Digital Commons Network^™

Broadcasters, Receivers, Functional Groups Of Metabolites, And The Link To Heart Failure By Revealing Metabolomic Network Connectivity, Azam Yazdani, Raul Mendez-Giraldez, Akram Yazdani, Rui-Sheng Wang, Daniel J Schaid, Sek Won Kong, M Reza Hadi, Ahmad Samiei, Esmat Samiei, Clemens Wittenbecher, Jessica Lasky-Su, Clary B Clish, Jochen D Muehlschlegel, Francesco Marotta, Joseph Loscalzo, Samia Mora, Daniel I Chasman, Martin G Larson, Sarah H Elsea

Faculty, Staff and Students Publications

Background and objective: Blood-based small molecule metabolites offer easy accessibility and hold significant potential for insights into health processes, the impact of lifestyle, and genetic variation on disease, enabling precise risk prevention. In a prospective study with records of heart failure (HF) incidence, we present metabolite profiling data from individuals without HF at baseline.

Methods: We uncovered the interconnectivity of metabolites using data-driven and causal networks augmented with polygenic factors. Exploring the networks, we identified metabolite broadcasters, receivers, mediators, and subnetworks corresponding to functional classes of metabolites, and provided insights into the link between metabolomic architecture and regulation in health. …

Dissociation Of Reading And Naming In Ventral Occipitotemporal Cortex, Oscar Woolnough, Nitin Tandon

Faculty, Staff and Student Publications

Lesions in the language-dominant ventral occipitotemporal cortex (vOTC) can result in selective impairment of either reading or naming, resulting in alexia or anomia. Yet, functional imaging studies that show differential activation for naming and reading do not reveal activity exclusively tuned to one of these inputs. To resolve this dissonance in the functional architecture of the vOTC, we used focused stimulation to the vOTC in 49 adult patients during reading and naming, and generated a population-level, probabilistic map to evaluate if reading and naming are clearly dissociable within individuals. Language mapping (50 Hz, 2829 stimulations) was performed during passage reading …

Reverse Phase Proteomic Array Profiling Of Asparagine Synthetase Expression In Newly Diagnosed Acute Myeloid Leukemia, Nisha Narayanan, Jennifer Marvin-Peek, Mohamad K Abouelnaaj, Dhabya Majid, Bofei Wang, Brandon D Brown, Yihua Qiu, Steven M Kornblau, Hussein A Abbas

Faculty, Staff and Student Publications

Asparaginase-based therapy is a cornerstone in acute lymphoblastic leukemia (ALL) treatment, capitalizing on the methylation status of the asparagine synthetase (ASNS) gene, which renders ALL cells reliant on extracellular asparagine. Contrastingly, ASNS expression in acute myeloid leukemia (AML) has not been thoroughly investigated, despite studies suggesting that AML with chromosome 7/7q deletions might have reduced ASNS levels. Here, we leverage reverse phase protein arrays to measure ASNS expression in 810 AML patients and assess its impact on outcomes. We find that AML with inv(16) has the lowest overall ASNS expression. While AML with deletion 7/7q had ASNS levels slightly lower …

Ai Driven Analysis Of Mri To Measure Health And Disease Progression In Fshd, Lara Riem, Olivia Ducharme, Matthew Cousins, Xue Feng, Allison Kenney, Jacob Morris, Stephen J Tapscott, Rabi Tawil, Jeff Statland, Dennis Shaw, Leo Wang, Michaela Walker, Leann Lewis, Michael A Jacobs, Doris G Leung, Seth D Friedman, Silvia S Blemker

Faculty, Staff and Student Publications

Facioscapulohumeral muscular dystrophy (FSHD) affects roughly 1 in 7500 individuals. While at the population level there is a general pattern of affected muscles, there is substantial heterogeneity in muscle expression across- and within-patients. There can also be substantial variation in the pattern of fat and water signal intensity within a single muscle. While quantifying individual muscles across their full length using magnetic resonance imaging (MRI) represents the optimal approach to follow disease progression and evaluate therapeutic response, the ability to automate this process has been limited. The goal of this work was to develop and optimize an artificial intelligence-based image …

Cell-Specific Single Viral Vector Crispr/Cas9 Editing And Genetically Encoded Tool Delivery In The Central And Peripheral Nervous Systems, Jamie C Moffa, India N Bland, Jessica R Tooley, Vani Kalyanaraman, Monique Heitmeier, Meaghan C Creed, Bryan A Copits

2020-Current year OA Pubs

CRISPR/Cas9 gene editing represents an exciting avenue to study genes of unknown function and can be combined with genetically encoded tools such as fluorescent proteins, channelrhodopsins, DREADDs, and various biosensors to more deeply probe the function of these genes in different cell types. However, current strategies to also manipulate or visualize edited cells are challenging due to the large size of Cas9 proteins and the limited packaging capacity of adeno-associated viruses (AAVs). To overcome these constraints, we developed an alternative gene editing strategy using a single AAV vector and mouse lines that express Cre-dependent Cas9 to achieve efficient cell-type specific …

Task And Stimulus Coding In The Multiple-Demand Network, Sneha Shashidhara, Moataz Assem, Matthew F Glasser, John Duncan

2020-Current year OA Pubs

In the human brain, a multiple-demand (MD) network plays a key role in cognitive control, with core components in lateral frontal, dorsomedial frontal and lateral parietal cortex, and multivariate activity patterns that discriminate the contents of many cognitive activities. In prefrontal cortex of the behaving monkey, different cognitive operations are associated with very different patterns of neural activity, while details of a particular stimulus are encoded as small variations on these basic patterns (Sigala et al, 2008). Here, using the advanced fMRI methods of the Human Connectome Project and their 360-region cortical parcellation, we searched for a similar result in …

Loss Of The Dna Repair Gene Rnase H2 Identifies A Unique Subset Of Ddr-Deficient Leiomyosarcomas, Michael S Nakazawa, Ian M Silverman, Victoria Rimkunas, Artur Veloso, Dominik Glodzik, Adrienne Johnson, Toshiro K Ohsumi, Shreyaskumar R Patel, Anthony P Conley, Christina L Roland, Pamela T Soliman, Hannah C Beird, Chia-Chin Wu, Davis R Ingram, Rossana Lazcano, Dawon Song, Khalida M Wani, Alexander J Lazar, Timothy A Yap, Wei-Lien Wang, J Andrew Livingston

Faculty, Staff and Student Publications

Targeting the DNA damage response (DDR) pathway is an emerging therapeutic approach for leiomyosarcoma (LMS), and loss of RNase H2, a DDR pathway member, is a potentially actionable alteration for DDR-targeted treatments. Therefore, we designed a protein- and genomic-based RNase H2 screening assay to determine its prevalence and prognostic significance. Using a selective RNase H2 antibody on a pan-tumor microarray (TMA), RNase H2 loss was more common in LMS (11.5%, 9/78) than across all tumors (3.8%, 32/843). In a separate LMS cohort, RNase H2 deficiency was confirmed in uterine LMS (U-LMS, 21%, 23/108) and soft-tissue LMS (ST-LMS; 30%, 39/102). In …

In Vivo Validation Of Late-Onset Alzheimer's Disease Genetic Risk Factors., Michael Sasner, Christoph Preuss, Ravi S Pandey, Asli Uyar, Dylan Garceau, Kevin P Kotredes, Harriet M. Jackson, Adrian L Oblak, Peter Bor-Chian Lin, Bridget Perkins, Disha Soni, Cindy Ingraham, Audrey Lee-Gosselin, Bruce T Lamb, Gareth R Howell, Gregory W. Carter

Faculty Research 2024

INTRODUCTION: Genome-wide association studies have identified over 70 genetic loci associated with late-onset Alzheimer's disease (LOAD), but few candidate polymorphisms have been functionally assessed for disease relevance and mechanism of action.

METHODS: Candidate genetic risk variants were informatically prioritized and individually engineered into a LOAD-sensitized mouse model that carries the AD risk variants APOE ε4/ε4 and Trem2*R47H. The potential disease relevance of each model was assessed by comparing brain transcriptomes measured with the Nanostring Mouse AD Panel at 4 and 12 months of age with human study cohorts.

RESULTS: We created new models for 11 coding and loss-of-function risk variants. …

Assessment Of Neurovascular Uncoupling: Apoe Status Is A Key Driver Of Early Metabolic And Vascular Dysfunction., Kristen D. Onos, Peter B Lin, Ravi S Pandey, Scott A Persohn, Charles P Burton, Ethan W Miner, Kierra Eldridge, Jonathan Nyandu Kanyinda, Kate E Foley, Gregory W. Carter, Gareth R Howell, Paul R Territo

Faculty Research 2024

BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia worldwide, with apolipoprotein Eε4 (APOEε4) being the strongest genetic risk factor. Current clinical diagnostic imaging focuses on amyloid and tau; however, new methods are needed for earlier detection.

METHODS: PET imaging was used to assess metabolism-perfusion in both sexes of aging C57BL/6J, and hAPOE mice, and were verified by transcriptomics, and immunopathology.

RESULTS: All hAPOE strains showed AD phenotype progression by 8 months, with females exhibiting the regional changes, which correlated with GO-term enrichments for glucose metabolism, perfusion, and immunity. Uncoupling analysis revealed APOEε4/ε4 exhibited significant Type-1 uncoupling (↓ …

Psychotropic Medication Usage In Pediatric Ckd: Reporting From The Ckd In Children Cohort., Ryan C. Ward, Amy J. Kogon, Matthew B. Matheson, Anne Dawson, Stephen R. Hooper, Stephen Molitor, Cynthia Wong, Susan L. Furth, Bradley A. Warady, Lyndsay A. Harshman

Manuscripts, Articles, Book Chapters and Other Papers

Background: Mental health disorders within the pediatric CKD population are prevalent. The frequency is unknown with which psychotropic medications that commonly treat these conditions are used in this population.

Methods: Data from the CKD in Children (CKiD) cohort study were used to describe the use of psychotropic medications and patient-related characteristics of use. Medications were classified into three groups: antidepressants, central nervous system (CNS) stimulants, and antipsychotic/mood stabilizing medications. Participant age, sex, CKD severity, and duration of medication use were ascertained. Medication use was evaluated in parallel with CKD disease type, presence of urological comorbidity, and hypertension. Chi-square tests compared …

Phase 1 Dose Escalation Study Of The Mdm2 Inhibitor Milademetan As Monotherapy And In Combination With Azacitidine In Patients With Myeloid Malignancies, Courtney D Dinardo, Rebecca Olin, Eunice S Wang, Barry Skikne, Joseph Rosenthal, Prasanna Kumar, Hiroyuki Sumi, Yoshiyuki Hizukuri, Ying Hong, Parul Patel, Takahiko Seki, Tao Duan, Arnaud Lesegretain, Michael Andreeff

Faculty, Staff and Student Publications

BACKGROUND: Mouse double minute-2 homolog (MDM2) plays a key role in downregulating p53 activity in hematologic malignancies, and its overexpression is associated with poor outcomes.

METHODS: This phase 1 study assessed the safety and efficacy of different dosing regimens of the MDM2 inhibitor milademetan as monotherapy and in combination with azacitidine (AZA) in patients with relapsed or refractory acute myeloid leukemia or high-risk myelodysplastic syndromes.

RESULTS: Seventy-four patients (monotherapy, n = 57; milademetan-AZA combination, n = 17) were treated. The maximum tolerated dose of milademetan was 160 mg once daily given for the first 14-21 days of 28-day cycles as …

Mutation Order In Acute Myeloid Leukemia Identifies Uncommon Patterns Of Evolution And Illuminates Phenotypic Heterogeneity, Matthew Schwede, Katharina Jahn, Jack Kuipers, Linde A Miles, Robert L Bowman, Troy Robinson, Ken Furudate, Hidetaka Uryu, Tomoyuki Tanaka, Yuya Sasaki, Asiri Ediriwickrema, Brooks Benard, Andrew J Gentles, Ross Levine, Niko Beerenwinkel, Koichi Takahashi, Ravindra Majeti

Faculty, Staff and Student Publications

Acute myeloid leukemia (AML) has a poor prognosis and a heterogeneous mutation landscape. Although common mutations are well-studied, little research has characterized how the sequence of mutations relates to clinical features. Using published, single-cell DNA sequencing data from three institutions, we compared clonal evolution patterns in AML to patient characteristics, disease phenotype, and outcomes. Mutation trees, which represent the order of select mutations, were created for 207 patients from targeted panel sequencing data using 1 639 162 cells, 823 mutations, and 275 samples. In 224 distinct orderings of mutated genes, mutations related to DNA methylation typically preceded those related to …

Wide-Field Optical Coherence Tomography Imaging Improves Rate Of Change Detection In Progressing Glaucomatous Eyes Compared With Standard-Field Imaging, Christopher Bowd, Akram Belghith, Jasmin Rezapour, Jost B. Jonas, Leslie Hyman, Robert N. Weinreb, Linda M. Zangwill

Wills Eye Hospital Papers

PURPOSE: To compare rates of retinal nerve fiber layer change over time in healthy, eyes with nonprogressing glaucoma and eyes with progressing glaucoma using single wide-field (SWF) and optic nerve head (ONH) cube scan optical coherence tomography (OCT) images.

METHODS: Forty-five eyes of 25 healthy individuals and 263 eyes of 161 glaucoma patients from the Diagnostic Innovations in Glaucoma Study were included. All eyes underwent 24-2 visual field testing and OCT (Spectralis SD-OCT) ONH and macular imaging. SWF images (up to 43° × 28°) were created by stitching together ONH cube scans centered on the optic disc and macular cube …

High Throughput Plasma Proteomics And Risk Of Heart Failure And Frailty In Late Life, Diego Ramonfaur, Leo F Buckley, Victoria Arthur, Yimin Yang, Brian L Claggett, Chiadi E Ndumele, Keenan A Walker, Thomas Austin, Michelle C Odden, James S Floyd, Sandra Sanders-Van Wijk, Joyce Njoroge, Jorge R Kizer, Dalane Kitzman, Suma H Konety, Jennifer Schrack, Fangyu Liu, B Gwen Windham, Priya Palta, Josef Coresh, Bing Yu, Amil M Shah

Faculty, Staff and Student Publications

Importance: Heart failure (HF) and frailty frequently coexist and may share a common pathobiology, although the underlying mechanisms remain unclear. Understanding these mechanisms may provide guidance for preventing and treating both conditions.

Objective: To identify shared pathways between incident HF and frailty in late life using large-scale proteomics.

Design, setting, and participants: In this cohort study, 4877 aptamers (Somascan v4) were measured among participants in the community-based longitudinal Atherosclerosis Risk In Communities (ARIC) cohort study at visit 3 (V3; 1993-1995; n = 10 638) and at visit 5 (V5; 2011-2013; n = 3908). Analyses were externally replicated among 3189 participants …

A Cytomics-On-A-Chip Platform And Diagnostic Model Stratifies Risk For Oral Lichenoid Conditions, Michael P Mcrae, Kritika Srinivasan Rajsri, A Ross Kerr, Nadarajah Vigneswaran, Spencer W Redding, Malvin Janal, Stella K Kang, Leena Palomo, Nicolaos J Christodoulides, Meena Singh, Jeffery Johnston, John T Mcdevitt

Faculty, Staff and Student Publications

Objective: A small fraction of oral lichenoid conditions (OLC) have potential for malignant transformation. Distinguishing OLCs from other oral potentially malignant disorders (OPMDs) can help prevent unnecessary concern or testing, but accurate identification by nonexpert clinicians is challenging due to overlapping clinical features. In this study, the authors developed a 'cytomics-on-a-chip' tool and integrated predictive model for aiding the identification of OLCs.

Study design: All study subjects underwent both scalpel biopsy for histopathology and brush cytology. A predictive model and OLC Index comprising clinical, demographic, and cytologic features was generated to discriminate between subjects with lichenoid (OLC+) (N = 94) …

Ccr2+ Monocytes Promote White Matter Injury And Cognitive Dysfunction After Myocardial Infarction, Edward B Thorp, Mallory Filipp, Maria Dima, Chunfeng Tan, Matthew Feinstein, Brian Popko, Matthew Deberge

Faculty, Staff and Student Publications

Survivors of myocardial infarction are at increased risk for vascular dementia. Neuroinflammation has been implicated in the pathogenesis of vascular dementia, yet little is known about the cellular and molecular mediators of neuroinflammation after myocardial infarction. Using a mouse model of myocardial infarction coupled with flow cytometric analyses and immunohistochemistry, we discovered increased monocyte abundance in the brain after myocardial infarction, which was associated with increases in brain-resident perivascular macrophages and microglia. Myeloid cell recruitment and activation was also observed in post-mortem brains of humans that died after myocardial infarction. Spatial and single cell transcriptomic profiling of brain-resident myeloid cells …

Response-Adapted Ultra-Low-Dose 4 Gy Radiation As Definitive Therapy Of Gastric Malt Lymphoma: A Single-Centre, Pilot Trial, Jillian R Gunther, Jie Xu, Manoop S Bhutani, Paolo Strati, Penny Q Fang, Susan Y Wu, Bouthaina S Dabaja, Wenli Dong, Priya R Bhosale, Christopher R Flowers, Ranjit Nair, Luis Malpica Castillo, Luis Fayad, Swaminathan P Iyer, Simrit Parmer, Michael Wang, Hun Ju Lee, Felipe Samaniego, Jason Westin, Sairah Ahmed, Chijioke C Nze, Preetesh Jain, Sattva S Neelapu, Maria A Rodriguez, Dai Chihara, Loretta J Nastoupil, Chelsea C Pinnix

Faculty, Staff and Student Publications

Background: Given the favourable prognosis of patients with gastric mucosa-associated lymphoid tissue (MALT) lymphoma, treatment-related toxicity should be minimised. We aimed to evaluate the efficacy of 4 Gy radiotherapy given in a response-adapted approach.

Methods: We conducted a single-centre, single-arm, prospective trial at MD Anderson Cancer Center (Houston, TX, USA) of response-adapted ultra-low-dose radiotherapy. Eligible patients were 18 years or older and had newly diagnosed or relapsed Helicobacter pylori-negative gastric MALT lymphoma, with stage I-IV disease. Given the expected low toxicity profile of treatment, performance status was not an exclusion criterion. Patients received external beam photon-based radiotherapy for a total …

Plasmacytoid Dendritic Cells Control Homeostasis Of Megakaryopoiesis, Florian Gaertner, Hellen Ishikawa-Ankerhold, Susanne Stutte, Wenwen Fu, Jutta Weitz, Anne Dueck, Bhavishya Nelakuditi, Valeria Fumagalli, Dominic Van Den Heuvel, Larissa Belz, Gulnoza Sobirova, Zhe Zhang, Anna Titova, Alejandro Martinez Navarro, Kami Pekayvaz, Michael Lorenz, Louisa Von Baumgarten, Jan Kranich, Tobias Straub, Bastian Popper, Vanessa Zheden, Walter Anton Kaufmann, Chenglong Guo, Guido Piontek, Saskia Von Stillfried, Peter Boor, Marco Colonna, Sebastian Clauß, Christian Schulz, Thomas Brocker, Barbara Walzog, Christoph Scheiermann, William C Aird, Claus Nerlov, Konstantin Stark, Tobias Petzold, Stefan Engelhardt, Michael Sixt, Robert Hauschild, Martina Rudelius, Robert A J Oostendorp, Matteo Iannacone, Matthias Heinig, Steffen Massberg

Faculty, Staff and Student Publications

Platelet homeostasis is essential for vascular integrity and immune defence1,2. Although the process of platelet formation by fragmenting megakaryocytes (MKs; thrombopoiesis) has been extensively studied, the cellular and molecular mechanisms required to constantly replenish the pool of MKs by their progenitor cells (megakaryopoiesis) remains unclear3,4. Here we use intravital imaging to track the cellular dynamics of megakaryopoiesis over days. We identify plasmacytoid dendritic cells (pDCs) as homeostatic sensors that monitor the bone marrow for apoptotic MKs and deliver IFNα to the MK niche triggering local on-demand proliferation and maturation of MK progenitors. This pDC-dependent feedback loop is crucial for MK …

Reliable Detection Of Generalized Convulsive Seizures Using An Off-The-Shelf Digital Watch: A Multisite Phase 2 Study, Yash Shashank Vakilna, Xiaojin Li, Jaison S Hampson, Yan Huang, John C Mosher, Yuri Dabaghian, Xi Luo, Blanca Talavera, Sandipan Pati, Masel Todd, Ryan Hays, Charles Akos Szabo, Guo-Qiang Zhang, Samden D Lhatoo

Faculty, Staff and Student Publications

Objective: The aim of this study was to develop a machine learning algorithm using an off-the-shelf digital watch, the Samsung watch (SM-R800), and evaluate its effectiveness for the detection of generalized convulsive seizures (GCS) in persons with epilepsy.

Methods: This multisite epilepsy monitoring unit (EMU) phase 2 study included 36 adult patients. Each patient wore a Samsung watch that contained accelerometer, gyroscope, and photoplethysmographic sensors. Sixty-eight time and frequency domain features were extracted from the sensor data and were used to train a random forest algorithm. A testing framework was developed that would better reflect the EMU setting, consisting of …

A Modular Trial Of Androgen Signaling Inhibitor Combinations Testing A Risk-Adapted Strategy In Patients With Metastatic Castration-Resistant Prostate Cancer, Ana M Aparicio, Rebecca S S Tidwell, Shalini S Yadav, Jiun-Sheng Chen, Miao Zhang, Jingjing Liu, Shuai Guo, Patrick G Pilié, Yao Yu, Xingzhi Song, Haswanth Vundavilli, Sonali Jindal, Keyi Zhu, Paul V Viscuse, Justin M Lebenthal, Andrew W Hahn, Rama Soundararajan, Paul G Corn, Amado Zurita-Saavedra, Sumit K Subudhi, Jianhua Zhang, Wenyi Wang, Chad Huff, Patricia Troncoso, James P Allison, Padmanee Sharma, Christopher J Logothetis

Faculty, Staff and Student Publications

Purpose: To determine the efficacy and safety of risk-adapted combinations of androgen signaling inhibitors and inform disease classifiers for metastatic castration-resistant prostate cancers.

Patients and methods: In a modular, randomized phase II trial, 192 men were treated with 8 weeks of abiraterone acetate, prednisone, and apalutamide (AAPA; module 1) and then allocated to modules 2 or 3 based on satisfactory (≥50% PSA decline from baseline and < 5 circulating tumor cell/7.5 mL) versus unsatisfactory status. Men in the former were randomly assigned to continue AAPA alone (module 2A) or with ipilimumab (module 2B). Men in the latter group had carboplatin + cabazitaxel added to AAPA (module 3). Optional baseline biopsies were subjected to correlative studies.

Results: Median overall survival (from allocation) was 46.4 [95% confidence interval (CI), 39.2-68.2], 41.4 (95% CI, 33.3-49.9), and 18.7 (95% CI, 14.3-26.3) months in modules 2A (n = 64), 2B (n = 64), and …

The Role Of Occipital Condyle And Atlas Anomalies On Occipital Cervical Fusion Outcomes In Chiari Malformation Type I With Syringomyelia: A Study From The Park-Reeves Syringomyelia Research Consortium, Alexander T Yahanda, Joyce Koueik, Laurie L Ackerman, P David Adelson, Gregory W Albert, Philipp R Aldana, Tord D Alden, Richard C E Anderson, David F Bauer, Tammy Bethel-Anderson, Karin Bierbrauer, Douglas L Brockmeyer, Joshua J Chern, Daniel E Couture, David J Daniels, Brian J Dlouhy, Susan R Durham, Richard G Ellenbogen, Ramin Eskandari, Herbert E Fuchs, Gerald A Grant, Patrick C Graupman, Stephanie Greene, Jeffrey P Greenfield, Naina L Gross, Daniel J Guillaume, Todd C Hankinson, Gregory G Heuer, Mark Iantosca, Bermans J Iskandar, Eric M Jackson, George I Jallo, James M Johnston, Bruce A Kaufman, Robert F Keating, Nickalus R Khan, Mark D Krieger, Jeffrey R Leonard, Cormac O Maher, Francesco T Mangano, Jonathan Martin, J Gordon Mccomb, Sean D Mcevoy, Thanda Meehan, Arnold H Menezes, Michael S Muhlbauer, Brent R O'Neill, Greg Olavarria, John Ragheb, Nathan R Selden, Manish N Shah, Chevis N Shannon, Joshua S Shimony, Matthew D Smyth, Scellig S D Stone, Jennifer M Strahle, Mandeep S Tamber, James C Torner, Gerald F Tuite, Elizabeth C Tyler-Kabara, Scott D Wait, John C Wellons, William E Whitehead, Tae Sung Park, David D Limbrick, Raheel Ahmed

Faculty, Staff and Student Publications

Objective: Congenital anomalies of the atlanto-occipital articulation may be present in patients with Chiari malformation type I (CM-I). However, it is unclear how these anomalies affect the biomechanical stability of the craniovertebral junction (CVJ) and whether they are associated with an increased incidence of occipitocervical fusion (OCF) following posterior fossa decompression (PFD). The objective of this study was to determine the prevalence of condylar hypoplasia and atlas anomalies in children with CM-I and syringomyelia. The authors also investigated the predictive contribution of these anomalies to the occurrence of OCF following PFD (PFD+OCF).

Methods: The authors analyzed the prevalence of condylar …

Endovascular Versus Medical Therapy In Posterior Cerebral Artery Stroke: Role Of Baseline Nihss Score And Occlusion Site, Davide Strambo, Patrik Michel, Thanh N Nguyen, Mohamad Abdalkader, Muhammad M Qureshi, Daniel Strbian, Christian Herweh, Markus A Möhlenbruch, Silja Räty, Marta Olivé-Gadea, Marc Ribo, Marios Psychogios, Urs Fischer, Anh Nguyen, Joji B Kuramatsu, David Haupenthal, Martin Köhrmann, Cornelius Deuschl, Jordi Kühne Escolà, Jelle Demeestere, Robin Lemmens, Lieselotte Vandewalle, Shadi Yaghi, Liqi Shu, Volker Puetz, Daniel P O Kaiser, Johannes Kaesmacher, Adnan Mujanovic, Dominique Cornelius Marterstock, Tobias Engelhorn, Manuel Requena, Hormuzdiyar H Dasenbrock, Piers Klein, Diogo C Haussen, Mahmoud H Mohammaden, Hend Abdelhamid, Lorena Souza Viana, Bruno Cunha, Isabel Fragata, Michele Romoli, Francesco Diana, Wei Hu, Chao Zhang, Pekka Virtanen, Riikka Lauha, Jessica Jesser, Judith Clark, Stavros Matsoukas, Johanna T Fifi, Sunil A Sheth, Sergio Salazar-Marioni, João Pedro Marto, João Nuno Ramos, Milena Miszczuk, Christoph Riegler, Sven Poli, Khouloud Poli, Ashutosh P Jadhav, Shashvat M Desai, Volker Maus, Maximilian Kaeder, Adnan H Siddiqui, Andre Monteiro, Hesham E Masoud, Neil Suryadareva, Maxim Mokin, Shail Thanki, Kemal Alpay, Pauli Ylikotila, James E Siegler, Italo Linfante, Guilherme Dabus, Negar Asdaghi, Vasu Saini, Christian H Nolte, Eberhard Siebert, Bettina L Serrallach, Charlotte S Weyland, Uta Hanning, Lukas Meyer, Anne Berberich, Peter A Ringleb, Raul G Nogueira, Simon Nagel

Faculty, Staff and Student Publications

Background: Acute ischemic stroke with isolated posterior cerebral artery occlusion (iPCAO) lacks management evidence from randomized trials. We aimed to evaluate whether the association between endovascular treatment (EVT) and outcomes in iPCAO acute ischemic stroke is modified by initial stroke severity (baseline National Institutes of Health Stroke Scale [NIHSS]) and arterial occlusion site.

Methods: Based on the multicenter, retrospective, case-control study of consecutive iPCAO acute ischemic stroke patients (PLATO study [Posterior Cerebral Artery Occlusion Stroke]), we assessed the heterogeneity of EVT outcomes compared with medical management (MM) for iPCAO, according to baseline NIHSS score (≤6 versus >6) and occlusion site …

The Beneficial Role Of Sunitinib In Tumor Immune Surveillance By Regulating Tumor Pd-L1, Vivian L Rose, Anaga Ajoy, Craig A Johnston, Gloria R Gogola, Pranav J Parikh

Faculty, Staff and Student Publications

Importance: There is a need for a pediatric hand function test that can be used to objectively assess movement quality. We have developed a toy-based test, the Bead Maze Hand Function (BMHF) test, to quantify how well a child performs an activity. This is achieved by assessing the control of forces applied while drawing a bead over wires of different complexity.

Objective: To study the psychometric properties of the BMHF test and understand the influence of age and task complexity on test measures.

Design: A cross-sectional, observational study performed in a single visit.

Setting: Clinical research laboratory.

Participants: Twenty-three participants …

Tumor-Immune Signatures Of Treatment Resistance To Brentuximab Vedotin With Ipilimumab And/Or Nivolumab In Hodgkin Lymphoma, Edgar Gonzalez-Kozlova, Hsin-Hui Huang, Opeyemi A Jagede, Kevin Tuballes, Diane M Del Valle, Geoffrey Kelly, Manishkumar Patel, Hui Xie, Jocelyn Harris, Kimberly Argueta, Kai Nie, Vanessa Barcessat, Radim Moravec, Jennifer Altreuter, Dzifa Y Duose, Brad S Kahl, Stephen M Ansell, Joyce Yu, Ethan Cerami, James R Lindsay, Ignacio I Wistuba, Seunghee Kim-Schulze, Catherine S Diefenbach, Sacha Gnjatic

Faculty, Staff and Student Publications

To investigate the cellular and molecular mechanisms associated with targeting CD30-expressing Hodgkin lymphoma (HL) and immune checkpoint modulation induced by combination therapies of CTLA4 and PD1, we leveraged Phase 1/2 multicenter open-label trial NCT01896999 that enrolled patients with refractory or relapsed HL (R/R HL). Using peripheral blood, we assessed soluble proteins, cell composition, T-cell clonality, and tumor antigen-specific antibodies in 54 patients enrolled in the phase 1 component of the trial. NCT01896999 reported high (>75%) overall objective response rates with brentuximab vedotin (BV) in combination with ipilimumab (I) and/or nivolumab (N) in patients with R/R HL. We observed a …

Randomized Placebo-Controlled, Biomarker-Stratified Phase Ib Microbiome Modulation In Melanoma: Impact Of Antibiotic Preconditioning On Microbiome And Immunity, Isabella C Glitza, Yongwoo David Seo, Christine N Spencer, Jennifer R Wortman, Elizabeth M Burton, Farah A Alayli, Christopher P Loo, Shikha Gautam, Ashish Damania, Julie Densmore, Justin Fairchild, Christopher R Cabanski, Matthew C Wong, Christine B Peterson, Brian Weiner, Nathan Hicks, John Aunins, Christopher Mcchalicher, Emily Walsh, Michael T Tetzlaff, Omid Hamid, Patrick A Ott, Genevieve M Boland, Ryan J Sullivan, Kenneth F Grossmann, Nadim J Ajami, Theresa Lavallee, Matthew R Henn, Hussein A Tawbi, Jennifer A Wargo

Faculty, Staff and Student Publications

Gut-microbiota modulation shows promise in improving immune-checkpoint blockade (ICB) response; however, precision biomarker-driven, placebo-controlled trials are lacking. We performed a multicenter, randomized placebo-controlled, biomarker-stratified phase I trial in patients with ICB-naïve metastatic melanoma using SER-401, an orally delivered Firmicutesenriched spore formulation. Fecal microbiota signatures were characterized at baseline; patients were stratified by high versus low Ruminococcaceae abundance prior to randomization to the SER-401 arm (oral vancomycin-preconditioning/SER-401 alone/nivolumab + SER-401), versus the placebo arm [placebo antibiotic/placebo microbiome modulation (PMM)/nivolumab + PMM (NCT03817125)]. Analysis of 14 accrued patients demonstrated that treatment with SER-401 + nivolumab was safe, with an overall response rate …

Impact Of Lifetime Stressor Exposure On Neuroenergetics In Schizophrenia Spectrum Disorders, Joshua Chiappelli, Anya Savransky, Yizhou Ma, Si Gao, Mark D Kvarta, Peter Kochunov, George M Slavich, L Elliot Hong

Faculty, Staff and Student Publications

N-acetylasparate and lactate are two prominent brain metabolites closely related to mitochondrial functioning. Prior research revealing lower levels of NAA and higher levels of lactate in the cerebral cortex of patients with schizophrenia suggest possible abnormalities in the energy supply pathway necessary for brain function. Given that stress and adversity are a strong risk factor for a variety of mental health problems, including psychotic disorders, we investigated the hypothesis that stress contributes to abnormal neuroenergetics in patients with schizophrenia. To test this hypothesis, we used the Stress and Adversity Inventory (STRAIN) to comprehensively assess the lifetime stressor exposure profiles of …

Paying A Heavy Price: Costs Of Care For People With Severe Obesity In Nursing Homes, Luisa Fernandez, Bianca Shieu, Alison Trinkoff, Nicholas Castle, David G Wolf, Steven Handler, John A Harris

Faculty, Staff and Student Publications

Background and objectives: The prevalence of resident obesity in nursing homes has increased dramatically from 22% to 28% between 2005 and 2015. To provide care for people with obesity, nursing homes have changed their admissions, staffing, and equipment, but underlying these changes are increased resources and financial costs of care. The purpose of this study is to describe nursing home organizational aspects of caring for older adults with obesity, with a focus on economic factors, from the perspective of nursing home staff and leadership.

Research design and methods: This qualitative study used descriptive approaches; data were collected through semistructured telephone …

Plozasiran (Aro-Apoc3) For Severe Hypertriglyceridemia: The Shasta-2 Randomized Clinical Trial, Daniel Gaudet, Denes Pall, Gerald F Watts, Stephen J Nicholls, Robert S Rosenson, Karen Modesto, Javier San Martin, Jennifer Hellawell, Christie M Ballantyne

Faculty, Staff and Students Publications

Importance: Severe hypertriglyceridemia (sHTG) confers increased risk of atherosclerotic cardiovascular disease (ASCVD), nonalcoholic steatohepatitis, and acute pancreatitis. Despite available treatments, persistent ASCVD and acute pancreatitis-associated morbidity from sHTG remains.

Objective: To determine the tolerability, efficacy, and dose of plozasiran, an APOC3-targeted small interfering-RNA (siRNA) drug, for lowering triglyceride and apolipoprotein C3 (APOC3, regulator of triglyceride metabolism) levels and evaluate its effects on other lipid parameters in patients with sHTG.

Design, setting, and participants: The Study to Evaluate ARO-APOC3 in Adults With Severe Hypertriglyceridemia (SHASTA-2) was a placebo-controlled, double-blind, dose-ranging, phase 2b randomized clinical trial enrolling adults with sHTG at 74 …

Liver Disease And Transplantation In Telomere Biology Disorders: An International Multicenter Cohort, Yunzu Michele Wang, Batul Kaj-Carbaidwala, Adam Lane, Suneet Agarwal, Fabian Beier, Alison Bertuch, Kristin A Borovsky, Steven K Brennan, Rodrigo T Calado, Luiz Fernando B Catto, Carlo Dufour, Christen L Ebens, Francesca Fioredda, Neelam Giri, Nicholas Gloude, Frederick Goldman, Paula M Hertel, Ryan Himes, Sioban B Keel, Divya T Koura, Christian P Kratz, Sakil Kulkarni, Iris Liou, Taizo A Nakano, Silvia Nastasio, Marena R Niewisch, Daniel D Penrice, Ghadir S Sasa, Sharon A Savage, Douglas A Simonetto, David S Ziegler, Alexander G Miethke, Kasiani C Myers

Faculty, Staff and Students Publications

Background: Patients with telomere biology disorders (TBD) develop hepatic disease, including hepatitis, cirrhosis, and hepatopulmonary syndrome. No specific treatment exists for TBD-related liver disease, and the role of liver transplantation (LT) remains controversial. Our study objectives were to describe the clinical characteristics, management, and outcomes in patients with TBD-related liver disease, and their LT outcomes.

Methods: Data from 83 patients with TBD-associated liver disease were obtained from 17 participating centers in the Clinical Care Consortium of Telomere-Associated Ailments and by self-report for our retrospective, multicenter, international cohort study.

Results: Group A ("Advanced") included 40 patients with advanced liver disease. Of …

Magnetic Resonance Imaging Signs Of Idiopathic Intracranial Hypertension, Dagmar Beier, Johanne Juhl Korsbæk, Gabriel Bsteh, Stefan Macher, Wolfgang Marik, Berthold Pemp, Hsiangkuo Yuan, Areeba Nisar, Lisbeth Høgedal, Laleh Dehghani Molander, Snorre Malm Hagen, Christoph Patrick Beier, Simon Bang Kristensen, Rigmor Højland Jensen

Department of Neurology Faculty Papers

IMPORTANCE: The magnetic resonance imaging (MRI) criteria currently used to diagnose idiopathic intracranial hypertension (IIH) are based on expert opinion and have limited accuracy. Additional neuroimaging signs have been proposed and used with contradictory results; thus, prospective evidence is needed to improve diagnostic accuracy.

OBJECTIVE: To provide evidence-based, accurate MRI signs for IIH diagnosis.

DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study was conducted from January 2018 to May 2021 with 3 validation cohorts at 2 Danish headache centers and with 3 independent international cohorts. Consecutive patients with suspected IIH were enrolled. Eligibility required the clinical suspicion of IIH, age …