Digital Commons Network^™

Role Of Cardiopulmonary Interactions In Development Of Ventilator-Induced Lung Injury-Experimental Evidence And Clinical Implications, Neel Shah, Bhushan H Katira

2020-Current year OA Pubs

Ventilator-induced lung injury (VILI) impacts outcomes in ARDS and optimization of ventilatory strategies improves survival. Decades of research has identified various mechanisms of VILI, largely focusing on airspace forces of plateau pressure, tidal volume and driving pressure. Experimental evidence indicates the role of adverse cardiopulmonary interaction during mechanical ventilation, contributing to VILI genesis mostly by modulating pulmonary vascular dynamics. Under passive mechanical ventilation, high transpulmonary pressure increases afterload on right heart while high pleural pressure reduces the RV preload. Together, they can result in swings of pulmonary vascular flow and pressure. Altered vascular flow and pressure result in increased vascular …

Multi-Omic Analysis Of The Tumor Microenvironment Shows Clinical Correlations In Ph1 Study Of Atezolizumab +/- Soc In Mm, Sandy Wong, Habib Hamidi, Luciano J Costa, Selma Bekri, Natalia Neparidze, Ravi Vij, Tina G Nielsen, Aparna Raval, Rajan Sareen, Elisabeth Wassner-Fritsch, Hearn J Cho

2020-Current year OA Pubs

Multiple myeloma (MM) remains incurable, and treatment of relapsed/refractory (R/R) disease is challenging. There is an unmet need for more targeted therapies in this setting; deep cellular and molecular phenotyping of the tumor and microenvironment in MM could help guide such therapies. This phase 1b study (NCT02431208) evaluated the safety and efficacy of the anti-programmed death-ligand 1 monoclonal antibody atezolizumab (Atezo) alone or in combination with the standard of care (SoC) treatments lenalidomide (Len) or pomalidomide (Pom) and/or daratumumab (Dara) in patients with R/R MM. Study endpoints included incidence of adverse events (AEs) and overall response rate (ORR). A novel …

Racial Disparities In Access To Dbs: Results Of A Real-World U.S. Claims Data Analysis, Michael Frassica, Drew S Kern, Mitra Afshari, Allison T Connolly, Chengyuan Wu, Nathan Rowland, Juan Ramirez-Castaneda, Mwiza Ushe, Claudia Salazar, Xenos Mason

2020-Current year OA Pubs

INTRODUCTION: Deep brain stimulation (DBS) is an effective and standard-of-care therapy for Parkinson's Disease and other movement disorders when symptoms are inadequately controlled with conventional medications. It requires expert care for patient selection, surgical targeting, and therapy titration. Despite the known benefits, racial/ethnic disparities in access have been reported. Technological advancements with smartphone-enabled devices may influence racial disparities. Real-world evidence investigations can shed further light on barriers to access and demographic disparities for DBS patients.

METHODS: A retrospective cross-sectional study was performed using Medicare claims linked with manufacturer patient data tracking to analyze 3,869 patients who received DBS. Patients were …

Caregiver Perspectives On The Continued Impact Of The Covid-19 Pandemic On Children With Intellectual/Developmental Disabilities, R A Northrup, E Jones, V Singh, C Holingue, M Meck, C A Gurnett, M Van Stone, L G Kalb

2020-Current year OA Pubs

The COVID-19 pandemic has significantly impacted caregivers, especially those raising a child with an intellectual/developmental disability (IDD). While research has shown substantial disruption to the family, school, and occupational lives of the IDD community, little is known about the long-term impacts of COVID-19. To address this question, 249 caregivers were surveyed via an online questionnaire, between April and August of 2022 (more than 2 years into the pandemic) about potential impacts of the COVID-19 pandemic on their child's access to health- and school-based therapeutic services, caregiver mental health, and family life. The majority of caregivers reported disruptions in access to …

Allele-Specific Quantification Of Human Leukocyte Antigen Transcript Isoforms By Nanopore Sequencing, Andrew E O Hughes, Maureen C Montgomery, Chang Liu, Eric T Weimer

2020-Current year OA Pubs

INTRODUCTION: While tens of thousands of HLA alleles have been identified by DNA sequencing, the contribution of alternative splicing to HLA diversity is not well characterized. In this study, we sought to determine if long-read sequencing could be used to accurately quantify allele-specific HLA transcripts in primary human lymphocytes.

METHODS: cDNA libraries were prepared from peripheral blood lymphocytes from 12 donors and sequenced by nanopore long-read sequencing. HLA reads were aligned to donor-specific reference sequences based on the known type of each donor. Allele-specific exon utilization was calculated as the proportion of reads aligning to each allele containing known exons, …

Lymphatic Contractile Dysfunction In Mouse Models Of Cantú Syndrome With Katp Channel Gain-Of-Function, Michael J Davis, Jorge A Castorena-Gonzalez, Hae Jin Kim, Min Li, Maria Remedi, Colin G Nichols

2020-Current year OA Pubs

Cantú Syndrome (CS) is an autosomal dominant disorder caused by gain-of-function (GoF) mutations in the Kir6.1 and SUR2 subunits of K

Plasma And Cerebrospinal Fluid Proteomic Signatures Of Acutely Sleep-Deprived Humans: An Exploratory Study, Ana Vaquer-Alicea, Jinsheng Yu, Haiyan Liu, Brendan P Lucey

2020-Current year OA Pubs

STUDY OBJECTIVES: Acute sleep deprivation affects both central and peripheral biological processes. Prior research has mainly focused on specific proteins or biological pathways that are dysregulated in the setting of sustained wakefulness. This exploratory study aimed to provide a comprehensive view of the biological processes and proteins impacted by acute sleep deprivation in both plasma and cerebrospinal fluid (CSF).

METHODS: We collected plasma and CSF from human participants during one night of sleep deprivation and controlled normal sleep conditions. One thousand and three hundred proteins were measured at hour 0 and hour 24 using a high-scale aptamer-based proteomics platform (SOMAscan) …

Development Of An In-Vitro High-Throughput Screening System To Identify Modulators Of Genitalia Development, Yan Yin, Meade Haller, Tian Li, Liang Ma

2020-Current year OA Pubs

Sexually dimorphic outgrowth and differentiation of the embryonic genital tubercles (GTs) give rise to the penis in males and the clitoris in females. Defects in androgen production or in response to androgen signaling can lead to various congenital penile anomalies in both mice and humans. Due to lack of a high-throughput screening system, identification of crucial regulators of GT sexual differentiation has been slow. To overcome this research barrier, we isolated embryonic GT mesenchymal (GTme) cells to model genitalia growth and differentiation in vitro. Using either a mechanical or fluorescence-activated cell sorting-assisted purification method, GTme cells were isolated and assayed …

A Systematic Framework For Predictive Biomarkers In Immune Effector Cell-Associated Neurotoxicity Syndrome, Omar H Butt, Alice Y Zhou, Beau M Ances, John F Dipersio, Armin Ghobadi

2020-Current year OA Pubs

Chimeric antigen receptor (CAR)-T cell therapy has revolutionized the management of several life-threatening malignancies, often achieving durable sustained responses. The number of patients treated with this new class of cell-based therapy, along with the number of Food and Drug Association (FDA) approved indications, are growing significantly. Unfortunately Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) can often occur after treatment with CAR-T cells, and severe ICANS can be associated with significant morbidity and mortality. Current standard treatments are mainly steroids and supportive care, highlighting the need for early identification. In the last several years, a range of predictive biomarkers have been proposed …

Predicting Continuous Amyloid Pet Values With Csf And Plasma Aβ42/Aβ40, Julie K Wisch, Brian A Gordon, Anna H Boerwinkle, Patrick H Luckett, James G Bollinger, Vitaliy Ovod, Yan Li, Rachel L Henson, Tim West, Mathew R Meyer, Kristopher M Kirmess, Tammie L S Benzinger, Anne M Fagan, John C Morris, Randall J Bateman, Beau M Ances, Suzanne E Schindler

2020-Current year OA Pubs

INTRODUCTION: Continuous measures of amyloid burden as measured by positron emission tomography (PET) are being used increasingly to stage Alzheimer's disease (AD). This study examined whether cerebrospinal fluid (CSF) and plasma amyloid beta (Aβ)42/Aβ40 could predict continuous values for amyloid PET.

METHODS: CSF Aβ42 and Aβ40 were measured with automated immunoassays. Plasma Aβ42 and Aβ40 were measured with an immunoprecipitation-mass spectrometry assay. Amyloid PET was performed with Pittsburgh compound B (PiB). The continuous relationships of CSF and plasma Aβ42/Aβ40 with amyloid PET burden were modeled.

RESULTS: Most participants were cognitively normal (427 of 491 [87%]) and the mean age was …

Abundance Of Acvr1b Transcript Is Elevated During Septic Conditions: Perspectives Obtained From A Hands-On Reductionist Investigation, Anucha Preechanukul, Thatcha Yimthin, Sarunporn Tandhavanant, Tobias Brummaier, Chalita Chomkatekaew, Sukanta Das, Basirudeen Syed Ahamed Kabeer, Mohammed Toufiq, Darawan Rinchai, T Eoin West, Damien Chaussabel, Narisara Chantratita, Mathieu Garand

2020-Current year OA Pubs

Sepsis is a complex heterogeneous condition, and the current lack of effective risk and outcome predictors hinders the improvement of its management. Using a reductionist approach leveraging publicly available transcriptomic data, we describe a knowledge gap for the role of ACVR1B (activin A receptor type 1B) in sepsis. ACVR1B, a member of the transforming growth factor-beta (TGF-beta) superfamily, was selected based on the following: 1) induction upon

A Critical Scientific Evaluation Of A Purportedly Negative Data Report - Response To Seneviratne Et Al. 2022, Bankole Johnson, Giovanni Addolorato, Otto Lesch, Lei Liu, Zachary A Rodd

2020-Current year OA Pubs

A core principle in the pursuit of scientific knowledge is that science is self-correcting and that important results should be replicable. Hypotheses need to be reinforced, adjusted, or rejected when novel results are obtained. Replication of results confirms hypotheses and enhances their integration into scientific practice. In contrast, publication of substantiated and replicated negative findings (i.e., non-significant or opposite findings) can be the basis to reject erroneous hypotheses or develop alternative strategies for investigation. Replication is a problem in all research fields. The Psychology Reproductivity Project reported that only 36% of 'highly influential' published research in highly ranked journals were …

Simple And Complex Cells Revisited: Toward A Selectivity-Invariance Model Of Object Recognition, Xin Li, Shuo Wang

2020-Current year OA Pubs

This paper presents a theoretical perspective on modeling ventral stream processing by revisiting the computational abstraction of simple and complex cells. In parallel to David Marr's vision theory, we organize the new perspective into three levels. At the computational level, we abstract simple and complex cells into space partitioning and composition in a topological space based on the redundancy exploitation hypothesis of Horace Barlow. At the algorithmic level, we present a hierarchical extension of sparse coding by exploiting the manifold constraint in high-dimensional space (i.e., the blessing of dimensionality). The resulting over-parameterized models for object recognition differ from existing hierarchical …

Case Report: Stereotactic Body Radiation Treatment For Immunotherapy Escaped Oligometastatic Progression In Cutaneous Melanoma And Merkel Cell Carcinoma, Karam Khaddour, Alice Zhou, Omar Butt, Jiayi Huang, George Ansstas

2020-Current year OA Pubs

Oligometastatic progression represents a unique manifestation of tumor immune-escape that can lead to disease progression during treatment with immune checkpoint inhibitor (ICI). The diagnosis and further optimal management of oligometastatic progression through ICI remains unclear. Diagnostic challenges include practical limitations due to the anatomical sites of oligometastatic progression, such as the para-aortic region, where traditional tissue biopsy carries high risk, and circulating-tumor DNA (ctDNA) could aid in diagnosis and disease monitoring as a supplement to surveillance imaging. In this report, we describe two cases of one patient with metastatic melanoma and the other with metastatic Merkel cell carcinoma (MCC) who …

The Immunology Of Takotsubo Syndrome, Kenji Rowel Q Lim, Douglas L Mann, Tsuneaki Kenzaka, Tomohiro Hayashi

2020-Current year OA Pubs

Takotsubo syndrome (TTS) is a disorder characterized by transient cardiac dysfunction with ventricular regional wall motion abnormalities, primarily thought to be caused by the effects of a sudden catecholamine surge on the heart. Although the majority of patients exhibit prompt recovery of their cardiac dysfunction, TTS remains associated with increased mortality rates acutely and at long-term, and there is currently no cure for TTS. Inflammation has been shown to play a key role in determining outcomes in TTS patients, as well as in the early pathogenesis of the disorder. There are also cases of TTS patients that have been successfully …

Leishmania Major- Derived Lipophosphoglycan Influences The Host's Early Immune Response By Inducing Platelet Activation And Dkk1 Production Via Tlr1/2, Olivia C Ihedioha, Anutr Sivakoses, Stephen M Beverley, Diane Mcmahon-Pratt, Alfred L M Bothwell

2020-Current year OA Pubs

BACKGROUND: Platelets are rapidly deployed to infection sites and respond to pathogenic molecules via pattern recognition receptors (TLR, NLRP). Dickkopf1 (DKK1) is a quintessential Wnt antagonist produced by a variety of cell types including platelets, endothelial cells, and is known to modulate pro-inflammatory responses in infectious diseases and cancer. Moreover, DKK1 is critical for forming leukocyte-platelet aggregates and induction of type 2 cell-mediated immune responses. Our previous publication showed activated platelets release DKK1 following

RESULTS: Here we probed the role of the key surface virulence glycoconjugate lipophosphoglycan (LPG), on DKK1 production using null mutants deficient in LPG synthesis (

CONCLUSION: …

Gene-Educational Attainment Interactions In A Multi-Population Genome-Wide Meta-Analysis Identify Novel Lipid Loci, Lisa De Las Fuentes, Karen L. Schwander, Yun Ju Sung, Mary F. Feitosa, Ahn Do, C. Charles Gu, Treva K. Rice, Mary K. Wojczynski, Michael M. Province, Dabeeru C. Rao, Et Al.

2020-Current year OA Pubs

No abstract provided.

Glial Regulation Of Critical Period Plasticity, Jacob Starkey, Eric J Horstick, Sarah D Ackerman

2020-Current year OA Pubs

Animal behavior, from simple to complex, is dependent on the faithful wiring of neurons into functional neural circuits. Neural circuits undergo dramatic experience-dependent remodeling during brief developmental windows called critical periods. Environmental experience during critical periods of plasticity produces sustained changes to circuit function and behavior. Precocious critical period closure is linked to autism spectrum disorders, whereas extended synaptic remodeling is thought to underlie circuit dysfunction in schizophrenia. Thus, resolving the mechanisms that instruct critical period timing is important to our understanding of neurodevelopmental disorders. Control of critical period timing is modulated by neuron-intrinsic cues, yet recent data suggest that …

Treg-Specific Deletion Of The Phosphatase Shp-1 Impairs Control Of Inflammation In Vivo, Qinlei Gu, Kenneth S Tung, Ulrike M Lorenz

2020-Current year OA Pubs

INTRODUCTION: To achieve a healthy and functional immune system, a delicate balance exists between the activation of conventional T cells (Tcon cells) and the suppression by regulatory T cells (Treg). The tyrosine phosphatase SHP-1, a negative regulator of TCR signaling, shapes this 'activation-suppression' balance by modulating Tcon cell resistance to Treg-mediated suppression. Treg cells also express SHP-1, but its role in influencing Treg function is still not fully understood.

METHODS: We generated a Treg-specific SHP-1 deletion model,

RESULTS: We show that SHP-1 modulates Treg suppressive function at different levels. First, at the intracellular signaling level in Treg cells, SHP-1 attenuates …

The Cerebrospinal Fluid Immune Cell Landscape In Animal Models Of Multiple Sclerosis, Gregory F Wu

2020-Current year OA Pubs

The fluid compartment surrounding the central nervous system (CNS) is a unique source of immune cells capable of reflecting the pathophysiology of neurologic diseases. While human clinical and experimental studies often employ cerebrospinal fluid (CSF) analysis, assessment of CSF in animal models of disease are wholly uncommon, particularly in examining the cellular component. Barriers to routine assessment of CSF in animal models of multiple sclerosis (MS) include limited sample volume, blood contamination, and lack of feasible longitudinal approaches. The few studies characterizing CSF immune cells in animal models of MS are largely outdated, but recent work employing transcriptomics have been …

Designing Implementation Strategies To Improve Identification, Cascade Testing, And Management Of Families With Familial Hypercholesterolemia: An Intervention Mapping Approach, Laney K Jones, Ross C Brownson, Anne C Goldberg, Et Al.

2020-Current year OA Pubs

INTRODUCTION: Familial hypercholesterolemia (FH) is a common inherited cholesterol disorder that, without early intervention, leads to premature cardiovascular disease. Multilevel strategies that target all components of FH care including identification, cascade testing, and management are needed to address gaps that exist in FH care. We utilized intervention mapping, a systematic implementation science approach, to identify and match strategies to existing barriers and develop programs to improve FH care.

METHODS: Data were collected utilizing two methods: a scoping review of published literature, related to any component of FH care, and a parallel mixed method study using interviews and surveys. The scientific …

Approach To Vaccinating The Pediatric Solid Organ Transplant Candidate And Recipient, Carol M Kao, Marian G Michaels

2020-Current year OA Pubs

Solid organ transplantation (SOT) candidates and recipients are at increased risk for morbidity and mortality from vaccine-preventable infections. Children are at particular risk given that they may not have completed their primary immunization series at time of transplant or have acquired natural immunity to pathogens from community exposures. Multiple society guidelines exist for vaccination of SOT candidate and recipients, although challenges remain given limited safety and efficacy data available for pediatric SOT recipients, particularly for live-vaccines. After transplant, individual patient nuances regarding exposure risks and net state of immunosuppression will impact timing of immunizations. The purpose of this review is …

The Vacc-Seqqc Project: Benchmarking Rna-Seq For Clinical Vaccine Studies, Johannes B Goll, Richard D Head, Et Al.

2020-Current year OA Pubs

[This corrects the article DOI: 10.3389/fimmu.2022.1093242.].

Conserved Gene Signatures Shared Among Mapt Mutations Reveal Defects In Calcium Signaling, Miguel A Minaya, Sidhartha Mahali, Abhirami K Iyer, Abdallah M Eteleeb, Rita Martinez, Guangming Huang, John Budde, Sally Temple, Alissa L Nana, William W Seeley, Salvatore Spina, Lea T Grinberg, Oscar Harari, Celeste M Karch

2020-Current year OA Pubs

No abstract provided.

From Perception To Behavior: The Neural Circuits Underlying Prey Hunting In Larval Zebrafish, Shuyu I Zhu, Geoffrey J Goodhill

2020-Current year OA Pubs

A key challenge for neural systems is to extract relevant information from the environment and make appropriate behavioral responses. The larval zebrafish offers an exciting opportunity for studying these sensing processes and sensory-motor transformations. Prey hunting is an instinctual behavior of zebrafish that requires the brain to extract and combine different attributes of the sensory input and form appropriate motor outputs. Due to its small size and transparency the larval zebrafish brain allows optical recording of whole-brain activity to reveal the neural mechanisms involved in prey hunting and capture. In this review we discuss how the larval zebrafish brain processes …

Slc-0111, An Inhibitor Of Carbonic Anhydrase Ix, Attenuates Hepatoblastoma Cell Viability And Migration, Katja Eloranta, Marjut Pihlajoki, Emmi Liljeström, Ruth Nousiainen, Tea Soini, Jouko Lohi, Stefano Cairo, David B Wilson, Seppo Parkkila, Markku Heikinheimo

2020-Current year OA Pubs

BACKGROUND: In response to hypoxia, tumor cells undergo transcriptional reprogramming including upregulation of carbonic anhydrase (CA) IX, a metalloenzyme that maintains acid-base balance. CAIX overexpression has been shown to correlate with poor prognosis in various cancers, but the role of this CA isoform in hepatoblastoma (HB) has not been examined.

METHODS: We surveyed the expression of CAIX in HB specimens and assessed the impact of SLC-0111, a CAIX inhibitor, on cultured HB cells in normoxic and hypoxic conditions.

RESULTS: CAIX immunoreactivity was detected in 15 out of 21 archival pathology HB specimens. The CAIX-positive cells clustered in the middle of …

Interactions Of Pathogenic Escherichia Coli With Ceacams, Alaullah Sheikh, James M Fleckenstein

2020-Current year OA Pubs

The pathogenic

The Pace Of Biological Aging Helps Explain The Association Between Insomnia And Chronic Low Back Pain, Edwin N Aroke, Asia M Wiggins, Joanna M Hobson, Vinodh Srinivasasainagendra, Tammie L Quinn, Pooja Kottae, Hemant K Tiwari, Robert E Sorge, Burel R Goodin

2020-Current year OA Pubs

Chronic low back pain (cLBP) is associated with insomnia and advanced age. Emerging evidence suggests that the severity of both sleep disorders (like insomnia) and chronic pain are associated with a faster pace of biological aging. We aimed to determine whether the pace of biological age mediates the relationship between insomnia and the impact of cLBP in a sample of community-dwelling adults ages 19 to 85 years. Participants (49 with no pain, 32 with low-impact pain, and 37 with high-impact pain) completed sociodemographic, pain, insomnia, and short physical performance battery assessments. We calculated the pace of biological aging using DunedinPACE …

Predicting Incident Cardiovascular Disease Among African-American Adults: A Deep Learning Approach To Evaluate Social Determinants Of Health In The Jackson Heart Study, Matthew C. Morris, Hamidreza Moradi, Maryam Aslani, Mario Sims, David Schlundt, Chrystyna D. Kouros, Burel Goodin, Crystal Lim, Kerry Kinney

2020-Current year OA Pubs

The present study sought to leverage machine learning approaches to determine whether social determinants of health improve prediction of incident cardiovascular disease (CVD). Participants in the Jackson Heart study with no history of CVD at baseline were followed over a 10-year period to determine first CVD events (i.e., coronary heart disease, stroke, heart failure). Three modeling algorithms (i.e., Deep Neural Network, Random Survival Forest, Penalized Cox Proportional Hazards) were used to evaluate three feature sets (i.e., demographics and standard/biobehavioral CVD risk factors [FS1], FS1 combined with psychosocial and socioeconomic CVD risk factors [FS2], and FS2 combined with environmental features [FS3]) …

Symmetric Data-Driven Fusion Of Diffusion Tensor Mri: Age Differences In White Matter, Andrea Mendez Colmenares, Michelle B Hefner, Vince D Calhoun, Elizabeth A Salerno, Jason Fanning, Neha P Gothe, Edward Mcauley, Arthur F Kramer, Agnieszka Z Burzynska

2020-Current year OA Pubs

In the past 20 years, white matter (WM) microstructure has been studied predominantly using diffusion tensor imaging (DTI). Decreases in fractional anisotropy (FA) and increases in mean (MD) and radial diffusivity (RD) have been consistently reported in healthy aging and neurodegenerative diseases. To date, DTI parameters have been studied individually (e.g., only FA) and separately (i.e., without using the joint information across them). This approach gives limited insights into WM pathology, increases the number of multiple comparisons, and yields inconsistent correlations with cognition. To take full advantage of the information in a DTI dataset, we present the first application of …