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Article: A Spatiotemporal Map of Co-Receptor Signaling Networks Underlying B Cell Activation.

Susa, Katherine J / Bradshaw, Gary A / Eisert, Robyn J / Schilling, Charlotte M / Kalocsay, Marian / Blacklow, Stephen C / Kruse, Andrew C

bioRxiv : the preprint server for biology

2023

Abstract: The B cell receptor (BCR) signals together with a multi-component co-receptor complex to initiate B cell activation in response to antigen binding. This process underlies nearly every aspect of proper B cell function. Here, we take advantage of ... ...

Abstract	The B cell receptor (BCR) signals together with a multi-component co-receptor complex to initiate B cell activation in response to antigen binding. This process underlies nearly every aspect of proper B cell function. Here, we take advantage of peroxidase-catalyzed proximity labeling combined with quantitative mass spectrometry to track B cell co-receptor signaling dynamics from 10 seconds to 2 hours after BCR stimulation. This approach enables tracking of 2,814 proximity-labeled proteins and 1,394 quantified phosphosites and provides an unbiased and quantitative molecular map of proteins recruited to the vicinity of CD19, the key signaling subunit of the co-receptor complex. We detail the recruitment kinetics of essential signaling effectors to CD19 following activation, and then identify new mediators of B cell activation. In particular, we show that the glutamate transporter SLC1A1 is responsible for mediating rapid metabolic reprogramming immediately downstream of BCR stimulation and for maintaining redox homeostasis during B cell activation. This study provides a comprehensive map of the BCR signaling pathway and a rich resource for uncovering the complex signaling networks that regulate B cell activation.
Language	English
Publishing date	2023-03-21
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.03.17.533227
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Article ; Online: Patient and researcher stakeholder preferences for use of electronic health record data: a qualitative study to guide the design and development of a platform to honor patient preferences.

Morse, Brad / Kim, Katherine K / Xu, Zixuan / Matsumoto, Cynthia G / Schilling, Lisa M / Ohno-Machado, Lucila / Mak, Selene S / Keller, Michelle S

Journal of the American Medical Informatics Association : JAMIA

2023

Abstract: Objective: This qualitative study aimed to understand patient and researcher perspectives regarding consent and data-sharing preferences for research and a patient-centered system to manage consent and data-sharing preferences.: Materials and methods!# ...

Abstract	Objective: This qualitative study aimed to understand patient and researcher perspectives regarding consent and data-sharing preferences for research and a patient-centered system to manage consent and data-sharing preferences. Materials and methods: We conducted focus groups with patient and researcher participants recruited from three academic health centers via snowball sampling. Discussions focused on perspectives on the use of electronic health record (EHR) data for research. Themes were identified through consensus coding, starting from an exploratory framework. Results: We held two focus groups with patients (n = 12 patients) and two with researchers (n = 8 researchers). We identified two patient themes (1-2), one theme common to patients and researchers (3), and two researcher themes (4-5). Themes included (1) motivations for sharing EHR data, (2) perspectives on the importance of data-sharing transparency, (3) individual control of personal EHR data sharing, (4) how EHR data benefits research, and (5) challenges researchers face using EHR data. Discussion: Patients expressed a tension between the benefits of their data being used in studies to benefit themselves/others and avoiding risk by limiting data access. Patients resolved this tension by acknowledging they would often share their data but wanted greater transparency on its use. Researchers expressed concern about incorporating bias into datasets if patients opted out. Conclusions: A research consent and data-sharing platform must consider two competing goals: empowering patients to have more control over their data and maintaining the integrity of secondary data sources. Health systems and researchers should increase trust-building efforts with patients to engender trust in data access and use.
Language	English
Publishing date	2023-05-04
Publishing country	England
Document type	Journal Article
ZDB-ID	1205156-1
ISSN	1527-974X ; 1067-5027
ISSN (online)	1527-974X
ISSN	1067-5027
DOI	10.1093/jamia/ocad058
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Article ; Online: Ingestion of Illicit Substances by Young Children Before and During the COVID-19 Pandemic.

Raffa, Brittany J / Schilling, Samantha / Henry, M Katherine / Ritter, Victor / Bennett, Colleen E / Huang, Jeannie S / Laub, Natalie

JAMA network open

2023 Volume 6, Issue 4, Page(s) e239549

Abstract: Importance: Information about the trend in illicit substance ingestions among young children during the pandemic is limited.: Objectives: To assess immediate and sustained changes in overall illicit substance ingestion rates among children younger ... ...

Abstract	Importance: Information about the trend in illicit substance ingestions among young children during the pandemic is limited. Objectives: To assess immediate and sustained changes in overall illicit substance ingestion rates among children younger than 6 years before and during the COVID-19 pandemic and to examine changes by substance type (amphetamines, benzodiazepines, cannabis, cocaine, ethanol, and opioids) while controlling for differing statewide medicinal and recreational cannabis legalization policies. Design, setting, and participants: Retrospective cross-sectional study using an interrupted time series at 46 tertiary care children's hospitals within the Pediatric Health Information System (PHIS). Participants were children younger than 6 years who presented to a PHIS hospital for an illicit substance(s) ingestion between January 1, 2017, and December 31, 2021. Data were analyzed in February 2023. Exposure: Absence or presence of the COVID-19 pandemic. Main outcome(s) and measure(s): The primary outcome was the monthly rate of encounters for illicit substance ingestions among children younger than 6 years defined by International Statistical Classification of Diseases, Tenth Revision, Clinical Modification diagnosis code(s) for poisoning by amphetamines, benzodiazepines, cannabis, cocaine, ethanol, and opioids. The secondary outcomes were the monthly rate of encounters for individual substances. Results: Among 7659 children presenting with ingestions, the mean (SD) age was 2.2 (1.3) years and 5825 (76.0%) were Medicaid insured/self-pay. There was a 25.6% (95% CI, 13.2%-39.4%) immediate increase in overall ingestions at the onset of the pandemic compared with the prepandemic period, which was attributed to cannabis, opioid, and ethanol ingestions. There was a 1.8% (95% CI, 1.1%-2.4%) sustained monthly relative increase compared with prepandemic trends in overall ingestions which was due to opioids. There was no association between medicinal or recreational cannabis legalization and the rate of cannabis ingestion encounters. Conclusions and relevance: In this study of illicit substance ingestions in young children before and during the COVID-19 pandemic, there was an immediate and sustained increase in illicit substance ingestions during the pandemic. Additional studies are needed to contextualize these findings in the setting of pandemic-related stress and to identify interventions to prevent ingestions in face of such stress, such as improved parental mental health and substance treatment services, accessible childcare, and increased substance storage education.
MeSH term(s)	United States ; Humans ; Child ; Child, Preschool ; Pandemics ; Retrospective Studies ; Cross-Sectional Studies ; COVID-19/epidemiology ; Cannabis ; Cocaine ; Amphetamines ; Analgesics, Opioid ; Ethanol ; Substance-Related Disorders/epidemiology ; Eating
Chemical Substances	Cocaine (I5Y540LHVR) ; Amphetamines ; Analgesics, Opioid ; Ethanol (3K9958V90M)
Language	English
Publishing date	2023-04-03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ISSN	2574-3805
ISSN (online)	2574-3805
DOI	10.1001/jamanetworkopen.2023.9549
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Article ; Online: Comment on "Aerosol Filtration Efficiency of Common Fabrics Used in Respiratory Cloth Masks".

Hancock, Jason N / Plumley, Michael J / Schilling, Katherine / Sheets, Donal / Wilen, Lawrence

ACS nano

2020 Volume 14, Issue 9, Page(s) 10758–10763

MeSH term(s)	Aerosols ; Filtration ; Masks ; Textiles
Chemical Substances	Aerosols
Keywords	covid19
Language	English
Publishing date	2020-09-22
Publishing country	United States
Document type	Letter ; Comment
ISSN	1936-086X
ISSN (online)	1936-086X
DOI	10.1021/acsnano.0c05827
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Article: A deep neural network estimation of brain age is sensitive to cognitive impairment and decline.

Yang, Yisu / Sathe, Aditi / Schilling, Kurt / Shashikumar, Niranjana / Moore, Elizabeth / Dumitrescu, Logan / Pechman, Kimberly R / Landman, Bennett A / Gifford, Katherine A / Hohman, Timothy J / Jefferson, Angela L / Archer, Derek B

bioRxiv : the preprint server for biology

2023

Abstract: The greatest known risk factor for Alzheimer's disease (AD) is age. While both normal aging and AD pathology involve structural changes in the brain, their trajectories of atrophy are not the same. Recent developments in artificial intelligence have ... ...

Abstract	The greatest known risk factor for Alzheimer's disease (AD) is age. While both normal aging and AD pathology involve structural changes in the brain, their trajectories of atrophy are not the same. Recent developments in artificial intelligence have encouraged studies to leverage neuroimaging-derived measures and deep learning approaches to predict brain age, which has shown promise as a sensitive biomarker in diagnosing and monitoring AD. However, prior efforts primarily involved structural magnetic resonance imaging and conventional diffusion MRI (dMRI) metrics without accounting for partial volume effects. To address this issue, we post-processed our dMRI scans with an advanced free-water (FW) correction technique to compute distinct FW-corrected fractional anisotropy (FA
Language	English
Publishing date	2023-10-11
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.08.10.552494
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Article ; Online: Substantial downregulation of mitochondrial and peroxisomal proteins during acute kidney injury revealed by data-independent acquisition proteomics.

Burton, Jordan B / Silva-Barbosa, Anne / Bons, Joanna / Rose, Jacob / Pfister, Katherine / Simona, Fabia / Gandhi, Tejas / Reiter, Lukas / Bernhardt, Oliver / Hunter, Christie L / Goetzman, Eric S / Sims-Lucas, Sunder / Schilling, Birgit

Proteomics

2023 Volume 24, Issue 5, Page(s) e2300162

Abstract: Acute kidney injury (AKI) manifests as a major health concern, particularly for the elderly. Understanding AKI-related proteome changes is critical for prevention and development of novel therapeutics to recover kidney function and to mitigate the ... ...

Abstract	Acute kidney injury (AKI) manifests as a major health concern, particularly for the elderly. Understanding AKI-related proteome changes is critical for prevention and development of novel therapeutics to recover kidney function and to mitigate the susceptibility for recurrent AKI or development of chronic kidney disease. In this study, mouse kidneys were subjected to ischemia-reperfusion injury, and the contralateral kidneys remained uninjured to enable comparison and assess injury-induced changes in the kidney proteome. A ZenoTOF 7600 mass spectrometer was optimized for data-independent acquisition (DIA) to achieve comprehensive protein identification and quantification. Short microflow gradients and the generation of a deep kidney-specific spectral library allowed for high-throughput, comprehensive protein quantification. Upon AKI, the kidney proteome was completely remodeled, and over half of the 3945 quantified protein groups changed significantly. Downregulated proteins in the injured kidney were involved in energy production, including numerous peroxisomal matrix proteins that function in fatty acid oxidation, such as ACOX1, CAT, EHHADH, ACOT4, ACOT8, and Scp2. Injured kidneys exhibited severely damaged tissues and injury markers. The comprehensive and sensitive kidney-specific DIA-MS assays feature high-throughput analytical capabilities to achieve deep coverage of the kidney proteome, and will serve as useful tools for developing novel therapeutics to remediate kidney function.
MeSH term(s)	Humans ; Mice ; Animals ; Aged ; Proteomics ; Proteome ; Down-Regulation ; Kidney ; Acute Kidney Injury
Chemical Substances	Proteome
Language	English
Publishing date	2023-09-29
Publishing country	Germany
Document type	Journal Article
ZDB-ID	2032093-0
ISSN	1615-9861 ; 1615-9853
ISSN (online)	1615-9861
ISSN	1615-9853
DOI	10.1002/pmic.202300162
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Article: Substantial Downregulation of Mitochondrial and Peroxisomal Proteins during Acute Kidney Injury revealed by Data-Independent Acquisition Proteomics.

bioRxiv : the preprint server for biology

2023

Abstract	Acute kidney injury (AKI) manifests as a major health concern, particularly for the elderly. Understanding AKI-related proteome changes is critical for prevention and development of novel therapeutics to recover kidney function and to mitigate the susceptibility for recurrent AKI or development of chronic kidney disease. In this study, mouse kidneys were subjected to ischemia-reperfusion injury, and the contralateral kidneys remained uninjured to enable comparison and assess injury-induced changes in the kidney proteome. A fast-acquisition rate ZenoTOF 7600 mass spectrometer was introduced for data-independent acquisition (DIA) for comprehensive protein identification and quantification. Short microflow gradients and the generation of a deep kidney-specific spectral library allowed for high-throughput, comprehensive protein quantification. Upon AKI, the kidney proteome was completely remodeled, and over half of the 3,945 quantified protein groups changed significantly. Downregulated proteins in the injured kidney were involved in energy production, including numerous peroxisomal matrix proteins that function in fatty acid oxidation, such as ACOX1, CAT, EHHADH, ACOT4, ACOT8, and Scp2. Injured mice exhibited severely declined health. The comprehensive and sensitive kidney-specific DIA assays highlighted here feature high-throughput analytical capabilities to achieve deep coverage of the kidney proteome and will serve as useful tools for developing novel therapeutics to remediate kidney function.
Language	English
Publishing date	2023-02-26
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.02.26.530107
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Article ; Online: Practice Variation in Use of Neuroimaging Among Infants With Concern for Abuse Treated in Children's Hospitals.

Henry, M Katherine / Schilling, Samantha / Shults, Justine / Feudtner, Chris / Katcoff, Hannah / Egbe, Teniola I / Johnson, Mitchell A / Andronikou, Savvas / Wood, Joanne N

JAMA network open

2022 Volume 5, Issue 4, Page(s) e225005

Abstract: Importance: Infants who appear neurologically well and have fractures concerning for abuse are at increased risk for clinically occult head injuries. Evidence of excess variation in neuroimaging practices when abuse is suspected may indicate opportunity ...

Abstract	Importance: Infants who appear neurologically well and have fractures concerning for abuse are at increased risk for clinically occult head injuries. Evidence of excess variation in neuroimaging practices when abuse is suspected may indicate opportunity for quality and safety improvement. Objective: To quantify neuroimaging practice variation across children's hospitals among infants with fractures evaluated for abuse, with the hypothesis that hospitals would vary substantially in neuroimaging practices. As a secondary objective, factors associated with neuroimaging use were identified, with the hypothesis that age and factors associated with potential biases (ie, payer type and race or ethnicity) would be associated with neuroimaging use. Design, setting, and participants: This cross-sectional study included infants with a femur or humerus fracture or both undergoing abuse evaluation at 44 select US children's hospitals in the Pediatric Health Information System (PHIS) from January 1, 2016, through March 30, 2020, including emergency department, observational, and inpatient encounters. Included infants were aged younger than 12 months with a femur or humerus fracture or both without overt signs or symptoms of head injury for whom a skeletal survey was performed. To focus on infants at increased risk for clinically occult head injuries, infants with billing codes suggestive of overt neurologic signs or symptoms were excluded. Multivariable logistic regression was used to investigate demographic, clinical, and temporal factors associated with use of neuroimaging. Marginal standardization was used to report adjusted percentages of infants undergoing neuroimaging by hospital and payer type. Data were analyzed from March 2021 through January 2022. Exposures: Covariates included age, sex, race and ethnicity, payer type, fracture type, presentation year, and hospital. Main outcomes and measures: Use of neuroimaging by CT or MRI. Results: Of 2585 infants with humerus or femur fracture or both undergoing evaluations for possible child abuse, there were 1408 (54.5%) male infants, 1726 infants (66.8%) who were publicly insured, and 1549 infants (59.9%) who underwent neuroimaging. The median (IQR) age was 6.1 (3.2-8.3) months. There were 748 (28.9%) Black non-Hispanic infants, 426 (16.5%) Hispanic infants, 1148 (44.4%) White non-Hispanic infants. In multivariable analyses, younger age (eg, odds ratio [OR] for ages <3 months vs ages 9 to <12 months, 13.2; 95% CI, 9.54-18.2; P < .001), male sex (OR, 1.47; 95% CI, 1.22-1.78; P < .001), payer type (OR for public vs private insurance, 1.48; 95% CI, 1.18-1.85; P = .003), fracture type (OR for femur and humerus fracture vs isolated femur fracture, 5.36; 95% CI, 2.11-13.6; P = .002), and hospital (adjusted range in use of neuroimaging, 37.4% [95% CI 21.4%-53.5%] to 83.6% [95% CI 69.6%-97.5%]; P < .001) were associated with increased use of neuroimaging, but race and ethnicity were not. Publicly insured infants were more likely to undergo neuroimaging (62.0%; 95% CI, 60.0%-64.1%) than privately insured infants (55.1%; 95% CI, 51.8%-58.4%) (P = .001). Conclusions and relevance: This study found that hospitals varied in neuroimaging practices among infants with concern for abuse. Apparent disparities in practice associated with insurance type suggest opportunities for quality, safety, and equity improvement.
MeSH term(s)	Aged ; Child ; Child Abuse/diagnosis ; Craniocerebral Trauma ; Cross-Sectional Studies ; Female ; Fractures, Bone ; Hospitals, Pediatric ; Humans ; Infant ; Male ; Neuroimaging
Language	English
Publishing date	2022-04-01
Publishing country	United States
Document type	Journal Article ; Observational Study ; Research Support, Non-U.S. Gov't
ISSN	2574-3805
ISSN (online)	2574-3805
DOI	10.1001/jamanetworkopen.2022.5005
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Article: Empirical assessment of the assumptions of ComBat with diffusion tensor imaging.

Kim, Michael E / Gao, Chenyu / Cai, Leon Y / Yang, Qi / Newlin, Nancy R / Ramadass, Karthik / Jefferson, Angela / Archer, Derek / Shashikumar, Niranjana / Pechman, Kimberly R / Gifford, Katherine A / Hohman, Timothy J / Beason-Held, Lori L / Resnick, Susan M / Winzeck, Stefan / Schilling, Kurt G / Zhang, Panpan / Moyer, Daniel / Landman, Bennett A

Journal of medical imaging (Bellingham, Wash.)

2024 Volume 11, Issue 2, Page(s) 24011

Abstract: Purpose: Diffusion tensor imaging (DTI) is a magnetic resonance imaging technique that provides unique information about white matter microstructure in the brain but is susceptible to confounding effects introduced by scanner or acquisition differences. ...

Abstract	Purpose: Diffusion tensor imaging (DTI) is a magnetic resonance imaging technique that provides unique information about white matter microstructure in the brain but is susceptible to confounding effects introduced by scanner or acquisition differences. ComBat is a leading approach for addressing these site biases. However, despite its frequent use for harmonization, ComBat's robustness toward site dissimilarities and overall cohort size have not yet been evaluated in terms of DTI. Approach: As a baseline, we match Results: ComBat remains well behaved for Conclusion: Prior to harmonization of DTI data with ComBat, the input cohort should be examined for size and covariate distributions of each site. Direct assessment of residual distributions is less informative on stability than bootstrap analysis. We caution use ComBat of in situations that do not conform to the above thresholds.
Language	English
Publishing date	2024-04-17
Publishing country	United States
Document type	Journal Article
ISSN	2329-4302
ISSN	2329-4302
DOI	10.1117/1.JMI.11.2.024011
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Article ; Online: A deep neural network estimation of brain age is sensitive to cognitive impairment and decline.

Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing

2023 Volume 29, Page(s) 148–162

Abstract	The greatest known risk factor for Alzheimer's disease (AD) is age. While both normal aging and AD pathology involve structural changes in the brain, their trajectories of atrophy are not the same. Recent developments in artificial intelligence have encouraged studies to leverage neuroimaging-derived measures and deep learning approaches to predict brain age, which has shown promise as a sensitive biomarker in diagnosing and monitoring AD. However, prior efforts primarily involved structural magnetic resonance imaging and conventional diffusion MRI (dMRI) metrics without accounting for partial volume effects. To address this issue, we post-processed our dMRI scans with an advanced free-water (FW) correction technique to compute distinct FW-corrected fractional anisotropy (FAFWcorr) and FW maps that allow for the separation of tissue from fluid in a scan. We built 3 densely connected neural networks from FW-corrected dMRI, T1-weighted MRI, and combined FW+T1 features, respectively, to predict brain age. We then investigated the relationship of actual age and predicted brain ages with cognition. We found that all models accurately predicted actual age in cognitively unimpaired (CU) controls (FW: r=0.66, p=1.62x10-32; T1: r=0.61, p=1.45x10-26, FW+T1: r=0.77, p=6.48x10-50) and distinguished between CU and mild cognitive impairment participants (FW: p=0.006; T1: p=0.048; FW+T1: p=0.003), with FW+T1-derived age showing best performance. Additionally, all predicted brain age models were significantly associated with cross-sectional cognition (memory, FW: β=-1.094, p=6.32x10-7; T1: β=-1.331, p=6.52x10-7; FW+T1: β=-1.476, p=2.53x10-10; executive function, FW: β=-1.276, p=1.46x10-9; T1: β=-1.337, p=2.52x10-7; FW+T1: β=-1.850, p=3.85x10-17) and longitudinal cognition (memory, FW: β=-0.091, p=4.62x10-11; T1: β=-0.097, p=1.40x10-8; FW+T1: β=-0.101, p=1.35x10-11; executive function, FW: β=-0.125, p=1.20x10-10; T1: β=-0.163, p=4.25x10-12; FW+T1: β=-0.158, p=1.65x10-14). Our findings provide evidence that both T1-weighted MRI and dMRI measures improve brain age prediction and support predicted brain age as a sensitive biomarker of cognition and cognitive decline.
MeSH term(s)	Humans ; Artificial Intelligence ; Cross-Sectional Studies ; Computational Biology ; Brain/diagnostic imaging ; Alzheimer Disease/diagnostic imaging ; Cognitive Dysfunction/diagnostic imaging ; Magnetic Resonance Imaging ; Neural Networks, Computer ; Biomarkers
Chemical Substances	Biomarkers
Language	English
Publishing date	2023-12-29
Publishing country	United States
Document type	Journal Article
ISSN	2335-6936
ISSN (online)	2335-6936
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