Nicholas Thomas, Courtney S. Ning, Robin E Gross, Tianwen Ma, Ebrahim Haroon, David R Goldsmith
OBJECTIVES/GOALS: Previous research has linked inflammation to changes in brain reward circuitry and subsequent negative symptoms in patients with schizophrenia. This project aims to understand brain-immune interactions using diffusion tensor imaging (DTI) to investigate the impact of inflammatory markers on white matter (WM) tracts. METHODS/STUDY POPULATION: Patients with schizophrenia, ages 18 to 45, were recruited at Grady Hospital in Atlanta, GA. All subjects were stable outpatients and underwent extensive medical screening to rule out medical causes of acute inflammation. DTI data was collected from 39 participants on a 3-Tesla Siemens scanner. Blood was collected between 9-11AM for later assay of serum inflammatory markers. Negative symptoms were assessed using the Brief Negative Symptom Scale (BNSS). A diffusion tensor imaging model will be fitted with the data to generate well-known diffusion tensor measures (fractional anisotropy and mean diffusivity). Linear regression will be used to analyze the relationship between DTI measures and inflammation (C-Reactive Protein, CRP), controlling for possible confounders. RESULTS/ANTICIPATED RESULTS: The hypothesis of this proposal is that decreased microstructural integrity in WM tracts between the nucleus accumbens (NAc) and insula will be associated with increased inflammation, which in turn are associated with increased negative symptoms. Negative symptoms include deficits in motivation/pleasure as well as diminished expressivity, and are strongly associated with poor functional outcomes. Based on previous data from this sample demonstrating relationships between CRP and negative symptoms as well as CRP and fMRI functional connectivity between the NAc and insula, we anticipate results that demonstrate similar relationships with WM microstructural integrity, such as functional anisotropy and mean diffusivity. DISCUSSION/SIGNIFICANCE: Given the lack of treatment options for negative symptoms, this research will provide key data to further our understanding of the potential role of inflammation on neural circuits that underlie these symptoms, including WM integrity. This research also has the potential to inform future anti-inflammatory therapies for patients with schizophrenia.
{"title":"485 Investigating the Impact of Inflammation on White Matter Tracts using Diffusion Tensor Imaging that may Contribute to Motivational Deficits and Negative Symptoms in Patients with Schizophrenia","authors":"Nicholas Thomas, Courtney S. Ning, Robin E Gross, Tianwen Ma, Ebrahim Haroon, David R Goldsmith","doi":"10.1017/cts.2024.411","DOIUrl":"https://doi.org/10.1017/cts.2024.411","url":null,"abstract":"OBJECTIVES/GOALS: Previous research has linked inflammation to changes in brain reward circuitry and subsequent negative symptoms in patients with schizophrenia. This project aims to understand brain-immune interactions using diffusion tensor imaging (DTI) to investigate the impact of inflammatory markers on white matter (WM) tracts. METHODS/STUDY POPULATION: Patients with schizophrenia, ages 18 to 45, were recruited at Grady Hospital in Atlanta, GA. All subjects were stable outpatients and underwent extensive medical screening to rule out medical causes of acute inflammation. DTI data was collected from 39 participants on a 3-Tesla Siemens scanner. Blood was collected between 9-11AM for later assay of serum inflammatory markers. Negative symptoms were assessed using the Brief Negative Symptom Scale (BNSS). A diffusion tensor imaging model will be fitted with the data to generate well-known diffusion tensor measures (fractional anisotropy and mean diffusivity). Linear regression will be used to analyze the relationship between DTI measures and inflammation (C-Reactive Protein, CRP), controlling for possible confounders. RESULTS/ANTICIPATED RESULTS: The hypothesis of this proposal is that decreased microstructural integrity in WM tracts between the nucleus accumbens (NAc) and insula will be associated with increased inflammation, which in turn are associated with increased negative symptoms. Negative symptoms include deficits in motivation/pleasure as well as diminished expressivity, and are strongly associated with poor functional outcomes. Based on previous data from this sample demonstrating relationships between CRP and negative symptoms as well as CRP and fMRI functional connectivity between the NAc and insula, we anticipate results that demonstrate similar relationships with WM microstructural integrity, such as functional anisotropy and mean diffusivity. DISCUSSION/SIGNIFICANCE: Given the lack of treatment options for negative symptoms, this research will provide key data to further our understanding of the potential role of inflammation on neural circuits that underlie these symptoms, including WM integrity. This research also has the potential to inform future anti-inflammatory therapies for patients with schizophrenia.","PeriodicalId":508693,"journal":{"name":"Journal of Clinical and Translational Science","volume":"23 7","pages":"143 - 143"},"PeriodicalIF":0.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140762563","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sarah B. Walker, Kyle Honegger, Michael S. Carroll, Debra E. Weese-Mayer, L. N. Sanchez-Pinto
OBJECTIVES/GOALS: Fluid boluses are administered to hypotensive, critically ill children but may not reverse hypotension, leading to delay of vasoactive infusion, end-organ damage, and mortality. We hypothesize that a machine learning-based model will predict which children will have sustained response to fluid bolus. METHODS/STUDY POPULATION: We will conduct a single-center retrospective observational cohort study of hypotensive critically ill children who received intravenous isotonic fluid of at least 10 ml/kg within 72 hours of pediatric intensive care unit admission between 2013 and 2023. We will extract physiologic variables from stored bedside monitors data and clinical variables from the EHR. Fluid responsive (FR) will be defined as a MAP increase by 310%. We will construct elastic net, random forest, and a long short-term memory models to predict FR. We will compare complicated course (multiple organ dysfunction on day 7 or death by day 28) between: 1) FRs and non-FRs, 2) predicted FRs and non-FRs, 3), FRs and non-FRs stratified by race/ethnicity, and 4) FRs and non-FRs stratified by sex as a biologic variable. RESULTS/ANTICIPATED RESULTS: We anticipate approximately 800 critically ill children will receive 2,000 intravenous isotonic fluid boluses, with a 60% rate of FR. We anticipate being able to complete all three models. We hypothesize that the model with the best performance will be the long short-term memory model and the easiest to interpret will be the tree-based random forest model. We hypothesize non-FRs will have a higher complicated course than FRs and that predicted non-FRs will have a higher rate of complicated course than FRs. Based on previous adult studies, we hypothesize that there will be a higher rate of complicated course in patients of black race and/or Hispanic ethnicity when compared to non-Hispanic white patients. We also hypothesize that there will be no difference in complicated course when comparing sex as a biologic variable. DISCUSSION/SIGNIFICANCE: We have a critical need for easily-deployed, real-time prediction of fluid response to personalize and improve resuscitation for children in shock. We anticipate the clinical application of such a model will decrease time with hypotension for critically ill children, leading to decreased morbidity and mortality.
{"title":"316 Machine Learning to Predict Fluid Responsiveness in Hypotensive Children","authors":"Sarah B. Walker, Kyle Honegger, Michael S. Carroll, Debra E. Weese-Mayer, L. N. Sanchez-Pinto","doi":"10.1017/cts.2024.286","DOIUrl":"https://doi.org/10.1017/cts.2024.286","url":null,"abstract":"OBJECTIVES/GOALS: Fluid boluses are administered to hypotensive, critically ill children but may not reverse hypotension, leading to delay of vasoactive infusion, end-organ damage, and mortality. We hypothesize that a machine learning-based model will predict which children will have sustained response to fluid bolus. METHODS/STUDY POPULATION: We will conduct a single-center retrospective observational cohort study of hypotensive critically ill children who received intravenous isotonic fluid of at least 10 ml/kg within 72 hours of pediatric intensive care unit admission between 2013 and 2023. We will extract physiologic variables from stored bedside monitors data and clinical variables from the EHR. Fluid responsive (FR) will be defined as a MAP increase by 310%. We will construct elastic net, random forest, and a long short-term memory models to predict FR. We will compare complicated course (multiple organ dysfunction on day 7 or death by day 28) between: 1) FRs and non-FRs, 2) predicted FRs and non-FRs, 3), FRs and non-FRs stratified by race/ethnicity, and 4) FRs and non-FRs stratified by sex as a biologic variable. RESULTS/ANTICIPATED RESULTS: We anticipate approximately 800 critically ill children will receive 2,000 intravenous isotonic fluid boluses, with a 60% rate of FR. We anticipate being able to complete all three models. We hypothesize that the model with the best performance will be the long short-term memory model and the easiest to interpret will be the tree-based random forest model. We hypothesize non-FRs will have a higher complicated course than FRs and that predicted non-FRs will have a higher rate of complicated course than FRs. Based on previous adult studies, we hypothesize that there will be a higher rate of complicated course in patients of black race and/or Hispanic ethnicity when compared to non-Hispanic white patients. We also hypothesize that there will be no difference in complicated course when comparing sex as a biologic variable. DISCUSSION/SIGNIFICANCE: We have a critical need for easily-deployed, real-time prediction of fluid response to personalize and improve resuscitation for children in shock. We anticipate the clinical application of such a model will decrease time with hypotension for critically ill children, leading to decreased morbidity and mortality.","PeriodicalId":508693,"journal":{"name":"Journal of Clinical and Translational Science","volume":"52 15","pages":"97 - 97"},"PeriodicalIF":0.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140765617","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ritesh Karsalia, Ritesh Isuri, J. Lee, Edward J. Delikatny
OBJECTIVES/GOALS: Distinguishing tumor tissue from normal brain parenchyma remains a major challenge during the resection of gliomas, leading to the persistence of tumor cells. This study aims to assess the choline kinase alpha-targeting fluorophore JAS239 as a novel fluorescent agent to intraoperatively visualize gliomas in an orthotopic murine model. METHODS/STUDY POPULATION: The human glioblastoma-derived U87 MG-Luc2 cell line will be intracranially implanted in nude mice and tumor growth will be assessed using bioluminescence imaging. After 14 days, the mice will be treated with either antiangiogenic therapy (10 mg/kg bevacizumab, twice/week) or saline (control). Tumor growth will be monitored until 21-28 days after initial implantation, at which point JAS239 (4.0 mg/kg, 90 min before sacrifice) and Evans Blue (4 ml/kg, 60 min before sacrifice) will be administered. The mice will be sacrificed, and their brains will be harvested and sectioned for near-infrared imaging. The brain sections will be processed for histopathologic analysis, allowing for the correlation of observed fluorescence with the distribution of tumor and comparison of signal-to-background ratios. RESULTS/ANTICIPATED RESULTS: JAS239 is an indocyanine-based choline mimetic (excitation 745 nm, emission 775 nm) that has been shown to cross the blood-tumor barrier (BTB) in rodent glioblastoma studies. PET imaging with choline-based radiotracers like 18F-choline has also been shown to delineate both contrast-enhancing tumor (CET) and non-contrast-enhancing tumor (NCET) regions, supporting the hypothesis that JAS239 will be able to visualize heterogeneous glioma tissue in our mouse model. Evans Blue is a passive dye in the visible light spectrum (excitation 620 nm, emission 680 nm) expected to only fluoresce in CET regions due to the disruption of the BTB. JAS239 is expected to fluoresce in both CET and NCET regions, which will be assessed by the fluorescence in mice treated with bevacizumab (expected to renormalize the BTB and model NCETs). DISCUSSION/SIGNIFICANCE: JAS239 may allow for real-time visualization of heterogeneous glioma tissue, which is important because there are no current intraoperative imaging agents for NCETs. Future research and clinical translation of this class of agents may allow surgeons to maximize the safe resection of gliomas, improving progression-free and overall survival rates.
{"title":"415 Intraoperative Molecular Imaging of Gliomas using Indocyanine-Conjugated Choline Kinase Alpha Inhibitor","authors":"Ritesh Karsalia, Ritesh Isuri, J. Lee, Edward J. Delikatny","doi":"10.1017/cts.2024.359","DOIUrl":"https://doi.org/10.1017/cts.2024.359","url":null,"abstract":"OBJECTIVES/GOALS: Distinguishing tumor tissue from normal brain parenchyma remains a major challenge during the resection of gliomas, leading to the persistence of tumor cells. This study aims to assess the choline kinase alpha-targeting fluorophore JAS239 as a novel fluorescent agent to intraoperatively visualize gliomas in an orthotopic murine model. METHODS/STUDY POPULATION: The human glioblastoma-derived U87 MG-Luc2 cell line will be intracranially implanted in nude mice and tumor growth will be assessed using bioluminescence imaging. After 14 days, the mice will be treated with either antiangiogenic therapy (10 mg/kg bevacizumab, twice/week) or saline (control). Tumor growth will be monitored until 21-28 days after initial implantation, at which point JAS239 (4.0 mg/kg, 90 min before sacrifice) and Evans Blue (4 ml/kg, 60 min before sacrifice) will be administered. The mice will be sacrificed, and their brains will be harvested and sectioned for near-infrared imaging. The brain sections will be processed for histopathologic analysis, allowing for the correlation of observed fluorescence with the distribution of tumor and comparison of signal-to-background ratios. RESULTS/ANTICIPATED RESULTS: JAS239 is an indocyanine-based choline mimetic (excitation 745 nm, emission 775 nm) that has been shown to cross the blood-tumor barrier (BTB) in rodent glioblastoma studies. PET imaging with choline-based radiotracers like 18F-choline has also been shown to delineate both contrast-enhancing tumor (CET) and non-contrast-enhancing tumor (NCET) regions, supporting the hypothesis that JAS239 will be able to visualize heterogeneous glioma tissue in our mouse model. Evans Blue is a passive dye in the visible light spectrum (excitation 620 nm, emission 680 nm) expected to only fluoresce in CET regions due to the disruption of the BTB. JAS239 is expected to fluoresce in both CET and NCET regions, which will be assessed by the fluorescence in mice treated with bevacizumab (expected to renormalize the BTB and model NCETs). DISCUSSION/SIGNIFICANCE: JAS239 may allow for real-time visualization of heterogeneous glioma tissue, which is important because there are no current intraoperative imaging agents for NCETs. Future research and clinical translation of this class of agents may allow surgeons to maximize the safe resection of gliomas, improving progression-free and overall survival rates.","PeriodicalId":508693,"journal":{"name":"Journal of Clinical and Translational Science","volume":"48 3","pages":"123 - 123"},"PeriodicalIF":0.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140772375","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
OBJECTIVES/GOALS: Transcriptional adaptation is a phenomenon in which a mutation in one gene leads to the genetic compensation of another homogenous gene. Understanding the mechanism of transcriptional adaptation may contribute to an explanation for variation in clinical manifestations of rare Amyotrophic lateral sclerosis patient phenotypes. METHODS/STUDY POPULATION: The presence of a premature termination codon triggers transcriptional activation. Therefore, we utilized CRISPR-Cas9 tool to generate a premature termination codon in CHCHD10 gene in multiple types of cells, including induced pluripotent stem cells derived from patient samples with known CHCHD10 mutations causative for Amyotrophic lateral sclerosis. CRISPR-Cas9 tool was delivered via ribonucleoprotein electroporation and transfect cell’s DNA was sequenced to validate gene editing. To confirm transcriptional adaption, changes in levels of protein and gene expression will be measured via immunoblot and quantification of CHCHD10 and CHCHCD2 from whole cells lysates of the edited cells. RESULTS/ANTICIPATED RESULTS: We anticipate that CHCHD2 transcriptional adaptation can functionally compensate for the locus loss of function of CHCHD10. This mechanism of transcriptional adaptation may contribute to an explanation for variation in clinical manifestations of patient phenotypes. DISCUSSION/SIGNIFICANCE: Our approach would advance discovery science towards by exploring transcriptional adaptation mechanism in humans, which can lead to novel therapies for rare Amyotrophic lateral sclerosis, such as CHCHD10.
{"title":"393 Harnessing the potential of transcriptional adaptation as a mechanism for rare Amyotrophic lateral sclerosis","authors":"A. Gomez, Nathan Staff, S. Ekker","doi":"10.1017/cts.2024.343","DOIUrl":"https://doi.org/10.1017/cts.2024.343","url":null,"abstract":"OBJECTIVES/GOALS: Transcriptional adaptation is a phenomenon in which a mutation in one gene leads to the genetic compensation of another homogenous gene. Understanding the mechanism of transcriptional adaptation may contribute to an explanation for variation in clinical manifestations of rare Amyotrophic lateral sclerosis patient phenotypes. METHODS/STUDY POPULATION: The presence of a premature termination codon triggers transcriptional activation. Therefore, we utilized CRISPR-Cas9 tool to generate a premature termination codon in CHCHD10 gene in multiple types of cells, including induced pluripotent stem cells derived from patient samples with known CHCHD10 mutations causative for Amyotrophic lateral sclerosis. CRISPR-Cas9 tool was delivered via ribonucleoprotein electroporation and transfect cell’s DNA was sequenced to validate gene editing. To confirm transcriptional adaption, changes in levels of protein and gene expression will be measured via immunoblot and quantification of CHCHD10 and CHCHCD2 from whole cells lysates of the edited cells. RESULTS/ANTICIPATED RESULTS: We anticipate that CHCHD2 transcriptional adaptation can functionally compensate for the locus loss of function of CHCHD10. This mechanism of transcriptional adaptation may contribute to an explanation for variation in clinical manifestations of patient phenotypes. DISCUSSION/SIGNIFICANCE: Our approach would advance discovery science towards by exploring transcriptional adaptation mechanism in humans, which can lead to novel therapies for rare Amyotrophic lateral sclerosis, such as CHCHD10.","PeriodicalId":508693,"journal":{"name":"Journal of Clinical and Translational Science","volume":"50 10","pages":"117 - 117"},"PeriodicalIF":0.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140772507","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
OBJECTIVES/GOALS: The objective is to assess the effect of pesticide exposure (individually and pesticide mixtures) on the immune response to COVID-19 in children. The goal is to improve scientific knowledge on factors affecting COVID-19 and identify a potentially modifiable factor to reduce disparities in COVID-19 morbidity. METHODS/STUDY POPULATION: Blood samples will be obtained from 50 children with asthma two time points; baseline and 12 months later. SARS-CoV-2 infection or vaccination will be determined with blood exposome RNA analyses.. Immunological response will be measured using neutralizing, phagocytizing, and NK-activating anti-body responses biomarkers. Pesticide exposure will be measured via urinary pesticide metabolites (UPMs). For individual metabolites multivariable analyses for each pesticide will be conducted using generalized estimating equation (GEE) models with compound symmetry correlation to account for the repeated measures design. To assess the pesticide mixture, weighted quantile sum regression (WQS) will be used. RESULTS/ANTICIPATED RESULTS: The main hypothesis is that increased pesticide exposure results in a reduction in the immunological response to SARS-CoV-2 infection and the COVID-19 vaccine. Therefore, we anticipate that increasing concentrations of individual UPMs as well as the increasing index will result in reductions in markers of the immune response to SARS-CoV-2 infection and the COVID-19 vaccine. DISCUSSION/SIGNIFICANCE: Exposure to pesticides is a modifiable environmental factor. If pesticides are found to alter the immune response to COVID-19 infection and vaccination, these data will provide an evidence base for efforts to reduce pesticide exposure in children.
{"title":"49 The Effect of Pesticide Exposure on Immunological Responses in Children against SARS-CoV-2","authors":"D. Werthmann, Elizabeth Norton, Felicia Rabito","doi":"10.1017/cts.2024.60","DOIUrl":"https://doi.org/10.1017/cts.2024.60","url":null,"abstract":"OBJECTIVES/GOALS: The objective is to assess the effect of pesticide exposure (individually and pesticide mixtures) on the immune response to COVID-19 in children. The goal is to improve scientific knowledge on factors affecting COVID-19 and identify a potentially modifiable factor to reduce disparities in COVID-19 morbidity. METHODS/STUDY POPULATION: Blood samples will be obtained from 50 children with asthma two time points; baseline and 12 months later. SARS-CoV-2 infection or vaccination will be determined with blood exposome RNA analyses.. Immunological response will be measured using neutralizing, phagocytizing, and NK-activating anti-body responses biomarkers. Pesticide exposure will be measured via urinary pesticide metabolites (UPMs). For individual metabolites multivariable analyses for each pesticide will be conducted using generalized estimating equation (GEE) models with compound symmetry correlation to account for the repeated measures design. To assess the pesticide mixture, weighted quantile sum regression (WQS) will be used. RESULTS/ANTICIPATED RESULTS: The main hypothesis is that increased pesticide exposure results in a reduction in the immunological response to SARS-CoV-2 infection and the COVID-19 vaccine. Therefore, we anticipate that increasing concentrations of individual UPMs as well as the increasing index will result in reductions in markers of the immune response to SARS-CoV-2 infection and the COVID-19 vaccine. DISCUSSION/SIGNIFICANCE: Exposure to pesticides is a modifiable environmental factor. If pesticides are found to alter the immune response to COVID-19 infection and vaccination, these data will provide an evidence base for efforts to reduce pesticide exposure in children.","PeriodicalId":508693,"journal":{"name":"Journal of Clinical and Translational Science","volume":"62 16","pages":"13 - 14"},"PeriodicalIF":0.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140761007","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sadaf Ghaderzadeh, Baiyee-Ndang Agbor-Baiyee, Chidera Obiwuma, N. Mohit, Kanwal K. Gambhir, C. Ecelbarger, Maurice B Fluitt
OBJECTIVES/GOALS: Diabetic Kidney Disease (DKD) is a common diabetes complication, often linked to end-stage renal disease in the United States (US). While autophagy and miRNAs are pivotal, miR-451’s specific role remains understudied. Our study explores its renoprotective effects in an accelerated DKD mouse model. METHODS/STUDY POPULATION: We assessed the effect of miR-451 mimic treatment on Diabetic Kidney Disease (DKD) in BTBR ob/ob mice, known for their rapid DKD-like renal lesions. Mice were divided into four groups: WT (wild-type), BTBR ob/ob, WT+miR-451 (wild-type with miR-451 mimic), and BTBR ob/ob+miR-451 (BTBR ob/ob with miR-451 mimic). MiR-451 mimics were administered at 2mg/kg body weight once weekly for three consecutive weeks. We collected spot urine and monitored blood glucose levels at each time point. After the treatment period, mice were euthanized for kidney and blood samples. Western blot analysis assessed autophagy-related protein markers. Statistical analysis included Student’s t-test and ANOVA (p<0.05). RESULTS/ANTICIPATED RESULTS: The study assessed the impact of miR-451 mimic treatment in BTBR ob/ob mice. Albumin:creatinine ratio increased fourfold (p=0.01) in BTBR ob/ob mice at 5 weeks. MiR-451 mimic treatment had no impact on body weight. Blood glucose levels were notably higher in both treated and untreated BTBR ob/ob mice at 12 (425±33.1 mg/dL; p=0.04) and 13 weeks (383±25.3 mg/dL; p=0.007). However, a significant drop occurred from week 13 (554.7±10.8 mg/dL) to week 14 (289±13.3 mg/dL; p=0.0002) in BTBR ob/ob miR-451 treated mice. Western blot analysis in whole kidney homogenates showed a 91% reduction (p=0.02) in YWHAZ, a predicted miR-451 target, in treated BTBR ob/ob mice and a 95% reduction (p=0.01) in WT mice. Furthermore, miR-451 mimic treatment led to a 68% increase (p=0.01) in ATG101 and a 44% increase in Beclin-1 in BTBR ob/ob mice. DISCUSSION/SIGNIFICANCE: The study uncovers miR-451-based interventions as a promising avenue to counter Diabetic Kidney Disease by modulating autophagy, potentially introducing novel therapies for at-risk individuals. However, practical DKD treatments will require further research and rigorous clinical validation to harness the full potential of these insights.
{"title":"395 Systemic Administration of miR-451 Improves Autophagy Response in an Accelerated Mouse Model of Diabetic Kidney Disease","authors":"Sadaf Ghaderzadeh, Baiyee-Ndang Agbor-Baiyee, Chidera Obiwuma, N. Mohit, Kanwal K. Gambhir, C. Ecelbarger, Maurice B Fluitt","doi":"10.1017/cts.2024.345","DOIUrl":"https://doi.org/10.1017/cts.2024.345","url":null,"abstract":"OBJECTIVES/GOALS: Diabetic Kidney Disease (DKD) is a common diabetes complication, often linked to end-stage renal disease in the United States (US). While autophagy and miRNAs are pivotal, miR-451’s specific role remains understudied. Our study explores its renoprotective effects in an accelerated DKD mouse model. METHODS/STUDY POPULATION: We assessed the effect of miR-451 mimic treatment on Diabetic Kidney Disease (DKD) in BTBR ob/ob mice, known for their rapid DKD-like renal lesions. Mice were divided into four groups: WT (wild-type), BTBR ob/ob, WT+miR-451 (wild-type with miR-451 mimic), and BTBR ob/ob+miR-451 (BTBR ob/ob with miR-451 mimic). MiR-451 mimics were administered at 2mg/kg body weight once weekly for three consecutive weeks. We collected spot urine and monitored blood glucose levels at each time point. After the treatment period, mice were euthanized for kidney and blood samples. Western blot analysis assessed autophagy-related protein markers. Statistical analysis included Student’s t-test and ANOVA (p<0.05). RESULTS/ANTICIPATED RESULTS: The study assessed the impact of miR-451 mimic treatment in BTBR ob/ob mice. Albumin:creatinine ratio increased fourfold (p=0.01) in BTBR ob/ob mice at 5 weeks. MiR-451 mimic treatment had no impact on body weight. Blood glucose levels were notably higher in both treated and untreated BTBR ob/ob mice at 12 (425±33.1 mg/dL; p=0.04) and 13 weeks (383±25.3 mg/dL; p=0.007). However, a significant drop occurred from week 13 (554.7±10.8 mg/dL) to week 14 (289±13.3 mg/dL; p=0.0002) in BTBR ob/ob miR-451 treated mice. Western blot analysis in whole kidney homogenates showed a 91% reduction (p=0.02) in YWHAZ, a predicted miR-451 target, in treated BTBR ob/ob mice and a 95% reduction (p=0.01) in WT mice. Furthermore, miR-451 mimic treatment led to a 68% increase (p=0.01) in ATG101 and a 44% increase in Beclin-1 in BTBR ob/ob mice. DISCUSSION/SIGNIFICANCE: The study uncovers miR-451-based interventions as a promising avenue to counter Diabetic Kidney Disease by modulating autophagy, potentially introducing novel therapies for at-risk individuals. However, practical DKD treatments will require further research and rigorous clinical validation to harness the full potential of these insights.","PeriodicalId":508693,"journal":{"name":"Journal of Clinical and Translational Science","volume":"22 5","pages":"118 - 118"},"PeriodicalIF":0.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140762575","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yolanda Jackson, Elizabeth K. Rhodus, Nancy G. Harrington
OBJECTIVES/GOALS: This study engaged Black adults who reside in a rural area of Kentucky to explore their beliefs, norms, knowledge, attitudes, and health-related behaviors about Alzheimer’s disease (AD) (RQ1) and what message elements are most relevant for designing a health message aimed at encouraging them to get screened for AD (RQ2). METHODS/STUDY POPULATION: This qualitative study was guided bythe Integrative Model of Behavior. Participants were recruited from a faith-based institution in rural Kentucky. Black adults aged 50+ years were invited to participate in the study, which consisted of two focus groups. Group 1 gained information about behavioral determinants (RQ1) and examined which message design elements were important to Black adults by asking for feedback on a handout from the Alzheimer’s Association that encouraged AD screening (RQ2). The handout was redesigned based on feedback from Group 1. Group 2 was involved in a discussion of the redesigned handout, asking for further feedback. Focus groups were audio recorded and transcribed verbatim. Data analysis included thematic analysis of transcripts of the focus groups and quantitative analysis. RESULTS/ANTICIPATED RESULTS: Participants (N=18) were all female and Black with a mean age of sixty-two years. For RQ1, Results revealed that 1) limited knowledge of AD led to feelings of not being able to do anything about the disease, whereas awareness and education led to hope; 2) past healthcare experiences informed subsequent beliefs and behaviors, and 3) culture impacted beliefs, with a cultural norm of “what happens in our house, stays in our house” being prominent. For RQ2, results revealed the importance of regionally specific messaging for AD. Generic statements that applied broadly did not appeal to participants. Message delivery, layout, and format for low literacy individuals are key for maximizing audience impact. Pictures give hints about the message and aid in understanding. DISCUSSION/SIGNIFICANCE: Barriers such as past experiences, lack of knowledge, and cultural norms negatively impact the likelihood that Black adults will get screened for AD, resulting in delayed healthcare or healthcare avoidance. Regionally specific health messaging for AD has the potential to encourage modifications in health-related behaviors.
{"title":"190 Translating Alzheimer’s Disease Research to Improve Dementia Screening Through Health Message Design in the Community: A Qualitative Study","authors":"Yolanda Jackson, Elizabeth K. Rhodus, Nancy G. Harrington","doi":"10.1017/cts.2024.181","DOIUrl":"https://doi.org/10.1017/cts.2024.181","url":null,"abstract":"OBJECTIVES/GOALS: This study engaged Black adults who reside in a rural area of Kentucky to explore their beliefs, norms, knowledge, attitudes, and health-related behaviors about Alzheimer’s disease (AD) (RQ1) and what message elements are most relevant for designing a health message aimed at encouraging them to get screened for AD (RQ2). METHODS/STUDY POPULATION: This qualitative study was guided bythe Integrative Model of Behavior. Participants were recruited from a faith-based institution in rural Kentucky. Black adults aged 50+ years were invited to participate in the study, which consisted of two focus groups. Group 1 gained information about behavioral determinants (RQ1) and examined which message design elements were important to Black adults by asking for feedback on a handout from the Alzheimer’s Association that encouraged AD screening (RQ2). The handout was redesigned based on feedback from Group 1. Group 2 was involved in a discussion of the redesigned handout, asking for further feedback. Focus groups were audio recorded and transcribed verbatim. Data analysis included thematic analysis of transcripts of the focus groups and quantitative analysis. RESULTS/ANTICIPATED RESULTS: Participants (N=18) were all female and Black with a mean age of sixty-two years. For RQ1, Results revealed that 1) limited knowledge of AD led to feelings of not being able to do anything about the disease, whereas awareness and education led to hope; 2) past healthcare experiences informed subsequent beliefs and behaviors, and 3) culture impacted beliefs, with a cultural norm of “what happens in our house, stays in our house” being prominent. For RQ2, results revealed the importance of regionally specific messaging for AD. Generic statements that applied broadly did not appeal to participants. Message delivery, layout, and format for low literacy individuals are key for maximizing audience impact. Pictures give hints about the message and aid in understanding. DISCUSSION/SIGNIFICANCE: Barriers such as past experiences, lack of knowledge, and cultural norms negatively impact the likelihood that Black adults will get screened for AD, resulting in delayed healthcare or healthcare avoidance. Regionally specific health messaging for AD has the potential to encourage modifications in health-related behaviors.","PeriodicalId":508693,"journal":{"name":"Journal of Clinical and Translational Science","volume":"152 2","pages":"57 - 58"},"PeriodicalIF":0.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140758296","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Deborah J. George, Aileen Cui, Shankar Thiru, Michael Deans, Thomas M. Coate
OBJECTIVES/GOALS: The primary research goal was to identify brain alterations reliably associated with obesity using coordinate-based meta-analysis. A secondary goal was to compare brain alterations in metabolically healthy (MHO) and unhealthy (MUO) obesity. METHODS/STUDY POPULATION: Source data were peer-reviewed studies reporting locations of gray-matter alterations in group-average, case-control contrasts (obese vs. non-obese) cohorts, performed in a whole-brain, voxel-wise manner. Both voxel-based morphometry and voxel-based physiology studies were included. Three coordinate-based meta-analyses were performed: Pooled (MUO + MHO), MHO, and MUO. RESULTS/ANTICIPATED RESULTS: Thirty-two studies reporting a total of 50 case-control contrasts (MHO, 23; MUO, 27) met inclusion criteria, representing 3,368 participants (obese, 1,781; non-obese, 1587). The pooled analysis yielded 8 cerebral foci (3 nuclear, 5 cortical) in regions implicated in reward-seeking, cognitive, and interoceptive behaviors. MHO yielded 7 cerebral foci (4 nuclear, 3 cortical), partially overlapping Pooled results, with similar behavioral loadings. The MUO pattern was distinct, with 3 cerebellar and 1 occipital foci. DISCUSSION/SIGNIFICANCE: Brain alterations occurred reliably in obesity. The dominant pattern (Pooled & MHO) involved cerebral reward-system circuits, evident even in metabolically healthy obesity. Cerebellar alterations occurred exclusively in metabolically unhealthy obesity, a pattern previously reported in metabolic syndrome.
{"title":"354 Brain Structural Alterations in Metabolically Healthy and Unhealthy Obesity: A Quantitative Comparison Using Coordinate-Based Meta-Analysis","authors":"Deborah J. George, Aileen Cui, Shankar Thiru, Michael Deans, Thomas M. Coate","doi":"10.1017/cts.2024.316","DOIUrl":"https://doi.org/10.1017/cts.2024.316","url":null,"abstract":"OBJECTIVES/GOALS: The primary research goal was to identify brain alterations reliably associated with obesity using coordinate-based meta-analysis. A secondary goal was to compare brain alterations in metabolically healthy (MHO) and unhealthy (MUO) obesity. METHODS/STUDY POPULATION: Source data were peer-reviewed studies reporting locations of gray-matter alterations in group-average, case-control contrasts (obese vs. non-obese) cohorts, performed in a whole-brain, voxel-wise manner. Both voxel-based morphometry and voxel-based physiology studies were included. Three coordinate-based meta-analyses were performed: Pooled (MUO + MHO), MHO, and MUO. RESULTS/ANTICIPATED RESULTS: Thirty-two studies reporting a total of 50 case-control contrasts (MHO, 23; MUO, 27) met inclusion criteria, representing 3,368 participants (obese, 1,781; non-obese, 1587). The pooled analysis yielded 8 cerebral foci (3 nuclear, 5 cortical) in regions implicated in reward-seeking, cognitive, and interoceptive behaviors. MHO yielded 7 cerebral foci (4 nuclear, 3 cortical), partially overlapping Pooled results, with similar behavioral loadings. The MUO pattern was distinct, with 3 cerebellar and 1 occipital foci. DISCUSSION/SIGNIFICANCE: Brain alterations occurred reliably in obesity. The dominant pattern (Pooled & MHO) involved cerebral reward-system circuits, evident even in metabolically healthy obesity. Cerebellar alterations occurred exclusively in metabolically unhealthy obesity, a pattern previously reported in metabolic syndrome.","PeriodicalId":508693,"journal":{"name":"Journal of Clinical and Translational Science","volume":"89 ","pages":"107 - 108"},"PeriodicalIF":0.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140763164","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
M. Prebeg, Izzar Linares, Brianna Dunstan, Edyta Marcon, Joseph Ferenbok
OBJECTIVES/GOALS: This integrated knowledgetranslationproject aims to increase youth engagement in mental health services through enhancing shared decision-making processes. To do this, a knowledge product to support greater involvement in measurement-based care practices will be evaluated and co-developed with youth study participants. METHODS/STUDY POPULATION: This study population includes youth (aged 12-25) with lived/living experience of accessing mental health services through an integrated service delivery model in Ontario. Study methods focus on co-designing a knowledge product with youth partners guided by the Knowledge-to-Action (KTA) Framework. The prototype knowledge product addressing identified barriers to MBC understanding, will be quantitatively evaluated by study participants. Through semi-structured focus groups, qualitative perspectives of the intervention’s impact on shared decision-making and overall engagement in treatment will be collected. The study’s design ensures active collaboration with the study population and aims to enhance MBC understanding and engagement in mental health care among youth. RESULTS/ANTICIPATED RESULTS: We anticipate increased youth involvement within MBC practices, and overall increased engagement in shared-decision making in treatment. We anticipate the developed knowledge product will enhance youth’s understanding of MBC, foster dialogue between youth and clinicians, and promote active involvement and informed decision-making in their mental health treatment. By involving youth in the co-design process, our project is poised to foster a sense of ownership and relevance, ultimately improving youth engagement, decision-making, and mental health outcomes within integrated mental health services. DISCUSSION/SIGNIFICANCE: Youth deserve to have an active role in shaping treatment decisions. This tool may bridge a gap by equipping youth with the knowledge needed to engage in decisions that are often practitioner-led. This study will discuss the impact and strategies for increasing involvement in MBC practices on youth engagement within treatment.
目的/目标：这项知识与翻译相结合的项目旨在通过加强共同决策过程，提高青少年对心理健康服务的参与度。为此，我们将评估并与青少年研究参与者共同开发一种知识产品，以支持他们更多地参与以测量为基础的护理实践。方法/研究对象：研究对象包括安大略省通过综合服务模式获得心理健康服务的青少年（12-25 岁）。研究方法侧重于在知识到行动（KTA）框架的指导下，与青少年合作伙伴共同设计知识产品。研究参与者将对知识产品原型进行定量评估，以解决已确定的心理健康障碍。通过半结构化焦点小组，将收集有关干预措施对共同决策和整体参与治疗的影响的定性观点。本研究的设计确保了与研究对象的积极合作，旨在提高青少年对小儿麻痹症的理解和对心理健康护理的参与度。结果/预期结果：我们预计，青少年将更多地参与到心理障碍治疗实践中，并在整体上更多地参与到治疗的共同决策中。我们预计所开发的知识产品将增强青少年对乳腺纤维瘤的了解，促进青少年与临床医生之间的对话，并推动青少年积极参与心理健康治疗和做出知情决策。通过让青少年参与共同设计过程，我们的项目将培养青少年的主人翁意识和相关性，最终在综合心理健康服务中提高青少年的参与度、决策力和心理健康成果。讨论/意义：青少年理应在治疗决策中发挥积极作用。这一工具可以为青少年提供参与决策所需的知识，从而弥补这一不足。本研究将讨论增加参与 MBC 实践对青少年参与治疗的影响和策略。
{"title":"237 Empowering Youth in Mental Health Treatment: A Co-Designed Approach to Measurement-Based Care","authors":"M. Prebeg, Izzar Linares, Brianna Dunstan, Edyta Marcon, Joseph Ferenbok","doi":"10.1017/cts.2024.219","DOIUrl":"https://doi.org/10.1017/cts.2024.219","url":null,"abstract":"OBJECTIVES/GOALS: This integrated knowledgetranslationproject aims to increase youth engagement in mental health services through enhancing shared decision-making processes. To do this, a knowledge product to support greater involvement in measurement-based care practices will be evaluated and co-developed with youth study participants. METHODS/STUDY POPULATION: This study population includes youth (aged 12-25) with lived/living experience of accessing mental health services through an integrated service delivery model in Ontario. Study methods focus on co-designing a knowledge product with youth partners guided by the Knowledge-to-Action (KTA) Framework. The prototype knowledge product addressing identified barriers to MBC understanding, will be quantitatively evaluated by study participants. Through semi-structured focus groups, qualitative perspectives of the intervention’s impact on shared decision-making and overall engagement in treatment will be collected. The study’s design ensures active collaboration with the study population and aims to enhance MBC understanding and engagement in mental health care among youth. RESULTS/ANTICIPATED RESULTS: We anticipate increased youth involvement within MBC practices, and overall increased engagement in shared-decision making in treatment. We anticipate the developed knowledge product will enhance youth’s understanding of MBC, foster dialogue between youth and clinicians, and promote active involvement and informed decision-making in their mental health treatment. By involving youth in the co-design process, our project is poised to foster a sense of ownership and relevance, ultimately improving youth engagement, decision-making, and mental health outcomes within integrated mental health services. DISCUSSION/SIGNIFICANCE: Youth deserve to have an active role in shaping treatment decisions. This tool may bridge a gap by equipping youth with the knowledge needed to engage in decisions that are often practitioner-led. This study will discuss the impact and strategies for increasing involvement in MBC practices on youth engagement within treatment.","PeriodicalId":508693,"journal":{"name":"Journal of Clinical and Translational Science","volume":"164 ","pages":"71 - 72"},"PeriodicalIF":0.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140768715","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alaguvalliappan Thiagarajan, Christopher McCarty, Edward Seh-Taylor
OBJECTIVES/GOALS: Our project aims to assess the composition or characteristics of research papers that score high on alternative metrics. These alternative metrics including the number of newspaper mentions, social media mentions, and the attention score as catalogued on Altmetric, a tool used to document community attention for a given research paper. METHODS/STUDY POPULATION: Our study intends to 1) Utilize topic modeling to identify prevalent themes on Altmetric, and 2) Apply network analysis to elucidate the interconnectedness among universities, funding sources, journals, and publishers associated with high-attention papers. 3) Examine how these patterns vary when attention metrics shift, such as social media mentions, newspaper mentions, or the Altmetric score. We'll first perform this analysis on all types of papers and then limit the networks to Biomedical and Clinical Sciences, and Public and Allied Health Sciences to help inform what health topics garner attention. RESULTS/ANTICIPATED RESULTS: Our initial Altmetric topic models revealed sustained attention for COVID-19 and vaccination-related publications well beyond the pandemic (specifically, papers from January 2023). Health topics like cancer, dementia, and obesity also garnered high attention. Additionally, political papers (elections, democracy), climate change, and battery research had notable attention values. Further analysis needs to be done to explain why these topics gain attention and the type of attention they garner. We will construct networks to see the relationship between attention and entities like universities, funding sources, journals, and publishers. This will identify whether certain clusters of these entities produce papers with high attention or if attention is distributed evenly amoung them. DISCUSSION/SIGNIFICANCE: To gauge the broader impact of scholarly research alternative metrics beyond citations are needed. Altmetric is used widely by CTSA’s to measure the community interest in research. Understanding the types of research that gain traction on Altmetric can help researchers understand how to garner interest from the community.
{"title":"167 An Evaluation of Altmetric Attention using Network Science and Natural Language Processing","authors":"Alaguvalliappan Thiagarajan, Christopher McCarty, Edward Seh-Taylor","doi":"10.1017/cts.2024.160","DOIUrl":"https://doi.org/10.1017/cts.2024.160","url":null,"abstract":"OBJECTIVES/GOALS: Our project aims to assess the composition or characteristics of research papers that score high on alternative metrics. These alternative metrics including the number of newspaper mentions, social media mentions, and the attention score as catalogued on Altmetric, a tool used to document community attention for a given research paper. METHODS/STUDY POPULATION: Our study intends to 1) Utilize topic modeling to identify prevalent themes on Altmetric, and 2) Apply network analysis to elucidate the interconnectedness among universities, funding sources, journals, and publishers associated with high-attention papers. 3) Examine how these patterns vary when attention metrics shift, such as social media mentions, newspaper mentions, or the Altmetric score. We'll first perform this analysis on all types of papers and then limit the networks to Biomedical and Clinical Sciences, and Public and Allied Health Sciences to help inform what health topics garner attention. RESULTS/ANTICIPATED RESULTS: Our initial Altmetric topic models revealed sustained attention for COVID-19 and vaccination-related publications well beyond the pandemic (specifically, papers from January 2023). Health topics like cancer, dementia, and obesity also garnered high attention. Additionally, political papers (elections, democracy), climate change, and battery research had notable attention values. Further analysis needs to be done to explain why these topics gain attention and the type of attention they garner. We will construct networks to see the relationship between attention and entities like universities, funding sources, journals, and publishers. This will identify whether certain clusters of these entities produce papers with high attention or if attention is distributed evenly amoung them. DISCUSSION/SIGNIFICANCE: To gauge the broader impact of scholarly research alternative metrics beyond citations are needed. Altmetric is used widely by CTSA’s to measure the community interest in research. Understanding the types of research that gain traction on Altmetric can help researchers understand how to garner interest from the community.","PeriodicalId":508693,"journal":{"name":"Journal of Clinical and Translational Science","volume":"105 2","pages":"50 - 50"},"PeriodicalIF":0.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140791993","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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