Digital Commons Network^™

Ctla4 Blockade Abrogates Keap1/Stk11-Related Resistance To Pd-(L)1 Inhibitors, Ferdinandos Skoulidis, Haniel A Araujo, Minh Truong Do, Yu Qian, Xin Sun, Ana Galan Cobo, John T Le, Meagan Montesion, Rachael Palmer, Nadine Jahchan, Joseph M Juan, Chengyin Min, Yi Yu, Xuewen Pan, Kathryn C Arbour, Natalie Vokes, Stephanie T Schmidt, David Molkentine, Dwight H Owen, Regan Memmott, Pradnya D Patil, Melina E Marmarelis, Mark M Awad, Joseph C Murray, Jessica A Hellyer, Justin F Gainor, Anastasios Dimou, Christine M Bestvina, Catherine A Shu, Jonathan W Riess, Collin M Blakely, Chad V Pecot, Laura Mezquita, Fabrizio Tabbó, Matthias Scheffler, Subba Digumarthy, Meghan J Mooradian, Adrian G Sacher, Sally C M Lau, Andreas N Saltos, Julia Rotow, Rocio Perez Johnson, Corinne Liu, Tyler Stewart, Sarah B Goldberg, Jonathan Killam, Zenta Walther, Kurt Schalper, Kurtis D Davies, Mark G Woodcock, Valsamo Anagnostou, Kristen A Marrone, Patrick M Forde, Biagio Ricciuti, Deepti Venkatraman, Eliezer M Van Allen, Amy L Cummings, Jonathan W Goldman, Hiram Shaish, Melanie Kier, Sharyn Katz, Charu Aggarwal, Ying Ni, Joseph T Azok, Jeremy Segal, Lauren Ritterhouse, Joel W Neal, Ludovic Lacroix, Yasir Y Elamin, Marcelo V Negrao, Xiuning Le, Vincent K Lam, Whitney E Lewis, Haley N Kemp, Brett Carter, Jack A Roth, Stephen Swisher, Richard Lee, Teng Zhou, Alissa Poteete, Yifan Kong, Tomohiro Takehara, Alvaro Guimaraes Paula, Edwin R Parra Cuentas, Carmen Behrens, Ignacio I Wistuba, Jianjun Zhang, George R Blumenschein, Carl Gay, Lauren A Byers, Don L Gibbons, Anne Tsao, J Jack Lee, Trever G Bivona, D Ross Camidge, Jhannelle E Gray, Natasha B Leighl, Benjamin Levy, Julie R Brahmer, Marina C Garassino, David R Gandara, Edward B Garon, Naiyer A Rizvi, Giorgio Vittorio Scagliotti, Jürgen Wolf, David Planchard, Benjamin Besse, Roy S Herbst, Heather A Wakelee, Nathan A Pennell, Alice T Shaw, Pasi A Jänne, David P Carbone, Matthew D Hellmann, Charles M Rudin, Lee Albacker, Helen Mann, Zhou Zhu, Zhongwu Lai, Ross Stewart, Solange Peters, Melissa L Johnson, Kwok K Wong, Alan Huang, Monte M Winslow, Michael J Rosen, Ian P Winters, Vassiliki A Papadimitrakopoulou, Tina Cascone, Philip Jewsbury, John V Heymach

Faculty, Staff and Student Publications

For patients with advanced non-small-cell lung cancer (NSCLC), dual immune checkpoint blockade (ICB) with CTLA4 inhibitors and PD-1 or PD-L1 inhibitors (hereafter, PD-(L)1 inhibitors) is associated with higher rates of anti-tumour activity and immune-related toxicities, when compared with treatment with PD-(L)1 inhibitors alone. However, there are currently no validated biomarkers to identify which patients will benefit from dual ICB1,2. Here we show that patients with NSCLC who have mutations in the STK11 and/or KEAP1 tumour suppressor genes derived clinical benefit from dual ICB with the PD-L1 inhibitor durvalumab and the CTLA4 inhibitor tremelimumab, but not from durvalumab alone, when added …

The Effect Of Smoking On Functional Outcomes And Implant Survival Of Anatomical Total Shoulder Arthroplasty, Isabella E Amador, Kevin A Hao, Timothy R Buchanan, Derek S Damrow, Keegan M Hones, Trevor Simcox, Bradley S Schoch, Kevin W Farmer, Thomas W Wright, Tyler J Lamonica, Joseph J King, Jonathan O Wright

Faculty, Staff and Student Publications

Aims: We sought to compare functional outcomes and survival between non-smokers, former smokers, and current smokers who underwent anatomical total shoulder arthroplasty (aTSA) in a large cohort of patients.

Methods: A retrospective review of a prospectively collected shoulder arthroplasty database was performed between August 1991 and September 2020 to identify patients who underwent primary aTSA. Patients were excluded for preoperative diagnoses of fracture, infection, or oncological disease. Three cohorts were created based on smoking status: non-smokers, former smokers, and current smokers. Outcome scores (American Shoulder and Elbow Surgeons (ASES), Constant-Murley score, Shoulder Pain and Disability Index (SPADI), Simple Shoulder Test …

Cross-Species Striatal Hubs: Linking Anatomy To Resting-State Connectivity, Xiaolong Peng, Lucas R Trambaiolli, Eun Young Choi, Julia F Lehman, Gary Linn, Brian E Russ, Charles E Schroeder, Suzanne N Haber, Hesheng Liu

Faculty, Staff and Student Publications

Corticostriatal connections are essential for motivation, cognition, and behavioral flexibility. There is broad interest in using resting-state functional magnetic resonance imaging (rs-fMRI) to link circuit dysfunction in these connections with neuropsychiatric disorders. In this paper, we used tract-tracing data from non-human primates (NHPs) to assess the likelihood of monosynaptic connections being represented in rs-fMRI data of NHPs and humans. We also demonstrated that existing hub locations in the anatomical data can be identified in the rs-fMRI data from both species. To characterize this in detail, we mapped the complete striatal projection zones from 27 tract-tracer injections located in the orbitofrontal …

Genetic Regulation Of Human Brain Proteome Reveals Proteins Implicated In Psychiatric Disorders, Jie Luo, Ling Li, Mingming Niu, Dehui Kong, Yi Jiang, Suresh Poudel, Annie W Shieh, Lijun Cheng, Gina Giase, Kay Grennan, Kevin P White, Chao Chen, Sidney H Wang, Dalila Pinto, Yue Wang, Chunyu Liu, Junmin Peng, Xusheng Wang

Faculty, Staff and Student Publications

Psychiatric disorders are highly heritable yet polygenic, potentially involving hundreds of risk genes. Genome-wide association studies have identified hundreds of genomic susceptibility loci with susceptibility to psychiatric disorders; however, the contribution of these loci to the underlying psychopathology and etiology remains elusive. Here we generated deep human brain proteomics data by quantifying 11,608 proteins across 268 subjects using 11-plex tandem mass tag coupled with two-dimensional liquid chromatography-tandem mass spectrometry. Our analysis revealed 788 cis-acting protein quantitative trait loci associated with the expression of 883 proteins at a genome-wide false discovery rate < 5%. In contrast to expression at the transcript level and complex diseases that are found to be mainly influenced by noncoding variants, we found protein expression level tends to be regulated by non-synonymous variants. We also provided evidence of 76 shared regulatory signals between gene expression and protein abundance. Mediation analysis revealed that for most (88%) of the colocalized genes, the expression levels of their corresponding proteins are regulated by cis-pQTLs via gene transcription. Using summary data-based Mendelian randomization analysis, we identified 4 proteins and 19 genes that are causally associated with schizophrenia. We further integrated multiple omics data with network analysis to prioritize candidate genes for schizophrenia risk loci. Collectively, our findings underscore the potential of proteome-wide linkage analysis in gaining mechanistic insights into the pathogenesis of psychiatric disorders.

Corpus Callosum Structure And Auditory Interhemispheric Transfer In Spina Bifida Myelomeningocele, Kailyn A Bradley, Jenifer J Juranek, H Julia Hannay, Paul T Cirino, Larry A Kramer, Jack M Fletcher

Faculty, Staff and Student Publications

Objective: Maldevelopment of the posterior corpus callosum is common in spina bifida myelomeningocele (SBM) due to hydrocephalus-related hypoplasia and congenital partial hypogenesis. This study examined the relations of macro- and microstructural integrity of the interhemispheric temporal tract in SBM and auditory interhemispheric transfer using consonant-vowel dichotic listening.

Method: We collected T₁-weighted and diffusion tensor imaging data from 46 individuals with SBM and 15 typically developing individuals. Probabilistic tractography was used to isolate the interhemispheric white matter connecting auditory processing regions in both hemispheres. Interhemispheric transfer was assessed with a dichotic listening task.

Results: Although the typically developing group and …

White Matter And Latency Of Visual Evoked Potentials During Maturation: A Miniature Pig Model Of Adolescent Development, Peter Kochunov, L Elliot Hong, Ann Summerfelt, Si Gao, P Leon Brown, Matthew Terzi, Ashley Acheson, Marty G Woldorff, Els Fieremans, Ali Abdollahzadeh, Korrapati V Sathyasaikumar, Sarah M Clark, Robert Schwarcz, Paul D Shepard, Greg I Elmer

Faculty, Staff and Student Publications

Background: Continuous myelination of cerebral white matter (WM) during adolescence overlaps with the formation of higher cognitive skills and the onset of many neuropsychiatric disorders. We developed a miniature-pig model of adolescent brain development for neuroimaging and neurophysiological assessment during this critical period. Minipigs have gyroencephalic brains with a large cerebral WM compartment and a well-defined adolescence period.

Methods: Eight Sinclair™ minipigs (Sus scrofa domestica) were evaluated four times during weeks 14-28 (40, 28 and 28 days apart) of adolescence using monocular visual stimulation (1 Hz)-evoked potentials and diffusion MRI (dMRI) of WM. The latency for the pre-positive 30 ms …

Increased White Blood Cell In Young Adults With Family Histories Of Alcohol And Other Substance Use Disorders, Mustafa N Mithaiwala, Nikki S Phillips, Dylan H Nguyen, Melanie S Beehler, Harrison S Ballard, Andrea S Vincent, William R Lovallo, Peter Kochunov, L Elliot Hong, Jason C O'Connor, Steve Cole, Ashley Acheson

Faculty, Staff and Student Publications

Individuals with a family history of alcohol or other substance use disorders (FH+) are at increased risk for developing alcohol and other substance use disorders (AUD/SUD) compared to individuals with no such family histories (FH-). FH+ young adults have blunted stress reactivity, lower cognitive performance and altered frontal white matter microstructure compared to FH- controls. We hypothesized that family history of AUD/SUD disrupts neuroendocrine regulation of the immune system in FH+ individuals, resulting in altered blood immune cell composition, inflammation and neurocognitive alterations that, ultimately, increases risk for AUD/SUD and associated psychopathology. We examined white blood cell (WBC) parameters derived …

Glymphatic Dysfunction In Multiple Sclerosis And Its Association With Disease Pathology And Disability, Ahmed Bayoumi, Khader M Hasan, Joseph A Thomas, Akram Yazdani, John A Lincoln

Faculty, Staff and Student Publications

Background: The role of the glymphatic system in multiple sclerosis (MS)-related disability remains underexplored. Diffusion-tensor image analysis along the perivascular space (DTI-ALPS) offers a non-invasive method to assess glymphatic function.

Objective: To evaluate glymphatic function in MS patients with lower and higher disability.

Methods: This study included 118 MS patients who underwent structural, diffusion-weighted imaging, and clinical assessment. The participants were divided into lower (MS-L, n = 57) and higher disability (MS-H, n = 61) subgroups. Brain parenchymal fraction (BPF), lesion load (LL), and DTI-ALPS index were measured. Subgroup differences and correlations between DTI-ALPS index and other measures were explored. …

A Novel Statistical Framework For Meta-Analysis Of Total Mediation Effect With High-Dimensional Omics Mediators In Large-Scale Genomic Consortia, Zhichao Xu, Peng Wei

Faculty, Staff and Student Publications

Meta-analysis is used to aggregate the effects of interest across multiple studies, while its methodology is largely underexplored in mediation analysis, particularly in estimating the total mediation effect of high-dimensional omics mediators. Large-scale genomic consortia, such as the Trans-Omics for Precision Medicine (TOPMed) program, comprise multiple cohorts with diverse technologies to elucidate the genetic architecture and biological mechanisms underlying complex human traits and diseases. Leveraging the recent established asymptotic standard error of the R-squared (R2)-based mediation effect estimation for high-dimensional omics mediators, we have developed a novel meta-analysis framework requiring only summary statistics and allowing inter-study heterogeneity. Whereas the proposed …

Association Analysis Of Mitochondrial Dna Heteroplasmic Variants: Methods And Application, Xianbang Sun, Katia Bulekova, Jian Yang, Meng Lai, Achilleas N Pitsillides, Xue Liu, Yuankai Zhang, Xiuqing Guo, Qian Yong, Laura M Raffield, Jerome I Rotter, Stephen S Rich, Goncalo Abecasis, April P Carson, Ramachandran S Vasan, Joshua C Bis, Bruce M Psaty, Eric Boerwinkle, Annette L Fitzpatrick, Claudia L Satizabal, Dan E Arking, Jun Ding, Daniel Levy, Chunyu Liu

Faculty, Staff and Student Publications

We rigorously assessed a comprehensive association testing framework for heteroplasmy, employing both simulated and real-world data. This framework employed a variant allele fraction (VAF) threshold and harnessed multiple gene-based tests for robust identification and association testing of heteroplasmy. Our simulation studies demonstrated that gene-based tests maintained an appropriate type I error rate at α = 0.001. Notably, when 5 % or more heteroplasmic variants within a target region were linked to an outcome, burden-extension tests (including the adaptive burden test, variable threshold burden test, and z-score weighting burden test) outperformed the sequence kernel association test (SKAT) and the original burden …

Contrasting Association Pattern Of Plasma Low-Density Lipoprotein With White Matter Integrity In Apoe4 Carriers Versus Non-Carriers, Zhenyao Ye, Yezhi Pan, Rozalina G Mccoy, Chuan Bi, Chen Mo, Li Feng, Jiaao Yu, Tong Lu, Song Liu, J Carson Smith, Minxi Duan, Si Gao, Yizhou Ma, Chixiang Chen, Braxton D Mitchell, Paul M Thompson, L Elliot Hong, Peter Kochunov, Tianzhou Ma, Shuo Chen

Faculty, Staff and Student Publications

Apolipoprotein E ε4 (APOE4) is a strong genetic risk factor of Alzheimer’s disease and metabolic dysfunction. However, whether APOE4 and markers of metabolic dysfunction synergistically impact the deterioration of white matter (WM) integrity in older adults remains unknown.

In the UK Biobank data, we conducted a multivariate analysis to investigate the interactions between APOE4 and 249 plasma metabolites (measured using nuclear magnetic resonance spectroscopy) with whole-brain WM integrity (measured by diffusion-weighted magnetic resonance imaging) in a cohort of 1,917 older adults (aged 65.0–81.0 years; 52.4% female).

Although no main association was observed between either APOE4 or metabolites with …

Associations Between Epilepsy, Respiratory Impairment, And Minor Ecg Abnormalities In Children, See Wai Chan, Angela Chun, Linh Nguyen, Beth Bubolz, Anne E Anderson, Yi-Chen Lai

Faculty, Staff and Students Publications

Objective: We sought to examine the effects of acute seizures and respiratory derangement on the cardiac electrical properties reflected on the electrocardiogram (ECG); and to analyze their potential interactions with a diagnosis of epilepsy in children.

Methods: Emergency center (EC) visits with seizure or epilepsy diagnostic codes from 1/2011-12/2013 were included if they had ECG within 24 h of EC visit. Patients were excluded if they had pre-existing cardiac conditions, ion channelopathy, or were taking specific cardiac medications. Control subjects were 1:1 age and gender matched. Abnormal ECG was defined as changes in rhythm, PR, QRS, or corrected QT intervals; …

Synaptic Plasticity In The Injured Brain Depends On The Temporal Pattern Of Stimulation, Quentin S Fischer, Djanenkhodja Kalikulov, Gonzalo Viana Di Prisco, Carrie A Williams, Philip R Baldwin, Michael J Friedlander

Faculty, Staff and Students Publications

Neurostimulation protocols are increasingly used as therapeutic interventions, including for brain injury. In addition to the direct activation of neurons, these stimulation protocols are also likely to have downstream effects on those neurons' synaptic outputs. It is well known that alterations in the strength of synaptic connections (long-term potentiation, LTP; long-term depression, LTD) are sensitive to the frequency of stimulation used for induction; however, little is known about the contribution of the temporal pattern of stimulation to the downstream synaptic plasticity that may be induced by neurostimulation in the injured brain. We explored interactions of the temporal pattern and frequency …

Residential Proximity To Oil And Gas Developments And Childhood Cancer Survival, Thanh T Hoang, Rutu A Rathod, Omar Rosales, Maria I Castellanos, Jeremy M Schraw, Elyse Burgess, Erin C Peckham-Gregory, Abiodun O Oluyomi, Michael E Scheurer, Amy E Hughes, Philip J Lupo

Faculty, Staff and Students Publications

Background: Environmental toxicants may impact survival in children with cancer, but the literature investigating these associations remains limited. Because oil and gas developments emit several hazardous air pollutants, the authors evaluated the relationship between residential proximity to oil or gas development and survival across 21 different pediatric cancers.

Methods: The Texas Cancer Registry had 29,730 children (≤19 years old) diagnosed with a primary cancer between 1995 to 2017. Geocoded data were available for 285,266 active oil or gas wells and 109,965 horizontal wells. The authors calculated whether each case lived within 1000 m (yes/no) from each type of oil or …

Exploring Latent Clusters In Pediatric Ocd Based On Symptoms, Severity, Age, Gender, And Comorbidity, Orri Smárason, Robert R Selles, Davíð R M A Højgaard, John R Best, Karin Melin, Tord Ivarsson, Per Hove Thomsen, Bernhard Weidle, Nicole Michelle Mcbride, Eric A Storch, Daniel Geller, Sabine Wilhelm, Lara J Farrell, Allison M Waters, Sharna Mathieu, Noam Soreni, S Evelyn Stewart, Gudmundur Skarphedinsson

Center for Medical Ethics and Health Policy Staff Publications

Given diverse symptom expression and high rates of comorbid conditions, the present study explored underlying commonalities among OCD-affected children and adolescents to better conceptualize disorder presentation and associated features. Data from 830 OCD-affected participants presenting to OCD specialty centers was aggregated. Dependent mixture modeling was used to examine latent clusters based on their age- and gender adjusted symptom severity (as measured by the Children's Yale-Brown Obsessive-Compulsive Scale; CY-BOCS), symptom type (as measured by factor scores calculated from the CY-BOCS symptom checklist), and comorbid diagnoses (as assessed via diagnostic interviews). Fit statistics favored a four-cluster model with groups distinguished primarily by …

Loss-Of-Function In Rbbp5 Results In A Syndromic Neurodevelopmental Disorder Associated With Microcephaly, Yue Huang, Kristy L Jay, Alden Yen-Wen Huang, Jijun Wan, Sharayu V Jangam, Odelia Chorin, Annick Rothschild, Ortal Barel, Milena Mariani, Maria Iascone, Han Xue, Undiagnosed Diseases Network, Jing Huang, Cyril Mignot, Boris Keren, Virginie Saillour, Annelise Y Mah-Som, Stephanie Sacharow, Farrah Rajabi, Carrie Costin, Shinya Yamamoto, Oguz Kanca, Hugo J Bellen, Jill A Rosenfeld, Christina G S Palmer, Stanley F Nelson, Michael F Wangler, Julian A Martinez-Agosto

Faculty, Staff and Students Publications

PURPOSE: Epigenetic dysregulation has been associated with many inherited disorders. RBBP5 (HGNC:9888) encodes a core member of the protein complex that methylates histone 3 lysine-4 and has not been implicated in human disease.

METHODS: We identify 5 unrelated individuals with de novo heterozygous variants in RBBP5. Three nonsense/frameshift and 2 missense variants were identified in probands with neurodevelopmental symptoms, including global developmental delay, intellectual disability, microcephaly, and short stature. Here, we investigate the pathogenicity of the variants through protein structural analysis and transgenic Drosophila models.

RESULTS: Both missense p.(T232I) and p.(E296D) variants affect evolutionarily conserved amino acids located at the …

Evaluation Of Combat Harmonization For Reducing Across-Tracer Differences In Regional Amyloid Pet Analyses, Braden Yang, Tom Earnest, Sayantan Kumar, Deydeep Kothapalli, Tammie Benzinger, Brian Gordon, Aristeidis Sotiras

2020-Current year OA Pubs

Differences in amyloid positron emission tomography (PET) radiotracer pharmacokinetics and binding properties lead to discrepancies in amyloid-β uptake estimates. Harmonization of tracer-specific biases is crucial for optimal performance of downstream tasks. Here, we investigated the efficacy of ComBat, a data-driven harmonization model, for reducing tracer-specific biases in regional amyloid PET measurements from [

National Liver Cancer Screening Trial (Tracer) Study Protocol, Amit G Singal, Neehar D Parikh, Fasiha Kanwal, Jorge A Marrero, Sneha Deodhar, Stephanie Page-Lester, Camden Lopez, Ziding Feng, Nabihah Tayob

Faculty, Staff and Students Publications

BACKGROUND: Professional guidelines recommend HCC screening in at-risk patients using semi-annual ultrasound with or without alpha-fetoprotein (AFP); however, this strategy has limited effectiveness due to low adherence and sensitivity. Increasing data support the potential role of blood-based biomarker panels, which could improve both aspects. The biomarker panel GALAD, comprised of sex, age, and 3 blood biomarkers (AFP, AFP-L3, and des-carboxy prothrombin des-carboxy prothrombin), has shown high sensitivity and specificity in biomarker phase II (case-control) and phase III (retrospective cohort) validation studies. However, prospective validation in a large phase IV biomarker clinical utility trial is necessary before its adoption in practice. …

Prognostic Stratification In Dlbcl Patients With Aberrant Myc Gene, Jian-Rong Li, Vikram R Shaw, Abi Parthasarathy, Yong Li, Christopher I Amos, Chao Cheng

Faculty, Staff and Students Publications

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease characterized by a subset of patients who exhibit treatment resistance and poor prognoses. Genomic assays have been widely employed to identify high-risk individuals characterized by rearrangements in the MYC, BCL2 and BCL6 genes. These patients typically undergo more aggressive therapeutic treatments; however, there remains a significant variation in their treatment outcomes. This study introduces an MYC signature score (MYCSS) derived from gene expression profiles, specifically designed to evaluate MYC overactivation in DLBCL patients. MYCSS was validated across several independent cohorts to assess its ability to stratify patients based on MYC-related genetic …

Identifying High-Risk Multiple Myeloma Patients: A Novel Approach Using A Clonal Gene Signature, Jian-Rong Li, Christiana Wang, Chao Cheng

Faculty, Staff and Students Publications

Multiple myeloma (MM) is a heterogeneous disease with a small subset of high-risk patients having poor prognoses. Identifying these patients is crucial for treatment management and strategic decisions. In this study, we developed a novel computational framework to define prognostic gene signatures by selecting genes with expression driven by clonal copy number alterations. We applied this framework to MM and developed a clonal gene signature (CGS) consisting of 22 genes and evaluated in five independent datasets. The CGS provided significant prognostic values after adjusting for well-established factors including cytogenetic abnormalities, International Staging System (ISS), and Revised ISS (R-ISS). Importantly, CGS …

Age Modulates The Predictive Value Of Self-Reported Sleepiness For All-Cause Mortality Risk: Insights From A Comprehensive National Database Of Veterans, Arash Maghsoudi, Mehrnaz Azarian, Amir Sharafkhaneh, Melissa B Jones, Hoormehr Nozari, Meir Kryger, Amin Ramezani, Javad Razjouyan

Faculty, Staff and Students Publications

Study objectives: Excessive daytime sleepiness is prevalent and overwhelmingly stems from disturbed sleep. We hypothesized that age modulates the association between excessive daytime sleepiness and increased all-cause mortality.

Methods: We utilized the Veterans' Health Administration data from 1999-2022. We enrolled participants with sleep related International Classification of Diseases 9/10 codes or sleep services. A natural language processing pipeline was developed and validated to extract the Epworth Sleepiness Scale (ESS) as a self-reported tool to measure excessive daytime sleepiness from physician progress notes. The natural language processing's accuracy was assessed through manual annotation of 470 notes. Participants were categorized into normal-ESS …

Determining The N-Glycan And Collagen/Extracellular Matrix Protein Compositions In A Novel Outcome Cohort Of Prostate Cancer Tissue Microarrays Using Maldi-Msi, Jordan P Hartig, Joseph E Ippolito, Et Al.

2020-Current year OA Pubs

Using matrix-assisted laser desorption/ionization mass spectrometry imaging techniques on a unique cohort of prostate cancer tissues, we highlighted several molecular characteristics of matrix that have potential to act as early predictors of prostate cancer metastasis.

An Artificial Intelligence-Generated Model Predicts 90-Day Survival In Alcohol-Associated Hepatitis: A Global Cohort Study, Winston Dunn, Yanming Li, Ashwani K Singal, Douglas A Simonetto, Luis A Díaz, Francisco Idalsoaga, Gustavo Ayares, Jorge Arnold, María Ayala-Valverde, Diego Perez, Jaime Gomez, Rodrigo Escarate, Eduardo Fuentes-López, Carolina Ramirez-Cadiz, Dalia Morales-Arraez, Wei Zhang, Steve Qian, Joseph C Ahn, Seth Buryska, Heer Mehta, Nicholas Dunn, Muhammad Waleed, Horia Stefanescu, Andreea Bumbu, Adelina Horhat, Bashar Attar, Rohit Agrawal, Joaquín Cabezas, Victor Echavaría, Berta Cuyàs, Maria Poca, German Soriano, Shiv K Sarin, Rakhi Maiwall, Prasun K Jalal, Fátima Higuera-De-La-Tijera, Anand V Kulkarni, P Nagaraja Rao, Patricia Guerra-Salazar, Lubomir Skladaný, Natália Kubánek, Veronica Prado, Ana Clemente-Sanchez, Diego Rincon, Tehseen Haider, Kristina R Chacko, Gustavo A Romero, Florencia D Pollarsky, Juan C Restrepo, Luis G Toro, Pamela Yaquich, Manuel Mendizabal, Maria L Garrido, Sebastián Marciano, Melisa Dirchwolf, Victor Vargas, César Jiménez, David Hudson, Guadalupe García-Tsao, Guillermo Ortiz, Juan G Abraldes, Patrick S Kamath, Marco Arrese, Vijay H Shah, Ramon Bataller, Juan Pablo Arab

Faculty, Staff and Students Publications

Background and aims: Alcohol-associated hepatitis (AH) poses significant short-term mortality. Existing prognostic models lack precision for 90-day mortality. Utilizing artificial intelligence in a global cohort, we sought to derive and validate an enhanced prognostic model.

Approach and results: The Global AlcHep initiative, a retrospective study across 23 centers in 12 countries, enrolled patients with AH per National Institute for Alcohol Abuse and Alcoholism criteria. Centers were partitioned into derivation (11 centers, 860 patients) and validation cohorts (12 centers, 859 patients). Focusing on 30 and 90-day postadmission mortality, 3 artificial intelligence algorithms (Random Forest, Gradient Boosting Machines, and eXtreme Gradient Boosting) …

Transcriptomic And Epigenomic Signatures Distinguish High- And Low-Risk Endotypes For Liver Tumor Development, Sandra L Grimm, Tia Talley, Rahul K Jangid, Amrit Koirala, Micah B Castillo, Preethi H Gunaratne, Cristian Coarfa, Cheryl L Walker

Faculty, Staff and Students Publications

The epigenome is a target for environmental exposures and a potential determinant of inter-individual differences in response. In genetically identical C57Bl/6 mice exposed from gestation to weaning to the endocrine-disrupting chemical (EDC) tributyltin (TBT), hepatic tumor development later in life varied across multiple cohorts over time and depending on sex and diet. In one cohort where approximately half of TBT-exposed male mice developed liver tumors at 10 months (Katz et al. Hepatic tumor formation in adult mice developmentally exposed to organotin, Environmental Health Perspectives, 128 (1), 17010, 2020), transcriptomic (RNA-seq) and epigenomic (ChIP-seq) profiling was performed on blood and liver …

Vagus Nerve Stimulation Recruits The Central Cholinergic System To Enhance Perceptual Learning, Kathleen A Martin, Eleni S Papadoyannis, Jennifer K Schiavo, Saba Shokat Fadaei, Habon A Issa, Soomin C Song, Sofia Orrey Valencia, Nesibe Z Temiz, Matthew J Mcginley, David A Mccormick, Robert C Froemke

Duncan NRI Faculty and Staff Publications

Perception can be refined by experience, up to certain limits. It is unclear whether perceptual limits are absolute or could be partially overcome via enhanced neuromodulation and/or plasticity. Recent studies suggest that peripheral nerve stimulation, specifically vagus nerve stimulation (VNS), can alter neural activity and augment experience-dependent plasticity, although little is known about central mechanisms recruited by VNS. Here we developed an auditory discrimination task for mice implanted with a VNS electrode. VNS applied during behavior gradually improved discrimination abilities beyond the level achieved by training alone. Two-photon imaging revealed VNS induced changes to auditory cortical responses and activated cortically …

Genetic Risk Factors In Isolated Dystonia Escape Genome-Wide Association Studies, Björn-Hergen Laabs, Katja Lohmann, Eva-Juliane Vollstedt, Tobias Reinberger, Lisa-Marie Nuxoll, Gamze Kilic-Berkmen, Joel S Perlmutter, Sebastian Loens, Carlos Cruchaga, Andre Franke, Valerija Dobricic, Frauke Hinrichs, Anne Grözinger, Eckart Altenmüller, Steven Bellows, Sylvia Boesch, Susan B Bressman, Kevin R Duque, Alberto J Espay, Andreas Ferbert, Jeanne S Feuerstein, Samuel Frank, Thomas Gasser, Bernhard Haslinger, Robert Jech, Frank Kaiser, Christoph Kamm, Katja Kollewe, Andrea A Kühn, Mark S Ledoux, Ebba Lohmann, Abhimanyu Mahajan, Alexander Münchau, Trisha Multhaupt-Buell, Alexander Pantelyat, Sarah E Pirio Richardson, Deborah Raymond, Stephen G Reich, Rachel Saunders Pullman, Barbara Schormair, Nutan Sharma, Azadeh Hamzehei Sichani, Kristina Simonyan, Jens Volkmann, Aparna Wagle Shukla, Juliane Winkelmann, Laura J Wright, Michael Zech, Kirsten E Zeuner, Simone Zittel, Meike Kasten, Yan V Sun, Tobias Bäumer, Norbert Brüggemann, Laurie J Ozelius, Hyder A Jinnah, Christine Klein, Inke R König

Faculty, Staff and Students Publications

Background: Despite considerable heritability, previous smaller genome-wide association studies (GWASs) have not identified any robust genetic risk factors for isolated dystonia.

Objective: The objective of this study was to perform a large-scale GWAS in a well-characterized, multicenter sample of >6000 individuals to identify genetic risk factors for isolated dystonia.

Methods: Array-based GWASs were performed on autosomes for 4303 dystonia participants and 2362 healthy control subjects of European ancestry with subgroup analysis based on age at onset, affected body regions, and a newly developed clinical score. Another 736 individuals were used for validation.

Results: This GWAS identified no common genome-wide significant …

A Finite Element Model For Biomechanical Characterization Of Ex Vivo Peripheral Nerve Dysfunction During Stretch, Nicholas C Vasas, Adam M Forrest, Nathaniel A Meyers, Michael B Christensen, Jenny L Pierce, Sidney M Kaufmann, Kimberly B Lanaghen, Randal C Paniello, Julie M Barkmeier-Kraemer, Jonathan P Vande Geest

2020-Current year OA Pubs

Peripheral nerve damage can cause debilitating symptoms ranging from numbness and pain to sensory loss and atrophy. To uncover the underlying mechanisms of peripheral nerve injury, our research aims to develop a relationship between biomechanical peripheral nerve damage and function through finite element modeling. A noncontact, ex vivo electrophysiology chamber, capable of axially stretching explanted nerves while recording electrical signals, was used to investigate peripheral nerve injury. Successive stretch trials were run on eight sciatic nerves (four females and four males) excised from Sprague-Dawley rats. Nerves were stretched until 50% compound action potential (CAP) amplitude reduction was obtained. A constitutive …

A Site-Wise Reliability Analysis Of The Abcd Diffusion Fractional Anisotropy And Cortical Thickness: Impact Of Scanner Platforms, Yezhi Pan, L Elliot Hong, Ashley Acheson, Paul M Thompson, Neda Jahanshad, Alyssa H Zhu, Jiaao Yu, Chixiang Chen, Tianzhou Ma, Ho-Ling Liu, Jelle Veraart, Els Fieremans, Nicole R Karcher, Peter Kochunov, Shuo Chen

2020-Current year OA Pubs

The Adolescent Brain and Cognitive Development (ABCD) project is the largest study of adolescent brain development. ABCD longitudinally tracks 11,868 participants aged 9-10 years from 21 sites using standardized protocols for multi-site MRI data collection and analysis. While the multi-site and multi-scanner study design enhances the robustness and generalizability of analysis results, it may also introduce nonbiological variances including scanner-related variations, subject motion, and deviations from protocols. ABCD imaging data were collected biennially within a period of ongoing maturation in cortical thickness and integrity of cerebral white matter. These changes can bias the classical test-retest methodologies, such as intraclass correlation …

Assessment Of Lesion Insertion Tool In Pelvis Pet/Mr Data With Applications To Attenuation Correction Method Development, Yutaka Natsuaki, Andrew Leynes, Kristen Wangerin, Mahdjoub Hamdi, Abhejit Rajagopal, Paul E Kinahan, Richard Laforest, Peder E Z Larson, Thomas A Hope, Sara St James

2020-Current year OA Pubs

BACKGROUND: In modern positron emission tomography (PET) with multi-modality imaging (e.g., PET/CT and PET/MR), the attenuation correction (AC) is the single largest correction factor for image reconstruction. One way to assess AC methods and other reconstruction parameters is to utilize software-based simulation tools, such as a lesion insertion tool. Extensive validation of these simulation tools is required to ensure results of the study are clinically meaningful.

PURPOSE: To evaluate different PET AC methods using a synthetic lesion insertion tool that simulates lesions in a patient cohort that has both PET/MR and PET/CT images. To further demonstrate how lesion insertion tool …

Ocular Myasthenia Gravis; A Case Report, Amy Garbo Maxey Od, Kristin Wilson Od

Optometric Clinical Practice

Abstract

Background: Myasthenia gravis (MG) is an autoimmune disease disorder that affects the skeletal muscles causing increased fatigability and weakness. When it affects the ocular muscles only, it is known as ocular myasthenia gravis (OMG). Patients with OMG will often have symptoms of diplopia and ptosis, which will be worse towards the end of the day. This case report will discuss the common symptoms of OMG as well as the appropriate treatment and management. It will also review the diagnostic tests used to aid in the diagnosis of OMG and discuss the prognosis of OMG. Case Report: A 67-year-old male …