Digital Commons Network^™

Clingen Api Platform For Classification Of Human Genetic Variants, Neethu Shah, Tierra Farris, Arturo Alejandro Zuniga, Andrew R Jackson, Jessie Arce, Kevin Riehle, Christine G Preston, Mark E Mandell, Bryan Wulf, Gloria Cheung, Keyang Yu, Deborah I Ritter, Dubravka Jevtic, Miroslav Milinkov, Novak Martinovic, Nevena Vucinic, Aleksandar Mihajlovic, Alan F Rubin, Melissa S Cline, Marina Distefano, Malachi Griffith, Obi L Griffith, Matt W Wright, Teri E Klein, Sharon E Plon, Aleksandar Milosavljevic

Faculty, Staff and Students Publications

In this commentary, we describe how the Clinical Genome Resource's (ClinGen's) application programming interface-based microservices accelerate growth and dissemination of knowledge about human genetic variation. By exposing findable, accessible, interoperable, reusable, and AI-ready variant data, ClinGen lays a foundation for next-generation software applications, AI systems, and variant classification workflows.

Developing Endpoints For The Cardiac Burden In Myotonic Dystrophy Type 1: A Workshop Report, Julia M Hartman, Samuel Carrell, William J Groh, Thomas A Cooper, Jordana Kron, Greg Hundley, Jennifer Jordan, Amy Ladd, Man Hung, Nicholas E Johnson

Faculty, Staff and Students Publications

Cardiac disease is a well-established manifestation of myotonic dystrophy type 1 (DM1), characterized by progressive cardiac conduction slowing with increased risk of atrial and ventricular arrhythmias, heart block, and sudden cardiac death. Multiple disease modifying therapies are in clinical trials for DM1 and show promise in improving skeletal muscle weakness and myotonia. Testing the effects of these medicines, or others, in the heart is of critical importance, but requires identification of endpoints of cardiac function that accurately reflect the state of DM1 cardiac disease. To better define cardiac endpoints, the Myotonic Dystrophy Clinical Research Network (DMCRN) and the Myotonic Dystrophy …

Versatile Smad2 And Smad3 Epitope-Tagged Mouse Models For Genomic Profiling Of Tgfβ Signaling: Uncovering Gdf9-Smad2/3 Targets, Zian Liao, Qian Zhang, Keisuke Shimada, Kaori Nozawa, Suni Tang, Masahito Ikawa, Diana Monsivais, Martin M Matzuk

Faculty, Staff and Students Publications

Transforming growth factor β (TGFβ) signaling pathways are integral for a plethora of biological processes. SMAD2 and SMAD3 are the principal transcriptional effectors of TGFβ superfamily ligands, yet quantitative, genome-wide mapping of their DNA-associated complexes under physiological contexts has remained limited due to the lack of specific, robust models. Here, we generated two versatile epitope-tagged mouse models in which endogenous SMAD2 and SMAD3 proteins are globally tagged with hemagglutinin (HA) and podoplanin (PA) sequences, respectively, enabling high-fidelity profiling of SMAD2 and SMAD3 binding across tissues. To demonstrate the broad application of our models, we exemplified the usage of our lines …

Multi-Organ Physiologic Deficits During Exercise Identify Clinical And Molecular Predisposition To Heart Failure With Preserved Ejection Fraction, Isabela Landsteiner, Lindsey K Stolze, Tess E Peterson, Andrew Perry, Phillip Lin, Quanhu Sheng, Shilin Zhao, Kaushik Amancherla, Michael Y Mi, Takenori Ikoma, Laura P Cohen, Ilya Giverts, Joseph Campain, Joao A C Lima, Wendy S Post, Kent D Taylor, Robert Gerszten, Stephen S Rich, Russell Tracy, Peter Durda, Alexis C Wood, Rajeev Malhotra, Jerome I Rotter, Clary Clish, Matthew Nayor, Eric R Gamazon, Ravi V Shah, Gregory D Lewis

Faculty, Staff and Students Publications

Background: Exercise unmasks limitations in multi-organ system reserve capacity characteristic of heart failure with preserved ejection fraction (HFpEF). However, the metabolic and genetic underpinnings of exercise deficits, and their cumulative contribution to HFpEF severity and prognosis, remain incompletely understood.

Methods: We used invasive cardiopulmonary exercise testing (iCPET), metabolite profiling, and genomics to simultaneously characterize seven exercise physiologic deficits in HFpEF patients: reduced exercise stroke volume and heart rate, steep pulmonary capillary wedge pressure/cardiac output (PCWP/CO) slope, elevated pulmonary vascular resistance, pulmonary mechanical limitation to exercise, impaired peripheral oxygen extraction, and obesity-related exaggerated metabolic cost of initiating exercise. We first mapped …

Structure-Preserving Multivariate Hypothesis Testing For Mass Spectrometry Imaging And Single-Cell Data, Keziah E Liebenberg, Erin Craig, Robert Tibshirani, Livia S Eberlin

Faculty, Staff and Students Publications

Motivation: Mass spectrometry imaging (MSI) and single-cell RNA sequencing (scRNA-seq) offer high-resolution views into tissue and cellular heterogeneity. However, conventional statistical analyses often treat sub-measurements (pixels or cells) as independent, ignoring their nested origin from individual samples. This assumption inflates the effective sample size, increases false discoveries, and undermines biological interpretation. Pixel- or cell-level averaging avoids this but sacrifices spatial or cellular resolution.

Results: We evaluated block-SAM on both simulated and real-world datasets. In DESI-MSI data from kidney, lung, and ovarian tumors, block-SAM consistently identified fewer-but more reliable-differential features compared to traditional-SAM. For example, in the kidney dataset, traditional-SAM identified …

Correction: The Formation Of Tau Pore-Like Structures Is Prevalent And Cell Specific: Possible Implications For The Disease Phenotypes, Cristian A Lasagna-Reeves, Urmi Sengupta, Diana Castillo-Carranza, Julia E Gerson, Marcos Guerrero-Munoz, Juan C Troncoso, George R Jackson, Rakez Kayed

Faculty, Staff and Students Publications

This corrects the article "The formation of tau pore-like structures is prevalent and cell specific: possible implications for the disease phenotypes" in volume 2, 56.

Relative Impact Of Multidomain Lifestyle Interventions On Deficit Accumulation Frailty Over 24 Months In The U.S. Pointer Trial, Mark A Espeland, Kayloni Olson, Christy C Tangney, Darren R Gitelman, Maryjo Cleveland, Amber A Thro, Yitbarek N Demesie, Heather M Snyder, Rachel A Whitmer, Pankaja Desai, Rifat Alam, Lucia Crivelli, Thomas M Holland, Olivia Preissle, Rema Raman, Michele K York, Laura D Baker

Faculty, Staff and Students Publications

Background: Multidomain lifestyle interventions hold promise as approaches to slow aging. Deficit accumulation frailty indices (FIs) are increasingly used to capture aging processes. Frailty is highly associated with increased mortality and chronic disease risk, but the degree to which multidomain lifestyle changes impact frailty is not clear.

Methods: The U.S. Study to Protect Brain Health through Lifestyle Intervention to Reduce Risk (U.S. POINTER) was a 2-year randomized clinical trial to compare two multidomain lifestyle interventions designed to increase exercise, improve diet, and promote social and cognitive stimulating activities and health monitoring. The Structured intervention incorporated greater structure, intensity, and accountability …

The Ki-67 Proliferation Index And Recurrence Risk Of Intracranial Meningioma: A Multicenter, Retrospective Cohort Study Of 5,050 Patients, Christian Mirian, Lasse Rehné Jensen, Tareq A Juratli, Andrea Daniela Maier, Anders Broechner, Sverre H Torp, Helen A Shih, Ramin A Morshed, Jacob S Young, Stephen T Magill, Luca Bertero, Walter Stummer, Dorothee Cäcilia Spille, Benjamin Brokinkel, Soichi Oya, Satoru Miyawaki, Nobuhito Saito, Martin Proescholdt, Yasuhiro Kuroi, Konstantinos Gousias, Matthias Simon, Jennifer Moliterno, Ricardo Prat-Acin, Stéphane Goutagny, Vikram C Prabhu, John T Tsiang, Johannes Wach, Erdem Güresir, Junkoh Yamamoto, Young Zoon Kim, Joo Ho Lee, Daniel W Kim, Matthew Koshy, Karthikeyan Perumal, Mustafa K Baskaya, Donald M Cannon, Dennis C Shrieve, Chang-Ok Suh, Jong Hee Chang, Maria Kamenova, Sven Straumann, Jehuda Soleman, Ilker Y Eyüpoglu, Tony Catalan, Austin Lui, Philip V Theodosopoulos, Michael W Mcdermott, Fang Wang, Pedro Góes, Aria Jamshidi, Ricardo Komotar, Michael Ivan, Evan Luther, Luis Souhami, Marie-Christine Guiot, Tamás Csonka, Toshiki Endo, Olivia Claire Barrett, Randy Jensen, Tejpal Gupta, Akash J Patel, Tiemo J Klisch, Jun Won Kim, Francesco Maiuri, Valeria Barresi, María Dolores Tabernero, Simon Skyrman, Ian Law, David Scheie, Bjarne Winther Kristensen, Tina Nørgaard Munch, Torstein Meling, Kåre Fugleholm, Paul Blanche, Tiit Mathiesen

Faculty, Staff and Students Publications

Purpose: The Ki-67 proliferation index (Ki-67 PI) has been associated with meningioma recurrence, yet its clinical utility remains debated. Whether Ki-67 PI provides prognostic information across subgroups defined by both WHO grade and extent of resection remains to be investigated.

Methods: We analyzed 5,050 patients with intracranial meningiomas from the international PERNS cohort (42 centers, diagnosed between 1989-2019) who underwent surgical resection without postoperative radiotherapy. Ki-67 PI prognostic accuracy was assessed up to 10 years postoperatively by using ROC analyses and estimating its association with the risk of recurrence.

Results: Results demonstrated that the prognostic value of Ki-67 PI differed …

Implementing Measurement-Based Care In Virtual Mental Health Services For Rural Veterans: Provider Insights From A Pre-Implementation Evaluation, Amanda Heeren, Kimberly Mccoy, Lindsey Fuhrmeister, Natalie Suiter, Jan A Lindsay, Chloe Hoang, Laura Marsh, John Fortney, Carolyn Turvey

Faculty, Staff and Students Publications

Background

Measurement-Based Care (MBC) uses repeated standardized psychological assessments to monitor treatment progress and guide clinical decision-making. Although MBC improves outcomes when results are discussed collaboratively, adoption across the Veterans Health Administration (VHA) remains below 50%, particularly in virtual and rural settings. This pre-implementation evaluation explored provider perspectives to inform development of a digital MBC workflow for rural tele-mental health settings.

Methods

Using the Alacrity Center’s Discover, Design, Build, and Test model and User Centered Design, we conducted a pre-implementation survey of mental health providers at a VHA Medical Center providing care to rural and highly rural Veterans in South …

Novel Variants Identified In Families With Snx27 -Related Neurodevelopmental Disorder, Aiding In Characterizing Its Genotypic And Phenotypic Spectrum, Tayyaba Shan, Abrar Hussain, Anushree Acharya, Mulazim Hussain, Yumei Li, Hafiz Muhammad Jafar Hussain, Kiran Afshan, Suzanne M Leal, Rui Chen, Asif Mir, Isabelle Schrauwen, Sabika Firasat

Faculty, Staff and Students Publications

Background:

Sorting Nexin 27 (SNX27), a key regulator of synaptic receptor trafficking and endosomal recycling, has been implicated in maintaining synaptic homeostasis and cognitive function. To date, variants in SNX27 have been reported in a small number of patients across three publications with severe neurodevelopmental phenotypes. However, the genetic and functional landscape of SNX27-related disorders remains poorly understood, and further evidence is needed to confirm its association with disease and to better delineate the associated phenotype.

Methods and Results:

Two unrelated Pakistani families with a total of five affected individuals segregating a neurodevelopmental disorder were investigated via exome …

Influence Of Gut Microbiota On Response To Immune Check Point Inhibitors In Masld Patients With Hcc: Unraveling The Connection, Mazen Elsheikh, Mohamad Ali Ibrahim, Sherry Fares, Megha Bhongade, Karim Adhem, Ximena I Ramirez-Morales, Ahmed O Kaseb, Joseph Petrosino, Manal M Hassan, Prasun K Jalal

Faculty, Staff and Students Publications

Immune checkpoint inhibitors (ICIs) have emerged as a promising treatment for various cancers, including advanced hepatocellular carcinoma (HCC). However, a significant proportion of patients with HCC, particularly those with metabolic dysfunction-associated liver disease (MASLD), exhibit resistance to ICI therapy. Studies have revealed that the presence of specific gut bacteria, such as Akkermansia, Bifidobacterium, and Lachnoclostridium, is associated with improved outcomes with ICI-treated HCC patients. Conversely, the overgrowth of bacteria like Enterobacteriaceae is linked to resistance to therapy. This review investigates the role of gut microbiota in shaping immune checkpoint inhibitor responses in MASLD-related hepatocellular carcinoma, focusing on how dysbiosis may …

Investigating Conjunctival Immune Pathways In Sjögren And Non-Sjögren Disease Associated Dry Eye, Kaitlin K Scholand, Laura Schaefer, Jianming Shao, Zhiyuan Yu, Stephen C Pflugfelder, Robert A Britton, Cintia S De Paiva

Faculty, Staff and Students Publications

Purpose: Dry eye disease (DED) is classified based on its predominant etiology into aqueous tear-deficient (ATD), evaporative, or mixed. Sjӧgren disease keratoconjunctivitis sicca (SjD-KCS) is a very severe autoimmune form of ATD DED. The purpose of this work was to compare transcriptomic changes in the conjunctiva sampled from patients with ATD, SjD-KCS, and healthy controls (HC) to evaluate distinctions in the immune response on the ocular surface based on diagnosis.

Methods: Impression cytology of the temporal bulbar conjunctiva was collected using the EyePrim device. RNA was extracted and submitted with the Nanostring nCounter Human Immunology V2 panel for gene expression …

Leveraging Untargeted Metabolomics In Combination With Machine Learning To Uncover Novel Insights Into Bladder Cancer, Abu Hena Mostafa Kamal, Vasanta Putluri, Tanmay Gandhi, Chandra Shekar R Ambati, Chandra Sekhar Amara, Karthik Reddy Kami Reddy, Meredith Lauren Spradlin, Amrit Koirala, Sachin B Jorvekar, Sandra L Grimm, Dexue Fu, Krishna Parsawar, Felice De Jong, Chris Beecher, Subrata Sen, Seth P Lerner, M Minhaj Siddiqui, Yair Lotan, Livia S Eberlin, Arun Sreekumar, Cristian Coarfa, Nagireddy Putluri

Faculty, Staff and Students Publications

Background

Untargeted metabolomics has emerged as a powerful approach to uncover metabolic dysregulation associated with cancer progression. When integrated with a machine learning strategy it facilitates the discovery of key metabolic pathways and predictive biomarkers with high diagnostic and prognostic value.

Methods

In this study, we employed liquid chromatography coupled to high-resolution Tribrid Orbitrap mass spectrometry to perform comprehensive metabolic profiling of bladder cancer (BLCA) as well as predict invasiveness of the disease.

Results

By leveraging both in-house retention time-based MS/MS spectral libraries and commercial databases, we robustly identify over 2000 metabolites. In addition, this platform allows identification of novel …

Serological Evidence Of Borrelia Turicatae In Raccoons (Procyon Lotor) From An Endemic Focus Of Tick-Borne Relapsing Fever In Mexico, Jose A Hernández Martínez, Valeria Leal-Sepúlveda, Alan A Zavala-Norzagaray, Emilio Rendón-Franco, César P Ley-Quiñonez, Patricio Pellegrini-Hernández, Job E Lopez, J Antonio Ibarra

Faculty, Staff and Students Publications

Tick-borne relapsing fever is a neglected and overlooked disease. In Mexico, numerous historical reports document the distribution of Ornithodoros turicata, the vector of Borrelia turicatae, as well as human cases of infection. However, the enzootic cycle and reservoir hosts in Mexico remain unknown. Here, to detect previous infections with relapsing fever Borreliae in wild fauna a retrospective serological analysis was conducted with serum samples collected from raccoons trapped from 2022 to 2025 in the Navachiste region of Sinaloa, Mexico. Using a species-specific antigen, BipA from B. turicatae, and bacterial lysates of this spirochete, we found high exposure among this cohort …

Effect Of Different Management Strategies On Outcomes In Subarachnoid Neurocysticercosis: A Descriptive, Multicentre, Retrospective Cohort Study In The Usa, Janitzio J Guzmán, Megan M Duffey, Jill Weatherhead, Eva H Clark, Jesica Herrick, Senate Amusu, Felicia C Chow, Paul R Allyn, Noah Wald-Dickler, J Martin Rodriguez, Natalie M Bowman, Timothy J Hatlen, Dannae Martin, Travis Larsen, Anna M Cervantes-Arslanian, Christina Coyle, A Clinton White, Elliott Welford, Annie N Cowell, Jeffrey D Jenks, Andrés F Henao-Martinez, Carlos Franco-Paredes, Glenn Mathisen, Paola Lichtenberger, Jose A Serpa, Rory Bouzigard, Laila M Castellino, Elise M O'Connell

Faculty, Staff and Students Publications

Background: Subarachnoid neurocysticercosis (SANCC) is an uncommon but severe form of Taenia solium infection. There is limited evidence to guide clinical management. We aimed to describe the clinical and laboratory features of a cohort of patients with SANCC, and assess the impact of different management strategies on their clinical course.

Methods: We performed a multicentre retrospective cohort study with patients from 15 medical centres across nine states in the USA. SANCC was defined based on histopathology; the presence of cysts in the basilar subarachnoid spaces/sylvian fissures/spine with antibody positivity to T. solium/meeting Del Brutto criteria; or inflammatory cerebrospinal fluid …

Non-Invasive Intracranial Pressure Estimation In The Intensive Care Unit: Narrative Review Of Methods And Clinical Applications, Edoardo Picetti, Daniele Guerino Biasucci, Elisa Gouvea Bogossian, Sérgio Brasil, Danilo Cardim, Marek Czosnyka, Daniel A Godoy, Gregory W J Hawryluk, Mohammad I Hirzallah, Frank A Rasulo, Carla Bittencourt Rynkowski, Andres M Rubiano, Fabio Silvio Taccone, Chiara Robba

Faculty, Staff and Students Publications

Despite invasive methods are the gold standard for intracranial pressure (ICP) measurement, several non-invasive techniques (nICP) have been proposed as surrogate, although their use remains insufficiently recognized in clinical practice. These include transcranial Doppler blood flow velocity  assessment (arterial or venous), optic nerve sheath diameter (ONSD), automated pupillometry, measurement of skull expansion and compliance, brain imaging, double-depth ophthalmic artery blood flow velocity, and ultrasound time-of-flight. The main limitations of all indirect methods are calibration and zeroing, which constrain the absolute accuracy of non-invasive ICP monitoring. For transcranial Doppler-based methods, the 95% limits of agreement are approximately ± 7-15 mmHg, while …

Author Correction: Foundation Model Of Neural Activity Predicts Response To New Stimulus Types, Eric Y Wang, Paul G Fahey, Zhuokun Ding, Stelios Papadopoulos, Kayla Ponder, Marissa A Weis, Andersen Chang, Taliah Muhammad, Saumil Patel, Zhiwei Ding, Dat Tran, Jiakun Fu, Casey M Schneider-Mizell, R Clay Reid, Forrest Collman, Nuno Maçarico Da Costa, Katrin Franke, Alexander S Ecker, Jacob Reimer, Xaq Pitkow, Fabian H Sinz, Andreas S Tolias

Faculty, Staff and Students Publications

This corrects the article "Foundation model of neural activity predicts response to new stimulus types" in volume 640 on page 470.

Androgen Activity In The Male Embryonic Hindbrain Drives Lethal Pfa Ependymoma, Jiao Zhang, Winnie Ong, Alexandra Rasnitsyn, Ricardo Daniel Gonzalez, Rodrigo Lopez Gutierrez, Polina Balin, Amr Saadeldin, Xiaochong Wu, Maria C Vladoiu, Vicente Santa-Maria Lopez, Fernando Gonzalez-Salinas, Navneesh Yadav, Dinesh Mohanakrishnan, Kannan Boosi Narayana Rao, Raja Gopal Reddy Mooli, Hinda Najem, Sebastian Pacheco, Kaitlin Kharas, Cory Richman, David Przelicki, Evan Y Wang, Haipeng Su, Rachel Naomi Curry, Runze Yang, Michelle Masayo Kameda-Smith, Bryn Livingston, David Scott, Zaili Luo, Mingyang Xia, Namal Abeysundara, Anders W Erickson, Ncedile Mankahla, Lucas Zhongming Hu, Chu Pan, Raul Suarez, Ning Huang, Yihao Wu, Hao Wang, Tajana Douglas, Jonelle Pallota, Steven Hébert, Karen Ng, Krystin Mantione, Heather Whetstone, Hassaan Maan, Hussein Lakkis, Juyeun Lee, Sadeesh K Ramakrishnan, Yanxin Pei, Yujie Tang, Frank Y Lin, Guillermo Aldave, Marco Gallo, Robert M Friedlander, Faiyaz Notta, Laura K Donovan, Murali Chintagumpala, Bo Wang, Yun Li, Daniel D De Carvalho, Zhaolei Zhang, Ying Mao, Wei Hua, Charles Eberhart, Calixto-Hope G Lucas, Sriram Venneti, Poul H Sorensen, Alberto Delaidelli, Hao Li, Wenhao Zhou, Jason Kirk, Dean G Tang, Tao Jiang, Hailong Liu, Justin D Lathia, Hiromichi Suzuki, Jeremy N Rich, Lincoln D Stein, Nada Jabado, Vijay Ramaswamy, Q Richard Lu, Amy B Heimberger, Craig Daniels, Kulandaimanuvel Antony Michealraj, Claudia L Kleinman, Michael D Taylor

Faculty, Staff and Students Publications

Posterior fossa type A (PFA) ependymoma is an unusual infantile brain tumour with few known somatic mutations, thought to be driven by epigenetic mechanisms1. PFA ependymoma has a markedly higher incidence and worse prognosis in male children than in female children2. The mechanisms that underlie these sex differences are at present unknown. Here we show that the cellular hierarchy of PFA ependymoma is less differentiated in male individuals than it is in female individuals. In the normal developing mouse hindbrain, male gliogenic progenitors are less differentiated than matched female sibling controls. To further parse the effects …

Da Vinci Single-Port Transvaginal Natural Orifice Transluminal Endoscopic Surgery (Vnotes) Sacrocolpopexy: A Case Report And Literature Review, Xiaoming Guan, Chunhua Zhang, Qiannan Yang, Shunjia Hong, Wai Ieng Fong

Faculty, Staff and Students Publications

Pelvic organ prolapse remains a common condition requiring durable surgical correction, with sacrocolpopexy considered the gold standard. Transvaginal natural orifice transluminal endoscopic surgery (vNOTES) has emerged as a scarless minimally invasive approach, while the integration of robotic single-port technology may further enhance surgical precision and ergonomics. However, data on robotic-assisted single-port vNOTES (RSP-vNOTES) sacrocolpopexy remains limited. We report a case of a 58-year-old Asian woman with symptomatic apical pelvic organ prolapse. The pelvic organ prolapse quantification (POP-Q) assessment demonstrated stage II uterine prolapse. She underwent robotic-assisted single-port vNOTES (RSP-vNOTES) sacrocolpopexy using the da Vinci single-port (SP) platform. The procedure was …

Robotic Single-Incision Laparoscopic Surgery For The Management Of Endometriosis: First Experience Via The Da Vinci Sp Platform, Qiannan Yang, Daniel Y Lovell, Xiaoming Guan

Faculty, Staff and Students Publications

Objective: To demonstrate the feasibility and mid-term outcomes of Robotic single-port single-incision laparoscopic surgery (RSP-SILS) for endometriosis management.

Methods: A retrospective analysis was conducted on 50 adult women with endometriosis who underwent RSP-SILS via the da Vinci SP platform between November 2023 and July 2025.

Results: Median total operative time was 142 min, robot dock time was 3 min, and robot console time was 99 min. Median estimated blood loss was 25 mL. No conversion occurred. Reported mid-term outcomes included 1 case each of pelvic haematoma, Clostridioides difficile colitis, and umbilical surgical site infection, as well as 3 cases of …

A Comprehensive Review Of Tear Fluid Proteome Alterations In Dry Eye Disease: Insights Into Pathophysiology And Biomarker Potential, Saleh Ahmed, Steven Safille, Victoria Clifton, Shruti Sharma, Cintia S De Paiva, Ashok Sharma

Faculty, Staff and Students Publications

Tear fluid is a highly specialized and dynamic biofluid composed of proteins, lipids, mucins, and electrolytes that is essential for maintaining ocular surface integrity, immune defense, and tear film stability. Growing evidence from tear proteomic studieshas revealed extensive alterations in protein composition in dry eye disease (DED), reflecting a complex interplay between local ocular surface pathology and systemic inflammatory influences. This review summarizes proteomic findings from 50 published studies to identify tear proteins that are consistently upregulated or downregulated in DED and to interpret their biological relevance in the context of ocular surface homeostasis. Across studies, proteins upregulated in DED …

Comprehensive Profiling Of The Human Tear Fluid Mirnome Using Small Rna Sequencing, Garrett Jones, Drew Mayernik, Saleh Ahmed, Eliza Williams, Jeremy Altman, Tae Jin Lee, Amy Estes, Cintia S De Paiva, Pamela Martin, Shruti Sharma, Ashok Sharma

Faculty, Staff and Students Publications

Purpose: To generate a comprehensive profile of microRNAs (miRNAs) present in human tear fluid using next-generation sequencing (NGS), establish a reference miRNome for healthy human tear fluid, and investigate whether miRNA expression varies by sex, race, or age.

Methods: Tear samples were collected from 32 adults using Schirmer strips. RNA was isolated using the miRNeasy Serum/Plasma Kit, and cDNA libraries were prepared using the QIAseq miRNA Library Kit. Barcoded libraries were sequenced on the NovaSeq 6000 platform. Bioinformatic analyses included adapter trimming, alignment to miRBase, normalization with DESeq2, and functional annotation using multiMiR and clusterProfiler. Differential expression analysis was performed …

Rexinoid Net-3ib Promotes Resident Macrophage Gene Expression And Mitigates Desiccation-Induced Ocular Surface Disease, Jehan Alam, Yangluowa Qu, Jianming Shao, Ebru Yaman, Karen Zheng, Hiroki Kakuta, Stephen C Pflugfelder

Faculty, Staff and Students Publications

Purpose: To evaluate the effects of rexinoid NEt-3IB on desiccating stress-induced dry eye, as well as monocyte/macrophage gene expression and cellular trajectory.

Methods: Eyes were topically treated with rexinoid NEt-3IB (5 µM) or vehicle three times a day for 5 days of desiccating stress-induced dry eye. Single-cell RNA sequencing (RNA-seq) profiled gene expression in conjunctival immune cells. RNA-seq was also used to evaluate gene expression in lipopolysaccharide (LPS)-stimulated, dexamethasone-treated (Dex, 1 µM), or NEt-3IB-treated (1-1000 nM) cultured monocytes. Cellular state trajectory and latent time were inferred with scVelo, and latent-time-associated genes were identified using Monocle 3. Permeability to Oregon Green-labeled …

Results Of A Randomized, Double-Masked, Placebo-Controlled Phase 1/2 Study Of A Trpv1 Antagonist Sjp-0132 In Participants With Dry Eye Disease, Tomoyuki Wada, Kazunori Omatsu, Stephen C Pflugfelder

Faculty, Staff and Students Publications

Purpose: To investigate the safety, tolerability, pharmacokinetic profile, and efficacy of SJP-0132 in participants with dry eye disease (DED).

Design: Phase 1/2, randomized, double-masked, single-center, placebo-controlled single and multiple ascending dose study.

Participants: Generally healthy adults aged ≥18 years with a patient-reported history of DED for ≥6 months, eye dryness visual analog scale (VAS: 0-100) ≥40 mm, 5-item dry eye questionnaire (DEQ-5) ≥6, and central corneal fluorescein staining (CFS) of 2 to 4 (Baylor scale: 0-5 for each of five zones).

Methods: This study consisted of Part A and Part B, containing four single- and two multiple-ascending dose cohorts, respectively. …

Avacincaptad Pegol For Geographic Atrophy Secondary To Age-Related Macular Degeneration: Two-Year Efficacy And Safety Results From The Gather2 Phase 3 Trial, Arshad M Khanani, Carl J Danzig, Jeffrey S Heier, Glenn J Jaffe, Peter K Kaiser, David R Lally, Sunil S Patel, Lejla Vajzovic, Christina Y Weng, Hersh Patel, Julie Clark, Dhaval Desai, Don Luo, Erin Henry, Frank G Holz

Faculty, Staff and Students Publications

Purpose: Avacincaptad pegol (ACP) is a pegylated RNA aptamer that inhibits complement C5. The efficacy and safety of ACP 2 mg was investigated in GATHER2, with positive year 1 results published. Herein, 2-year results are reported.

Design: Phase 3, randomized, sham-controlled study (ClinicalTrials.gov identifier, NCT04435366).

Participants: Patients with non-center point-involving geographic atrophy (GA).

Methods: Eligible patients were randomized 1:1 to receive monthly ACP 2 mg (n = 225) or sham (n = 222) for 1 year. At month 12, patients who received ACP 2 mg were randomized again 1:1 to dosing every month (EM; n = 96) or every …

Utility Of Diagnostic Arthroscopy Before Medial Patellofemoral Ligament Reconstruction In Pediatric And Adolescent Patients Without Articular Findings On Magnetic Resonance Imaging, Holden Archer, Kaleb Patterson, Jonathan D Schwartzman, Scott D Mckay, Indranil Kushare

Faculty, Staff and Students Publications

BACKGROUND: Medial patellofemoral ligament (MPFL) reconstruction is frequently used to manage recurrent patellar instability. Diagnostic arthroscopy is commonly performed before MPFL reconstruction to identify, confirm, and address intra-articular pathology. However, when preoperative magnetic resonance imaging (MRI) does not demonstrate intra-articular lesions, it is unclear how often diagnostic arthroscopy in pediatric patients alters surgical management.

PURPOSE: To determine the utility of diagnostic arthroscopy in young patients undergoing MPFL reconstruction who had no intra-articular chondral or osteochondral pathology, meniscal tears, or loose bodies identified on preoperative MRI, and to characterize intra-articular pathology detected on arthroscopy but not identified on MRI.

STUDY DESIGN: …

Empiric Azithromycin Alters The Upper Respiratory Microbiome And Resistome Without Anti-Inflammatory Benefit In Covid-19, Abigail Glascock, Cole Maguire, Hoang Van Phan, Emily C Lydon, Joanna Schaenman, Carolyn S Calfee, Esther Melamed, John Greenland, David B Corry, Farrah Kheradmand, Lindsey R Baden, Rafick Sekaly, Grace A Mccomsey, Elias K Haddad, Charles B Cairns, Linda N Geng, Bali Pulendran, Ana Fernandez-Sesma, Viviana Simon, Jordan P Metcalf, Nelson I Agudelo Higuita, William B Messer, Mark M Davis, Kari C Nadeau, Monica Kraft, Christian Bime, David J Erle, Mark A Atkinson, Scott C Brakenridge, Lauren I R Ehrlich, Ruth R Montgomery, Albert C Shaw, Catherine L Hough, David A Hafler, Alison D Augustine, Patrice M Becker, Bjoern Peters, Al Ozonoff, Annmarie Hoch, Seunghee Kim-Schulze, Florian Krammer, Steven Bosinger, Walter Eckalbar, Matthew C Altman, Michael Wilson, Leying Guan, Holden Maecker, Hanno Steen, Impacc Network, Joann Diray-Arce, Nadine Rouphael, Steven H Kleinstein, Naresh Doni Jayavelu, Elaine F Reed, Ofer Levy, Victoria T Chu, Charles R Langelier

Faculty, Staff and Students Publications

Azithromycin is a widely used antibiotic and was frequently used to treat hospitalized patients during the COVID-19 pandemic. The impact of empiric azithromycin use on the respiratory microbiome in patients with viral respiratory infections is unclear. Here we used longitudinal metatranscriptomics on nasal swabs from a prospective multicentre cohort of 1,164 patients hospitalized for COVID-19. We compared the upper respiratory microbiome, resistome and systemic immune response in patients treated with azithromycin (n = 366) with those who received no antibiotics (n = 474) or other antibiotics (n = 324). We found that azithromycin altered microbiome composition and increased the expression …

Body Mass Index And Survival In Children Receiving Extracorporeal Membrane Oxygenation, Pilar Anton-Martin, Keith Baxelbaum, Shilpa Vellore, Erika O'Neil, Vinai Modem, Sameer Thadani

Faculty, Staff and Students Publications

Importance: Underweight and obesity represent opposite ends of the nutritional risk spectrum that negatively affect children's health worldwide. Both conditions have been associated with increased mortality in pediatric patients receiving extracorporeal membrane oxygenation (ECMO) support.

Objective: To investigate the association of underweight and obesity status with pediatric ECMO outcomes using body mass index (BMI) z scores.

Design, setting, and participants: This retrospective cohort analysis used data from the Extracorporeal Life Support Organization (ELSO) database from January 1, 2019, to December 31, 2023. Participants included all pediatric patients from international ECMO centers aged 29 days to 18 years who received ECMO …

Physiological Peristaltic-Like Reactions Of The Tracheobronchial Tree Move Pulmonary Mycobacterium Tuberculosis Bacilli Into The Gastrointestinal Tract, Andrew R Dinardo, George W Kasule, Alberto L Garcia-Basteiro, Stool4tb Global Partnership

Faculty, Staff and Students Publications

No abstract provided.

Complement Anaphylatoxin C5a-Induced Mouse Lymphatic Functions Modulate Interactions Between Endothelial Cells And T Lymphocytes, Haydn E Rich, Yi-Dong Li, Kathryn D Hok, Stacey L Mueller-Ortiz, Aleksey Y Domozhirov, Anthony Shadid, Rajarajan A Thandavarayan, Hari Krishna Yalamanchili, Marie-Francoise Doursout, Tingting Weng-Mills, Faraz Bishehsari, Nirmal K Banda, Kristin L Eckel-Mahan, Marcos I Restrepo, Pooja Shivshankar

Faculty, Staff and Students Publications

The lymphatic system is a highly branched endothelial tubular network that facilitates the migration of immune cells from the peripheral tissues to lymph nodes (LNs) and other lymphoid organs. Complement factors are essential for innate and adaptive immune functions. Complement anaphylatoxin C5a is crucial in vascular endothelial cell activation and lymphocyte polarization. Understanding the impact of C5a and its cognate receptor C5ar1 signaling on lymphatic function could provide new insights into the mechanisms of immune dysregulation observed in chronic inflammatory diseases. We demonstrate that acute C5a challenge in wildtype C57B6/J mice significantly reduced lymph propulsion compared to their C5ar1-deficient counterparts. …