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Item Acute kidney injury in Ugandan children with severe malaria is associated with long-term behavioral problems(Public Library of Science, 2019-12-17) Hickson, Meredith R.; Conroy, Andrea L.; Bangirana, Paul; Opoka, Robert O.; Idro, Richard; Ssenkusu, John M.; John, Chandy C.; Pediatrics, School of MedicineBackground Acute kidney injury (AKI) is a risk factor for neurocognitive impairment in severe malaria (SM), but the impact of AKI on long-term behavioral outcomes following SM is unknown. Methods We conducted a prospective study on behavioral outcomes of Ugandan children 1.5 to 12 years of age with two forms of severe malaria, cerebral malaria (CM, n = 226) or severe malarial anemia (SMA, n = 214), and healthy community children (CC, n = 173). AKI was defined as a 50% increase in creatinine from estimated baseline. Behavior and executive function were assessed at baseline and 6, 12, and 24 months later using the Child Behavior Checklist and Behavior Rating Inventory of Executive Function, respectively. Age-adjusted z-scores were computed for each domain based on CC scores. The association between AKI and behavioral outcomes was evaluated across all time points using linear mixed effect models, adjusting for sociodemographic variables and disease severity. Results AKI was present in 33.2% of children with CM or SMA at baseline. Children ≥6 years of age with CM or SMA who had AKI on admission had worse scores in socio-emotional function in externalizing behaviors (Beta (95% CI), 0.52 (0.20, 0.85), p = 0.001), global executive function (0.48 (0.15, 0.82), p = 0.005) and behavioral regulation (0.66 (0.32, 1.01), p = 0.0002) than children without AKI. There were no behavioral differences associated with AKI in children <6 years of age. Conclusions AKI is associated with long-term behavioral problems in children ≥6 years of age with CM or SMA, irrespective of age at study enrollment.Item Assessing Communication Effectiveness in Interprofessional Healthcare Teams(2019-07) Binion, Kelsey Elizabeth; Brann, Maria; Goering, Elizabeth; Hoffmann-Longtin, KristaInterprofessional education and practice is a collaborative approach in equipping health professional students with the skills to become effective team members to improve patient outcomes. This research study used a grounded theory approach to identify the communication characteristics and behaviors that influenced a team’s communication effectiveness. Two-hundred and twenty-two students participated in an interprofessional simulation at a Midwestern university. Ninety-two standardized patients assessed the students’ communication skills and their ability to collaborate as a team using a CARE Patient Feedback form, which served as data for the study. The study found four characteristics of effective interprofessional team experiences: aware of the patient’s situation, participate in the interaction equally, create a safe space, and nurture and strengthen a relationship. Students demonstrated an increase in communication effectiveness between encounter one and two; teams worked collaboratively rather than individually; students demonstrated five of the eight IPEC communication competencies; and negative and positive behaviors had a significant impact on patient outcomes. This study informs educators the need for repeated exposure of interprofessional practice experiences, such as simulation activities. These opportunities allow students to practice, learn, and refine their communication skills before entering their clinical practice.Item Behavioral Effects of the Mixture and the Single Compounds Carbendazim, Fipronil, and Sulfentrazone on Zebrafish (Danio rerio) Larvae(MDPI, 2024-05-25) Gomes, Samara da Silva; da Silva, Jadson Freitas; Padilha, Renata Meireles Oliveira; de Vasconcelos, João Victor Alves; Neto, Luís Gomes de Negreiros; Marrs, James A.; Cadena, Pabyton Gonçalves; Biology, School of SciencePesticides are often detected in freshwater, but their impact on the aquatic environment is commonly studied based on single compounds, underestimating the potential additive effects of these mixtures. Even at low concentrations, pesticides can negatively affect organisms, altering important behaviors that can have repercussions at the population level. This study used a multi-behavioral approach to evaluate the effects of zebrafish larvae exposure to carbendazim (C), fipronil (F), and sulfentrazone (S), individually and mixed. Five behavioral tests, thigmotaxis, touch sensitivity, optomotor response, bouncing ball test, and larval exploratory behavior, were performed to assess potential effects on anxiety, fear, and spatial and social interaction. Significant changes were observed in the performance of larvae exposed to all compounds and their mixtures. Among the single pesticides, exposure to S produced the most behavioral alterations, followed by F and C, respectively. A synergistic effect between the compounds was observed in the C + F group, which showed more behavioral effects than the groups exposed to pesticides individually. The use of behavioral tests to evaluate pesticide mixtures is important to standardize methods and associate behavioral changes with ecologically relevant events, thus creating a more realistic scenario for investigating the potential environmental impacts of these compounds.Item Breast lesions of uncertain malignant nature and limited metastatic potential: proposals to improve their recognition and clinical management(Wiley, 2016-08-16) Rakha, Emad A.; Badve, Sunil; Eusebi, Vincenzo; Reis-Filho, Jorge S.; Fox, Stephen B.; Dabbs, David J.; Decker, Thomas; Hodi, Zsolt; Ichihara, Shu; Lee, Andrew HS.; Palacios, José; Richardson, Andrea L.; Vincent-Salomon, Anne; Schmitt, Fernando C.; Tan, Puay-Hoon; Tse, Gary M.; Ellis, Ian O.; Department of Pathology and Laboratory Medicine, IU School of MedicineBreast lesions comprise a family of heterogeneous entities with variable patterns of presentation, morphology and clinical behaviour. The majority of breast lesions are classified traditionally into benign and malignant conditions and their behaviour can, in the vast majority of cases, be predicted with a reasonable degree of accuracy. However, there remain lesions which show borderline features and lie in a grey zone between benign and malignant, as their behaviour cannot be predicted reliably. Defined pathological categorization of such lesions is challenging, and for some entities is recognized to be subjective and include a range of diagnoses, and forms of terminology, which may trigger over- or undertreatment. The rarity of these lesions makes the acquisition of clinical evidence problematic and limits the development of a sufficient evidence base to support informed decision-making by clinicians and patients. Emerging molecular evidence is providing a greater understanding of the biology of these lesions, but this may or may not be reflected in their clinical behaviour. Herein we discuss some breast lesions that are associated with uncertainty regarding classification and behaviour, and hence management. These include biologically invasive malignant lesions associated with uncertain metastatic potential, such as low-grade adenosquamous carcinoma, low-grade fibromatosis-like spindle cell carcinoma and encapsulated papillary carcinoma. Other lesions of uncertain malignant nature remain, such as mammary cylindroma, atypical microglandular adenosis, mammary pleomorphic adenoma and infiltrating epitheliosis. The concept of categories of (1) breast lesions of uncertain malignant nature and (2) breast lesions of limited metastatic potential are proposed with details of which histological entities could be included in each category, and their management implications are discussed.Item Caenorhabditis elegans as a Model to Study the Molecular and Genetic Mechanisms of Drug Addiction(Elsevier, 2016) Engleman, Eric A.; Katner, Simon N.; Neal-Beliveau, Bethany S.; Department of Psychiatry, IU School of MedicineDrug addiction takes a massive toll on society. Novel animal models are needed to test new treatments and understand the basic mechanisms underlying addiction. Rodent models have identified the neurocircuitry involved in addictive behavior and indicate that rodents possess some of the same neurobiologic mechanisms that mediate addiction in humans. Recent studies indicate that addiction is mechanistically and phylogenetically ancient and many mechanisms that underlie human addiction are also present in invertebrates. The nematode Caenorhabditis elegans has conserved neurobiologic systems with powerful molecular and genetic tools and a rapid rate of development that enables cost-effective translational discovery. Emerging evidence suggests that C. elegans is an excellent model to identify molecular mechanisms that mediate drug-induced behavior and potential targets for medications development for various addictive compounds. C. elegans emit many behaviors that can be easily quantitated including some that involve interactions with the environment. Ethanol (EtOH) is the best-studied drug-of-abuse in C. elegans and at least 50 different genes/targets have been identified as mediating EtOH's effects and polymorphisms in some orthologs in humans are associated with alcohol use disorders. C. elegans has also been shown to display dopamine and cholinergic system-dependent attraction to nicotine and demonstrate preference for cues previously associated with nicotine. Cocaine and methamphetamine have been found to produce dopamine-dependent reward-like behaviors in C. elegans. These behavioral tests in combination with genetic/molecular manipulations have led to the identification of dozens of target genes/systems in C. elegans that mediate drug effects. The one target/gene identified as essential for drug-induced behavioral responses across all drugs of abuse was the cat-2 gene coding for tyrosine hydroxylase, which is consistent with the role of dopamine neurotransmission in human addiction. Overall, C. elegans can be used to model aspects of drug addiction and identify systems and molecular mechanisms that mediate drug effects. The findings are surprisingly consistent with analogous findings in higher-level organisms. Further, model refinement is warranted to improve model validity and increase utility for medications development.Item Cerebral malaria is associated with long-term mental health disorders: a cross sectional survey of a long-term cohort(Springer (Biomed Central Ltd.), 2016) Idro, Richard; Kakooza-Mwesige, Angelina; Asea, Benjamin; Ssebyala, Keron; Bangirana, Paul; Opoka, Robert O.; Lubowa, Samson K.; Semrud-Clikeman, Margaret; John, Chandy C.; Nalugya, Joyce; Department of Pediatrics, IU School of MedicineBACKGROUND: Cerebral malaria (CM) and severe malarial anaemia (SMA) are associated with neuro-developmental impairment in African children, but long-term mental health disorders in these children are not well defined. METHODS: A cohort of children previously exposed to CM (n = 173) or SMA (n = 99) had neurologic assessments performed and screening for behaviour difficulties using the Strengths and Difficulties Questionnaire (SDQ) a median of 21 months after the disease episode. These findings were compared to concurrently recruited community children (CC, n = 108). Participants with SDQ total difficulties score ≥ 17 had a mental health interview with the child and adolescent version of the Mini-International Neuropsychiatric Interview (MINI-KID) and a sample had brain magnetic resonance imaging (MRI). RESULTS: Fifty-five children had SDQ score ≥ 17. On the MINI-KID, these children were classified as having no difficulties (n = 18), behaviour difficulties only (n = 13) or a mental health disorder (n = 24). Behaviour difficulties were seen in similar frequencies in CM (3.5%), SMA (4.0%) and CC (2.8%). In contrast, mental health disorders were most frequent in CM (10.4%), followed by SMA (4.0%) and CC (1.8%). Externalizing disorders (conduct, oppositional defiance and attention deficit hyperactivity) were the most common mental health disorders. The median total coma duration was 72 (IQR 36.0-115.0) h in patients with mental health disorders compared to 48 (IQR 28.5-78.7) h in those without, p = 0.039. Independent risk factors for mental health disorder included neurologic deficit at discharge (OR 4.09 (95% CI 1.60, 10.5) and seizure recurrences during hospitalization, (OR 2.80, 95% CI 1.13, 6.97). Brain MRI findings consistent with small vessel ischaemic neural injury was seen in over half of these children. CONCLUSIONS: Cerebral malaria may predispose children to mental health disorders, possibly as a consequence of ischaemic neural injury. There is urgent need for programmes of follow-up, diagnosis and interventions for these children.Item Characterizing Sleep Phenotypes in Children With Newly Diagnosed Epilepsy(Elsevier, 2022-12) Oyegbile-Chidi, Temitayo; Harvey, Danielle; Dunn, David; Jones, Jana; Hermann, Bruce; Byars, Anna; Austin , Joan; Psychiatry, School of MedicineBackground: Children with epilepsy frequently have sleep, behavior, and cognitive problems at the time of or before the epilepsy diagnosis. The primary goal of this study was to determine if specific sleep disturbance phenotypes exist in a large cohort of children with new-onset epilepsy and if these phenotypes are associated with specific cognitive and behavioral signatures. Methods: A total of354 children with new-onset epilepsy, aged six to 16 years, were recruited within six weeks of initial seizure onset. Each child underwent evaluation of their sleep along with self, parent, and teacher ratings of emotional-behavioral status. Two-step clustering using sleep disturbance (Sleep Behavior Questionnaire), naps, and sleep latency was employed to determine phenotype clusters. Results: Analysis showed three distinct sleep disturbance phenotypes-minimal sleep disturbance, moderate sleep disturbance, and severe sleep disturbance phenotypes. Children who fell into the minimal sleep disturbance phenotype had an older age of onset with the best cognitive performance compared with the other phenotypes and the lowest levels of emotional-behavioral problems. In contrast, children who fell into the severe sleep disturbance phenotype had the youngest age of onset of epilepsy with poor cognitive performance and highest levels of emotional-behavioral problems. Conclusions: This study indicates that there are indeed specific sleep disturbance phenotypes that are apparent in children with newly diagnosed epilepsy and are associated with specific comorbidities. Future research should determine if these phenotypic groups persist over time and are predictive of long-term difficulties, as these subgroups may benefit from targeted therapy and intervention.Item Development of a step-down method for altering male C57BL/6 mouse housing density and hierarchical structure: Preparations for spaceflight studies(Elsevier, 2018-05) Scofield, David C.; Rytlewski, Jeffrey D.; Childress, Paul; Shah, Kishan; Tucker, Aamir; Khan, Faisal; Peveler, Jessica; Li, Ding; McKinley, Todd O.; Chu, Tien-Min G.; Hickman, Debra L.; Kacena, Melissa A.; Orthopaedic Surgery, School of MedicineThis study was initiated as a component of a larger undertaking designed to study bone healing in microgravity aboard the International Space Station (ISS). Spaceflight experimentation introduces multiple challenges not seen in ground studies, especially with regard to physical space, limited resources, and inability to easily reproduce results. Together, these can lead to diminished statistical power and increased risk of failure. It is because of the limited space, and need for improved statistical power by increasing sample size over historical numbers, NASA studies involving mice require housing mice at densities higher than recommended in the Guide for the Care and Use of Laboratory Animals (National Research Council, 2011). All previous NASA missions in which mice were co-housed, involved female mice; however, in our spaceflight studies examining bone healing, male mice are required for optimal experimentation. Additionally, the logistics associated with spaceflight hardware and our study design necessitated variation of density and cohort make up during the experiment. This required the development of a new method to successfully co-house male mice while varying mouse density and hierarchical structure. For this experiment, male mice in an experimental housing schematic of variable density (Spaceflight Correlate) analogous to previously established NASA spaceflight studies was compared to a standard ground based housing schematic (Normal Density Controls) throughout the experimental timeline. We hypothesized that mice in the Spaceflight Correlate group would show no significant difference in activity, aggression, or stress when compared to Normal Density Controls. Activity and aggression were assessed using a novel activity scoring system (based on prior literature, validated in-house) and stress was assessed via body weights, organ weights, and veterinary assessment. No significant differences were detected between the Spaceflight Correlate group and the Normal Density Controls in activity, aggression, body weight, or organ weight, which was confirmed by veterinary assessments. Completion of this study allowed for clearance by NASA of our bone healing experiments aboard the ISS, and our experiment was successfully launched February 19, 2017 on SpaceX CRS-10.Item Development, validation, and characterization of a novel preclinical animal model of social familiarity-induced anxiolysis(2017-09-29) Lungwitz, Elizabeth Ann; Shekhar, Anantha; Truitt, William; Oxford, Gerry; Rodd, Zachary; Lapish, ChristopherSocial support is a powerful therapeutic against fear and anxiety and is utilized in many psychotherapies. The concept that a familiar or friendly presence helps a person learn to overcome anxiety has been well-known for decades, yet, the basic neural mechanisms that regulate this psychosocial learning remain unknown. A first step towards elucidating these basic mechanisms is the development of a valid preclinical animal model. However, preclinical behavioral models exploring the use of a social presence in reducing anxiety have not been fully characterized. Therefore, it was our goal to identify a useful way in which to study the mechanisms of how a social presence can induce anxiolysis (the reduction of anxiety). We accomplished this goal by characterizing and validating a preclinical model, as well as demonstrating that the model was capable of measuring deficits in rats given a mild traumatic brain injury. To this end, we identified an existing, but uncharacterized model, the social interaction-habituation model, as an effective model of social familiarity-induced anxiolysis (SoFiA), which demonstrates socially enhanced safety learning, or psychosocial learning. We find that as social familiarity develops across time, anxiolysis develops. We identified that the use of a Bright Light Challenge is a useful anxiogenic stimulus to use during SI-habituation training. The anxiolysis acquired following SI-habituation testing is partner specific, and can be blocked by an inhibition of the medical prefrontal cortex, while it can be enhanced by D-cycloserine. We found that this model identified deficits in SoFiA acquisition in rodents exposed to a mild traumatic brain injury, which, in humans, has been linked to psychosocial deficits. This work is a step in creating ways in which we can study and better understand the regulatory processes of emotions mediated by social behavior.Item Diagnostic criteria for apathy in neurocognitive disorders(Wiley, 2021) Miller, David S.; Robert, Philippe; Ereshefsky, Larry; Adler, Lawrence; Bateman, Daniel; Cummings, Jeff; DeKosky, Steven T.; Fischer, Corinne E.; Husain, Masud; Ismail, Zahinoor; Jaeger, Judith; Lerner, Alan J.; Li, Abby; Lyketsos, Constantine G.; Manera, Valeria; Mintzer, Jacobo; Moebius, Hans J.; Mortby, Moyra; Meulien, Didier; Pollentier, Stephane; Porsteinsson, Anton; Rasmussen, Jill; Rosenberg, Paul B.; Ruthirakuhan, Myuri T.; Sano, Mary; Zucchero Sarracini, Carla; Lanctôt, Krista L.; Psychiatry, School of MedicineIntroduction: Apathy is common in neurocognitive disorders (NCD) but NCD-specific diagnostic criteria are needed. Methods: The International Society for CNS Clinical Trials Methodology Apathy Work Group convened an expert group and sought input from academia, health-care, industry, and regulatory bodies. A modified Delphi methodology was followed, and included an extensive literature review, two surveys, and two meetings at international conferences, culminating in a consensus meeting in 2019. Results: The final criteria reached consensus with more than 80% agreement on all parts and included: limited to people with NCD; symptoms persistent or frequently recurrent over at least 4 weeks, a change from the patient's usual behavior, and including one of the following: diminished initiative, diminished interest, or diminished emotional expression/responsiveness; causing significant functional impairment and not exclusively explained by other etiologies. Discussion: These criteria provide a framework for defining apathy as a unique clinical construct in NCD for diagnosis and further research.
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