10 results on '"Grace H. Choi"'
Search Results
2. Impaired Maternal‐Fetal Environment and Risk for Preoperative Focal White Matter Injury in Neonates With Complex Congenital Heart Disease
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Daniel J. Licht, Marin Jacobwitz, Jennifer M. Lynch, Tiffany Ko, Timothy Boorady, Mahima Devarajan, Kristina N. Heye, Kobina Mensah‐Brown, John J. Newland, Alexander Schmidt, Peter Schwab, Madeline Winters, Susan C. Nicolson, Lisa M. Montenegro, Stephanie Fuller, Christopher Mascio, J. William Gaynor, Arjun G. Yodh, Juliana Gebb, Arastoo Vossough, Grace H. Choi, and Mary E. Putt
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congenital brain injuries ,heart defects ,maternal fetal environment ,placenta ,risk factors ,white matter injury ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
Background Infants with congenital heart disease (CHD) are at risk for white matter injury (WMI) before neonatal heart surgery. Better knowledge of the causes of preoperative WMI may provide insights into interventions that improve neurodevelopmental outcomes in these patients. Methods and Results A prospective single‐center study of preoperative WMI in neonates with CHD recorded data on primary cardiac diagnosis, maternal‐fetal environment (MFE), delivery type, subject anthropometrics, and preoperative care. Total maturation score and WMI were assessed, and stepwise logistic regression modeling selected risk factors for WMI. Among subjects with severe CHD (n=183) who received a preoperative brain magnetic resonance imaging, WMI occurred in 40 (21.9%) patients. WMI prevalence (21.4%–22.1%) and mean volumes (119.7–160.4 mm3) were similar across CHD diagnoses. Stepwise logistic regression selected impaired MFE (odds ratio [OR], 2.85 [95% CI, 1.29–6.30]), male sex (OR, 2.27 [95% CI, 1.03–5.36]), and older age at surgery/magnetic resonance imaging (OR, 1.20 per day [95% CI, 1.03–1.41]) as risk factors for preoperative WMI and higher total maturation score values (OR, 0.65 per unit increase [95% CI, 0.43–0.95]) as protective. A quarter (24.6%; n=45) of subjects had ≥1 components of impaired MFE (gestational diabetes [n=12; 6.6%], gestational hypertension [n=11; 6.0%], preeclampsia [n=2; 1.1%], tobacco use [n=9; 4.9%], hypothyroidism [n=6; 3.3%], and other [n=16; 8.7%]). In a subset of 138 subjects, an exploratory analysis of additional MFE‐related factors disclosed other potential risk factors for WMI. Conclusions This study is the first to identify impaired MFE as an important risk factor for preoperative WMI. Vulnerability to preoperative WMI was shared across CHD diagnoses.
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- 2023
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3. Activation of Glutamate Transport Increases Arteriole Diameter in vivo: Implications for Neurovascular Coupling
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Joshua G. Jackson, Elizabeth Krizman, Hajime Takano, Meredith Lee, Grace H. Choi, Mary E. Putt, and Michael B. Robinson
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glutamate transport ,arteriole diameter ,neurovascular coupling ,astrocyte ,in vivo microscopy ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
In order to meet the energetic demands of cell-to-cell signaling, increases in local neuronal signaling are matched by a coordinated increase in local blood flow, termed neurovascular coupling. Multiple different signals from neurons, astrocytes, and pericytes contribute to this control of blood flow. Previously, several groups demonstrated that inhibition/ablation of glutamate transporters attenuates the neurovascular response. However, it was not determined if glutamate transporter activation was sufficient to increase blood flow. Here, we used multiphoton imaging to monitor the diameter of fluorescently labeled cortical arterioles in anesthetized C57/B6J mice. We delivered vehicle, glutamate transporter substrates, or a combination of a glutamate transporter substrate with various pharmacologic agents via a glass micropipette while simultaneously visualizing changes in arteriole diameter. We developed a novel image analysis method to automate the measurement of arteriole diameter in these time-lapse analyses. Using this workflow, we first conducted pilot experiments in which we focally applied L-glutamate, D-aspartate, or L-threo-hydroxyaspartate (L-THA) and measured arteriole responses as proof of concept. We subsequently applied the selective glutamate transport substrate L-THA (applied at concentrations that do not activate glutamate receptors). We found that L-THA evoked a significantly larger dilation than that observed with focal saline application. This response was blocked by co-application of the potent glutamate transport inhibitor, L-(2S,3S)-3-[3-[4-(trifluoromethyl)-benzoylamino]benzyloxy]-aspartate (TFB-TBOA). Conversely, we were unable to demonstrate a reduction of this effect through co-application of a cocktail of glutamate and GABA receptor antagonists. These studies provide the first direct evidence that activation of glutamate transport is sufficient to increase arteriole diameter. We explored potential downstream mechanisms mediating this transporter-mediated dilation by using a Ca2+ chelator or inhibitors of reversed-mode Na+/Ca2+ exchange, nitric oxide synthetase, or cyclo-oxygenase. The estimated effects and confidence intervals suggested some form of inhibition for a number of these inhibitors. Limitations to our study design prevented definitive conclusions with respect to these downstream inhibitors; these limitations are discussed along with possible next steps. Understanding the mechanisms that control blood flow are important because changes in blood flow/energy supply are implicated in several neurodegenerative disorders and are used as a surrogate measure of neuronal activity in widely used techniques such as functional magnetic resonance imaging (fMRI).
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- 2022
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4. Nucleocapsid-specific antibody function is associated with therapeutic benefits from COVID-19 convalescent plasma therapy
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Jonathan D. Herman, Chuangqi Wang, John Stephen Burke, Yonatan Zur, Hacheming Compere, Jaewon Kang, Ryan Macvicar, Sabian Taylor, Sally Shin, Ian Frank, Don Siegel, Pablo Tebas, Grace H. Choi, Pamela A. Shaw, Hyunah Yoon, Liise-anne Pirofski, Boris D. Julg, Katharine J. Bar, Douglas Lauffenburger, and Galit Alter
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SARS-CoV-2 ,Immunization, Passive ,Humans ,COVID-19 ,Antibodies, Viral ,Nucleocapsid ,General Biochemistry, Genetics and Molecular Biology ,COVID-19 Serotherapy - Abstract
Coronavirus disease 2019 (COVID-19) convalescent plasma (CCP), a passive polyclonal antibody therapeutic agent, has had mixed clinical results. Although antibody neutralization is the predominant approach to benchmarking CCP efficacy, CCP may also influence the evolution of the endogenous antibody response. Using systems serology to comprehensively profile severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) functional antibodies of hospitalized people with COVID-19 enrolled in a randomized controlled trial of CCP (ClinicalTrials.gov: NCT04397757), we find that the clinical benefits of CCP are associated with a shift toward reduced inflammatory Spike (S) responses and enhanced nucleocapsid (N) humoral responses. We find that CCP has the greatest clinical benefit in participants with low pre-existing anti-SARS-CoV-2 antibody function and that CCP-induced immunomodulatory Fc glycan profiles and N immunodominant profiles persist for at least 2 months. We highlight a potential mechanism of action of CCP associated with durable immunomodulation, outline optimal patient characteristics for CCP treatment, and provide guidance for development of a different class of COVID-19 hyperinflammation-targeting antibody therapeutic agents.
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- 2022
5. Persistent Disparities in Smoking Rates Among PLWH Compared to the General Population in Philadelphia, 2009–2014
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Antonios Mashas, Pamela A. Shaw, Kathleen A. Brady, Grace H Choi, Cedric H Bien-Gund, Robert E. Gross, and Melissa Miller
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Adult ,Male ,medicine.medical_specialty ,Tobacco use ,Adolescent ,Social Psychology ,medicine.medical_treatment ,Population ,HIV Infections ,Logistic regression ,Article ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Humans ,Medicine ,030212 general & internal medicine ,education ,Philadelphia ,education.field_of_study ,030505 public health ,business.industry ,Public health ,Smoking ,Public Health, Environmental and Occupational Health ,Odds ratio ,Middle Aged ,Mental health ,Health psychology ,Infectious Diseases ,Smoking cessation ,Female ,Smoking Cessation ,0305 other medical science ,business ,Demography - Abstract
Despite reductions in smoking rates in the general population, little is known about recent smoking trends among people living with HIV (PLWH). We compared the risk for smoking and temporal trends in smoking among PLWH and the general population in the Philadelphia metropolitan area between 2009 and 2014. We used weighted logistic regression to assess the relation between HIV and smoking, and examined temporal smoking trends. The adjusted odds ratio (OR) for smoking comparing PLWH to the general population was 1.80 (95% CI 1.55-2.09) after adjusting for socio-economic, demographic, and mental health diagnosis variables. Smoking prevalence decreased in both the PLWH and general populations during the study period, and we did not observe a significant difference in rates of decline between groups (P = 0.54). Despite overall progress in smoking cessation, a disparity persisted in smoking rates between PLWH and the general population, with and without adjustment for socio-economic, demographic, and mental health variables. Further research is needed to understand the mechanisms linking HIV and tobacco use in order to inform public health efforts to reduce smoking among PLWH.
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- 2020
6. A Role for Nucleocapsid-Specific Antibody Function in COVID-19 Convalescent Plasma Therapy
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Jonathan D. Herman, Chuangqi Wang, John Stephen Burke, Yonatan Zur, Hacheming Compere, Jaewon Kang, Ryan Macvicar, Sally Shin, Ian Frank, Don Siegel, Pablo Tebas, Grace H. Choi, Pamela A. Shaw, Hyunah Yoon, Liise-anne Pirofski, Boris Juelg, Katharine J. Bar, Douglas Lauffenburger, and Galit Alter
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musculoskeletal diseases ,History ,Polymers and Plastics ,immune system diseases ,Business and International Management ,skin and connective tissue diseases ,Industrial and Manufacturing Engineering - Abstract
SummaryCOVID-19 convalescent plasma (CCP), a passive polyclonal antibody therapeutic, has exhibited mixed results in the treatment of COVID-19. Given that the therapeutic effect of CCP may extend beyond the ability of SARS-CoV-2-specific antibody binding and neutralization to influence the evolution of the endogenous antibody response, we took a systematic and comprehensive approach to analyze SARS-CoV-2 functional antibody profiles of participants in a randomized controlled trial of CCP treatment of individuals hospitalized with COVID-19 pneumonia where CCP was associated with both decreased mortality and improved clinical severity. Using systems serology, we found that the clinical benefit of CCP is related to a shift towards reduced inflammatory Spike (S) responses and enhanced Nucleocapsid (N) humoral responses. We found CCP had the greatest clinical benefit in participants with low pre-existing anti-SARS-CoV-2 antibody function, rather than S or N antibody levels or participant demographic features. Further, CCP induced immunomodulatory changes to recipient humoral profiles persisted for at least two months, marked by the selective evolution of anti-inflammatory Fc-glycan profiles and persistently expanded nucleocapsid-specific humoral immunity following CCP therapy. Together, our findings identify a novel mechanism of action of CCP, suggest optimal patient characteristics for CCP treatment, identify long-last immunomodulatory effects of CCP, and provide guidance for development of novel N-focused antibody therapeutics for severe COVID-19 hyperinflammation.
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- 2022
7. Decrease in Angiotensin-Converting Enzyme activity but not concentration in plasma/lungs in COVID-19 patients offers clues for diagnosis/treatment
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Henry Daniell, Smruti K. Nair, Yao Shi, Ping Wang, Kathleen T. Montone, Pamela A. Shaw, Grace H. Choi, Danyal Ghani, JoEllen Weaver, Daniel J. Rader, Kenneth B. Margulies, Ronald G. Collman, Krzysztof Laudanski, and Katharine J. Bar
- Subjects
Genetics ,Molecular Medicine ,Molecular Biology - Abstract
Although several therapeutics are used to treat coronavirus disease 2019 (COVID-19) patients, there is still no definitive metabolic marker to evaluate disease severity and recovery or a quantitative test to end quarantine. Because severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infects human cells via the angiotensin-converting-enzyme 2 (ACE2) receptor and COVID-19 is associated with renin-angiotensin system dysregulation, we evaluated soluble ACE2 (sACE2) activity in the plasma/saliva of 80 hospitalized COVID-19 patients and 27 non-COVID-19 volunteers, and levels of ACE2/Ang (1-7) in plasma or membrane (mACE2) in lung autopsy samples. sACE2 activity was markedly reduced (p 0.0001) in COVID-19 plasma (n = 59) compared with controls (n = 27). Nadir sACE2 activity in early hospitalization was restored during disease recovery, irrespective of patient age, demographic variations, or comorbidity; in convalescent plasma-administered patients (n = 45), restoration was statistically higher than matched controls (n = 22, p = 0.0021). ACE2 activity was also substantially reduced in the saliva of COVID-19 patients compared with controls (p = 0.0065). There is a strong inverse correlation between sACE2 concentration and sACE2 activity and Ang (1-7) levels in participant plasmas. However, there were no difference in membrane ACE2 levels in lungs of autopsy tissues of COVID-19 (n = 800) versus other conditions (n = 300). These clinical observations suggest sACE2 activity as a potential biomarker and therapeutic target for COVID-19.
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- 2021
8. A randomized controlled study of convalescent plasma for individuals hospitalized with COVID-19 pneumonia
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James D. Gordon, Kathleen O. Degnan, Leah Irwin, Don L. Siegel, Maria Caturla, Ian Frank, Andrew D. Fesnak, Raeann Thomas, Pamela A. Shaw, Sigrid Gouma, Holly Barilla, Miranda Mastellone, Nicole A. Aqui, M. Alexandra Monroy, Anne M Mullin, Marie Buchanan, Eline T. Luning Prak, Maureen DeMarshall, Risa A Eichinger, Pablo Tebas, Geoff Feret, Michal A. Elovitz, Katharine J. Bar, Faye Demuth, William R. Short, Jose L. Pascual, Haideliza Soto-Calderon, Julie Starr, Felicity Mampe, Jasper B Yang, Scott E. Hensley, Nuala J. Meyer, Alan Wanicur, Anastasiya Pronina, Chigozie Amonu, Michelle Andronov, Jillian Baron, Grace H Choi, Lizette Grajales, and Emily Lindemuth
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Adult ,Male ,medicine.medical_specialty ,Convalescent plasma ,Coronavirus disease 2019 (COVID-19) ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,medicine.medical_treatment ,Pneumonia, Viral ,Antibodies, Viral ,law.invention ,Randomized controlled trial ,Risk Factors ,law ,Internal medicine ,Immune Tolerance ,medicine ,Humans ,COVID-19 Serotherapy ,Aged ,Immunosuppression Therapy ,Mechanical ventilation ,SARS-CoV-2 ,business.industry ,Incidence ,Immunization, Passive ,COVID-19 ,Immunosuppression ,General Medicine ,Middle Aged ,medicine.disease ,Respiration, Artificial ,Hospitalization ,Oxygen ,Clinical trial ,Pneumonia ,Treatment Outcome ,RNA, Viral ,Female ,Clinical Medicine ,business - Abstract
BACKGROUND: Antibody-based strategies for COVID-19 have shown promise in prevention and treatment of early disease. COVID-19 convalescent plasma (CCP) has been widely used but results from randomized trials supporting its benefit in hospitalized patients with pneumonia are limited. Here, we assess the efficacy of CCP in severely ill, hospitalized adults with COVID-19 pneumonia. METHODS: We performed a randomized control trial (PennCCP2), with 80 adults hospitalized with COVID-19 pneumonia, comparing up to 2 units of locally sourced CCP plus standard care versus standard care alone. The primary efficacy endpoint was comparison of a clinical severity score. Key secondary outcomes include 14- and 28-day mortality, 14- and 28-day maximum 8-point WHO ordinal score (WHO8) score, duration of supplemental oxygenation or mechanical ventilation, respiratory SARS-CoV-2 RNA, and anti–SARS-CoV-2 antibodies. RESULTS: Eighty hospitalized adults with confirmed COVID-19 pneumonia were enrolled at median day 6 of symptoms and day 1 of hospitalization; 60% were anti–SARS-CoV-2 antibody seronegative. Participants had a median of 3 comorbidities, including risk factors for severe COVID-19 and immunosuppression. CCP treatment was safe and conferred significant benefit by clinical severity score (median [MED] and interquartile range [IQR] 10 [5.5–30] vs. 7 [2.75–12.25], P = 0.037) and 28-day mortality (n = 10, 26% vs. n = 2, 5%; P = 0.013). All other prespecified outcome measures showed weak evidence toward benefit of CCP. CONCLUSION: Two units of locally sourced CCP administered early in hospitalization to majority seronegative participants conferred a significant benefit in clinical severity score and 28-day mortality. Results suggest CCP may benefit select populations, especially those with comorbidities who are treated early. TRIAL REGISTRATION: ClinicalTrials.gov NCT04397757. FUNDING: University of Pennsylvania.
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- 2021
9. Activation of Glutamate Transport Increases Arteriole Diameter
- Author
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Joshua G, Jackson, Elizabeth, Krizman, Hajime, Takano, Meredith, Lee, Grace H, Choi, Mary E, Putt, and Michael B, Robinson
- Abstract
In order to meet the energetic demands of cell-to-cell signaling, increases in local neuronal signaling are matched by a coordinated increase in local blood flow, termed neurovascular coupling. Multiple different signals from neurons, astrocytes, and pericytes contribute to this control of blood flow. Previously, several groups demonstrated that inhibition/ablation of glutamate transporters attenuates the neurovascular response. However, it was not determined if glutamate transporter activation was sufficient to increase blood flow. Here, we used multiphoton imaging to monitor the diameter of fluorescently labeled cortical arterioles in anesthetized C57/B6J mice. We delivered vehicle, glutamate transporter substrates, or a combination of a glutamate transporter substrate with various pharmacologic agents via a glass micropipette while simultaneously visualizing changes in arteriole diameter. We developed a novel image analysis method to automate the measurement of arteriole diameter in these time-lapse analyses. Using this workflow, we first conducted pilot experiments in which we focally applied L-glutamate, D-aspartate, or L
- Published
- 2021
10. Lack of Atorvastatin Effect on Monocyte Gene Expression and Inflammatory Markers in HIV-1-infected ART-suppressed Individuals at Risk of non-AIDS Comorbidities
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Ronald G. Collman, Grace H Choi, Pamela A. Shaw, Anjana Yadav, Louise C. Showe, Luis J. Montaner, Andrew V. Kossenkov, Sarah J. Ratcliffe, and Pablo Tebas
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Microbiology (medical) ,CCR2 ,CD14 ,Atorvastatin ,Immunology ,Inflammation ,CCL2 ,Monocyte ,medicine ,Immunology and Allergy ,Molecular Biology ,Cytokine ,Immune activation ,business.industry ,Antiretroviral therapy ,Infectious Diseases ,medicine.anatomical_structure ,CXCL9 ,HIV/AIDS ,Gene expression ,medicine.symptom ,business ,CD163 ,medicine.drug ,Research Article - Abstract
Background: Many people living with HIV have persistent monocyte activation despite viral suppression by antiretroviral therapy (ART), which contributes to non-AIDS complications including neurocognitive and other disorders. Statins have immunomodulatory properties that might be beneficial by reducing monocyte activation. Methods: We previously characterized monocyte gene expression and inflammatory markers in 11 HIV-positive individuals on long-term ART (HIV/ART) at risk for non-AIDS complications because of low nadir CD4+ counts (median 129 cells/uL) and elevated hsCRP. Here, these individuals participated in a double-blind, randomized, placebo-controlled crossover study of 12 weeks of atorvastatin treatment. Monocyte surface markers were assessed by flow cytometry, plasma mediators by ELISA and Luminex, and monocyte gene expression by microarray analysis. Results: Among primary outcome measures, 12 weeks of atorvastatin treatment led to an unexpected increase in CCR2+ monocytes (P=0.04), but did not affect CD16+ or CD163+ monocytes, nor levels in plasma of CCL2/MCP-1 or sCD14. Among secondary outcomes, atorvastatin treatment was associated with decreased plasma hsCRP (P=0.035) and IL-2R (P=0.012). Treatment was also associated with increased total CD14+ monocytes (P=0.015), and increased plasma CXCL9 (P=0.003) and IL-12 (P
- Published
- 2021
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