Publications by authors named "Ryan Schubert"

21 Publications

  • Page 1 of 1

Distinctive waves of innate immune response in the retina in experimental autoimmune encephalomyelitis.

JCI Insight 2021 Jun 8;6(11). Epub 2021 Jun 8.

Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, San Francisco, California, USA.

Neurodegeneration mediates neurological disability in inflammatory demyelinating diseases of the CNS. The role of innate immune cells in mediating this damage has remained controversial with evidence for destructive and protective effects. This has complicated efforts to develop treatment. The time sequence and dynamic evolution of the opposing functions are especially unclear. Given limits of in vivo monitoring in human diseases such as multiple sclerosis (MS), animal models are warranted to investigate the association and timing of innate immune activation with neurodegeneration. Using noninvasive in vivo retinal imaging of experimental autoimmune encephalitis (EAE) in CX3CR1GFP/+-knock-in mice followed by transcriptional profiling, we are able to show 2 distinct waves separated by a marked reduction in the number of innate immune cells and change in cell morphology. The first wave is characterized by an inflammatory phagocytic phenotype preceding the onset of EAE, whereas the second wave is characterized by a regulatory, antiinflammatory phenotype during the chronic stage. Additionally, the magnitude of the first wave is associated with neuronal loss. Two transcripts identified - growth arrest-specific protein 6 (GAS6) and suppressor of cytokine signaling 3 (SOCS3) - might be promising targets for enhancing protective effects of microglia in the chronic phase after initial injury.
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http://dx.doi.org/10.1172/jci.insight.149228DOI Listing
June 2021

Transcriptome prediction performance across machine learning models and diverse ancestries.

HGG Adv 2021 Apr 5;2(2). Epub 2021 Jan 5.

Program in Bioinformatics, Loyola University Chicago, Chicago, IL, USA.

Transcriptome prediction methods such as PrediXcan and FUSION have become popular in complex trait mapping. Most transcriptome prediction models have been trained in European populations using methods that make parametric linear assumptions like the elastic net (EN). To potentially further optimize imputation performance of gene expression across global populations, we built transcriptome prediction models using both linear and non-linear machine learning (ML) algorithms and evaluated their performance in comparison to EN. We trained models using genotype and blood monocyte transcriptome data from the Multi-Ethnic Study of Atherosclerosis (MESA) comprising individuals of African, Hispanic, and European ancestries and tested them using genotype and whole-blood transcriptome data from the Modeling the Epidemiology Transition Study (METS) comprising individuals of African ancestries. We show that the prediction performance is highest when the training and the testing population share similar ancestries regardless of the prediction algorithm used. While EN generally outperformed random forest (RF), support vector regression (SVR), and K nearest neighbor (KNN), we found that RF outperformed EN for some genes, particularly between disparate ancestries, suggesting potential robustness and reduced variability of RF imputation performance across global populations. When applied to a high-density lipoprotein (HDL) phenotype, we show including RF prediction models in PrediXcan revealed potential gene associations missed by EN models. Therefore, by integrating other ML modeling into PrediXcan and diversifying our training populations to include more global ancestries, we may uncover new genes associated with complex traits.
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http://dx.doi.org/10.1016/j.xhgg.2020.100019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087249PMC
April 2021

Gut microbiota-specific IgA B cells traffic to the CNS in active multiple sclerosis.

Sci Immunol 2020 11;5(53)

Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.

Changes in gut microbiota composition and a diverse role of B cells have recently been implicated in multiple sclerosis (MS), a central nervous system (CNS) autoimmune disease. Immunoglobulin A (IgA) is a key regulator at the mucosal interface. However, whether gut microbiota shape IgA responses and what role IgA cells have in neuroinflammation are unknown. Here, we identify IgA-bound taxa in MS and show that IgA-producing cells specific for MS-associated taxa traffic to the inflamed CNS, resulting in a strong, compartmentalized IgA enrichment in active MS and other neuroinflammatory diseases. Unlike previously characterized polyreactive anti-commensal IgA responses, CNS IgA cross-reacts with surface structures on specific bacterial strains but not with brain tissue. These findings establish gut microbiota-specific IgA cells as a systemic mediator in MS and suggest a critical role of mucosal B cells during active neuroinflammation with broad implications for IgA as an informative biomarker and IgA-producing cells as an immune subset to harness for therapeutic interventions.
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http://dx.doi.org/10.1126/sciimmunol.abc7191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043673PMC
November 2020

Comparing local ancestry inference models in populations of two- and three-way admixture.

PeerJ 2020 2;8:e10090. Epub 2020 Oct 2.

Department of Biology, Loyola University Chicago, Chicago, IL, United States of America.

Local ancestry estimation infers the regional ancestral origin of chromosomal segments in admixed populations using reference populations and a variety of statistical models. Integrating local ancestry into complex trait genetics has the potential to increase detection of genetic associations and improve genetic prediction models in understudied admixed populations, including African Americans and Hispanics. Five methods for local ancestry estimation that have been used in human complex trait genetics are LAMP-LD (2012), RFMix (2013), ELAI (2014), Loter (2018), and MOSAIC (2019). As users rather than developers, we sought to perform direct comparisons of accuracy, runtime, memory usage, and usability of these software tools to determine which is best for incorporation into association study pipelines. We find that in the majority of cases RFMix has the highest median accuracy with the ranking of the remaining software dependent on the ancestral architecture of the population tested. Additionally, we estimate the O(n) of both memory and runtime for each software and find that for both time and memory most software increase linearly with respect to sample size. The only exception is RFMix, which increases quadratically with respect to runtime and linearly with respect to memory. Effective local ancestry estimation tools are necessary to increase diversity and prevent population disparities in human genetics studies. RFMix performs the best across methods, however, depending on application, other methods perform just as well with the benefit of shorter runtimes. Scripts used to format data, run software, and estimate accuracy can be found at https://github.com/WheelerLab/LAI_benchmarking.
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http://dx.doi.org/10.7717/peerj.10090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537619PMC
October 2020

Multi-ethnic transcriptome-wide association study of prostate cancer.

PLoS One 2020 28;15(9):e0236209. Epub 2020 Sep 28.

Department of Chemistry & Biochemistry, Loyola University Chicago, Chicago, IL, United States of America.

The genetic risk for prostate cancer has been governed by a few rare variants with high penetrance and over 150 commonly occurring variants with lower impact on risk; however, most of these variants have been identified in studies containing exclusively European individuals. People of non-European ancestries make up less than 15% of prostate cancer GWAS subjects. Across the globe, incidence of prostate cancer varies with population due to environmental and genetic factors. The discrepancy between disease incidence and representation in genetics highlights the need for more studies of the genetic risk for prostate cancer across diverse populations. To better understand the genetic risk for prostate cancer across diverse populations, we performed PrediXcan and GWAS in a case-control study of 4,769 self-identified African American (2,463 cases and 2,306 controls), 2,199 Japanese American (1,106 cases and 1,093 controls), and 2,147 Latin American (1,081 cases and 1,066 controls) individuals from the Multiethnic Genome-wide Scan of Prostate Cancer. We used prediction models from 46 tissues in GTEx version 8 and five models from monocyte transcriptomes in the Multi-Ethnic Study of Atherosclerosis. Across the three populations, we predicted 19 gene-tissue pairs, including five unique genes, to be significantly (lfsr < 0.05) associated with prostate cancer. One of these genes, NKX3-1, replicated in a larger European study. At the SNP level, 110 SNPs met genome-wide significance in the African American study while 123 SNPs met significance in the Japanese American study. Fine mapping revealed three significant independent loci in the African American study and two significant independent loci in the Japanese American study. These identified loci confirm findings from previous GWAS of prostate cancer in diverse populations while PrediXcan-identified genes suggest potential new directions for prostate cancer research in populations across the globe.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0236209PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521738PMC
October 2020

A pathogenic and clonally expanded B cell transcriptome in active multiple sclerosis.

Proc Natl Acad Sci U S A 2020 09 28;117(37):22932-22943. Epub 2020 Aug 28.

Weill Institute for Neurosciences, University of California, San Francisco, CA 94158;

Central nervous system B cells have several potential roles in multiple sclerosis (MS): secretors of proinflammatory cytokines and chemokines, presenters of autoantigens to T cells, producers of pathogenic antibodies, and reservoirs for viruses that trigger demyelination. To interrogate these roles, single-cell RNA sequencing (scRNA-Seq) was performed on paired cerebrospinal fluid (CSF) and blood from subjects with relapsing-remitting MS (RRMS; = 12), other neurologic diseases (ONDs; = 1), and healthy controls (HCs; = 3). Single-cell immunoglobulin sequencing (scIg-Seq) was performed on a subset of these subjects and additional RRMS ( = 4), clinically isolated syndrome ( = 2), and OND ( = 2) subjects. Further, paired CSF and blood B cell subsets (RRMS; = 7) were isolated using fluorescence activated cell sorting for bulk RNA sequencing (RNA-Seq). Independent analyses across technologies demonstrated that nuclear factor kappa B (NF-κB) and cholesterol biosynthesis pathways were activated, and specific cytokine and chemokine receptors were up-regulated in CSF memory B cells. Further, SMAD/TGF-β1 signaling was down-regulated in CSF plasmablasts/plasma cells. Clonally expanded, somatically hypermutated IgM+ and IgG1+ CSF B cells were associated with inflammation, blood-brain barrier breakdown, and intrathecal Ig synthesis. While we identified memory B cells and plasmablast/plasma cells with highly similar Ig heavy-chain sequences across MS subjects, similarities were also identified with ONDs and HCs. No viral transcripts, including from Epstein-Barr virus, were detected. Our findings support the hypothesis that in MS, CSF B cells are driven to an inflammatory and clonally expanded memory and plasmablast/plasma cell phenotype.
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http://dx.doi.org/10.1073/pnas.2008523117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502747PMC
September 2020

Genomic and serologic characterization of enterovirus A71 brainstem encephalitis.

Neurol Neuroimmunol Neuroinflamm 2020 05 5;7(3). Epub 2020 Mar 5.

From the Medical Scientist Training Program (K.E.L.), University of California, San Francisco; Biomedical Sciences Graduate Program (K.E.L., I.A.H.), University of California, San Francisco; Weill Institute for Neurosciences (R.D.S., I.A.H., P.S.R., A.R., M.R.W.), University of California, San Francisco; Department of Neurology (R.D.S., I.A.H., P.S.R., A.R., M.R.W.), University of California, San Francisco; Institut de Recerca Pediàtrica Hospital Sant Joan de Déu (D.C.-A., C.L., A.V.-R., C.M.-A.), Barcelona, Spain; Chan Zuckerberg Biohub (J.E.P., W.W., C.K.C., E.D.C., J.L.D.), San Francisco; Department of Biochemistry and Biophysics (L.M.K., H.A.S., K.C.Z., J.L.D.), University of California, San Francisco; CIBER Epidemiología y Salud Pública (CIBERESP) (C.L., M.C., C.M.-A.), Health Institute Carlos III; Department of Pediatrics (C.L.), Universitat de Barcelona, Barcelona; Enterovirus Unit (M.C.), Spanish National Centre for Microbiology, Instituto de Salud Carlos III, Madrid, Spain; Division of Infectious Diseases (C.L.), Department of Medicine, University of California, San Francisco; and Department of Medicine. Universitat Internacional de Catalunya (C.M.-A.), Barcelona, Spain.

Objective: In 2016, Catalonia experienced a pediatric brainstem encephalitis outbreak caused by enterovirus A71 (EV-A71). Conventional testing identified EV in the periphery but rarely in CSF. Metagenomic next-generation sequencing (mNGS) and CSF pan-viral serology (VirScan) were deployed to enhance viral detection and characterization.

Methods: RNA was extracted from the CSF (n = 20), plasma (n = 9), stool (n = 15), and nasopharyngeal samples (n = 16) from 10 children with brainstem encephalitis and 10 children with meningitis or encephalitis. Pathogens were identified using mNGS. Available CSF from cases (n = 12) and pediatric other neurologic disease controls (n = 54) were analyzed with VirScan with a subset (n = 9 and n = 50) validated by ELISA.

Results: mNGS detected EV in all samples positive by quantitative reverse transcription polymerase chain reaction (qRT-PCR) (n = 25). In qRT-PCR-negative samples (n = 35), mNGS found virus in 23% (n = 8, 3 CSF samples). Overall, mNGS enhanced EV detection from 42% (25/60) to 57% (33/60) (-value = 0.013). VirScan and ELISA increased detection to 92% (11/12) compared with 46% (4/12) for CSF mNGS and qRT-PCR (-value = 0.023). Phylogenetic analysis confirmed the EV-A71 strain clustered with a neurovirulent German EV-A71. A single amino acid substitution (S241P) in the EVA71 VP1 protein was exclusive to the CNS in one subject.

Conclusion: mNGS with VirScan significantly increased the CNS detection of EVs relative to qRT-PCR, and the latter generated an antigenic profile of the acute EV-A71 immune response. Genomic analysis confirmed the close relation of the outbreak EV-A71 and neuroinvasive German EV-A71. A S241P substitution in VP1 was found exclusively in the CSF.
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http://dx.doi.org/10.1212/NXI.0000000000000703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136061PMC
May 2020

The Physical-Virtual Patient Simulator: A Physical Human Form With Virtual Appearance and Behavior.

Simul Healthc 2020 04;15(2):115-121

From the College of Nursing at the University of Central Florida (S.D., L.G., M.A., D.A.D., G.F.W.), Institute for Simulation and Training at the University of Central Florida (S.D., J.H., R.S., G.F.W.); and Department of Medical Education at the University of Central Florida (J.C.), Orlando, FL.

Introduction: We introduce a new type of patient simulator referred to as the Physical-Virtual Patient Simulator (PVPS). The PVPS combines the tangible characteristics of a human-shaped physical form with the flexibility and richness of a virtual patient. The PVPS can exhibit a range of multisensory cues, including visual cues (eg, capillary refill, facial expressions, appearance changes), auditory cues (eg, verbal responses, heart sounds), and tactile cues (eg, localized temperature, pulse).

Methods: We describe the implementation of the technology, technical testing with healthcare experts, and an institutional review board-approved pilot experiment involving 22 nurse practitioner students interacting with a simulated child in 2 scenarios: sepsis and child abuse. The nurse practitioners were asked qualitative questions about ease of use and the cues they noticed.

Results: Participants found it easy to interact with the PVPS and had mixed but encouraging responses regarding realism. In the sepsis scenario, participants reported the following cues leading to their diagnoses: temperature, voice, mottled skin, attitude and facial expressions, breathing and cough, vitals and oxygen saturation, and appearance of the mouth and tongue. For the child abuse scenario, they reported the skin appearance on the arms and abdomen, perceived attitude, facial expressions, and inconsistent stories.

Conclusions: We are encouraged by the initial results and user feedback regarding the perceived realism of visual (eg, mottling), audio (eg, breathing sounds), and tactile (eg, temperature) cues displayed by the PVPS, and ease of interaction with the simulator.
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http://dx.doi.org/10.1097/SIH.0000000000000409DOI Listing
April 2020

Minimal breast milk transfer of rituximab, a monoclonal antibody used in neurological conditions.

Neurol Neuroimmunol Neuroinflamm 2020 01 12;7(1). Epub 2019 Nov 12.

From the Department of Neurology (K.M.K., S.C.L., A.A., A.R., W.R., R.D.S., R.B.), University of California, San Francisco; Weill Institute for Neurosciences (K.M.K., S.C.L., A.A., A.R., W.R., R.D.S., R.B.), Department of Neurology, University of California, San Francisco; Department of Neurology (J.M.), Kaiser Permanente, San Francisco; Department of Neurology (C.S.R.), Columbia University, New York, New York; Department of Neurology (C.B.), Northwestern University, Chicago, Illinois; and Department of Pediatrics (T.W.H.), Texas Tech University School of Medicine, Amarillo.

Objective: To determine the transfer of rituximab, an anti-CD20 monoclonal antibody widely used for neurologic conditions, into mature breast milk.

Methods: Breast milk samples were collected from 9 women with MS who received rituximab 500 or 1,000 mg intravenous once or twice while breastfeeding from November 2017 to April 2019. Serial breast milk samples were collected before infusion and at 8 hours, 24 hours, 7 days, and 18-21 days after rituximab infusion in 4 patients. Five additional patients provided 1-2 samples at various times after rituximab infusion.

Results: The median average rituximab concentration in mature breast milk was low at 0.063 μg/mL (range 0.046-0.097) in the 4 patients with serial breast milk collection, with an estimated median absolute infant dose of 0.0094 mg/kg/d and a relative infant dose (RID) of 0.08% (range 0.06%-0.10%). Most patients had a maximum concentration at 1-7 days after infusion. The maximum concentration occurred in a woman with a single breast milk sample and was 0.29 μg/mL at 11 days postinfusion, which corresponds with an estimated RID of 0.33%. Rituximab concentration in milk was virtually undetectable by 90 days postinfusion.

Conclusions: We determined minimal transfer of rituximab into mature breast milk. The RID for rituximab was less than 0.4% and well below theoretically acceptable levels of less than 10%. Low oral bioavailability would probably also limit the absorption of rituximab by the newborn. In women with serious autoimmune neurologic conditions, monoclonal antibody therapy may afford an acceptable benefit to risk ratio, supporting both maternal treatment and breastfeeding.
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http://dx.doi.org/10.1212/NXI.0000000000000637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857908PMC
January 2020

Pan-viral serology implicates enteroviruses in acute flaccid myelitis.

Nat Med 2019 11 21;25(11):1748-1752. Epub 2019 Oct 21.

Department of Pediatric Infectious Diseases, Kaiser Permanente Oakland Medical Center, Oakland, CA, USA.

Since 2012, the United States of America has experienced a biennial spike in pediatric acute flaccid myelitis (AFM). Epidemiologic evidence suggests non-polio enteroviruses (EVs) are a potential etiology, yet EV RNA is rarely detected in cerebrospinal fluid (CSF). CSF from children with AFM (n = 42) and other pediatric neurologic disease controls (n = 58) were investigated for intrathecal antiviral antibodies, using a phage display library expressing 481,966 overlapping peptides derived from all known vertebrate and arboviruses (VirScan). Metagenomic next-generation sequencing (mNGS) of AFM CSF RNA (n = 20 cases) was also performed, both unbiased sequencing and with targeted enrichment for EVs. Using VirScan, the viral family significantly enriched by the CSF of AFM cases relative to controls was Picornaviridae, with the most enriched Picornaviridae peptides belonging to the genus Enterovirus (n = 29/42 cases versus 4/58 controls). EV VP1 ELISA confirmed this finding (n = 22/26 cases versus 7/50 controls). mNGS did not detect additional EV RNA. Despite rare detection of EV RNA, pan-viral serology frequently identified high levels of CSF EV-specific antibodies in AFM compared with controls, providing further evidence for a causal role of non-polio EVs in AFM.
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http://dx.doi.org/10.1038/s41591-019-0613-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858576PMC
November 2019

Diversity Within Urban Freshwaters.

Front Microbiol 2019 15;10:195. Epub 2019 Feb 15.

Bioinformatics Program, Loyola University Chicago, Chicago, IL, United States.

Freshwater lakes are home to bacterial communities with 1000s of interdependent species. Numerous high-throughput 16S rRNA gene sequence surveys have provided insight into the microbial taxa found within these waters. Prior surveys of Lake Michigan waters have identified bacterial species common to freshwater lakes as well as species likely introduced from the urban environment. We cultured bacterial isolates from samples taken from the Chicago nearshore waters of Lake Michigan in an effort to look more closely at the genetic diversity of species found there within. The most abundant genus detected was , whose presence in freshwaters is often attributed to storm water or runoff. Whole genome sequencing was conducted for 15 Lake Michigan strains, representative of eight species and three isolates that could not be resolved with named species. These genomes were examined specifically for genes encoding functionality which may be advantageous in their urban environment. Antibiotic resistance, amidst other known virulence factors and defense mechanisms, were identified in the genome annotations and verified in the lab. We also tested the Lake Michigan strains for siderophore production and resistance to the heavy metals mercury and copper. As the study presented here shows, a variety of pseudomonads have inhabited the urban coastal waters of Lake Michigan.
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http://dx.doi.org/10.3389/fmicb.2019.00195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6384249PMC
February 2019

A novel cause of chronic viral meningoencephalitis: Cache Valley virus.

Ann Neurol 2017 Jul;82(1):105-114

Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA.

Objective: Immunodeficient patients are particularly vulnerable to neuroinvasive infections that can be challenging to diagnose. Metagenomic next generation sequencing can identify unusual or novel microbes and is therefore well suited for investigating the etiology of chronic meningoencephalitis in immunodeficient patients.

Methods: We present the case of a 34-year-old man with X-linked agammaglobulinemia from Australia suffering from 3 years of meningoencephalitis that defied an etiologic diagnosis despite extensive conventional testing, including a brain biopsy. Metagenomic next generation sequencing of his cerebrospinal fluid and brain biopsy tissue was performed to identify a causative pathogen.

Results: Sequences aligning to multiple Cache Valley virus genes were identified via metagenomic next generation sequencing. Reverse transcription polymerase chain reaction and immunohistochemistry subsequently confirmed the presence of Cache Valley virus in the brain biopsy tissue.

Interpretation: Cache Valley virus, a mosquito-borne orthobunyavirus, has only been identified in 3 immunocompetent North American patients with acute neuroinvasive disease. The reported severity ranges from a self-limiting meningitis to a rapidly fatal meningoencephalitis with multiorgan failure. The virus has never been known to cause a chronic systemic or neurologic infection in humans. Cache Valley virus has also never previously been detected on the Australian continent. Our research subject traveled to North and South Carolina and Michigan in the weeks prior to the onset of his illness. This report demonstrates that metagenomic next generation sequencing allows for unbiased pathogen identification, the early detection of emerging viruses as they spread to new locales, and the discovery of novel disease phenotypes. Ann Neurol 2017;82:105-114.
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http://dx.doi.org/10.1002/ana.24982DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5546801PMC
July 2017

Human Immunodeficiency Virus Presenting as Progressive Multifocal Leukoencephalopathy Restricted to the Posterior Fossa.

JAMA Neurol 2017 05;74(5):597-598

Department of Neurology, School of Medicine, University of California, San Francisco.

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http://dx.doi.org/10.1001/jamaneurol.2017.0085DOI Listing
May 2017

HuSIS: A Dedicated Space for Studying Human Interactions.

IEEE Comput Graph Appl 2016 Nov-Dec;36(6):26-36

To support the study of effective human-surrogate interaction techniques and modalities, the Office of Naval Research awarded an equipment grant to support the development of a Human-Surrogate Interaction Space (HuSIS) at the University of Central Florida in the Institute for Simulation & Training. The HuSIS consists of a dedicated physical space, structures, and components designed specifically for carrying out controlled studies related to human-surrogate interactions. This article describes the motivation, design, and realization of the HuSIS and the benefits of the common data-collection and analysis framework developed for HuSIS research.
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http://dx.doi.org/10.1109/MCG.2016.114DOI Listing
May 2018

The severe side of the IgG4-related hypertrophic pachymeningitis disease spectrum.

Neurol Neuroimmunol Neuroinflamm 2016 Feb 7;3(1):e197. Epub 2016 Jan 7.

MS and Neuroinflammation Center, Department of Neurology (R.D.S., J.M.G.), Neuropathology Division, Department of Pathology (M.W., A.P.), and Neuro-ophthalmology Division, Department of Ophthalmology (M.H.L.), University of California, San Francisco.

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http://dx.doi.org/10.1212/NXI.0000000000000197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4708924PMC
February 2016

A tale of two approaches: how metagenomics and proteomics are shaping the future of encephalitis diagnostics.

Curr Opin Neurol 2015 Jun;28(3):283-7

Department of Neurology, University of California San Francisco, San Francisco, California, USA.

Purpose Of Review: We highlight how metagenomics and proteomics-based approaches are being applied to the problem of diagnosis in idiopathic encephalitis.

Recent Findings: Low cost, high-throughput next-generation sequencing platforms have enabled unbiased sequencing of biological samples. Rapid sequence-based computational algorithms then determine the source of all the nonhost (e.g., pathogen-derived) nucleic acids in a sample. This approach recently identified a case of neuroleptospirosis, resulting in a patient's dramatic clinical improvement with intravenous penicillin. Metagenomics also enabled the discovery of a neuroinvasive astrovirus in several patients. With regard to autoimmune encephalitis, advances in high throughput and efficient phage display of human peptides resulted in the discovery of autoantibodies against tripartite motif family members in a patient with paraneoplastic encephalitis. A complementary assay using ribosomes to display full-length human proteins identified additional autoantibody targets.

Summary: Metagenomics and proteomics represent promising avenues of research to improve upon the diagnostic yield of current assays for infectious and autoimmune encephalitis, respectively.
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http://dx.doi.org/10.1097/WCO.0000000000000198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4418212PMC
June 2015

IFN-β treatment requires B cells for efficacy in neuroautoimmunity.

J Immunol 2015 Mar 2;194(5):2110-6. Epub 2015 Feb 2.

Department of Arthritis and Clinical Immunology Research, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104

IFN-β remains the most widely prescribed treatment for relapsing remitting multiple sclerosis. Despite widespread use of IFN-β, the therapeutic mechanism is still partially understood. Particularly, the clinical relevance of increased B cell activity during IFN-β treatment is unclear. In this article, we show that IFN-β pushes some B cells into a transitional, regulatory population that is a critical mechanism for therapy. IFN-β treatment increases the absolute number of regulatory CD19(+)CD24(++)CD38(++) transitional B cells in peripheral blood relative to treatment-naive and Copaxone-treated patients. In addition, we found that transitional B cells from both healthy controls and IFN-β-treated MS patients are potent producers of IL-10, and that the capability of IFN-β to induce IL-10 is amplified when B cells are stimulated. Similar changes are seen in mice with experimental autoimmune encephalomyelitis. IFN-β treatment increases transitional and regulatory B cell populations, as well as IL-10 secretion in the spleen. Furthermore, we found that IFN-β increases autoantibody production, implicating humoral immune activation in B cell regulatory responses. Finally, we demonstrate that IFN-β therapy requires immune-regulatory B cells by showing that B cell-deficient mice do not benefit clinically or histopathologically from IFN-β treatment. These results have significant implications for the diagnosis and treatment of relapsing remitting multiple sclerosis.
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http://dx.doi.org/10.4049/jimmunol.1402029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4340715PMC
March 2015

Nanoparticle diffusion measures bulk clot permeability.

Biophys J 2011 Aug;101(4):943-50

Department of Physics and Astronomy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

A clot's function is to achieve hemostasis by resisting fluid flow. Permeability is the measurement of a clot's hemostatic potential. It is sensitive to a wide range of biochemical parameters and pathologies. In this work, we consider the hydrodynamic phenomenon that reduces the mobility of fluid near the fiber surfaces. This no-slip boundary condition both defines the gel's permeability and suppresses nanoparticle diffusion in gel interstices. Here we report that, unlike previous work where steric effects also hindered diffusion, our system-nanoparticles in fibrin gel-was subject exclusively to hydrodynamic diffusion suppression. This result enabled an automated, high-throughput permeability assay that used small clot volumes. Permeability was derived from nanoparticle diffusion using the effective medium theory, and showed one-to-one correlation with measured permeability. This technique measured permeability without quantifying gel structure, and may therefore prove useful for characterizing similar materials (e.g., extracellular matrix) where structure is uncontrolled during polymerization and difficult to measure subsequently. We also report that PEGylation reduced, but did not eliminate, the population of immobile particles. We studied the forces required to pull stuck PEG particles free to confirm that the attachment is a result of neither covalent nor strong electrostatic binding, and discuss the relevance of this force scale to particle transport through physiological clots.
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http://dx.doi.org/10.1016/j.bpj.2011.06.052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3175063PMC
August 2011

Hospital costs, incidence, and inhospital mortality rates of traumatic subdural hematoma in the United States.

J Neurosurg 2011 Nov 5;115(5):1013-8. Epub 2011 Aug 5.

Department of Neurosurgery, Stanford University Hospitals and Clinics, and Outcomes Research Center, VA Palo Alto Health Care System, Palo Alto, CA, USA.

Object: This study provides the first US national data regarding frequency, cost, and mortality rate of traumatic subdural hematoma (SDH), and identifies demographic factors affecting morbidity and death in patients with traumatic SDH undergoing surgical drainage.

Methods: A retrospective analysis was conducted by querying the Nationwide Inpatient Sample, the largest all-payer database of nonfederal community hospitals. All cases of traumatic SDH were identified using ICD-9 codes. The study consisted of 2 parts: 1) trends data, which were abstracted from the years 1993-2006, and 2) univariate analysis and multivariate logistic regression of demographic variables on inhospital complications and deaths for the years 1993-2002.

Results: Admissions for traumatic SDH increased 154% from 17,328 in 1993 to 43,996 in 2006. Inhospital deaths decreased from 16.4% to 11.6% for traumatic SDH. Average costs increased 67% to $47,315 per admission. For the multivariate regression analysis, between 1993 and 2002, 67,864 patients with traumatic SDH underwent operative treatment. The inhospital mortality rate was 14.9% for traumatic SDH drainage, with an 18% inhospital complication rate. Factors affecting inhospital deaths included presence of coma (OR = 2.45) and more than 2 comorbidities (OR = 1.60). Increased age did not worsen the inhospital mortality rate.

Conclusions: Nationally, frequency and cost of traumatic SDH cases are increasing rapidly.
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http://dx.doi.org/10.3171/2011.6.JNS101989DOI Listing
November 2011

Trends in median, ulnar, radial, and brachioplexus nerve injuries in the United States.

Neurosurgery 2010 May;66(5):953-60

Outcomes Research Lab, VA/Palo Alto Health Care System, and Department of Neurosurgery, Stanford University School of Medicine, Stanford, California 94304, USA.

Unlabelled: significant constraints on an individual's quality of life.

Objective: To promote efforts to reduce exposure to injury risk factors and to utilize effective therapies when damage does occur, it is important to understand historical trends in both the demographics of peripheral nerve injury (PNI) patients and their treatment. We sought to examine some of these trends.

Methods: We searched the Nationwide Inpatient Sample for discharges classified with International Classification of Diseases, Ninth Revision diagnosis codes of median, ulnar, radial, or brachioplexus nerve injury between 1993 and 2006. We analyzed these data to obtain trend information for the number of discharges, hospital charges, treatment course, patient demographics, and other measures.

Results: Although aggregate discharges involving these injuries decreased slightly between 1993 and 2006, mean nominal hospital charges for their treatment increased significantly, in particular, for brachial plexus injuries. In 2006 30 to 40% of median, ulnar, and radial nerve injuries required acute repair by direct nerve suture. PNI patients in 2006 were more likely to be male, between the ages of 18 and 44 years, and from regions where the median income level is greater than $36 000. Approximately 75% of PNIs were treated in academic hospitals and 95% in metropolitan areas.

Conclusion: PNIs are complex injuries that primarily affect males in key years of adulthood, frequently requiring high-cost acute surgical repair. Although there has been a slight decline in their incidence in the past decade, treatment cost has increased.
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http://dx.doi.org/10.1227/01.neu.0000368545.83463.91DOI Listing
May 2010