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Item Advancing cognitive engineering methods to support user interface design for electronic health records(Elsevier, 2014-04) Thyvalikakath, Thankam P.; Dziabiak, Michael P.; Johnson, Raymond; Torres-Urquidy, Miguel Humberto; Acharya, Amit; Yabes, Jonathan; Schleyer, Titus K.; Department of Cariology, Operative Dentistry and Dental Public Health, IU School of DentistryBackground Despite many decades of research on the effective development of clinical systems in medicine, the adoption of health information technology to improve patient care continues to be slow, especially in ambulatory settings. This applies to dentistry as well, a primary care discipline with approximately 137,000 practitioners in the United States. A critical reason for slow adoption is the poor usability of clinical systems, which makes it difficult for providers to navigate through the information and obtain an integrated view of patient data. Objective In this study, we documented the cognitive processes and information management strategies used by dentists during a typical patient examination. The results will inform the design of a novel electronic dental record interface. Methods We conducted a cognitive task analysis (CTA) study to observe ten general dentists (five general dentists and five general dental faculty members, each with more than two years of clinical experience) examining three simulated patient cases using a think-aloud protocol. Results Dentists first reviewed the patient’s demographics, chief complaint, medical history and dental history to determine the general status of the patient. Subsequently, they proceeded to examine the patient’s intraoral status using radiographs, intraoral images, hard tissue and periodontal tissue information. The results also identified dentists’ patterns of navigation through patient’s information and additional information needs during a typical clinician-patient encounter. Conclusion This study reinforced the significance of applying cognitive engineering methods to inform the design of a clinical system. Second, applying CTA to a scenario closely simulating an actual patient encounter helped with capturing participants’ knowledge states and decision-making when diagnosing and treating a patient. The resultant knowledge of dentists’ patterns of information retrieval and review will significantly contribute to designing flexible and task-appropriate information presentation in electronic dental records.Item Angiogenic potential of skeletal muscle derived extracellular vesicles differs between oxidative and glycolytic muscle tissue in mice(Nature, 2023-11) Kargl, Christopher K.; Jia, Zhihao; Shera, Deborah A.; Sullivan, Brian P.; Burton, Lundon C.; Kim, Kun Ho; Nie, Yaohui; Hubal, Monica J.; Shannahan, Jonathan H.; Kuang, Shihuan; Gavin, Timothy P.; Exercise & Kinesiology, School of Health and Human SciencesSkeletal muscle fibers regulate surrounding endothelial cells (EC) via secretion of numerous angiogenic factors, including extracellular vesicles (SkM-EV). Muscle fibers are broadly classified as oxidative (OXI) or glycolytic (GLY) depending on their metabolic characteristics. OXI fibers secrete more pro-angiogenic factors and have greater capillary densities than GLY fibers. OXI muscle secretes more EV than GLY, however it is unknown whether muscle metabolic characteristics regulate EV contents and signaling potential. EVs were isolated from primarily oxidative or glycolytic muscle tissue from mice. MicroRNA (miR) contents were determined and endothelial cells were treated with OXI- and GLY-EV to investigate angiogenic signaling potential. There were considerable differences in miR contents between OXI- and GLY-EV and pathway analysis identified that OXI-EV miR were predicted to positively regulate multiple endothelial-specific pathways, compared to GLY-EV. OXI-EV improved in vitro angiogenesis, which may have been mediated through nitric oxide synthase (NOS) related pathways, as treatment of endothelial cells with a non-selective NOS inhibitor abolished the angiogenic benefits of OXI-EV. This is the first report to show widespread differences in miR contents between SkM-EV isolated from metabolically different muscle tissue and the first to demonstrate that oxidative muscle tissue secretes EV with greater angiogenic signaling potential than glycolytic muscle tissue.Item The auditory steady-state response (ASSR): a translational biomarker for schizophrenia(Elsevier, 2013) O'Donnell, Brian F.; Vohs, Jenifer L.; Krishnan, Giri P.; Rass, Olga; Hetrick, William P.; Morzorati, Sandra L.; Department of Psychiatry, IU School of MedicineElectrophysiological methods have demonstrated disturbances of neural synchrony and oscillations in schizophrenia which affect a broad range of sensory and cognitive processes. These disturbances may account for a loss of neural integration and effective connectivity in the disorder. The mechanisms responsible for alterations in synchrony are not well delineated, but may reflect disturbed interactions within GABAergic and glutamatergic circuits, particularly in the gamma range. Auditory steady-state responses (ASSRs) provide a non-invasive technique used to assess neural synchrony in schizophrenia and in animal models at specific response frequencies. ASSRs are electrophysiological responses entrained to the frequency and phase of a periodic auditory stimulus generated by auditory pathway and auditory cortex activity. Patients with schizophrenia show reduced ASSR power and phase locking to gamma range stimulation. We review alterations of ASSRs in schizophrenia, schizotypal personality disorder, and first-degree relatives of patients with schizophrenia. In vitro and in vivo approaches have been used to test cellular mechanisms for this pattern of findings. This translational, cross-species approach provides support for the role of N-methyl-D-aspartate and GABAergic dysregulation in the genesis of perturbed ASSRs in schizophrenia and persons at risk.Item Autonomic Nerve Activity and Blood Pressure in Ambulatory Dogs(Elsevier, 2014-02) Hellyer, Jessica; Akingba, A. George; Rhee, Kyoung-Suk; Tan, Alex Y.; Lane, Kathleen A.; Shen, Changyu; Patel, Jheel; Fishbein, Michael C; Chen, Peng-Sheng; Department of Medicine, IU School of MedicineBackground The relationship between cardiac autonomic nerve activity and blood pressure (BP) changes in ambulatory dogs is unclear. Objective To test the hypotheses that simultaneous termination of stellate ganglion nerve activity (SGNA) and vagal nerve activity (VNA) predisposes to spontaneous orthostatic hypotension and that specific β2 adrenoceptor blockade prevents the hypotensive episodes. Methods We used a radiotransmitter to record SGNA, VNA and blood pressure (BP) in 8 ambulatory dogs. Video imaging was used to document postural changes. Results Out of these 8 dogs, 5 showed simultaneous sympathovagal discharges in which the minute by minute integrated SGNA correlated with integrated VNA in a linear pattern (“Group 1”). In these dogs abrupt termination of simultaneous SGNA-VNA at the time of postural changes (as documented by video imaging) was followed by abrupt (>20 mmHg over 4 beats) drops in BP. Dogs without simultaneous on/off firing (“Group 2”) did not have drastic drops in pressure. ICI 118,551 (ICI, a specific β2-blocker) infused at 3.1 µg/kg/hr for 7 days significantly increased BP from 126 (95% confidence interval, CI: 118 to 133) mmHg to 133 (95% CI 125 to141) mmHg (p=0.0001). The duration of hypotension (mean systolic BP < 100 mmHg) during baseline accounted for 7.1% of the recording. The percentage was reduced by ICI to 1.3% (p = 0.01). Conclusions Abrupt simultaneous termination of SGNA-VNA was observed at the time of orthostatic hypotension in ambulatory dogs. Selective β2 adrenoceptor blockade increased BP and reduced the duration of hypotension in this model.Item Autophagy dysregulation in cell culture and animals models of Spinal Muscular Atrophy(Elsevier, 2014-07) Custer, Sara K.; Androphy, Elliot J.; Department of Dermatology, IU School of MedicineAbnormal autophagy has become a central thread linking neurodegenerative diseases, particularly of the motor neuron. One such disease is spinal muscular atrophy (SMA), a genetic neuromuscular disorder caused by mutations in the SMN1 gene resulting in low levels of Survival Motor Neuron (SMN) protein. Despite knowing the causal protein, the exact intracellular processes that are involved in the selective loss of motor neurons remains unclear. Autophagy induction can be helpful or harmful depending on the situation, and we sought to understand the state of the autophagic response in SMA. We show that cell culture and animal models demonstrate induction of autophagy accompanied by attenuated autophagic flux, resulting in the accumulation of autophagosomes and their associated cargo. Expression of the SMN-binding protein a-COP, a known modulator of autophagic flux, can ameliorate this autophagic traffic jam.Item The Axolotl Fibula as a Model for the Induction of Regeneration across Large Segment Defects in Long Bones of the Extremities(Public Library of Science, 2015) Chen, Xiaoping; Song, Fengyu; Jhamb, Deepali; Li, Jiliang; Bottino, Marco C.; Palakal, Mathew J.; Stocum, David L.; Department of Biology, School of ScienceWe tested the ability of the axolotl (Ambystoma mexicanum) fibula to regenerate across segment defects of different size in the absence of intervention or after implant of a unique 8-braid pig small intestine submucosa (SIS) scaffold, with or without incorporated growth factor combinations or tissue protein extract. Fractures and defects of 10% and 20% of the total limb length regenerated well without any intervention, but 40% and 50% defects failed to regenerate after either simple removal of bone or implanting SIS scaffold alone. By contrast, scaffold soaked in the growth factor combination BMP-4/HGF or in protein extract of intact limb tissue promoted partial or extensive induction of cartilage and bone across 50% segment defects in 30%-33% of cases. These results show that BMP-4/HGF and intact tissue protein extract can promote the events required to induce cartilage and bone formation across a segment defect larger than critical size and that the long bones of axolotl limbs are an inexpensive model to screen soluble factors and natural and synthetic scaffolds for their efficacy in stimulating this process.Item Beyond Survey Self-Reports: Using Physiology to Tap Political Orientations(Oxford, 2015) Wagner, Michael W.; Deppe, Kristen D.; Jacobs, Carly M.; Friesen, Amanda; Smith, Kevin B.; Hibbing, John R.; Department of Political Science, School of Liberal ArtsSome aspects of our attitudes are composed of things outside of our consciousness. However, traditional survey research does not use measurements that are able to tap into these aspects of public opinion. We describe, recommend, and demonstrate a procedure by which non-self-reported responses can be measured in order to test whether these responses have independent effects on individuals’ preferences. We use one of the better-known physiological measures—electrodermal activity or skin conductance—and illustrate its potential by reporting our own study of attitudes toward President Barack Obama. We find that both self-reported emotional responses and physiological responses to Obama’s image independently correlate with variation in the intensity of attitudes regarding his job approval and his central policy proposal: health-care reform.Item Blockade of the programmed death-1 pathway restores sarcoidosis CD4(+) T-cell proliferative capacity(American Thoracic Society, 2014-09-01) Braun, Nicole A.; Celada, Lindsay J.; Herazo-Maya, Jose D.; Abraham, Susamma; Shaginurova, Guzel; Sevin, Carla M.; Grutters, Jan; Culver, Daniel A.; Dworski, Ryszard; Sheller, James; Massion, Pierre P.; Polosukhin, Vasiliy V.; Johnson, Joyce E.; Kaminski, Naftali; Wilkes, David S.; Oswald-Richter, Kyra A.; Drake, Wonder P.; Department of Medicine, IU School of MedicineRATIONALE: Effective therapeutic interventions for chronic, idiopathic lung diseases remain elusive. Normalized T-cell function is an important contributor to spontaneous resolution of pulmonary sarcoidosis. Up-regulation of inhibitor receptors, such as programmed death-1 (PD-1) and its ligand, PD-L1, are important inhibitors of T-cell function. OBJECTIVES: To determine the effects of PD-1 pathway blockade on sarcoidosis CD4(+) T-cell proliferative capacity. METHODS: Gene expression profiles of sarcoidosis and healthy control peripheral blood mononuclear cells were analyzed at baseline and follow-up. Flow cytometry was used to measure ex vivo expression of PD-1 and PD-L1 on systemic and bronchoalveolar lavage-derived cells of subjects with sarcoidosis and control subjects, as well as the effects of PD-1 pathway blockade on cellular proliferation after T-cell receptor stimulation. Immunohistochemistry analysis for PD-1/PD-L1 expression was conducted on sarcoidosis, malignant, and healthy control lung specimens. MEASUREMENTS AND MAIN RESULTS: Microarray analysis demonstrates longitudinal increase in PDCD1 gene expression in sarcoidosis peripheral blood mononuclear cells. Immunohistochemistry analysis revealed increased PD-L1 expression within sarcoidosis granulomas and lung malignancy, but this was absent in healthy lungs. Increased numbers of sarcoidosis PD-1(+) CD4(+) T cells are present systemically, compared with healthy control subjects (P < 0.0001). Lymphocytes with reduced proliferative capacity exhibited increased proliferation with PD-1 pathway blockade. Longitudinal analysis of subjects with sarcoidosis revealed reduced PD-1(+) CD4(+) T cells with spontaneous clinical resolution but not with disease progression. CONCLUSIONS: Analogous to the effects in other chronic lung diseases, these findings demonstrate that the PD-1 pathway is an important contributor to sarcoidosis CD4(+) T-cell proliferative capacity and clinical outcome. Blockade of the PD-1 pathway may be a viable therapeutic target to optimize clinical outcomes.Item Bone and skeletal muscle: Key players in mechanotransduction and potential overlapping mechanisms(Elsevier, 2015-11) Goodman, Craig A.; Hornberger, Troy A.; Robling, Alexander G.; Department of Anatomy & Cell Biology, IU School of MedicineThe development and maintenance of skeletal muscle and bone mass is critical for movement, health and issues associated with the quality of life. Skeletal muscle and bone mass are regulated by a variety of factors that include changes in mechanical loading. Moreover, bone mass is, in large part, regulated by muscle-derived mechanical forces and thus by changes in muscle mass/strength. A thorough understanding of the cellular mechanism(s) responsible for mechanotransduction in bone and skeletal muscle is essential for the development of effective exercise and pharmaceutical strategies aimed at increasing, and/or preventing the loss of, mass in these tissues. Thus, in this review we will attempt to summarize the current evidence for the major molecular mechanisms involved in mechanotransduction in skeletal muscle and bone. By examining the differences and similarities in mechanotransduction between these two tissues, it is hoped that this review will stimulate new insights and ideas for future research and promote collaboration between bone and muscle biologists.(1).Item Brief report: Endothelial colony-forming cells and inflammatory monocytes in HIV(Ovid Technologies (Wolters Kluwer) - Lippincott Williams & Wilkins, 2015-04-15) Hays, Travis R.; Mund, Julie A.; Liu, Ziyue; Case, Jamie; Ingram, David A.; Gupta, Samir K.; Department of Medicine, IU School of MedicineThe relationships between HIV infection, monocyte activation, and endothelial colony-forming cells (ECFCs) are unknown. We compared ECFC, intermediate monocytes (CD14 CD16), and nonclassical monocytes (CD14 CD16) levels in HIV-infected participants virologically suppressed on antiretroviral therapy, HIV-infected treatment-naive participants, and HIV-uninfected healthy controls. ECFC levels were significantly higher in the HIV-infected virologically suppressed group compared with the uninfected controls. CD14 CD16 percentages (but not CD14 CD16 cells) were significantly higher in both HIV-infected groups vs. uninfected controls. In the HIV-infected groups, ECFCs and CD14 CD16 intermediate monocytes were significantly and inversely correlated. Lower availability of ECFCs may partly explain the relationship between greater intermediate monocytes and atherosclerosis in HIV.