallergy prediction method. This method involves a three-step approach: (1) ultraviolet (UV) absorption analysis; (2) determination of no observed adverse effect level for skin phototoxicity based on LLNA; and (3) photoallergy evaluation based on LLNA. Photoallergic potential of chemicals was evaluated by comparing lymph node cell proliferation among groups treated with chemicals with minimal effect levels of skin sensitization and skin phototoxicity under UV irradiation (UV+) or non-UV irradiation (UV-). A case showing significant difference (P < .05) in lymph node cell proliferation rates between UV- and UV+ groups was considered positive for photoallergic reaction. After testing 13 chemicals, seven human photoallergens tested positive and the other six, with no evidence of causing photoallergic dermatitis or UV absorption, tested negative. Among these chemicals, both doxycycline hydrochloride and minocycline hydrochloride were tetracycline antibiotics with different photoallergic properties, and the new method clearly distinguished between the photoallergic properties of these chemicals. These findings suggested high predictability of our method; therefore, it is promising and effective in predicting human photoallergens. Copyright © 2018 John Wiley & Sons, Ltd.

Pharmacogenetics of drug-metabolizing enzymes: implications for a safer and more effective drug therapy

PubMed Central

Ingelman-Sundberg, Magnus; Rodriguez-Antona, Cristina

2005-01-01

The majority of phase I- and phase II-dependent drug metabolism is carried out by polymorphic enzymes which can cause abolished, quantitatively or qualitatively decreased or enhanced drug metabolism. Several examples exist where subjects carrying certain alleles do not benefit from drug therapy due to ultrarapid metabolism caused by multiple genes or by induction of gene expression or, alternatively, suffer from adverse effects of the drug treatment due to the presence of defective alleles. It is likely that future predictive genotyping for such enzymes might benefit 15–25% of drug treatments, and thereby allow prevention of adverse drug reactions and causalities, and thus improve the health of a significant fraction of the patients. However, it will take time before this will be a reality within the clinic. We describe some important aspects in the field with emphasis on cytochrome P450 and discuss also polymorphic aspects of foetal expression of CYP3A5 and CYP3A7. PMID:16096104

The Australian experience in dental classification.

PubMed

Mahoney, Greg

2008-01-01

The Australian Defence Health Service uses a disease-risk management strategy to achieve two goals: first, to identify Australian Defence Force (ADF) members who are at high risk of developing an adverse health event, and second, to deliver intervention strategies efficiently so that maximum benefits for health within the ADF are achieved with the least cost. The present dental classification system utilized by the ADF, while an excellent dental triage tool, has been found not to be predictive of an ADF member having an adverse dental event in the following 12-month period. Clearly, there is a need for further research to establish a predictive risk-based dental classification system. This risk assessment must be sensitive enough to accurately estimate the probability that an ADF member will experience dental pain, dysfunction, or other adverse dental events within a forthcoming period, typically 12 months. Furthermore, there needs to be better epidemiological data collected in the field to assist in the research.

Validity and reliability of a novel immunosuppressive adverse effects scoring system in renal transplant recipients.

PubMed

Meaney, Calvin J; Arabi, Ziad; Venuto, Rocco C; Consiglio, Joseph D; Wilding, Gregory E; Tornatore, Kathleen M

2014-06-12

After renal transplantation, many patients experience adverse effects from maintenance immunosuppressive drugs. When these adverse effects occur, patient adherence with immunosuppression may be reduced and impact allograft survival. If these adverse effects could be prospectively monitored in an objective manner and possibly prevented, adherence to immunosuppressive regimens could be optimized and allograft survival improved. Prospective, standardized clinical approaches to assess immunosuppressive adverse effects by health care providers are limited. Therefore, we developed and evaluated the application, reliability and validity of a novel adverse effects scoring system in renal transplant recipients receiving calcineurin inhibitor (cyclosporine or tacrolimus) and mycophenolic acid based immunosuppressive therapy. The scoring system included 18 non-renal adverse effects organized into gastrointestinal, central nervous system and aesthetic domains developed by a multidisciplinary physician group. Nephrologists employed this standardized adverse effect evaluation in stable renal transplant patients using physical exam, review of systems, recent laboratory results, and medication adherence assessment during a clinic visit. Stable renal transplant recipients in two clinical studies were evaluated and received immunosuppressive regimens comprised of either cyclosporine or tacrolimus with mycophenolic acid. Face, content, and construct validity were assessed to document these adverse effect evaluations. Inter-rater reliability was determined using the Kappa statistic and intra-class correlation. A total of 58 renal transplant recipients were assessed using the adverse effects scoring system confirming face validity. Nephrologists (subject matter experts) rated the 18 adverse effects as: 3.1 ± 0.75 out of 4 (maximum) regarding clinical importance to verify content validity. The adverse effects scoring system distinguished 1.75-fold increased gastrointestinal adverse effects (p=0.008) in renal transplant recipients receiving tacrolimus and mycophenolic acid compared to the cyclosporine regimen. This finding demonstrated construct validity. Intra-class correlation was 0.81 (95% confidence interval: 0.65-0.90) and Kappa statistic of 0.68 ± 0.25 for all 18 adverse effects and verified substantial inter-rater reliability. This immunosuppressive adverse effects scoring system in stable renal transplant recipients was evaluated and substantiated face, content and construct validity with inter-rater reliability. The scoring system may facilitate prospective, standardized clinical monitoring of immunosuppressive adverse drug effects in stable renal transplant recipients and improve medication adherence.

Immediate effects of lumacaftor/ivacaftor administration on lung function in patients with severe cystic fibrosis lung disease.

PubMed

Popowicz, Natalia; Wood, Jamie; Tai, Anna; Morey, Sue; Mulrennan, Siobhain

2017-05-01

Safety-data for lumacaftor/ivacaftor (LUM/IVA) combination therapy in patients with severe lung disease (percent predicted forced expiratory volume in 1s [ppFEV 1 ] <40) remain limited. We report immediate post-dose respiratory-related adverse events in 12 patients with severe cystic fibrosis (CF) lung disease (median [IQR] ppFEV 1 : 34 [31-36]) prescribed LUM/IVA. All patients experienced a decline in ppFEV 1 from baseline at 2-hours (median [IQR] relative change: -19 [-21 to -11]%, p<0.001) that persisted at 24-hours but recovered in most patients at 1-month. No pre- and post-differences in bronchodilator response were observed. Ten (83.3%) patients reported non-severe respiratory-related adverse events within 24-hours of LUM/IVA initiation. At 1-month, eight (67%) patients had persistent symptoms and six (50%) were treated for a pulmonary exacerbation. Our results highlight that LUM/IVA respiratory-related adverse events are common in patients with a ppFEV 1 <40. We recommend close assessment of adverse events. Further studies are required to evaluate the efficacy of LUM/IVA in patients with severe lung disease. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

Genomic scar signatures associated with homologous recombination deficiency predict adverse clinical outcomes in patients with ovarian clear cell carcinoma.

PubMed

Chao, Angel; Lai, Chyong-Huey; Wang, Tzu-Hao; Jung, Shih-Ming; Lee, Yun-Shien; Chang, Wei-Yang; Yang, Lan-Yang; Ku, Fei-Chun; Huang, Huei-Jean; Chao, An-Shine; Wang, Chin-Jung; Chang, Ting-Chang; Wu, Ren-Chin

2018-05-03

We investigated whether genomic scar signatures associated with homologous recombination deficiency (HRD), which include telomeric allelic imbalance (TAI), large-scale transition (LST), and loss of heterozygosity (LOH), can predict clinical outcomes in patients with ovarian clear cell carcinoma (OCCC). We enrolled patients with OCCC (n = 80) and high-grade serous carcinoma (HGSC; n = 92) subjected to primary cytoreductive surgery, most of whom received platinum-based adjuvant chemotherapy. Genomic scar signatures based on genome-wide copy number data were determined in all participants and investigated in relation to prognosis. OCCC had significantly lower genomic scar signature scores than HGSC (p < 0.001). Near-triploid OCCC specimens showed higher TAI and LST scores compared with diploid tumors (p < 0.001). While high scores of these genomic scar signatures were significantly associated with better clinical outcomes in patients with HGSC, the opposite was evident for OCCC. Multivariate survival analysis in patients with OCCC identified high LOH scores as the main independent adverse predictor for both cancer-specific (hazard ratio [HR] = 3.22, p = 0.005) and progression-free survival (HR = 2.54, p = 0.01). In conclusion, genomic scar signatures associated with HRD predict adverse clinical outcomes in patients with OCCC. The LOH score was identified as the strongest prognostic indicator in this patient group. Genomic scar signatures associated with HRD are less frequent in OCCC than in HGSC. Genomic scar signatures associated with HRD have an adverse prognostic impact in patients with OCCC. LOH score is the strongest adverse prognostic factor in patients with OCCC.

Changes in Brain Metabolite Concentrations after Neonatal Hypoxic-ischemic Encephalopathy.

PubMed

Shibasaki, Jun; Aida, Noriko; Morisaki, Naho; Tomiyasu, Moyoko; Nishi, Yuri; Toyoshima, Katsuaki

2018-06-12

Purpose To investigate the time-course changes and predictive utility of brain metabolite concentrations in neonatal hypoxic-ischemic encephalopathy (HIE). Materials and Methods Sixty-eight neonates (age, 35-41 gestational weeks) with HIE were admitted to a neonatal intensive care unit between September 2009 and March 2016 and examined by using proton MR spectroscopy at 18-96 hours (n = 25) and 7-14 days (n = 64) after birth (35-43 postmenstrual weeks) to estimate metabolite concentrations in the deep gray matter. Adverse outcome was defined as death or neurodevelopmental impairment at 18-22 months of age. Areas under the receiver operating characteristic curves were calculated to evaluate the prognostic values of metabolites. Results At 18-96 hours, N-acetylaspartate and creatine concentrations were lower, whereas lactate, and glutamate and glutamine (Glx) concentrations were higher in neonates with adverse outcomes than in those with favorable outcomes. Metabolite concentrations at 18-96 hours decreased during days 7-14 in neonates with adverse outcomes but did not change in those with favorable outcomes. For N-acetylaspartate, creatine, lactate, and Glx concentrations measured at 18-96 hours to predict adverse outcomes, areas under the receiver operating characteristic curve were 0.98, 0.89, 0.96, and 0.88, respectively, whereas at 7-14 days, the areas under the receiver operating characteristic curve were 0.97, 0.97, 0.59, and 0.36, respectively. Conclusion Time-dependent reductions in N-acetylaspartate and creatine concentrations at both 18-96 hours and 7-14 days accurately predicted adverse outcomes. However, higher lactate and glutamate and glutamine concentrations were often transient. © RSNA, 2018 Online supplemental material is available for this article.

Evaluation of third trimester uterine artery flow velocity indices in relationship to perinatal complications.

PubMed

Ghosh, G; Breborowicz, A; Brazert, M; Maczkiewicz, M; Kobelski, M; Dubiel, M; Gudmundsson, S

2006-09-01

Uterine artery Doppler is becoming a routine part of pregnancy surveillance in high-risk pregnancies. Which blood flow velocity waveform index to measure is debated and the 'notch' in early diastole is not widely accepted, as it is a subjective measure. The aim of the present study was to evaluate the different indices in the prediction of adverse outcome of pregnancies suspected for intrauterine fetal growth restriction (IUGR). Uterine artery blood flow was recorded in 217 pregnancies admitted for Doppler ultrasound surveillance due to suspected IUGR. The median gestational age at examination was 38 weeks (range 25-42 weeks). Only cases having bilateral uterine artery notching were included in the evaluation. The uterine artery Doppler spectrum was analyzed for different indices, including evaluation of notch and end-diastolic velocities. Umbilical artery Doppler velocimetry was also performed. The outcome variables chosen were: a small-for-gestational-age (SGA) newborn, preterm birth, and abdominal delivery. ROC-curve calculations were used to compare the different indices. The uterine artery blood velocity pulsatility index (PI) and resistance indices (RI) were the best predictors of adverse outcome of pregnancy. Apart from premature birth, the systolic/end-diastolic ratio was less predictive of adverse outcome. The indices including only diastolic blood velocities were the least predictive of adverse outcome. The group with notch velocity above end-diastolic velocity was compared with those having notch velocity below the end-diastolic velocity. No difference in outcome was seen between the two groups. RI and PI as measures of third trimester utero-placental vascular impedance are the best predictors of adverse outcome of IUGR-suspected pregnancies.

Added Value of Physical Performance Measures in Predicting Adverse Health-Related Events: Results from the Health, Aging, and Body Composition Study

PubMed Central

Cesari, Matteo; Kritchevsky, Stephen B; Newman, Anne B; Simonsick, Eleanor M; Harris, Tamara B; Penninx, Brenda W; Brach, Jennifer S; Tylavsky, Frances A; Satterfield, Suzanne; Bauer, Doug C; Rubin, Susan M; Visser, Marjolein; Pahor, Marco

2009-01-01

Objectives To determine how three different physical performance measures (PPM) combine for added utility in predicting adverse health events in elders. Design Prospective cohort study. Setting Health, Aging, and Body Composition Study. Participants 3,024 well-functioning older persons (mean age 73.6 years). Measurements Timed gait, repeated chair stands and balance (semi- and full-tandem, and single leg stands each held for 30 seconds) tests were administered at baseline. Usual gait speed was categorized to distinguish high and low risk participants using the previously established 1 m/sec cut-point. The same population-percentile (21.3%) was used to identify cut-points for repeated chair stands (17.05 sec) and balance (53 sec) tests. Cox proportional hazard analyses were performed to evaluate the added value of PPM in predicting mortality, hospitalization, and (severe) mobility limitation events over 6.9 years of follow-up. Results Risk estimates for developing adverse health-related events were similarly large for each of the three high risk groups considered separately. A greater number of PPM scores at the high risk level was associated with a greater risk of developing adverse health-related events. When all three PPMs were considered, having only one poor performance was sufficient to indicate a highly significant higher risk of (severe) lower extremity and mortality events. Conclusion Although gait speed is considered the most important predictor of adverse health events, these findings demonstrate that poor performance on other tests of lower extremity function are equally prognostic. This suggests that chair stand and standing balance performance may be adequate substitutes when gait speed is unavailable. PMID:19207142

Computed Tomography Imaging Features in Acute Uncomplicated Stanford Type-B Aortic Dissection Predict Late Adverse Events.

PubMed

Sailer, Anna M; van Kuijk, Sander M J; Nelemans, Patricia J; Chin, Anne S; Kino, Aya; Huininga, Mark; Schmidt, Johanna; Mistelbauer, Gabriel; Bäumler, Kathrin; Chiu, Peter; Fischbein, Michael P; Dake, Michael D; Miller, D Craig; Schurink, Geert Willem H; Fleischmann, Dominik

2017-04-01

Medical treatment of initially uncomplicated acute Stanford type-B aortic dissection is associated with a high rate of late adverse events. Identification of individuals who potentially benefit from preventive endografting is highly desirable. The association of computed tomography imaging features with late adverse events was retrospectively assessed in 83 patients with acute uncomplicated Stanford type-B aortic dissection, followed over a median of 850 (interquartile range 247-1824) days. Adverse events were defined as fatal or nonfatal aortic rupture, rapid aortic growth (>10 mm/y), aneurysm formation (≥6 cm), organ or limb ischemia, or new uncontrollable hypertension or pain. Five significant predictors were identified using multivariable Cox regression analysis: connective tissue disease (hazard ratio [HR] 2.94, 95% confidence interval [CI]: 1.29-6.72; P =0.01), circumferential extent of false lumen in angular degrees (HR 1.03 per degree, 95% CI: 1.01-1.04, P =0.003), maximum aortic diameter (HR 1.10 per mm, 95% CI: 1.02-1.18, P =0.015), false lumen outflow (HR 0.999 per mL/min, 95% CI: 0.998-1.000; P =0.055), and number of intercostal arteries (HR 0.89 per n, 95% CI: 0.80-0.98; P =0.024). A prediction model was constructed to calculate patient specific risk at 1, 2, and 5 years and to stratify patients into high-, intermediate-, and low-risk groups. The model was internally validated by bootstrapping and showed good discriminatory ability with an optimism-corrected C statistic of 70.1%. Computed tomography imaging-based morphological features combined into a prediction model may be able to identify patients at high risk for late adverse events after an initially uncomplicated type-B aortic dissection. © 2017 American Heart Association, Inc.

Modification of the MML turbulence model for adverse pressure gradient flows. M.S. Thesis - Akron Univ., 1993

NASA Technical Reports Server (NTRS)

Conley, Julianne M.

1994-01-01

Computational fluid dynamics is being used increasingly to predict flows for aerospace propulsion applications, yet there is still a need for an easy to use, computationally inexpensive turbulence model capable of accurately predicting a wide range of turbulent flows. The Baldwin-Lomax model is the most widely used algebraic model, even though it has known difficulties calculating flows with strong adverse pressure gradients and large regions of separation. The modified mixing length model (MML) was developed specifically to handle the separation which occurs on airfoils and has given significantly better results than the Baldwin-Lomax model. The success of these calculations warrants further evaluation and development of MML. The objective of this work was to evaluate the performance of MML for zero and adverse pressure gradient flows, and modify it as needed. The Proteus Navier-Stokes code was used for this study and all results were compared with experimental data and with calculations made using the Baldwin-Lomax algebraic model, which is currently available in Proteus. The MML model was first evaluated for zero pressure gradient flow over a flat plate, then modified to produce the proper boundary layer growth. Additional modifications, based on experimental data for three adverse pressure gradient flows, were also implemented. The adapted model, called MMLPG (modified mixing length model for pressure gradient flows), was then evaluated for a typical propulsion flow problem, flow through a transonic diffuser. Three cases were examined: flow with no shock, a weak shock and a strong shock. The results of these calculations indicate that the objectives of this study have been met. Overall, MMLPG is capable of accurately predicting the adverse pressure gradient flows examined in this study, giving generally better agreement with experimental data than the Baldwin-Lomax model.

Outpatient management of low-risk patients with upper gastrointestinal bleeding: can we safely extend the Glasgow Blatchford Score in clinical practice?

PubMed

Mustafa, Zia; Cameron, Allan; Clark, Elaine; Stanley, Adrian J

2015-05-01

The Glasgow Blatchford Score (GBS) is a validated prognostic score for patients presenting with upper gastrointestinal (GI) bleeding (UGIB). The score predicts the need for therapeutic intervention or death, and studies have suggested that outpatient management is safe for patients with a GBS of zero. Our aim was to assess whether we could safely extend the threshold for outpatient management to patients with GBS≤1. Following assessment of our historical data, our UGIB protocol was changed to recommend outpatient management for patients with a GBS≤1, unless required for other reasons. Data on all patients presenting with UGIB over the following 12 months were prospectively recorded, including GBS and clinical Rockall scores. Adverse outcomes were defined by a 30-day combined endpoint of death, endotherapy, interventional radiology, surgery or transfusion. Negative predictive value (NPV) of GBS≤1 for adverse outcomes in UGIB was calculated. A total of 514 patients presented with UGIB in the 12 month study period. Of the patients, 183 (35.6%) had GBS≤1 (111, GBS=0; 72, GBS=1). Of these, 88 (48.1%) were managed as outpatients, and none had an adverse outcome. Of the 95 (51.9%) patients with GBS≤1 managed as inpatients, 80 (84.2%) had comorbidities requiring inpatient care. Within this admitted group with GBS≤1, one patient required transfusion and one died from a nongastrointestinal malignancy. GBS≤1 had an NPV of 99.45% (95% confidence interval 95.53-99.97%) in predicting adverse outcomes within 30 days. GBS≤1 has a high NPV for adverse outcomes in UGIB. This suggests outpatient management of patients with UGIB and that GBS≤1 is safe in our population.

Fatty acid amide hydrolase-morphine interaction influences ventilatory response to hypercapnia and postoperative opioid outcomes in children.

PubMed

Chidambaran, Vidya; Pilipenko, Valentina; Spruance, Kristie; Venkatasubramanian, Raja; Niu, Jing; Fukuda, Tsuyoshi; Mizuno, Tomoyuki; Zhang, Kejian; Kaufman, Kenneth; Vinks, Alexander A; Martin, Lisa J; Sadhasivam, Senthilkumar

2017-01-01

Fatty acid amide hydrolase (FAAH) degrades anandamide, an endogenous cannabinoid. We hypothesized that FAAH variants will predict risk of morphine-related adverse outcomes due to opioid-endocannabinoid interactions. In 101 postsurgical adolescents receiving morphine analgesia, we prospectively studied ventilatory response to 5% CO 2 (HCVR), respiratory depression (RD) and vomiting. Blood was collected for genotyping and morphine pharmacokinetics. We found significant FAAH-morphine interaction for missense (rs324420) and several regulatory variants, with HCVR (p < 0.0001) and vomiting (p = 0.0339). HCVR was more depressed in patients who developed RD compared with those who did not (p = 0.0034), thus FAAH-HCVR association predicts risk of impending RD from morphine use. FAAH genotypes predict risk for morphine-related adverse outcomes.

Modeling cumulative dose and exposure duration provided insights regarding the associations between benzodiazepines and injuries.

PubMed

Abrahamowicz, Michal; Bartlett, Gillian; Tamblyn, Robyn; du Berger, Roxane

2006-04-01

Accurate assessment of medication impact requires modeling cumulative effects of exposure duration and dose; however, postmarketing studies usually represent medication exposure by baseline or current use only. We propose new methods for modeling various aspects of medication use history and employment of them to assess the adverse effects of selected benzodiazepines. Time-dependent measures of cumulative dose or duration of use, with weighting of past exposures by recency, were proposed. These measures were then included in alternative versions of the multivariable Cox model to analyze the risk of fall related injuries among the elderly new users of three benzodiazepines (nitrazepam, temazepam, and flurazepam) in Quebec. Akaike's information criterion (AIC) was used to select the most predictive model for a given benzodiazepine. The best-fitting model included a combination of cumulative duration and current dose for temazepam, and cumulative dose for flurazepam and nitrazepam, with different weighting functions. The window of clinically relevant exposure was shorter for flurazepam than for the two other products. Careful modeling of the medication exposure history may enhance our understanding of the mechanisms underlying their adverse effects.

Early life adversity potentiates the effects of later life stress on cumulative physiological dysregulation.

PubMed

Dich, Nadya; Hansen, Åse Marie; Avlund, Kirsten; Lund, Rikke; Mortensen, Erik Lykke; Bruunsgaard, Helle; Rod, Naja Hulvej

2015-01-01

Previous research indicates that early life adversity may heighten stress reactivity and impair mechanisms for adaptive coping, suggesting that experience of stress in early life may also potentiate adults' physiological vulnerability to stress in later life. The study tested this hypothesis by investigating whether the experience of stressful events and circumstances (SEC) in childhood or adolescence amplified the effect of adulthood SEC on physiological dysregulation (allostatic load, AL) in later midlife. Observational data were used in the present study. Physiological functioning was measured in later midlife (participants' age ranged from 49 to 63 years). Both childhood/adolescence and adulthood SEC were reported retrospectively on the same occasion. Participants were 5309 Danish men and women from Copenhagen Aging and Midlife Biobank (CAMB). SEC included socioeconomic and family factors. The AL index was based on nine cardiovascular, metabolic, and immune biomarkers. Experience of SEC in both early life and adulthood independently predicted higher AL. In men, experience of SEC in early life also potentiated the effect of SEC in adulthood on AL. The results provide further insight into the mechanisms behind the "biological embedding" of childhood stress.